Vol. 2, No.

4, 2019

Regulatory
Intelligence
and Policy:
Shaping the Global Landscape
 Regulatory Intelligence and Policy: Shaping the Global Landscape ......................... 3
Table of Contents
By Gloria Hall

Proactive Regulatory Intelligence Communication ................................................. 7

By Emily Huddle, BSc and Kirsten Messmer, PhD, RAC

FDA Meetings – the Application of RI in Preparation and Execution ........................ 14

By Matt Medlin, PhD, RAC

Managing Regulatory Intelligence for Medical Devices........................................... 18

By Richard Vincins, RAC

The Emerging Role of Artificial Intelligence in Healthcare....................................... 25

By Pei-Ting Sarah Chou, RAC

Regulatory Intelligence Communication for Business Impact .................................. 30

By Kirsten Messmer, PhD, RAC and Charity Schuller, PharmD, MS, RAC

The Overview of Chinese Health Policy and Regulatory Authorities.......................... 39

By Yingying Liu, MSc

Comparison of Data Requirements for the Approval of a Biosimilar Versus

the Reference Medicine ........................................................................................ 47
By Olivia McBride

Protecting The Healthcare Infrastructure: Global Cybersecurity Compliance............ 59

By Suzanne Schwartz, MD, MBA and Michelle Jump, MS, MSRS, RAC

Regulatory Strategist Toolbox: 2018 FDA Changes Regulatory

Intelligence Briefing ............................................................................................. 65
By Meredith Brown Tuttle, RAC FRAPS

The Value of Engagement With Trade Associations in Policymaking,

Regulation and Standardization – The Example of the Medical
Nutrition International Industry (MNI) .................................................................... 92
By Léa Coulet

The Botanical Safety Consortium (BSC): The Development of a 21st Century

Framework for Assessing the Safety of Botanical Dietary Supplements ................... 103
By Daniel S. Marsman, DVM, PhD, Joseph T. Dever, PhD, Stefan Gafner, PhD, Cynthia Rider,
PhD, Sibyl Swift, PhD and James C. Griffiths, PhD

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 2

 So all you see are
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Our team of experts are ready to partner
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your product, helping to reduce your risk
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CARDINAL HEALTH, the Cardinal Health LOGO and
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other countries. Lit. No. 1SS19-1016714 (8/2019)

approvals.
Regulatory Intelligence and Policy:
Shaping the Global Landscape
By Meredith Brown-Tuttle

Welcome to the fourth edition of the 2019 Regulatory Focus Article Series. Inside you will
find a collection of insightful articles covering global best practices in regulatory intelligence
and policy. It is a pleasure to bring together some of the top regulatory intelligence thought
leaders from around the world—all with diverse experience—to offer their perspectives on
the importance of regulatory intelligence and the integral role RI professionals play in defin-
ing strategy for companies in regard to development, approval and maintenance of products,
as well any changes to regulations impacting the global regulatory landscape.

Communication is Key
To stay current with the rapidly changing landscape, regulatory professionals must monitor
and identify pertinent regulatory information on a continual basis. This information must
be analyzed and interpreted for the application and implications to team projects, the or-
ganization and potentially other partners or clients. But generating this intelligence is just
the first step. In their article, “Proactive Regulatory Intelligence Communication,” regula-
tory experts, Emily Huddle and Kirsten Messmer, identify communication approaches for
medium to large companies and highlight the advantages and disadvantages of each.
Regulatory Intelligence (RI), in one form or another, has always been a component in
a successful FDA meeting. However, in past years, as specialization of functional areas
has continued to fracture and diverge, the need for quality, relevant and timely RI has
increased. Regulatory manager, Matt Medlin, illustrates how to best leverage a dedicated
RI function or skill set to prepare for and have the most successful regulatory interaction
with FDA. “FDA Meetings: The Application of Regulatory Intelligence in Preparation and
Execution” provides insight and suggestions regarding the role RI professionals can play
to help assure a successful interaction during each FDA meeting phase.

Gathering Data and Analyzing Information

How do you keep track of everything, read everything and know how to get regulatory
intelligence?
Regulatory and quality expert, Richard Vincins, addresses this question and more in
“Managing Regulatory Intelligence for Medical Devices.” He covers how medical device
guidance documents, regulations, standards and requirements are presented in increas-
ing amounts and how regulatory professionals can access, assess, manage and ultimately
report to their organizations on the potential impact of regulatory changes. He includes
“tips” for making the hard work of international regulatory intelligence for medical devices
easier and more efficient.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 3

 By 2018, a significant number of artificial intelligence (AI) applications had been devel-
oped for use in healthcare. For example, 2018 saw the first medical device using AI to
provide a screening decision—without the need for a clinician’s opinion. Experienced reg-
ulatory professional, Pei-Ting Sarah Chou, explores the topic in “The Emerging Role of Ar-
tificial Intelligence in Healthcare,” presents current and future AI healthcare applications,
examines AI’s potential for adding efficiency to pharmaceutical research and medical
practice and suggests the potential for providing better healthcare and patient diagnostic
and treatment outcomes. The article also examines AI applications’ ethical concerns, the
potential for misuse and the case for developing ethical standards.

Regulatory Strategy
Regulatory intelligence professionals support the drug development process with strategic
information, serve as liaisons with regulatory agencies and channel information to appropri-
ate stakeholders. In “Regulatory Intelligence Communication for Business Impact,” regulato-
ry experts, Kirsten Messmer and Charity-Anne Schuller, present an overview of applicable
delivery methods and general considerations for communicating information via spread-
sheets, text documents, slide presentations, strategy reports and competitive intelligence
reports. The authors explain how to maximize regulatory intelligence when responding to
specific stakeholder requests and offer recommendations for clear communication.
With the Chinese regulatory landscape constantly changing, it has become necessary
to reevaluate the roles and restructure how the healthcare regulatory authorities and
healthcare policy administrations are organized. In “Chinese Health Policy and Regulatory
Authorities Overview,” Yingying Liu describes the recent changes to China’s healthcare
regulatory authorities and healthcare policy administration. Liu outlines how the reorgani-
zation and restructuring of the former Chinese Food and Drug Administration (CFDA) and
several other organizations in March 2018 affects the responsibilities and functions of the
many government departments, agencies and regulatory bodies responsible for oversee-
ing drugs, food, medical devices, testing and evaluation.
Biomedical research is advancing rapidly and a key part its advancement is in the ana-
lytical capabilities allowing comparison between a reference biological product and a biosim-
ilar product. In “Comparison of Data Requirements for the Approval of a Biosimilar Versus
the Reference Medicine,” senior regulatory affairs consultant, Olivia McBride, defines both
biologics and biosimilars and explains how and why the two differ in terms of their organic
natures. She also guides the reader through the biologic vs. biosimilar developmental and
testing stages and through agency approval and postmarketing surveillance.
Regulatory experts, Suzanne Schwartz and Michelle Jump, review past and current
efforts to protect medical devices and other connected healthcare infrastructure from
security breaches in “Protecting the Healthcare Infrastructure: Global Cybersecurity Com-
pliance.” The authors cover recent regulatory efforts in Australia, Canada, China, Europe,
Japan and the US aimed at enhancing cybersecurity and industry’s efforts in cybersecurity
regulatory compliance to protect patients as well as healthcare infrastructure.
If you thought 2017 had a lot of changes, 2018 was even busier and 2019 is shap-
ing up to be another groundbreaking year for transformation. Global intelligence expert,
Meredith Brown-Tuttle, has assembled the major changes during 2018 in “Regulatory
Strategist Toolbox: 2018 FDA Regulatory Intelligence Briefing.” She provides resources
for guidance documents drafted and finalized, new legislation, other areas of interest and
regulatory intelligence tools to help you explore additional areas.
Léa Coulet presents an argument for the value trade associations bring to healthcare
in terms of promoting best practices, policies, regulations and standards in “The Value of
Engagement With Trade Associations in Policymaking, Regulation and Standardization.”
The author defines trade associations and lays out their functions and the value of those
functions for regulators and policy makers and also presents defining characteristics of

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 4

good regulations and good policies. The focus is on foods for special medical purposes
and the author shares examples from the work of the Medical Nutrition International
Industry (MNI) in these areas.
Since the introduction of the Dietary Supplement Health and Education Act of 1994
(DSHEA), the dietary supplement market has flourished with the addition of various
product streams including products containing one or more botanical/herbal ingredients.
In parallel, substantial advancements in analytical methodologies have led to a better
understanding of the complexity and diversity of botanical chemistry and botanical
preparations. In “the Botanical Safety Consortium (BSC): The Development of a 21st
Century Framework for Assessing the Safety of Botanical Dietary Supplements,” experts
Daniel Marsman, Joseph Dever, Stefan Gafner, Cynthia Rider, Sibyl Swift and James
Griffiths, share their insights into steps to improve the safety of botanicals in dietary
supplements. These leaders explore several US legislative initiatives and efforts by
several nongovernmental organizations, such as the Council for Responsible Nutrition
and the American Botanical Council, to track patterns of botanical use, and the Congress
of the European Societies of Toxicology’s efforts to approach safety issues, including its
establishment of the Botanical Safety Consortium and its working groups.

Conclusion
While RAPS offers a complete book on Regulatory Intelligence 101, these short summa-
ries are meant to update and provide different perspectives in RI since in regulatory there
are many ways to accomplish the same thing. We hope you spend some time reading the
complete articles and benefit from the shared experiences of our authors. This collection
was meant to give you the information needed to enhance your knowledge and keep your
company up-to-date on current regulations affecting the development, approval and mainte-
nance of products, as well any changes to the regulations and/or regulatory landscape that
may impact your efforts. Your feedback is always welcome.

Want more on regulatory intelligence?

Mark your calendar for a lively Regulatory Exchange discussion on 11 December 2019
with the expert authors of the series. More details to come.

Meredith Brown-Tuttle, RAC, FRAPS, is the principal consultant for Regulatorium a company specializing in regulatory intelli-
gence, writing and strategy. She is the author of IND Submissions: A Primer, published by Barnett, Regulatory Intelligence 101,
published by RAPS, numerous articles and currently serves as the chair of RAPS Editorial Advisory Committee. She can be
reached at [email protected].

Cite as: Brown-Tuttle M. “Regulatory Intelligence and Policy: Shaping the Global Landscape.” Regulatory Focus. November 2019.
Regulatory Affairs Professionals Society.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 5

 REGULATORY FOCUS

Proactive Regulatory Intelligence Communication

By Emily Huddle, BSc and Kirsten Messmer, PhD, RAC

This article focuses on regulatory intelligence communication approaches for medium to

large companies and highlights the advantages and disadvantages of each.

Introduction

To stay current with the rapidly changing landscape, regulatory affairs professionals must
monitor and identify pertinent regulatory information on a continual basis. This information
must then be analyzed and interpreted for the application and implications to team projects,
the organization and potentially other partners or clients. Generating this intelligence is just
the first step. Communication is an important next step to ensure intelligence is
implemented, whether to facilitate efficient drug development or a successful regulatory
strategy. Communication strategies might depend on the type of information, company
size, industry type (e.g., pharmaceutical, biotechnology, contract research organization
(CRO), consulting, etc.) and audience size.

Compliance with regulatory requirements is integral to the research, testing, approval and
continued ability to market new medicinal products. As regulatory approvals are sought in
new markets, the spectrum of regulatory requirements likewise will multiply. The rapid
development of new scientific and technological advances has demanded an ever-
increasing pace of new regulatory guidance to ensure the development of safe, effective
and high quality medicinal products. Additionally, new precedents are established in the
form of innovative trial designs, endpoints and statistical analysis to answer scientific and
regulatory questions during the drug development process. It is an essential part of a
regulatory intelligence (RI) professional’s role to follow these updates/trends, analyze the
impact to the organization and disseminate the information more broadly. The RI

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 7

professional’s responsibilities are best summarized within the Drug Information Association
Regulatory Intelligence Working Group definition of regulatory intelligence:

“The act of gathering and analyzing publicly available information. This includes
communicating the implications of that information and monitoring the regulatory
environment for opportunities to shape future regulations, guidance, policy and legislation.”1

The specific responsibilities of an RI professional will depend on a variety of factors,

including business needs, company size and the background and experience of the
individual. Assigned RI responsibilities also will depend on whether the person is solely
dedicated to the RI role or only devotes a portion of time toward RI. Regardless of whether
it’s a dedicated or part-time role, it is paramount that pertinent regulatory intelligence be
effectively captured and communicated via the appropriate channels in order to reach its
intended audience so it can be leveraged for the greatest benefit.

The presentation of RI most likely will depend on the intended audience or customers and
the type of information. The term customers can refer to individuals within the same
company such as regulatory affairs colleagues or other departments, or may be outside of
the company, in the case that services are provided to external clients, partners and
collaborators.

The intended use of RI also determines how polished the output from the RI is required.
For example, if the RI will be used as part of a larger report or contract proposal, it may be
provided in a raw format since it will be shaped by the entire team to fit into the overall
presentation. On the other hand, something that will be provided directly to the ultimate
customer will need to be extremely polished.

The communication of RI in response to a specific request or ad hoc query is not the

subject of this article, but will be addressed in a follow up article. Proactive communication
as addressed in this article has to be concise, precise and with actionable RI clearly
identified.

Proactive Communication of Regulatory Intelligence

Essential to the role of an RI professional is the proactive communication of changes in

legislation, regulations, guidance documents and other pertinent regulatory updates. An
effective communication strategy includes dissemination to key stakeholders to ensure
implementation of relevant changes, with potential impacts to regulatory compliance, time
and cost-effective medicinal product development and/or successful regulatory strategies.
The US Food and Drug Administration (FDA) issued a suite of draft guidance documents to
support efficient development of oncology products (e.g., first-in-human expansion cohorts,
master protocols, adaptive clinical trials, etc.). While analyzing the guidance documents, it
is essential to highlight key aspects that could provide gains in efficiency or cost-
effectiveness through the use of innovative trial designs described within the guidances:

• First-in-human expansion cohorts:2 A single protocol allows seamless progression

from dose-escalation phase to three or more expansion cohorts addressing specific
research questions.
• Master protocols:3 Umbrella, basket and/or platform trial designs allow the
assessment of multiple therapeutic products and/or multiple indications or both
within one protocol.
• Adaptive clinical trials:4 Adaptive trial designs allow prospectively planned changes
to one or more aspects of trial design based on the data accumulated from
patients.

The communication strategy to disseminate RI depends on the size of the company and on
the overall impact and relevance of the guidance documents to the company. This article
will focus on communication approaches for medium to large companies (including but not

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 8

limited to pharmaceutical, medical device, contract manufacturing, contract research
companies and consultancies). For small companies (less than 100 employees for the
purpose of this article), it may be likely to inform all employees across the company at the
same time. The complexity of departments and reporting lines within a larger company may
necessitate more defined communication strategies.

In the case of large companies with multiple oncology products at different stages of
development the suite of oncology guidance documents likely has a major impact on
planning of future oncology clinical trials. Therefore, the information will need to be
communicated in various ways to ensure all applicable stakeholders are informed.

Horizontal Communication

Horizontal communication can be described as “flat” and involves disseminating information

across a team, for instance a RI professional’s regulatory affairs colleagues involved in
oncology clinical trials. In turn, these colleagues would engage the appropriate
stakeholders in order to discuss the new guidance documents and to implement a
regulatory agency’s recommendations to support their medicinal product development
programs and regulatory strategies. However, this horizontal communication only would
address projects already under way or are upcoming. A guidance of significant impact also
should be leveraged in communication with future customers, i.e., business development.
Using the example of the oncology guidance documents, multiple scenarios come to mind.
Two of them are:

1. When communicating with a future potential customer at a very early stage of

development, the first in-human expansion cohort guidance could be explored for
applicability to that customer’s program. Highlighting the applicability of the
guidance and how it could be applied to the program based on the presenting
company’s experience likely would instill confidence in the potential client that the
presenter is well-positioned to support the early stage program cost and time
efficiently.
2. In the second scenario, the business development department is talking to a later
stage client with a product that might be used in multiple indications. Here, to
showcase the presenting company’s expertise, the implementation master protocol
guidance and internal experience can be leveraged to demonstrate an efficient
drug development program to the potential client.
The necessity of communicating regulatory changes beyond a single department or
team can be determined by a triage team in order to escalate the new information
to a broader audience or what would be considered vertical communication.

Vertical Communication

Due to the broad impact of the suite of oncology guidance documents and implications
outside of the regulatory affairs department, their release also should be communicated
vertically, that is upward to senior leadership and across to the impacted functional areas or
departments. Depending on the company size and choice of communication strategy will
dictate whether the communications are initiated by a single person or a team, such as a
cross-functional committee. A single person could communicate the potential impact to
other department heads who then would be responsible for further dissemination of the
information among their respective teams. Likewise, a cross-functional team comprised of
pertinent members from various departments could determine the impact and then
disseminate the information across their respective teams.

Companywide Communication

Information that will affect the operations of multiple departments within a large company
necessitates a communication channel that will reach a wide audience in order to educate

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 9

internal stakeholders on the pertinent changes as well as overall impacts to the
organization. The format used to distribute information on a company wide level depends
on the content to be provided and audience expectations. Some examples of formats are
email alerts or blasts, bulletins and newsletters.

Email alerts or blasts generally should contain high-level, easy-to-understand information

and timely distribution is paramount. An effective email alert or blast, although an informal
way to distribute RI to a large audience, should be focused and concise, concentrating on
key details describing the change, the impact to the organization and any pertinent
deadlines or timelines.

For less time-sensitive news, it may be more logical to compile numerous regulatory news
items together in a bulletin, newsletter or digest—each of which serves a slightly different
purpose. The RI professional should consider these forms of wider communication, taking
into account the definitions and aims of each. From the Merriam Webster Dictionary, the
definitions are as follows:

Bulletin:5 “A brief notice issuing usually from an authoritative source.”

Newsletter:6 “A small publication (such as a leaflet or newspaper) containing news of

interest chiefly to a special group.”

Digest:7 “A summation or condensation of a body of information …,” “a product of

digestion.”

Each of these publication forms serve a specific purpose and based on the definition of RI
presented earlier in the article, “The act of gathering and analyzing publicly available
information …” a newsletter or digest likely would be the most appropriate communication
tool. Independent of how the type of format is used to communicate information at a
companywide level, it is critical to include references and/or links to the original sources of
information and/or further information.

A bulletin generally is a compilation of news with high-level updates. It can serve to keep a
special interest group updated and/or to inform other stakeholders of updates in a certain
area. A bulletin also can cover a wide array of topics, providing information in short
summaries. However, within a bulletin, these summaries only convey very limited
information without the provision of any type of further analysis. Often, the bulletin
summaries are based on a single news release or published paper. A bulletin strictly serves
to inform of events and left to the readers to draw their own conclusions or analysis.

A newsletter, according to the Merriam Webster Dictionary is a small publication conveying

information to a special interest group, such as a regulatory affairs department. Newsletters
and the articles within them come in all shapes and sizes. Similar to a local daily
newspaper, depending on the topic and author, the analysis and depth of information will
vary. The distinction between a newsletter and digest may be somewhat blurry, but a digest
implies some digestion or interpretation of the information, in this case, into actionable RI.
Independent of the name, a recurring RI publication should be: timely, addressing topics
important to the company’s and/or client’s business needs; supported by references;
informative; and concise.

The issue of timeliness can be subjective and can vary from company to company. The
pertinent question to consider is: “When does news become old news for the company?”
The topic selection to be covered by each issue of the newsletter/digest will be guided by
the importance to the company’s business, e.g., a device company will be less interested in
updates to guidance and legislation addressing pharmaceuticals unless some its products
are combination products. Similarly, if the company or clients are operating in a very
specific market, news outside of that market will be less important unless the market may
be a future target market.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 10

In the example of the suite of FDA oncology draft guidance documents, it would be outside
the scope of a newsletter/digest to go into significant detail for each of the guidance.
Providing high-level summaries, relevance for ongoing and future projects, providing links
and/or reference to the guidance document or any other source of information provided
would be an appropriate amount of detail to include within a newsletter or digest article.
As a general rule, any news article should be well written, free of grammatical and spelling
mistakes and easy to understand. Summaries, bullet points and call-out boxes could
effectively highlight the main points of a longer article. This article will not address issues of
confidentiality since it assumes information would be drawn from publicly available sources.
The composition of the newsletter/digest and length of individual articles depends on
various factors that may include:

• Is the topic being addressed very focused (e.g., specific guidance – short article) or
has a long history or complex ramifications (e.g., larger ethical issue – longer
article)
• Number of updates or guidance documents released within the time period covered
(e.g., the suite of oncology guidance documents, gene therapy guidance
documents)
• Number of countries covered within the newsletter/digest (in the case of cross-
country collaboration)

As noted earlier, it’s critically important to include references to information obtained from
other sources so as to avoid the act of plagiarism, which is, by definition, passing off
someone else’s work as one’s own. Plagiarism is a significant issue and sometimes
copying as few as five consecutive words in the same order can be considered plagiarism
and carries the charge of literal fraud. However, there is no fast and safe rule. 8 Citing
sources of information appropriately will clearly indicate where the information came from
and how conclusions were drawn.

Copyright infringement, which is the unauthorized use of a work protected by copyright law,
is also an important potential issue to avoid. The RI professional responsible for issuing any
information that contains copyrighted works must first ensure that proper authorization has
been secured from the copyright holder for the intended use, republication, etc., of such a
protected work. If the RI professional is uncertain about compliance with copyright law,
advice of legal counsel should be sought, particularly as copyright law varies between
jurisdictions. Further, the use rights authorized by individual copyright holders varies widely
as well.

For example, looking at FDA and the European Medicines Agency (EMA) only, the
authorizations granted and conditions required by each entity for use of content made
available on their respective websites are handled very differently:

FDA: FDA’s website cites that "unless otherwise noted, the contents of the FDA website
(www.fda.gov)—both text and graphics—are not copyrighted. They are in the public domain
and may be republished, reprinted and otherwise used freely by anyone without the need to
obtain permission from FDA. Credit to the US Food and Drug Administration as the source
is appreciated but not required.”9

EMA: EMA’s website states that “in particular, unless otherwise stated, the Agency,
according to current European Union and international legislation, is the owner of copyright
and other intellectual property rights for documents and other content published on this
website.”

“Information and documents made available on the Agency's webpages are public and may
be reproduced and/or distributed, totally or in part, irrespective of the means and/or the
formats used, for non-commercial and commercial purposes, provided that the Agency is

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 11

always acknowledged as the source of the material. Such acknowledgement must be
included in each copy of the material.”

“Citations may be made from such material without prior permission, provided the source is
always acknowledged.”

“The above-mentioned permissions do not apply to content supplied by third parties.

Therefore, for documents where the copyright vests in a third party, permission for
reproduction must be obtained from this copyright holder.”10

Another consideration is the layout of the finished publication. Newsletters/digests usually

contain multiple pages of text with imagery and other features to enhance readability. Can
a busy executive grasp the main updates from quickly looking over the article? Choosing
appropriate vehicles to highlight pertinent information and conclusions is paramount to
inform the busy reader with little time. The full article text always will be available for further
information.

Summary

New regulations, guidance documents and other regulatory information are issued from
multiple agencies on a daily basis. The RI professional is responsible for identifying
information relevant to their company and/or client and also evaluating its impact. A
communication strategy for identified regulatory intelligence is a critical next step. Either a
horizontal, vertical and/or companywide communication flow could be considered,
depending on the essential stakeholders that need to be notified. There are a variety of
formats that can be employed to communicate RI, such as email blasts or alerts, bulletins,
newsletters or digests. Depending on factors such as time sensitivity, topic complexity and
number of updates to be communicated, one format may be more advantageous over
another. Utilization of features such as call-out boxes, bullet points, pictures and graphical
representations of data may help with the readability and comprehension of the information.
While making sure RI summaries are well-written, consideration also must be paid to
appropriately referencing sources and legal restrictions regarding copyrighted information.

References

1. Brown-Tuttle M: Regulatory Intelligence 101. 2014. Regulatory Affairs Professionals Society.

2. US Food and Drug Administration: Expansion Cohorts: use in First-in-Human Clinical Trials to Expedite Development
of Oncology Drugs and Biologics (August 2018). FDA website. https://www.fda.gov/ucm/groups/fdagov-
public/@fdagov-drugs-gen/documents/document/ucm616325.pdf. Accessed 10 January 2019.
3. US Food and Drug Administration: Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development
of Oncology Drugs and Biologics (September 2018). FDA website.
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM621817.pdf.
Accessed 10 January 2019.
4. US Food and Drug Administration: Adaptive Designs for Clinical Trials of Drugs and Biologics (September 2018). FDA
website. https://www.fda.gov/downloads/drugs/guidances/ucm201790.pdf. Accessed 10 January 2019.
5. Merriam-Webster: Bulletin. Dictionary Website. https://www.merriam-webster.com/dictionary/bulletin. Accessed 10
January 2019.
6. Merriam-Webster: Newsletter. Dictionary Website. https://www.merriam-webster.com/dictionary/newsletter. Accessed
10 January 2019.
7. Merriam-Webster: Digest. Dictionary Website. https://www.merriam-webster.com/dictionary/digest. Accessed 10
January 2019.
8. Cooper H. “Principles of Good Writing: Avoiding Plagiarism.” APA Style Blog, 12 May 2016.
https://blog.apastyle.org/apastyle/plagiarism/. Accessed 10 January 2019.
9. US Food and Drug Administration: Website Policies. FDA Website, last update 20 March 2018.
https://www.fda.gov/aboutfda/aboutthiswebsite/websitepolicies/default.htm. Accessed 10 January 2019.
10. European Medicines Agency: Legal Notice: European Medicines Agency Copyright and Limited Reproduction Notices.
EMA website. https://www.ema.europa.eu/en/about-us/legal-notice. Accessed 10 January 2019.

About the Authors

Emily Huddle, BSc, is US senior regulatory intelligence manager for Gilead Sciences, Inc. and (outgoing) co-chair of the DIA
Regulatory Intelligence Working Group. Huddle has worked in the pharmaceutical industry (both human and veterinary) for more
than 20 years, including 10 years in regulatory intelligence. She can be contacted [email protected]

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 12

Kirsten Messmer, PhD, RAC, is a principal regulatory affairs specialist in regulatory intelligence solutions at PPD. She is co-chair
of the DIA Regulatory Intelligence Working Group. Messmer received a PhD in neuroscience from the University of Sheffield, UK.
She can be contacted at [email protected].

Cite as: Huddle E and Messmer K. “Proactive Regulatory Intelligence Communication.” Regulatory Focus. January 2019.
Regulatory Affairs Professionals Society.

© 2019 by the Regulatory Affairs Professionals Society. All rights reserved.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 13

 REGULATORY FOCUS

FDA Meetings: The Application of Regulatory

Intelligence in Preparation and Execution

By Matt Medlin, PhD, RAC

This article illustrates how to best leverage a dedicated Regulatory Intelligence (RI) function
or skill set to prepare for and have the most successful regulatory interaction with FDA. It
provides insight and suggestions regarding the role RI professionals can play to help
assure a successful interaction during each FDA meeting phase.

Introduction

Regulatory Intelligence (RI), in one form or another, has always been a component in a
successful FDA meeting. However, in past years, as specialization of functional areas has
continued to fracture and diverge, the need for quality, relevant and timely RI has
increased. While all stakeholders within the organization are keen to see that the firm’s next
meeting with FDA is successful, regulatory interactions, and in particular, during milestone
FDA meetings, come with unavoidable high risks. Yet, such meetings are a potentially high
reward aspect of drug development. At the center of this is the regulatory professional and
his or her ability to orchestrate meeting preparation and carry it through efficiently.

Background

Agreements reflected in the 21st Century Cures Act,1 along with commitments made during
the PDUFA VI2 negotiations and other initiatives/voices in industry and government alike,
contributed to the issuance of two key guidances in December 2017. 3,4 Those guidances,
“Draft Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products”
and “Best Practices for Communication Between IND Sponsors and FDA During Drug
Development,” had a substantial impact on the role that RI plays in meeting preparation
and execution. While this article is not the venue for an expansive dissection of changes or
updates in guidance, several examples, including increased reliance on and the role for

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 14

non-division specific regulatory project managers and a commitment of five calendar days
for receipt of meeting preliminary comments for some interactions, provide the RI
professional with an opportunity to have great impact on having successful meeting
outcomes.

In addition to recent legislation, market forces and other factors, there is also an increasing
“avalanche” of guidance, FDA-sponsored presentations, Ad Comm and Public Meeting
materials, and precedent, all of which require analysis. Along with the increase in regulatory
fodder for review, personnel turnover at FDA is resulting in less institutional knowledge and
fewer seasoned reviewers who can interpret intended meaning in an a drafted regulatory
strategy and/or provide reliable direction to a sponsor to avoid “landmines” during future
interactions. Each of these changes increase the importance of having reliable, thorough,
thoughtful RI and heightens the value of RI’s contribution FDA meeting preparation and
execution.

Interaction Planning Phase

An essential question to ask the company (and yourself) before submitting questions to
FDA is, “Do answers to these questions already exist?” This kind of industry introspection is
the realm of RI. Of course, members from any functional area of a project team will review
for themselves if their question for the agency (often phrased as a proposed approach) has
been addressed. However, these “needle-in-a-haystack” searches often come up empty.
Here, two activities a regulatory function serves are, first, to decode the proposed questions
from various functional areas and rephrase in regulatory terminology and second, to begin
a targeted search of guidances, approval packages, advisory committee materials, etc., to
determine if similar questions related to similar products/indications have been addressed
in the past. Measured and thorough information management is critical. Establishing a
centralized, curated, project-specific repository of RI documents is well worth the time
required during interaction planning and will pay dividends throughout the preparation.
Once established, share this resource and work diligently to provide specific guidance to
various team members for information that should be reviewed.

At the end of the day, there is a limit to the amount of information the agency can review in
one package. That reality is reflected in the number and quality of responses to individual
questions. Filtering out and removing superfluous questions is a key activity during a
regulatory interaction and planning phase. Also, it is important to produce and hone clear,
unambiguous questions. To help achieve this, the RI professional’s work product should
help to translate questions into regulatory language so that all parties - before, during and
after the interaction - are speaking the same “language.” Finally, be sure that your project
team is putting their best foot forward and timelines are correctly established. RI should be
sure that the correct meeting subtypes are being applied to the planned interaction. This
effort can be a “moving target” in cases of meeting re-categorization in response to updated
PDUFA commitments. Keeping the team apprised of the impact this has on the eventual
timelines for submission, agency response, meeting dates and final meeting minutes, will
help to avoid the landmines and surprises in future internal company milestones meetings.

Authoring Phase

The more work done to familiarize team members with regulatory requirements, guidance,
precedent and terminology during the preparation phase, means less work is required
during authoring. Regardless, RI reminders and ongoing surveillance of the evolving
regulatory landscape is required throughout authoring of documents to be submitted. In
addition to these ongoing activities, the authoring phase is an appropriate time to begin
looking closely at key players within the agency related to your
program/technology/indication. If that previous precedent or established expertise of a
resource within the agency, even if not within the review division is important to conducting
a successful interaction, then RI should identify this individual(s), discuss their participation
with the team and invite them to the interaction.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 15

Also, increased turnover within the agency should be accounted for at this time. Prior to
submission, make certain the team is informed and documents are updated to account for
a change in the appropriate Office of Division due to restructuring, Division or Deputy
Directors, and other invitees named within documents to be submitted. Requesting
reviewers with previous experience in the indication/technology, those who have had
provided past helpful guidance to other sponsors, or to your company, is also advisable. RI
also should find the best selected reviewers for specific invites and confirm that they are
still employed with the agency before making such a request. As mentioned previously,
personnel turnover at FDA has increased in recent years, increasing the likelihood that
assembling the same review team for each milestone interaction is not a realistic
assumption.

With increased turnover also comes less familiarity with even long-established regulations
or guidance, particularly if the guidance under consideration is related to an aspect of
development with which your particular review division may not be familiar. Be sure the
team considers including additional detail regarding regulations and guidance in submitted
documents. Do not take for granted that those within the agency are familiar with all FDA
guidance and regulation. Additional RI work to identify selected reviewers with specialized
expertise from outside the Division also should be considered. Finally, do not overlook the
submissions work at the end of this Phase. Technical submission requirements, as with all
other regulatory matters, are constantly evolving and increasing at a substantial pace.
However, your company chooses to manage regulatory operations, be sure that those on
the team involved in final submission via the Electronic Submissions Gateway (ESG) is
aware of any changes in these requirements.

Meeting Execution Phase

Under new guidance, in some kinds of meetings your ability to access, review and provide
curated information will be put to the test. In some instances, the agency will provide
Meeting Preliminary Comments (MPCs) five calendar days ahead of the interaction. This
affords an opportunity for a much more thorough response and discussion with the agency
when the face-to-face or teleconference occurs. Also, it allows a review of any newly
released guidance, precedent or other information to be conducted to further support the
rationale contained within the meeting package.

Also note the MPCs will contain a finalized list of meeting attendees. This will bring more
certainty to who will be “running lead” for the agency from various functional areas. Finding
summary review documents authored by/signed off on from reviewers with whom you will
be interacting can be helpful for the team to level-set and understand the expectations and
point-of-view of a reviewer before the interaction. In addition to review documents, unofficial
or non-FDA based publications, PowerPoint presentations and white papers can also be
very helpful in understanding the rationale, rebuttals or suggestions provided by a particular
reviewer.

RI and logistics also should be accounted for at this stage. It is not uncommon for project
teams to be nervous or have “angst” about the interaction itself, particularly if they have
limited experience interacting with the agency. There is, after all, a lot on the line and, if
face-to-face, you are going to the agency’s “turf.” Taking the time to review and determine if
there have been any changes in security procedures (lobby guard badges, parking
restrictions, attendee screening, foreign visitor forms, passport/visa requirements, etc.) is
worth the effort. Along with these preparations comes the work to inform the project team of
these procedures ahead of time to relieve any anxieties that may come with the “safety
precautions” taken as part of any trip to FDA’s campus.

Lastly, RI in response to Meeting Minutes adds value. If clarification is needed in meeting

minutes in the form of an addendum to the minutes there is value in reviewing other
meeting minute addendums - either from that division or from similar disagreements - that
resulted from development of other products. Providing the team with relevant examples of

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final language adopted for other minute resolution processes will allow the group to
formulate the best language from the start.

Conclusion

As with so many other aspects of drug development, RI has an increasingly valuable role to
play in FDA meeting preparation and execution. Thorough exploration and knowledge of
management principals from the outset, and for the duration of the interaction, followed by
targeted and tactical regulatory intelligence contributions during authoring and execution,
are indispensable factors in thorough preparation and flawless execution of an interaction
with FDA.

References

1. FDA Implementation 21st Century Cures Act:

https://www.fda.gov/regulatoryinformation/lawsenforcedbyfda/significantamendmentstothefdcact/21stcenturycuresact/d
efault.htm. Accessed 22 January 2019.
2. PDUFA VI Reauthorization: https://www.fda.gov/forindustry/userfees/prescriptiondruguserfee/ucm446608.htm.
Accessed 22 January 2019.
3. US Food and Drug Administration/Center for Drug Evaluation and Research/Center for Biologics Evaluation and
Research. (December 2017). Guidance for Industry: Formal Meetings Between the FDA and Sponsors or Applicants of
PDUFA Products Draft Guidance.
4. US Food and Drug Administration/Center for Drug Evaluation and Research/Center for Biologics Evaluation and
Research. (December 2017). Guidance for Industry: Best Practices for Communication Between IND Sponsors and
FDA During Drug Development.

About the Author

Matt Medlin, PhD, RAC, is manager, US Regulatory Affairs R&D – Pipeline for Chiesi USA, Inc. His professional interests include
the application of Regulatory Intelligence, Policy and Strategy toward the development of drugs and biologics for the treatment of
rare diseases. He can be contacted at [email protected] or via LinkedIn.

Cite as: Medlin MD. “FDA Meetings: The Application of Regulatory Intelligence in Preparation and Execution.” Regulatory Focus.
January 2019. Regulatory Affairs Professionals Society.

© 2019 by the Regulatory Affairs Professionals Society. All rights reserved.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 17

 REGULATORY FOCUS

Managing Regulatory Intelligence for

Medical Devices

By Richard Vincins

This article discusses how medical device guidance documents, regulations, standards and
requirements are presented in increasing amounts and how regulatory professionals can
access, assess, manage and ultimately report to their organizations on the potential impact
of regulatory changes. The author covers where and how to access documents and
methods for keeping up with regulatory changes using searchable databases, such as
provided by FDA, as well as how to find information where such databases are not
provided. The article includes “tips” for making the hard work of international regulatory
intelligence for medical devices easier and more efficient, such as through subscribing to
email feeds, attending conferences and “networking.”

Introduction

From an industry perspective, due to complexity of different devices, the medical device
industry is one of the world’s most regulated and one of the most challenging in terms of
regulatory requirements and compliance. For the quality and/or regulatory professional
responsible for Class I, low-risk and non-sterile devices, Regulatory Intelligence (RI) may
be straightforward. However, for the RI professional working with a Class III, high-risk,
implant, electronic-based, sterile and attached to a software application (App), RI may often
keep one awake at night. This reality is compounded by several factors requiring constant
and careful management by medical device RI professionals. The first difficulty factor is to
do more with less; the luxury of having staff of 20 people no longer exists and the RI
professional may have to manage multiple work activities alone. The second factor has to
do with the new, fast-paced, socially connected, “Internet of Everything Age,” where the
proliferation of information is difficult to manage and continuously increasing, seeming
exponentially and every day. These factors make the medical device industry challenging

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not only from a regulatory perspective, but also just keeping up with the large amounts of
information presented each day.

Several previous articles published on regulatory intelligence provide helpful information for
managing regulatory intelligence.1-3 This article discusses how to keep up-to-date with
regulatory intelligence primarily with US Food and Drug Administration (FDA), the
European Union (EU) requirements and touches on ideas for other countries. This effort is
compounded by there being (at last count) more than 30 countries each with some type of
regulation for medical devices. Countries regulating medical devices for many years, such
as FDA, Health Canada and the European Union, have well-established regulatory
frameworks. They utilize their regulatory framework to continually release guidance,
position papers and other industry notifications that can be challenging for an individual to
keep up-to-date. This means that regulatory expectations are increasing, requiring
continuous review, updates, adjustment and assessment on how new developments
impacts each organization. Keeping up with these guidances, regulations, standards and
other regulatory requirements can be a full-time function quality and regulatory
professionals must find a way to “fit” into their already busy schedules.

In addition to local regulatory requirements for medical devices, there are a multitude of
national and international standards published for wide-ranging application of quality
management systems, regulatory requirements or product specific requirements. For
example, ISO 13485 published by the International Standards Organization (ISO) as a
management system standard has been around for more than two decades. 4 ISO 14971
describes the fundamentals for implementing a risk management system and processes
within the medical device industry. Many of these international standards have been
recognized by regulatory authorities around the world to the point that expectation for
compliance, even as a “voluntary” standard, is expected.5 Many national and international
standards are beneficial in the medical device industry because they create a harmonized
platform both regulators and industry can follow. For example, ISO 13485 was revised in
2016 to create more harmonized quality management system requirements rather than
have 30 different quality system requirements around the world. Without these standards,
because of the regulatory variations between each agency, the medical device industry
would have a more difficult job in terms of compliance. Fortunately, national and
international standards provide consistent ways to administer regulations, although they
also create yet another level of regulatory intelligence to maintain.

US FDA

FDA was originally created to regulate drugs that may or may not be effective in treating
ailments. Fast forward just over a hundred years since its creation, FDA is one of the
strongest, well-funded and regulated administrations in the US or elsewhere. FDA is
responsible for drugs, medical devices, food, cosmetics, blood and blood products and
tobacco, along with many of the derivations of those. In the last 10 to 15 years, FDA also
has implemented a number of regulations for medical devices, including one of the major
and most recent ones, the Medical Device User Fee and Modernization Act of 2002
(MDUFMA).6 This act helped allow FDA to become almost self-funded to provide it with
resources for regulating one of the world’s largest medical device markets. From time-to-
time, FDA publishes guidance documents and now has funding for reviewing medical
devices, but this function also created a need for the proliferation of ever more information.
Fortunately, today, the Internet can be used to access information. FDA has established a
process for releasing guidance documents outlining the agency’s current thinking and,
more importantly, their expectations for regulating medical devices. Even with the Internet,
finding this information is challenging on the best of days.

A few years ago, FDA consolidated their guidance documents into a centralized database,
greatly assisting in locating draft and final guidance. Figure 1 shows FDA’s guidance
database with links provided in the sidebar allows different search categories along with

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search criteria in a dynamic results page. This site is a “main-stay” website that should be
bookmarked as a central location finding FDA information.

Figure 1. Searching Guidance Documents

FDA also has an invaluable resource for identifying national and international standards
they have recognized for quality system processes, product performance and product
testing requirements. The website for recognized consensus standards, with link shown in
the sidebar, also has a good search interface that can be used, including title, standard
number, product code, etc., as seen in Figure 2. This information is important during any
type of premarket submission to FDA, as expectations are that recognized consensus
standards are utilized as part of product performance testing for safety and/or efficacy. As
an example, almost all electronic or electrical medical devices must comply with the
American National Standards Institute (ANSI) and Association for the Advancement of
Medical Instrumentation (AAMI) ANSI/AAMI ES 60601-1, which is a recognized consensus
standard by FDA.

Figure 2. Search Database

With hundreds of pages of information on FDA’s website, how does one stay up-to-date?
One way is by subscribing to a daily email list serve through which FDA sends notification
of advisory meetings, newly published guidance, finalized guidance, webinars, premarket
approvals, safety notices and myriad of other information. Do this by either bookmarking
the “CDRH News and Updates” page using the link shown in Table A or subscribing to

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email updates via the link shown in the sidebar. When subscribing, one may select a
variety of areas, ranging across many branches of FDA, including CDRH specific
information. This information should help in keeping up with large amount of regulatory
intelligence FDA generates daily. While this is helpful, please note that you will be receiving
emails at least daily and some do not like continuous emails cluttering their inbox. The
option to visit the news page may be useful.

Table A. Available FDA Weblinks

FDA Guidance Document Search Database
FDA Recognized Consensus Search Database
FDA CDRH News and Updates
FDA Subscription Management Center

European Union/European Commission

The European Union recently published two new medical device regulations with a
proliferation of new guidance documents with which quality and regulatory professionals
must keep up-to-date.7-9 There are challenges on the European Union side for regulatory
intelligence as their website is not easily navigable and information in the regulatory
intelligence stream is not always transparent. Under the current Medical Device Directive
(MDD) 93/42/EEC, there are a few guidance documents published under the “MEDDEV”
designation with links shown in Table B. Several other informative documents and
statements by the European Commission are also provided (Figure 3). With publication of
the new regulations, Medical Device Regulation EU 2017/745 and In Vitro Diagnostics
Medical Device Regulation EU 2017/746, expect many guidance documents to be
published and existing guidance updated.

Figure 3. EU Guidance Documents

Like FDA, the European Union has published a listing of harmonized standards for current
medical device-related directives, including the MDD 93/42/EEC. Unfortunately, as seen in
the link provided in Table B, this list is a scroll-through list, not a searchable database. This

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structure can make it difficult to locate current information as there is no notification of
updates - searching must be done through the local browser search function. In addition,
this information is not always updated on a regular basis, so there are out-of-date national
and international standards which can cause difficulty during product technical reviews
understanding which standards must be applied.
The European Commission also publishes other informative documents that, while not
guidance or requirements documents, do contain helpful information. This publicly available
information referred to as “DocsRoom,” contains helpful references any quality or
regulatory professional responsible for CE Marking will find useful (Table B). This is
particularly important with the new regulations published along with a promise for more
transparency by European authorities. Maintaining regulatory intelligence in the European
Union also requires a larger net of capture information as there is not one centralized
location, i.e., Notified Body Operating Group (NBOG) documents, Competent Authority for
Medical Devices information and other trade industry groups.

Table B. Available EU Weblinks

Guidance MEDDEV
Summary List of Harmonized Standards for the MDD
European Union DocsRoom

Other Regulated Country Requirements

Outside the US or European Union, the two main markets, regulatory information can be
sufficient to sporadic. Other larger medical device markets, such Canada and Australia,
have regulatory authority websites dedicated to medical device information, while smaller
markets, such as Malaysia or India, medical device information is more likely “buried” in
pharmaceutical pages. An article previously published in RAPS Regulatory Focus has
detailed links to various regulatory authorities around the world.10 While some may have
changed, many are still the main site to visit for further links to specific medical device
regulations. Other sources, such as the World Health Organization’s medical device atlas,
provide links to regulatory sites.11 Regulatory intelligence also can be challenging in
markets where local authorities only have information published in the local language.
Japan, China and Brazil also are large medical device markets usually requiring local
presence for regulatory intelligence because most information either on the website or
publicly available is in the local language. Still, there are a variety of methods for keeping
up with regulatory intelligence, including those in more obscure markets that can be
significantly challenging.

Methods for Regulatory Intelligence

The first step in understanding where to get regulatory intelligence is not only knowing
when regulatory documents are new or changed, but also knowing how to keep track of
these documents. There are a variety of methods, depending on each individual’s
organization skills, resources available in the company, and availability of funds.

Manual Regulatory Intelligence

Developing regulatory intelligence can be daunting at first, but once a system is established
it is not difficult to maintain, although it requires time each day or week to visit websites,
read through email notifications, check electronic databases and update the information. A
simple method for keeping track of documents is to create an Excel sheet with identification
number, title, version, publication date, effective/transition date and impact assessment
(other variations can be used). It is often helpful to keep track of archived regulatory
documents, although usually this is not required. Below is a list of methods for manually
keeping up-to-date on regulatory intelligence.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 22

 • Enter your email address in websites, list servers or email distribution with
regulatory authorities for published information; many major regulatory agencies
have some type of email notification system, i.e., FDA, Health Canada.
• Join mailing lists of consulting firms or other regulatory support groups, i.e.,
AdvaMed, that often give free webinars, white papers or other information about
new and changing regulations/standards. The difficulty with this approach is in
receiving even more emails based on marketing their products and services.
• Become part of a professional organization such as Regulatory Affairs
Professionals Society (RAPS) or American Society for Quality (ASQ). These
groups also provide learning sources, free educational webinars, forums and
networking groups.
• There are other professional organizations and private companies such as
Association for the Advancement of Medical Instrumentation (AAMI), Medtech
Europe or Notified Bodies that once a member or customer usually have
educational information on a regular basis.
• Network with friends and colleagues. When attending conferences, such as RAPS
Convergence or other industry conferences, use the opportunity to get to know new
people.
• Establish “regulatory intelligence time” in your schedule, perhaps an hour on Friday
morning or afternoon devoted solely to gathering information from these sources.

Depending on the number of markets to which the organization distributes, manual

methods may be appropriate; if part of a large organization or distributing in more than 10
countries, manual methods can prove difficult to manage.

Electronic Automated Regulatory Intelligence

In years past, there was little option beyond manually finding information. This entailed
visiting the local library to search through articles or going to industry meetings. This has
changed dramatically with the availability of information via accessible databases and
cloud-based applications. However, depending on the service provided, these resources
usually involve a subscription or a flat fee.

• A few organizations provide purchase of standards that sometimes - for a small

additional fee - will notify you when the standard is updated. This usually applies
only to standards such as ISO or IEC documents.
• Services providing access to standards usually do not cover guidance documents
or other regulatory documents, leaving a gap in regulatory intelligence. There are
an increasing number of providers bridging this gap by providing notification on
other regulatory documents.
• As part of the service package, subscription-based service can not only provide
notification of standards and guidance documents, but also electronic copies.
• Often these services have a cloud-based system, so this regulatory intelligence is
kept in one location able to be accessed via the Internet. This is helpful for keeping
all related standards, guidance documents, registrations, etc., in one central
location.
• Electronic automated services are exceptional at filtering through identified
regulatory markets by providing notification of standards, guidance documents,
new regulations and other information. But this service comes at a price. It also
should be noted that many companies, depending on their needs and depending
on the markets they distribute product, use a mixture of both manual and
automated methods.

Conclusion

During a training session or when going through a long list of standards from memory, the
question ‘How do you keep track of everything, read everything and know how to get

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 23

regulatory intelligence?’ is often raised. The answer is fairly simple. Before you go to bed at
night, close your laptop, put it under your pillow and hopefully, by osmosis, information gets
into your memory cells! The real answer is, unfortunately, not so simple. We all know too
well the challenges inherent in keeping track of so much regulatory information today, and it
is not going to get any easier. Fifteen to twenty years ago, there were perhaps a half
dozen, well-documented regulatory markets. Today, there are at least triple that number
and the number will continue to increase. The citations, links and information provided in
this article have been located, found and reviewed being on mailing lists, involved in RAPS
forums, and being part of other regulatory forums. Using a method of osmosis for some
people may work, though most will find that they need to establish methods that are
manageable and appropriate for their organization.

Keeping up with new and revised regulatory requirements is the first step and probably the
most challenging. With an understanding this is not a static process and depending on the
organization, there are different methods that can be applied for regulatory intelligence. As
regulatory requirements continue to increase, so will the bulk and speed of accompanying
information increase. Once becoming aware of new and revised regulatory requirements,
one must assess them for their potential to impact the quality system or product
compliance. Because of continuing regulatory changes for the medical device industry, it is
important for each organization to establish defined methods for gathering, reviewing,
updating, and maintaining regulatory intelligence.

References

1. Brown-Tuttle, M. "Regulatory Intelligence Tools Compendium." Regulatory Focus. February 2017. Regulatory Affairs
Professionals Society.
2. Slabiak T and Brown-Tuttle M. "Regulatory Information and Intelligence Tools: Devices." Regulatory Focus. April 2012.
Regulatory Affairs Professionals Society.
3. Brown-Tuttle M. "Regulatory Intelligence 101." Regulatory Focus. December 2004. Regulatory Affairs Professionals
Society
4. International Organization for Standardization (ISO) website. Accessed 23 January 2019.
5. OECD/ISO (2016), “International Regulatory Co-Operation and International Organisations: The Case of the
International Organization for Standardization (ISO),” OECD and ISO.
6. Background on MDUFMA. FDA website.
https://www.fda.gov/ForIndustry/UserFees/MedicalDeviceUserFee/ucm109149.htm. Accessed 23 January 2019.
7. Brooks P. “Six Things You Need to Do to Prepare for the New EU Medical Devices Regulation.” Regulatory Focus.
Posted 15 June 2017. Regulatory Affairs Professionals Society. Accessed 23 January 2019.
8. Richard K. "Complying with the New IVDR Regulations." Regulatory Focus. August 2018. Regulatory Affairs
Professionals Society.
9. Fillmore R. "Implementing the New EU Medical Devices Regulations." Regulatory Focus. November 2017. Regulatory
Affairs Professionals Society.
10. Op cit 2.
11. Global Atlas of Medical Devices. Geneva: World Health Organization; 2017. Licence: CC BY-NC-SA 3.0 IGO.

About the Author

Richard A. Vincins, RAC is part of Oriel STAT A MATRIX team as vice president global regulatory affairs responsible for
regulatory affairs and quality activities. In this role, he is responsible for regulatory strategies, regulatory submissions, remediation
of technical documentation, conducting quality system audits and providing regulatory expertise in national and international
regulations. He brings more than 25 years of experience in the medical industry, including worldwide regulatory compliance efforts
for medical device, IVD and pharmaceutical companies. Vincins is a Chartered Quality Professional, ASQ Certified Biomedical
Auditor and Certified Quality Auditor. He holds the RAPS RAC (US) and RAC (EU).He can be contacted at [email protected].

Cite as: Vincins R. “Managing Regulatory Intelligence for Medical Devices,” Regulatory Focus. January 2019. Regulatory Affairs
Professionals Society.

© 2019 by the Regulatory Affairs Professionals Society. All rights reserved.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 24

 REGULATORY FOCUS

The Emerging Role of Artificial Intelligence in

Healthcare

By Pei-Ting Sarah Chou, RAC

This article discusses current and future Artificial Intelligence (AI) applications in healthcare
and examines AI's potential for adding efficiency to pharmaceutical research and medical
practice as well as AI potentially providing better healthcare and patient outcomes,
especially in terms of diagnostics and treatment. The author presents ethical concerns of AI
applications, the potential for AI misuse and the case for developing ethical standards.

Introduction

"AlphaGo" is a computer program that plays the board game "Go," developed
by Alphabet Inc.'s Google "DeepMind" in London, England. In October 2015, the original
AlphaGo became the first computer Go program to beat a human professional Go player.
Having AlphaGo defeat the best Go players in the world1 demonstrates not only a
milestone for Artificial Intelligence (AI) technology, but also a new era for AI. Not long after
the AI Go victory, Google introduced DeepMind to the energy-saving system of its data
center. This application of AI saved more than 30% of the system's energy and did so in
ways never implemented by humans and, thus, paved the way for AI to be used in more
future applications.2 Google has used DeepMind since then in collaborating with the UK's
National Health Service (NHS) to build an eye-imaging machine learning system to help
combat sight-threatening conditions, such as wet age-related macular degeneration,
diabetic retinopathy and others.3

By 2018, more AI applications had been developed for use in healthcare. For example,
2018 saw the first medical device using AI provide a screening decision-without the need
for the opinion of a clinician. The device was
subsequently approved by the US Food and Drug Administration (FDA). 4 FDA has

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 25

approved several AI applications for medical devices, including IDx-DR screening for
patients for diabetic retinopathy. FDA determined there was no need for a second opinion
from human expert.5 Also, ARTERYS liver and lung AI lesion spotting software for cancer
diagnostics was approved, Viz.AI's CT scan analysis along with healthcare provider
notification of potential strokes in patients and Bayer's AI Software for Chronic
Thromboembolic Pulmonary Hypertension (CTEPH) Pattern Recognition. 6,7 These AI-
driven medical technologies are being used today to diagnose and treat a variety of
diseases. Most of these applications using AI are for medical imaging and disease pattern
recognition and aim at both improving clinical decision-making and facilitating earlier
disease diagnoses.

As demonstrated by the recent AI-driven technologies approved by FDA, AI has become

increasingly used by medical professionals for image analysis, therapeutic selection, data
filtering and quality control. As a result, forums for discussing the healthcare benefits of AI-
driven technology have been increasingly organized. In 2018, two United Nations agencies,
the International Telecommunication Union (ITU) and the World Health Organization
(WHO), initiated focus groups on Artificial Intelligence for Health8 this following the first
program on Artificial Intelligence and Robotics conducted in 2015. 9 Also in 2018, ITU and
WHO co-organized the workshop on AI for Health workshop at
Columbia University10 in which Deputy Director of the Office of Medical Policy
(OMP) at CDER, Khair ElZarrad, addressed opportunities and challenges for AI
therapeutic development.

Recently, AI applications for medical imaging, disease diagnostics, digital data and
electronic health records have been developed, all of which have demonstrated the ability
of AI to help protect privacy and assist in data security. These developments not only
illustrate AI's applicability along the healthcare supply chain, but also demonstrate how AI
could potentially revolutionize healthcare systems by improving efficiency and patient
outcomes.

As seen in Figure 1, emerging AI technologies can be further categorized according to

their categorical roles in the supply chain:

• raw material
• data collection
• supplier
• healthcare professional training
• healthcare product or service
• vendor
• hospital/healthcare professionals
• end consumer
• patient/insurance company

Figure 1. Artificial Intelligence Application in the Healthcare Supply Chain

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 26

In the category of raw material, AI could assist with the manufacturing as well as research
and development of therapeutic drug format selection using AI's ability to predict a potential
drug's molecular structure, chemical composition and possible therapeutic effect. AI also
could assist with the proper selection of material or stereo-presentation for constructing
medical devices to be compatible with human engineering factors or for data collection. AI
also could support data filtering, data classifying and data analysis throughout the data
collection process and, in doing so, turn the electronic health record into a reliable predictor
of risk as well as providing extensive vocabulary selection for data summarization.

For suppliers, AI could customize the service and the product to be supplied in such a way
as to better meet the customer's needs. AI could adopt machine learning to develop
customized tutorials for healthcare professional training and, in doing so, improve training
outcomes. For healthcare products or services, AI could be used to improve diagnostic
accuracy and efficiency by creating more precise analytics for photo images for disease
diagnostics and advancing the use of immunotherapy for cancer treatment. For vendors,
regardless of whether the need originates in wholesale or retail, AI could recommend
proper marketing strategies for a particular disease therapy or healthcare product. For
hospitals and healthcare professionals, clinical decision making could be revolutionized
with AI at the patient's bedside where it could assist physicians in identifying which
treatments are best for specific patients or for specific groups of patients. With AI at the
bedside, the potential for the development of complications could be assessed sooner and
possibly eliminate their potential. AI also could significantly improve therapeutic outcomes
and reduce costs related to hospital-acquired conditions.

For healthcare consumers, AI could assist with self-monitoring one's health status and
recommend proper healthcare product selection and purchase. For patients or health
insurance companies, AI applications for mobile devices could expand healthcare access
for underserved populations or for people living in developing, remote regions of the world.
Finally, AI could help identify homogeneous populations within a disease category and
calculate the cost of medical insurance in terms of both risk and safety considerations. 11

Because the recent development of AI technologies covers a broader range of applications

when compared to previous innovative technologies, AI's impact on human health will be
on a larger scale and come at greater speed than offered by previous technologies.
However, there is insufficient information and a lack of studies about the accountability of
AI devices, which means there is an inherent risk in integrating these technologies too
soon. There can be drawbacks and caution may be necessary. For example, if we become
highly reliant on the human decision patterns designed by AI, and if the AI decision pattern
is built upon a biased data pool,12 such decisions may not reflect a logical neutral result but,
rather, be based on a prejudicial view. This issue could drive potentially risky outcomes if
users falsely believe the decisions provided by AI are based on neutral analysis. There is
also the possibility that AI could be used for committing crimes by generating undetectable
fraudulent images or videos mimicking authentic ones in order to mislead decision-
makers.13 Further, preventing personal information and medical records from being used
without personal consent of disclosure, and having data being wrongfully accessed via the
advanced AI technologies by an unauthorized party is also an issue to consider.14

Because serious ramifications can result from AI misjudging or misdiagnosing, challenges

include examination of decisions related to whether we should rely highly on the decision
patterns recommended by AI.

Conclusion

Al applications can offer support for the healthcare provider, strengthen the delivery of
healthcare to better ensure healthy lives and work to promote well- being for humans of all
ages. However, ethical concerns regarding the use of AI must be considered before
introducing such powerful technology into our daily lives. Accordingly, a team from the
Massachusetts Institute of Technology established a platform for studying the moral

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 27

decisions and ethical standards related to new technologies. However, developing ethical
standards does not guarantee that behavioral transformation will follow. 15 Legal
professionals will likely develop consensus for adopting some of the standards pertaining to
international human rights and apply them to governing the use of AI, but a simple and
straightforward approach to the current trends and demands for AI applications also may
serve a variety of industries in advance of formal and legal ethics and standards. As shown
in the proposal published by the Data and Society Research Institute, technology
companies are encouraged to borrow from the opinions of civil rights groups and ethics
researchers and use these considerations when developing a human rights impact
assessment throughout their AI systems' lifecycle.16 Some reports on AI have been
published by the Wellcome Trust, the think-tank Future Advocacy17 and the European
Group on Ethics in Science and New Technologies,18 all of which illustrate some of the
ethical, political and social impacts of AI. The relationships between economic growth and
AI have also been discussed in a report offered by the McKinsey Global Institute. 19

For the healthcare domain, It may be that Institutional Review Boards (IRBs)/Ethics
Committees (ECs) will face greater challenges in AI-related clinical trial applications and in
research protocols seeking to adopt AI technologies. Proposed standards for AI should be
accommodated within a global framework to avoid the inherent risk of having AI used by
authoritarian leaders in their efforts to deprive people of their dignity and rights. There is
also a need to develop standards addressing the potential harm caused by the misuse of
AI.

As Albert Einstein, still a pillar in contemporary physics, once said, "It has become
appallingly obvious that our technology has exceeded our humanity."20
His observation should remind us that only when pioneering research in healthcare is
advanced on basis of human concern and ethics can it contribute to genuine good deeds in
the long term. As we debate the value of AI in healthcare, it would be prudent to reflect
upon the current debate regarding stem cell and embryonic research.

References

1. "AlphaGo" Wikipedia website. https://en.wikipedia.org/wiki/AlphaGo. Accessed 11 February 2019.

2. "Google, Deepmind: Artificial intelligence to Save Energy." AboutEnergy website. 21 July 2016.
https://www.aboutenergy.com/en_IT/briefs/Google-DeepMind-eng.shtml.Accessed 11 February 2019.
3. Hern A. "Google DeepMind Pairs With NHS to use Machine Learning to Fight Blindness." The Guardian website. 5 July
2016. https://www.theguardian.com/technology/2016/jul/05/google-deepmind-nhs-machine- learning-blindness.
Accessed 11 February 2019.
4. "FDA Permits Marketing of Artificial Intelligence-Based Device To Detect Certain Diabetes-Related eye Problems."
FDA News Release. 11 April 2018. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm604357.htm.
Accessed 11 February 2019.
5. Ibid.
6. "The AI Industry Series: Top Healthcare AI Trends to Watch." CB Insight Research Report.
https://www.cbinsights.com/research/report/ai-trends-healthcare/. Accessed 11 February 2019.
7. Pabla N. "Bayer Gets FDA Approval for CTEPH Pattern Recognition AI Software." Healthcare Weekly. 14 December
2018. https://healthcareweekly.com/bayer-cteph/. Accessed 11 February 2019.
8. Salathé M, et al. Whitepaper of Focus Group on Artificial Intelligence for Health. International Telecommunication
Union. November 2018.
9. "AI Policy - United Nations." Future of Life Institute website. https://futureoflife.org/ai- policy-united-nations/?cn-
reloaded=1. Accessed 11 February 2019.
10. ITU-WHO Workshop on "Artificial Intelligence for Health." ITU website. 14 November 2018. https://www.itu.int/en/ITU-
T/Workshops-and-Seminars/20181114/Pages/default.aspx. Accessed 11 February 2019.
11. Op cit 6.
12. "AI has a Culturally Biased World View That Google has a Plan to Change." MIT Technology Review. 2 December
2018. https://www.technologyreview.com/the- download/612502/ai-has-a-culturally-biased-worldview-that-google-has-
a-plan-to- change/. Accessed 11 February 2019.
13. Schwartz MJ. "Face Off: Researchers Battle AI-Generated Deep Fake Videos." Bank Info Security. 7 December 2018.
https://www.bankinfosecurity.com/face-off-researchers- battle-ai-generated-deep-fake-videos-a-11814. Accessed 11
February 2019.
14. Meyer D. "AI has a big Privacy Problem and Europe's new Data Protection law is About to Expose it." Fortune website.
25 May 2018. http://fortune.com/2018/05/25/ai- machine-learning-privacy-gdpr/. Accessed 11 February 2019.
15. Hao K. "Establishing an AI Code of Ethics Will be Harder Than People Think." MIT Technology Review. 21 October
2018. https://www.technologyreview.com/s/612318/establishing-an-ai-code-of-ethics-will- be-harder-than-people-think/.
Accessed 11 February 2019.
16. Latonero M. "Governing Artificial Intelligence: Upholding Human Rights and Dignity." Data and Society Research
Institute. 10 October 2018. https://datasociety.net/output/governing-artificial-intelligence/. Accessed 11 February 2019.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 28

 17. Fenech M, et al. "Ethical, Social, and Political Challenges of Artificial Intelligence in Health the Wellcome Trust."
Wellcome Trust website. April 2018. https://wellcome.ac.uk/sites/default/files/ai-in-health-ethical-social-political-
challenges.pdf. Accessed 11 February 2019.
18. European Group on Ethics in Science and New Technologies. "Statement on Artificial Intelligence, Robotics, and
'Autonomous' Systems." European Commission. 9 March 2018.
https://ec.europa.eu/research/ege/pdf/ege_ai_statement_2018.pdf. Accessed 11 February 2019.
19. Jacques Bughin, et al. "Notes From the AI Frontier: Modeling the Impact of AI on the World Economy." McKinsey
Global Institute Discussion Paper. September 2018. https://www.mckinsey.com/featured-insights/artificial-
intelligence/notes-from-the-ai- frontier-modeling-the-impact-of-ai-on-the-world-economy. Accessed 11 February 2019.
20. Goodreads website. https://www.goodreads.com/quotes/7091-it-has-become- appallingly-obvious-that-our-technology-
has-exceeded. Accessed 11 February 2019.

About the Author

Pei-Ting Sarah Chou, RAC, is a US-certified regulatory professional with scientific and professional training in the US, Europe
and Taiwan. Chou is a founding member of the RAPS Taiwan Chapter board. She served as an adjunct research fellow for a non-
profit intellectual property foundation, a lecturer at professional training programs organized by IRB and the Ministry of Economics
in Taiwan, ROC, a member of AHWP working group, a roundtable contributor of ISO conference, an article reviewer and a medical
writer. She is currently RA/QA/IP manager at Sourcing Overseas and Virgilant Health. She can be contacted at
[email protected].

Cite as: Chou PTS. "The Emerging Role of Artificial Intelligence in Healthcare." Regulatory Focus. February 2019. Regulatory
Affairs Professionals Society.

© 2019 by the Regulatory Affairs Professionals Society. All rights reserved.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 29

 REGULATORY FOCUS

Regulatory Intelligence Communication for

Business Impact

By Kirsten Messmer, PhD, RAC and Charity-Anne M. Schuller, PharmD, MS, RAC

This article focuses on maximizing Regulatory Intelligence (RI) in response to specific

stakeholder requests and offers best practices recommendations for RI communication.
The authors provide an overview of information delivery methods and their applicability and
present general considerations for communicating RI information by spreadsheets, text
documents, slide presentations, strategy reports and competitive intelligence reports. They
also highlight the use of due diligence and carrying out gap analyses. The article concludes
by noting future trends in RI.

Introduction

RI professionals support the drug development process with strategic information, serve as
liaisons with regulatory agencies and channel RI to the appropriate stakeholders. Typically,
an RI professional is asked for an outline of the regulatory requirements and asked to
identify existing precedent for regulatory actions and landscape opportunities for a certain
product in a specific country, region or globally. Project-specific assimilation and analysis of
the relevant information available through public sources, internal experience and/or
subscription services to avoid regulatory pitfalls, requires the necessary skills for seeing
“the big picture,” evaluating the details involved and developing a specific and creative
regulatory strategy to support a time- and cost-efficient product development program.
However, strategy needs to be reviewed throughout the drug development process to
update the strategy with regard to any changes in the development plan and/or regulatory
requirements. This article concentrates on information provision approaches to maximize
the use of RI in response to a specific stakeholder request (for proactive RI communication
see Huddle and Messmer.1)

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 30

RI Requests

Requests (both ad hoc and project-specific) for RI can vary widely in content and purpose.
The purpose, requested content and teams involved determine, in part, the presentation
method and level of detail provided. However, the RI professional also needs to include
her/his own judgement on what level of content and information delivery method provides
the best strategic support to the requestor. Knowing the information needs and
presentation preferences of the customer is paramount, as noted in the previous article on
proactive RI communication by Huddle and Messmer. 2 In ad hoc requests, the primary
customer is the person requesting the information. However, the RI ultimately might be
presented to a secondary customer, as would be the case if the internal business
development (sales) department requests RI to support a proposal to a specific customer.
In this case, the RI professional needs to cater to both the internal and external customer
based on the request specifications and any prior experience with similar requests.

RI Communication: General Considerations

The RI provided should always be concise, complete, current and accurate. Independent of
the presentation vehicle, the writing always should be of the highest quality and free of
spelling and grammatical errors. The material should be presented in an easy-to-
understand manner, yet without being overly simplified to suit the requestor’s background
understanding of the subject matter, perhaps for someone who is likely not as intimately
familiar with the material as is the RI professional.

The most powerful reports combine text, tables and graphics to communicate the RI.
Overly lengthy and text-dense reports are generally not helpful due to the significant time
pressures of drug development. RI is an exciting, fast-moving field with a potentially high
business impact. It is important to translate that ‘buzz’ into the key outputs needed by the
customer.

Original sources need to be cited whenever possible as this will help avoid any potential
issues regarding copyright infringement. Although one might consider the risk to be limited,
it is always advisable to err on the side of caution and, when in doubt, seek input from the
legal department. Second, and perhaps more importantly, citing original sources allows for
easier updates and vetting of the information. While this practice might be less necessary
for responses to specific questions and time-limited use information, such as the
assessment of a clinical trial feasibility, citing original sources will become more important
for regulatory strategy reports, competitive intelligence and due diligence. These latter
works will likely be used as “roadmaps” for extended periods of time. In an ever-changing
regulatory environment, it is important to revisit the information provided in regular intervals
or even more frequently because guidances can change swiftly. It is paramount for any
updated assessments to have access to the original information sources to be able to
accurately compare the new information to that provided in the initial report. The ability to
time-efficiently update RI will add value for the customer. “Re-inventing the wheel” for every
update of RI reports adds unnecessary cost.

Spreadsheets and Text Documents

With a specific customer request or notification, probably the simplest presentation of large
amounts of information is represented as a spreadsheet, or a briefing document, focused
on key elements relevant to the request. Information topics, such as a set of specific
regulatory questions, can be represented against target countries in tables. For
spreadsheets, the topic covered in each column or line needs to be focused and precise.
The breadth and depth of the information should be comparable for each data point for a
given topic (e.g., country when assessing regulatory questions for various countries) while
succinctly providing key information.

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While a “yes” or a “no” answer might be preferable, in regulatory affairs such simple
answers are not possible. Thus, it becomes paramount to fully understand the question in
relation to the general context and to subsequently formulate the response as precisely,
and as to the point, as possible. The shorter the presented information can be for each
country (and overall) the better; additional information always can be provided in further
commentary.

The main advantage of spreadsheets is that they can present large amounts of information
in a concise and consistent format (Figure 1). However, this type of presentation requires
further data analysis to draw the pertinent conclusion. The RI professional should analyze
the collected data and provide the main findings, including conclusions drawn based on
that information, as well as the RI professional’s experience to the ‘customer’ as an
analytical overview.

Figure 1. A spreadsheet can provide a lot of information, but often requires

further data analysis to draw the pertinent conclusion.

Slide Presentations

Generally, most of us can take in and understand large amounts of information much faster
if conveyed in a visual medium, such as a slide presentation. However, there are typically
two manners in which slide presentations are provided - summaries of information without
commentary for each single slide sent to the customer, and slides presented to the
customer in a meeting.

Slides presented during a customer-facing meeting should contain enough text to

summarize main messages. It is the speaker’s responsibility to provide the context and
crux of the slide’s message by verbally capturing the attention of the audience. It is equally
important to create the slides so they tell ‘the story’ by guiding the listener and, at the same
time, conveying critical information. Wherever possible, pictures and graphics should
replace text to convey complex concepts.

While an Internet search for “slide presentation rules” generates an abundance of articles,
all results provide suggestions that lead to the same general principles - slides presented
verbally should not contain full sentences unless they are direct quotes. Large amounts of
text on slides – particularly in complete sentences – entices the audience to read the slides
rather than listen to the information provided by the speaker. Figure 2 and Figure 3 show
two presentations of the same information. While Figure 2 is crowded with text, Figure 3
represents the same information graphically.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 32

Figure 2. Sample Text-Rich Slide That Appears Crowded

Figure 3. Sample Slide Representing the Same Information as in Figure 2

Graphically.

Other things to consider when designing the slides include font size, font color, and
background color. Although presentation of RI to a specific requestor is likely to be
conducted in a smaller room, there might be an opportunity for follow-up with a larger
audience. Choosing the largest font size possible for the text will ensure readability from
the back rows in large conference rooms. When choosing colors, it is important to use high-
contrast differences and test the chosen colors for any colorblindness impediments.
Although slide deck presentations provide the opportunity for visualizing complex
information, any images, graphics, and infographics used should all support key points, not
detract from them.

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Strategy Reports

Strategy reports are probably one of the most valuable presentations of RI because they
often combine the information, knowledge and experience of various experts. A good
strategy report begins with an executive summary outlining a “roadmap” for tackling the
project at-hand. The summary frames the discussion for the audience and, if possible,
includes a high level SWOT analysis (Strengths, Weaknesses, Opportunities and Threats)
outlining strategies for taking advantage of opportunities and to address the threats. The
summary will conclude with a succinct outline of the strategy and suggested actions.
The main text of the strategy report depends on the question(s) asked, so it is important to
ensure a complete understanding of the question(s) and the purpose of the report. For
example, if the aim of the report is to propose a strategy for developing a medicinal product
in a select group of countries, the presentation of information will differ from a strategy
report aimed at filling in gaps for a specific product identified during due diligence.
Considering the first issue for developing a gene therapy and gaining approval for the first
clinical trial (Figure 4) could suggest the submission sequence needed to obtain clinical
trial approvals at approximately the same time.

In the select country example, the executive summary likely will be followed by a side-by-
side overview of information for all countries considered, before addressing each country in
more detail. The concluding section will then provide the proposed strategy to ensure
smooth execution of the development program in as many suggested countries as
possible, or for a core group of priority countries.

Figure 4. Sample Regulatory Strategy to Accompany a Strategy Report for

Obtaining Gene Therapy Approval in Several Jurisdictions at the Same Time

In the specific product example, due diligence may have identified gaps in a submission
package that need to be addressed before the submission can proceed. The executive
summary should include a brief overview of the product, the product’s development status,
and a listing of the issues identified. The report should then address each issue in detail
and provide steps to achieve resolution. The summary will outline steps to be taken in order
of priority.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 34

Competitive Intelligence

The RI professional as a strategist provides internal and external customers with

competitive intelligence to guide successful product development and commercialization.
Competitive intelligence may include information on:

• Commercialized products for the same indication and/or mechanism of action,

• Revenues for these products,
• Products under development for a specific indication including the development
stage,
• Product availability in various markets, indication prevalence and
• Clinical trial information and precedents (case studies).

The type of information obtained during intelligence gathering depends on the questions
asked. Common questions include, but are not limited to:

• How many other products are at the same development stage and how do they
compare? (e.g., mechanism of action, expedited program designation)
• How many clinical trials are conducted in countries A, B, C, etc., that would directly
compete with a trial the requestor may be considering (e.g., prevalence of
indication, number of trials and patient enrollment target number, available
marketed treatments)?
• Requestor wants to use a specific approval pathway – Has this been done before;
if so, how was it done and was it successful? (e.g., precedent, publicly available
agency interactions for similar product/pathway; Figure 5 would support the report
by illustrating the search strategy employed to develop the precedent)?

Figure 5. Sample Search Strategy For Development of a Regulatory

Precedent

Spreadsheets and slide deck presentations may be suitable for some of the smaller
requests, such as showing products under development against development phase.
Figure 6 provides a mock-up of a development landscape. However, most competitive
intelligence-informing product development questions will require a formal report, one
illustrated by graphics summarizing the information obtained from all available information

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sources, and provides a clear analysis and shows the conclusions drawn in respect to the
specific questions asked. Key information, processes, and data should be highlighted by
appropriate illustrations throughout the report.

Figure 6. Sample Product Development Landscape Showing Development

Stage for Various Products

Like the strategy reports, competitive intelligence reports will provide a regulatory strategy
of product development based on RI analysis but also will add an operational and/or
commercial strategy for product development and positioning.

Due Diligence and Gap Analysis

Although due diligence and gap analysis have slightly different meanings, they require
similar thought processes to generate a high-quality RI output, one providing actionable
recommendations.

Due diligence is defined as “action that is considered reasonable for people to be expected
to take in order to keep themselves or others and their property safe.”3 This term might be
best known from the business and real estate world where due diligence is performed to
ensure that a purchase (acquisition, merger) provides the desired return on investment with
no potential loss. In RI or regulatory affairs, due diligence may be called upon to lead or
contribute to product and/or entity. In the case of a medicinal product, this entails ensuring
that the product development pathway is adequate, including assuring that regulatory
requirements have been met and all necessary documentation is available.

Gap analysis is defined as “a system that compares how a company works now with how it
would like to work, and then calculates how the company can use time, money, etc. to
achieve the success it would like.”4 Paraphrased: how does it look now and what does it
need to look like to be successful? In the regulatory world, a gap analysis is generally
performed on an individual product to determine whether all regulatory requirements have
been met and to identify any ‘gaps’ needing to be addressed before the product can be
successfully developed, approved and commercialized.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 36

Gap analysis likely will form a vital part of the overall due diligence process. For due
diligence/gap analysis during product development, it is paramount to understand the
product itself to be able to accurately assess the current product status and any actions
(and potential costs) needed to move the product through development to approval and
commercialization.

The pharmaceutical market necessitates accurate and precise product assessment and
regulatory outcome predictions to support corporate goals. The RI professional must
ensure regulatory precedents have been correctly interpreted and applied, that all
regulatory requirements are noted, and any opportunities to use expedited pathways are
highlighted to maximize benefits for the requestor. The most appropriate format is a
detailed and concise report supplemented by well-designed graphics and summary tables
with pertinent information.

What does the future hold?

The ever-increasing pace of pharmaceutical product development and subsequent

regulatory updates necessitates engaging new tools to support effectiveness and efficiency
in the delivery to clients. Also, quick access to key points supports faster decision-making
and process adjustments.

The use of Artificial Intelligence (AI) has dramatically increased over the recent years. AI
applications in RI include “trend spotting” and identification of differentiators for a
customer’s product against competitors. AI can support many process of gathering,
assimilating and reporting of information. This activity includes looking for gaps, identifying
trends and testing new ideas. However, responsibility for the interpretation will still fall to
the RI professional. Because innovation is guided by novelty and not existing regulations
and laws, RI delivered to the customer needs to go beyond the regulations, pathways and
guidelines, many of which are set retrospectively. For example, as a result of a novel
efficacy endpoint created during the development of a gene therapy product for the
treatment of a hereditary retinal disorder, FDA specifically began encouraging sponsors to
develop and propose novel endpoints in the guidance addressing gene therapies for retinal
disorders.5 Regulators are generally open for early discussions of innovative products and
product development processes in order to understand the drug developers’ rational since
there is no comparable benchmark. It becomes the RI professional’s responsibility to ‘read
between the lines,’ link trends across multiple disciplines, and assimilate the information
available for fast and accurate communication. The RI professional must also possess the
skill to separate fact from fiction and the practical from publicity headlines to be able to
create RI communications beneficial for clients, regulators and colleagues.

Conclusion

RI is an important, ever-evolving, always changing science. The pace of information

release by regulatory agencies and other stakeholders continues to accelerate, reflecting
the increase in experience with medicinal product development and approval. Additionally,
the complexity of products has been increasing significantly in recent years (e.g., advanced
therapy approvals). Information acceleration and complexity necessitates gaining an
intimate understanding of the product at-issue and the regulatory requirements to guide
product development and approval at every step. Also, taking advantage of innovative
pathways regulatory agencies are implementing to support faster product approval is
important. While RI delivery can take on many formats, support multiple objectives, and be
developed using a variety of tools, the skillsets and methods for obtaining, providing and
maintaining information remain the same. It will always be important to know the intended
customers, utilize the most appropriate resources, carrying out thorough searches, and
obtain an attentive secondary review. All of these processes go into ensuring successful RI
provision and strategic support for drug development.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 37

References

1. Huddle E and Messmer K. “Proactive Regulatory Intelligence Communication.” Regulatory Focus. January 2019.
Regulatory Affairs Professionals Society.
2. Ibid.
3. Cambridge Dictionary: Due Diligence. Dictionary website.
https://dictionary.cambridge.org/us/dictionary/english/due-diligence. Accessed 11 February 2019.
4. Cambridge Dictionary: Gap Analysis. Dictionary website.
https://dictionary.cambridge.org/us/dictionary/english/gap-analysis. Accessed 11 February 2019.
5. US Food and Drug Administration: Human Gene Therapy for Retinal Disorders. July 2018. FDA website.
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/
CellularandGeneTherapy/UCM610804.pdf. Accessed 11 February 2019.

About the Authors

Kirsten Messmer, PhD, RAC, is a principal regulatory affairs specialist in the Regulatory Intelligence, Policy and Advocacy (RIPA)
team at PPD, where she provides regulatory intelligence to clients and within PPD to support efficient, compliant and successful
clinical research and drug development. Messmer is currently the chair of the DIA Regulatory Intelligence Working Group. She can
be contacted at [email protected].

Charity-Anne M. Schuller, PharmD, MS, RAC, is senior director of regulatory affairs leading the RIPA team and the US
regulatory solutions team at PPD. Her current role also includes regulatory project management, regulatory consultation,
preparation and review of regulatory agency documents, development plans, support of REMS products and risk management
programs, pediatric product development and FDA meeting support. Schuller has more than 20 years of regulatory affairs
experience across a range of therapeutic areas. She can be contacted at [email protected].

Cite as: Messmer K and Schuller CAM. “Regulatory Intelligence Communication for Business Impact.” Regulatory Focus. February
2019. Regulatory Affairs Professionals Society.

© 2019 by the Regulatory Affairs Professionals Society. All rights reserved.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 38

 REGULATORY FOCUS

Chinese Health Policy and Regulatory

Authorities Overview

By Yingying Liu, MSc

This article covers recent changes to China’s healthcare regulatory authorities and
healthcare policy administration. The author explains the responsibilities and functions of
the many government departments, agencies and regulatory bodies responsible for
overseeing drugs, food, medical devices, testing and evaluation since the reorganization
and restructuring of the former Chinese Food and Drug Administration (CFDA) and several
other organizations in March 2018.

Introduction

China is a large country with a territory of 9.6 million square kilometres and a population of
1.39 billion people.1 The nation has 23 provinces, five municipalities, four municipalities
directly under the Central Government (namely Beijing, Shanghai, Tianjin and Chongqing)
and two special administrative regions.2 A variety of authorities, administrations, agencies,
bureaus, affiliates and institutions are involved in the national and local level in developing
health policy as well as drafting, formulating, implementing and supervising healthcare
regulations. The roles and responsibilities of these agencies have been subjected to a
series of reformation and reorganization efforts. The latest and perhaps the most important
reorganization occurred in March 2018, when the State Council was restructured during
the first meeting session of the 13th National People’s Congress. 3 Since this restructuring,
it has become important to understand the health and regulatory authority organization and
the various responsibilities and processes for successfully placing medical products on the
Chinese market.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 39

 The Health Administration Organization in China

Organization

In China, the health administration organization is comprised of bodies at the central and
local levels. The State Council of the People’s Republic of China is the highest executive
body of the state and the highest-level body of the state administration, also called the
“Central People’s Government.” The State Council oversees 26 ministries and
commissions, 10 organizations, nine institution, and 16 administrations and bureaus. 4

The National Health Commission (NHC) 5 is one of the 26 ministries and commissions. It
was newly established on 21 March 2018. Its establishment effectively reorganized the
roles and responsibilities of the former National Health and Family Planning Commission
(NHFPC) and several other organizations. Having replaced the former Ministry of Health
(MOH) and the former National Population and Family Planning Commission (NPFPC), 6 the
NHC has a number of key responsibilities, including:7

• drafting laws and regulations concerning national health policies, and plans
for the development of public health services
• coordinating the reform of the medical and health system
• implement the plans for disease prevention and control and the national
immunization program
• organizing and implement the health policies for the aging population
• organizing the formulation of national drug policies and the national essential
medicine catalogue, and other health policy related responsibilities

The State Administration for Market Regulation (SAMR) 8 is one of the 10

organizations directly under the State Council. It was newly established on 21 March
2018. After reorganization, the key responsibilities include:9

• managing NMPA and National Intellectual Property Administration (NIPA)

• drafting laws and regulations concerning marketing supervision
• business registration and grants
• organizing and providing the instruction for market supervision
• implementing anti-monopoly rules
• quality relevant issues and the general supervision for food safety

The National Healthcare Security Administration (NHSA)10 is another one of the 10

organizations directly under the State Council. It, too, was newly established in March
2018. The establishment of this new organization aimed at improving the medical insurance
system and ensuring insurance funding is manageable and controllable. Its key
responsibilities include:11

• drafting and implementing laws and regulations concerning medical

insurance, maternity insurance, medical assistance
• formulating and implementing the administration of medical insurance
funding
• formulating the list of reimbursement and payment standards for medical
products and services
• establishing a dynamic adjustment system
• formulating the rules for granting reimbursement
• developing and supervising the implementation of the regulation for bid
invitation and procurement of medical products and medical consumable
materials
• determining the price of medical products, consumable materials and
medical services
• establishing the pricing system and the dynamic adjustment system

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 The China National Medical Products Administration (NMPA)12

At the local level, there are 31 provincial and municipal administration bodies for market
regulation. Accordingly, the 31 local drug administrations are responsible for local health
policy and regulatory affairs within their local jurisdiction.

The following discussion covers the important regulatory bodies and presents their key
regulatory responsibilities.

Table 1. Chinese Drug Administration: Historic Overview

Year China’s National Health Organizational Level/Remit
Authority’s Name
1998 State Drug Administration (SDA) Directly report to the State Council
2003 State Food and Drug Added food administration
Administration (SFDA) Directly report to the State Council
2008 SFDA Reporting to the former Ministry of
Health (MOH)
March China Food and Drug Name change
2013 Administration (CFDA) Reporting to the State Council
March China National Drug Name change as food was excluded
2018 Administration (CNDA) from the remit
Reporting to the State Administration for
Market Regulation (SAMR)
August National Medical Pharmaceutical Name change and reporting to the
2018 Administration (NMPA) SAMR

The former CFDA, now the National Medical Products Administration (NMPA), directly
reports to SAMR. NMPA is responsible for the administration of drugs, including chemicals,
biologics, Traditional Chinese Medicines (TCM), medical devices and cosmetic products.
Food is excluded. The responsibilities of NMPA include, but are not limited to the
following:13

• supervising the safety for drugs, medical devices and cosmetic products
• managing the standardization, such as formulating and publishing the
Chinese Pharmacopeia (ChP), formulating and publishing the standards for
medical devices and cosmetic products, drafting and publishing the National
Essential Medicine List
• managing the registration of drugs, medical devices and cosmetic products,
including drafting the registration regulation, improving and implementing the
marketing authorization review and approval system
• conducting quality management for drugs, medical devices and cosmetic
products
• conducting postapproval risk management for drugs, medical devices and
cosmetic products
• inspecting drugs, medical devices and cosmetic products

The 31 provincial and municipal drug administrations, such as the Beijing drug
administration14 or the Shanghai drug administration,15 have the following roles and
responsibilities:16

• manufacturing authorization, inspecting and penalizing companies in case

of compliance violations within their local jurisdiction
• authorizing and managing the supply licenses for retailers, pharmacy chain
stores and headquarters, internet marketing
• monitoring and inspecting the use of drugs, medical devices and cosmetics

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 41

 The Center of Drug Evaluation (CDE)

Early in 1985, the first review commission was established within the former Ministry of
Health and the drug review office was established, responsible for the technical evaluation
of drugs.17 As a directly affiliated agency within NMPA since 2015, this regulatory authority
underwent organizational reform. Staff numbers were increased significantly from around
190 in 2015 to 700 in 2018.18 In addition, CDE changed their project management system
to streamline the technical review and approval process. As the most important regulatory
body for drug authorization, CDE has the following key responsibilities:19

• performing technical evaluation of drug regulatory affairs applications

• providing protocol assistance, scientific advice and regulatory consultation
• performing generic drug consistency evaluation
• participating in the formulation of drug registration law, regulations,
guidance, opinions, etc.
• organizing and implementing good evaluation practice
• assisting with relevant inspections and testing
• performing ICH guidance adoption activities
• performing research into the technical evaluation related theory, technology
and development trends
• conducting other activities assigned to CDE by NMPA

CDE has 19 departments. The following are the main departments relevant to technical
evaluation and clinical trials:

• Department of Traditional Chinese Medicine (TCM) - CMC and clinical

• Departments I and II for Chemical Products - CMC and clinical
• Department of Biological Products - CMC and clinical
• Department of Pharmacology and Toxicology
• Department of Statistics and Clinical Pharmacology
• Department of Clinical Trial Management

The Center of Medical Devices Evaluation (CMDE)

CMDE20 performs the technical evaluation of medical devices. The following are its main
responsibilities:21

• performing technical review of medical devices

• drafting medical device relevant law, regulations, guidance and best
practices
• providing training and consultation
• participating in inspections and other relevant activities

CMDE has about 100 employees working in 14 departments. Six departments are
responsible for technical evaluation of the various types of medical devices and two
departments cover clinical trials and biostatistics evaluation for medical devices.

The Center for Food and Drug Inspection (CFDI)

CFDI22 is directly affiliated with NMPA and plays an important role in safeguarding the
quality of drugs, medical devices, cosmetics and food. CFDI is organized into several
departments responsible for managing inspections and administrative tasks. The main
responsibilities include, but are not limited to the following:23

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 42

 • formulating and amending inspection relevant regulations for drugs, medical
devices and cosmetics
• performing clinical trial and non-clinical trial site authorization
• performing R&D site inspections, inspections for the purpose of registration,
for-cause inspections during manufacturing and overseas inspections
• performing inspections of medical device clinical trials and for-cause
inspections during manufacturing and conducting overseas inspections
• performing inspections of Research and Development (R&D) for cosmetics
and for-cause inspections during manufacturing and conducting overseas
inspections
• performing food establishment inspections
• managing the certification of national inspectors, providing consultation,
conducting research into inspection related new theories, technology and
development trends and regional/international cooperation

CFDI is expected to increase overseas inspections for drugs and medical devices. The
inspection scope will be extended from manufacturing to include R&D. NMPA published an
administrative regulation concerning overseas inspections of drugs and medical devices. 24

CFDI has 10 departments, six of which are responsible for conducting inspections of a
variety of products. NMPA regularly updates the list of inspectors who are responsible for
conducting specific inspections.25

The National Institutes for Food and Drug Control (NIFDC)

NIFDC26 has been directly affiliated institution within the former China Food and Drug
Administration (currently named NMPA) since 1998 and is the statutory body and the
highest technical arbitration institution for testing the quality of drugs in China. NIFDC
covers the testing for drugs, medical devices, health foods, cosmetics, ingredients and
packaging materials. NIFDC has the following responsibilities:27

• performing testing for the purpose of product registration and conducting

specification verification
• conducting testing for the purpose of safety supervision for these products
• performing batch release for biological products
• formulating and performing validation and specification verification for
ingredients and packaging materials
• performing testing of ingredients and packaging materials
• formulating and updating the technical standards/requirements,
specifications and analytical methods
• organizing the standard reference planning, development, distribution and
management, and conducting other testing relevant activities

NIFDC has about 800 employees and is comprised of 28 departments and agencies. The
following comprise the important testing relevant agencies within NIFDC:

• Testing Agency for Food

• Testing Agency for Traditional Chinese Medicine (TCM)
• Testing Agency for Chemical Products
• Testing Agency for Biological Products
• Testing Agency for Medical Devices
• Testing Agency for In-Vitro Diagnostics
• Testing Agency for Cosmetics
• Testing Agency for Ingredients and Packaging Materials
• Institution of Medical Devices Standards Management

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 43

 • Re-Evaluation Center for the Safety of Cosmetics
• Management Center of Reference Standards and Standardization

In addition, NIFDC plays an important role in testing of biological products. In special

circumstances, it is mandatory to perform testing of biological products, such as the testing
for obtaining marketing authorization approval or for the batch release of biological
products.

The Chinese Pharmacopoeia Commission (CPC)

CPC28 is an agency within NMPA. It is responsible for reviewing and granting product
names before marketing authorization can be obtained. In addition, the following are some
of its responsibilities:29

• compiling and updating the Chinese Pharmacopoeia (ChP) and its

addendums
• evaluating the implementation status of the ChP
• formulating and updating the standards, requirements and specification for
drugs, ingredients and packaging materials
• providing relevant ChP training and consultation

CPC has nine departments and approximately 50 employees.

The Center for Drug Re-Evaluation – National Center for ADR Monitoring (CDR-ADR)

CDR-ADR30 is directly affiliated agency with NMPA and is responsible for safety re-
evaluation and adverse events monitoring for drugs, medical devices and cosmetics. CDR-
ADR has the following responsibilities:31

• performing adverse events monitoring for drugs, medical devices and

cosmetics
• monitoring drug abuse
• drafting regulations and technical standards for the following items:
o adverse event re-evaluation and monitoring for drugs and medical
devices
o drug abuse monitoring
o adverse events monitoring for cosmetics
• performing the safety re-evaluation for drugs and medical devices
• participating in the formulation of the national essential medicines catalogue
• participating in the formulation of the Over-the-Counter (OTC) medicines
catalogue and other relevant activities

CDR-ADR has approximately 60 employees working in eight departments.

Figure 1 describes the structure of Chinese health and regulatory authorities.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 44

 Figure 1. Chinese Health and Regulatory Authorities Structure

Conclusion

This article provided a “snapshot” of the history of the Chinese government its willingness
to reform and reorganize the structure of the administration if and when necessary. Staying
up-to-date with the changes is essential for those involved with regulatory affairs for
products manufactured in China or products placed on the market in China. Most of the
information regarding these issues and regulations is only available in Chinese.

References

1. Macroeconomic Performance. Chinese Government Network (CGN) website. http://www.gov.cn/shuju/index.htm.

Accessed 9 April 2019.
2. National Conditions. CGN website. http://www.gov.cn/guoqing/index.htm. Accessed 9 April 2019.
3. State Council Institutional Reform Plan. NPC website. http://www.npc.gov.cn/npc/xinwen/2018-
03/18/content_2050371.htm. Accessed 9 April 2019.
4. National Assembly of the PRC. CGN website. http://www.gov.cn/guowuyuan/zuzhi.htm. Accessed 9 April 2019.
5. National Health Commission (NHC) website. http://en.nhc.gov.cn/. Accessed 9 April 2019.
6. Notice of the State Council on the Establishment of Institutions. CGN website.
http://www.gov.cn/gongbao/content/2013/content_2371590.htm. Accessed 9 April 2019.
7. What we do. NHC website. http://en.nhc.gov.cn/2018-09/22/c_46917.htm. Accessed 9 April 2019.
8. China Office of the State Council Issued the "Guiding Opinions on Promoting the Healthy Development of SMEs."
State Administration for Market Regulation (SAMR) website. http://samr.saic.gov.cn/. Accessed 9 April 2019.
9. Ibid.
10. National Healthcare Security Administration (NHSA) website. http://www.nhsa.gov.cn/. Accessed 9 April 2019.
11. Institutional Function. Main Duty. NHSA website. http://www.nhsa.gov.cn/col/col16/index.html. Accessed 9 April 2019.
12. Xi Jinping Made Important Instructions on Civil Affairs Work. National Medical Products Administration (NMPA)
website. http://www.nmpa.gov.cn/WS04/CL2042/. Accessed 9 April 2019.
13. Main Duties of the State Drug Administration. NMPA website. http://www.nmpa.gov.cn/WS04/CL2073/. Accessed 9
April 2019.
14. Beijing Municipal Market Supervision Administration Officially Established. http://scjgj.beijing.gov.cn/. Accessed 9 April
2019.
15. SHFDA website. http://www.shfda.gov.cn. Accessed 9 April 2019.
16. State Drug Administration's Functional Allocation, Internal Organization and Staffing Requirements.
https://mp.weixin.qq.com/s?__biz=MzA3Mzg0MTY1Nw==&mid=2650168646&idx=1&sn=9249c55d7386d1394536a6ae
319693c6&chksm=870a13d0b07d9ac68bb385f0649caf925e2ba75fed3f7b5e6c86bc603a649c56f78afe08847a&mpsha
re=1&scene=1&srcid=1004iXQUYu2x1PKiwDZyVoUo&pass_ticket=yedettmNOTvS5E0xAmszFxR3G8HjiybvI6XzHJLT
%2Frm0uYDqiVpMMWOPgPYbzRd%2F#rd. Accessed 9 April 2019.
17. Center for Drug Evaluation (CDE) website. http://www.cde.org.cn/htmlPage.jsp?htmlPageId=4. Accessed 9 April 2019.
18. Pharmaceutical Reform.
https://mp.weixin.qq.com/s?__biz=MzUzNjA1ODg4NQ==&mid=2247485421&idx=1&sn=d8c8e2bee4be3d8258a3ded9
aa99b79d&chksm=fafd4a87cd8ac3913dd551138b811b7d7a6a03a471bbdee46d09747bef5cef52f11110d59fbd&mpsha
re=1&scene=1&srcid=1130I6yzrd6UrAny4lwLEtTp&pass_ticket=l6ZtKe6Am%2F4wyHsqrtIctKCd0sTSztIeENECuARi%
2B%2Bb9zUoIZvrhaLpihbfx7B2i#rd. Accessed 9 April 2019.
19. CDE website. http://www.cde.org.cn/htmlPage.jsp?htmlPageId=2. Accessed 9 April 2019.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 45

 20. Center for Medical Device Evaluation (CMDE) website. https://www.cmde.org.cn/CL0001/. Accessed 9 April 2019.
21. CMDE website. https://www.cmde.org.cn/CL0015/. Accessed 9 April 2019.
22. Center for Food and Drug Inspection (CFDI) website. https://www.cfdi.org.cn/cfdi/index_en . Accessed 9 April 2019.
23. CFDI website. https://www.cfdi.org.cn/cfdi/index_en?module=A002&m1=11&m2=&nty=STE001&tcode=STE00101.
Accessed 9 April 2019.
24. NMPA website. http://www.nmpa.gov.cn/WS04/CL2138/334163.html. Accessed 9 April 2019.
25. NMPA website.
http://so.kaipuyun.cn/s?qt=%E6%A3%80%E6%9F%A5%E5%91%98&siteCode=bm35000001&database=all&noTools
=true. Accessed 9 April 2019.
26. National Institutes for Food and Drug Control (NICPBP) website. http://www.nicpbp.org.cn/CL0001/. Accessed 9 April
2019.
27. NIFDC website. http://www.nicpbp.org.cn/directory/web/WS02/CL0050/6948.html. Accessed 9 April 2019.
28. Chinese Pharmacopoeia Commission (CPC) website. http://wp.chp.org.cn/front/chpint/en/. Accessed 9 April 2019.
Accessed 9 April 2019.
29. CPC website. http://wp.chp.org.cn/en/content.html?id=ff8080814fd5ba0a014fd6f1b5580154. Accessed 9 April 2019.
30. Center for Drug Re-Evaluation (CDR) website. http://www.cdr-adr.org.cn/sy_80/sy0/. Accessed 9 April 2019.
31. CDR website. http://www.cdr-adr.org.cn/zxjj/jgzn/. Accessed 9 April 2019.

About the Author

Yingying Liu, MSc, is a senior consultant with Michor Consulting in Vienna. She is a regulatory affairs professional with a
background in pharmaceutical science and technology. She has worked on local and global projects for various blue-chip
healthcare companies in China. She can be contacted at [email protected].

Cite as: Liu Y. “Chinese Health Policy and Regulatory Authorities Overview.” Regulatory Focus. April 2019. Regulatory Affairs
Professionals Society.

© 2019 by the Regulatory Affairs Professionals Society. All rights reserved.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 46

 REGULATORY FOCUS

Comparison of Data Requirements for the

Approval of a Biosimilar Versus the
Reference Medicine
By Olivia McBride

This article compares and contrasts several aspects of biological products versus biosimilar
products. The author defines both biologics and biosimilars and explains how and why the
two differ in terms of their organic natures. She also guides the reader through the biologic
vs. biosimilar developmental and testing stages and through agency approval and
postmarketing surveillance. The author clarifies important points to consider when
developing biologic and biosimilar products, including approval processes for both,
comparing data requirements, the step-wise process for biosimilar approvals, clinical and
nonclinical trials and issues of “interchangeability.” She concludes by suggesting the impact
biosimilar products will have on the market will not be unlike the market impact of generic
drugs.

Introduction

Biomedical research is advancing rapidly, and a key part of that advancement is in the
analytical capabilities allowing comparison between a reference biological product and a
biosimilar product. To understand how biological products and biosimilar products differ, it
is first necessary to understand how a biological product is different from a standard drug
product.

What is a biological product?

A biological medicinal product is defined as one with an active substance made by or

derived from a biological source, such as living cells or organisms. These organisms may
include viruses, therapeutic serum, toxin, antitoxin, vaccine, blood, blood components or
derivatives, allergenic products and proteins (except any chemically synthesized
polypeptide). Biologics also may include growth factors, hormones, enzymes, allergenic

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 47

products and proteins, such as insulin and growth hormones, coagulation factors and
monoclonal antibodies. These substances are isolated from natural sources, such as
humans, animals, plants or microorganisms, often using cutting-edge biotechnology
methods.1-6

While small molecule drugs have a fixed molecular formula allowing their structure to be
completely defined and easily copied by generic manufacturers,7 biological products
(usually proteins), by contrast, are molecularly large and complex. Differences can occur in
protein structure, including amino acid sequence, post-translational modifications
(glycosylation) and protein folding. Once more, they are not easily characterized and are
often immunogenic, which means they can cause an immune response within the body.
Their structure may not be completely defined or known, and there are often natural
variations between products because they are made from living organisms.8 Protein
complexities must be carefully considered because even minor differences in protein
structure can significantly impact a product’s safety and efficacy profile. Advanced
analytical methods, such as mass spectrometry, peptide mapping and cell assays are used
to identify a biological product’s physiochemical and functional properties, such as protein
modifications, biological activity and molecular structure.

Fragility in biological molecules makes manufacturing complicated. Too, differences in the

biological system used to manufacture the product can cause post-translational
modifications. Aseptic processing and careful storage and handling are required as there is
potential for microbiological contamination because the molecules tend to be heat
sensitive. Higher order structure and protein modifications can be affected by the
formulation and by certain environmental conditions, such as light, temperature, moisture,
packaging materials, container closure system and delivery device materials. These
alterations in the protein product all have the potential to adversely affect the safety and
efficacy of the biological product. These minor variations, which can be within and between
batches of the same biological medicine, particularly when scaling up a production batch,
must fall within acceptable ranges to ensure consistency in terms of safety and efficacy. 9

Guidance and Approval Process for Biological Products

United States

In the US, the US Food and Drug Administration’s (FDA’s) Center for Biologics Evaluation
and Research (CBER) issues guidance on how to submit a Biologics Licence Application
(BLA). There are a variety of guidance documents available for each type of biological,
such as blood products or rDNA derived vaccines. Information can be found on FDA’s
website.

Reviewing and approving a biological in the US follows a pathway similar to that of a New
Drug Application (NDA). If nonclinical testing is successful, the product moves into clinical
trials with an Investigational New Drug Application (INDA). If the product proves to be safe
and efficacious in the intended patient population, the manufacturer can submit a BLA to
CBER to gain a marketing approval. The BLA should contain both nonclinical and clinical
data demonstrating safety, purity and potency along with a description of manufacturing
methods, stability data supporting the expiry date. The addresses of the manufacturing
sites, as well as the proposed labelling, closures and containers, should be included. 10

European Union

In the EU, the European Medicines Agency (EMA) issues scientific guidelines for biological
products. Available on the EMA website.

Review and approval of a biological in the EU follows much the same pathway as a
Marketing Authorization Application (MAA). Once preclinical testing is successful, clinical

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 48

trials are required. The Clinical Trial Directive and Clinical Trial Regulation 11,12 describes
the general requirements for clinical trials for medicines, including biologicals. The
company also must submit an Investigational Medicinal Product Dossier (IMPD). 13 If the
product is safe and efficacious, the manufacturer can apply for an MAA. The MAA must
meet standard dossier requirements (Directive 2001/83/EC) complying with CTD format
and including Module 1 (administrative information and labelling/mockups), Module 2
(expert summaries), Module 3 (chemical, pharmaceutical and biological information),
Module 4 (nonclinical reports) and Module 5 (clinical study reports). 14

Table 1 provides details of some other guidances to be considered, including those

developed by the International Council for Harmonisation (ICH).

Table 1. Other Guidance to Consider When Developing a Biological Product

ICH S6 Preclinical Testing
ICH Q5A – Q5E: Quality
Guideline on Preclinical Safety Evaluation of Biotechnology Derived
Pharmaceuticals (ICH S6) (CPMP/ICH/302/95)
Guideline on the Requirements for Quality Documentation Concerning Biological
Investigational Medicinal Products in Clinical Trials. EMA/CHMP/BWP/534898/2008
EMA/CHMP/ICH/731268/1998 (July 2011) (ICH S6 addendum)
The Human Tissues and Cells Directive: Directive 2004/23/EC, 2006/17/EC,
2006/86/EC
Regulation (EC) No 141/2000 on Orphan Medicinal Products
The Small and Medicine Sized Enterprises (SME) Regulation – (EC) No 2049/2005
The Paediatric Regulation 2007 (Regulation (EC) No 1901/2006 and Regulation (EC)
No 1902/2006)
Guideline on the Quality, Nonclinical and Clinical Aspects of Gene Therapy
Medicinal Products CHMP/GTWP/671639/2008
Guideline on Human Cell-Based Medicinal Products EMEA/CHMP/410869/2006

Data Requirements for a Biological Product

Both FDA and EMA have adopted the International Council for Harmonisation of Technical
Requirements (ICH) guidelines, making the data requirements for a biological product
generally similar for both the US and EU. The guidelines are also similar to those for a drug
product. However, assessment of immunogenicity is a critical aspect for biologicals.
Evaluation of the viral safety of biological products derived from characterized cell lines of
human or animal origin (i.e., mammalian, avian, insect) is also required. 15

The manufacturer of a biological product must clearly demonstrate safety and efficacy in
the intended indication and with the appropriate number of patients in clinical trials. The first
step is to produce an analytical package specifying the product’s composition and formula.
Then, before moving into clinical trials, laboratory and animal testing are carried out to
understand the pharmacological and potential toxicity of the biological.

Biologicals often cannot be tested in standard rat and dog species due to their biological or
tissue- specific activity. As such, a variety of tests are required, including in vitro binding
assays and functional tests, to identify one or two relevant species. If a relevant species
cannot be found in animal models, homologous proteins or transgenic animals, human
receptors are an alternative approach to gathering the required animal data.

Many biologicals are immunogenic, which means they can elicit an immune response
within the body, affecting the preclinical results. If these effects are not desired (for example
in the case that the product is not a vaccine), samples are needed for antibody testing
during repeat dose toxicity studies. The effects of antibody formation on pharmacokinetics
(PK), pharmacodynamics (PD) and adverse events must be carefully considered.
Immunogenicity in animal models is important in terms of exposure and toxicity as Anti-

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Drug Antibodies (ADAs) can result in reduced exposure. Nonclinical studies are not useful
in predicting potential immunogenicity in humans.16

Sponsors will need to perform single and multiple dose PK and/or toxicokinetic studies to
provide information on the Absorption, Distribution, Metabolism, Excretion (ADME) and
dose response. These studies help predict safety margins for clinical trials. PD studies
must be conducted including in vitro binding assays and in vivo studies conducted to define
pharmacological activity and mechanism of action. Both single and repeat dose toxicity
studies using a relevant species are needed as well as safety pharmacology to evaluate
the product’s effects on major body systems, specific organs and local tolerance.
Carcinogenicity studies may be warranted based on duration of dosing, patient population
and/or biological activity. Reproductive and developmental toxicity studies may not be
needed depending on the product, indication and patient population. Classic
biotransformation studies are not required as biologics generally degrade into peptides and
amino acids; genotoxicity studies are usually not applicable to biotechnology derived
products because they are not expected to interact with DNA or chromosomes.

To start clinical trials in humans, an Investigational Medicinal Product Dossier (IMPD) in the
EU or Investigational New Drug (IND) in the US is required to allow the agencies to assess
safety issues and patient risk. This investigational new drug application package must
provide information on everything learned to date regarding the product’s pharmacological
effects, mechanism of action and ADME to conclude clinical trials are reasonably safe. The
package should include an investigational plan with protocols for the planned studies. It
must also contain manufacturing information to allow safety evaluations. 17

As with drug products, the clinical development of biological products has three phases, but
also must include an assessment of immunogenicity because antibodies could be raised
against the medicine, thereby reducing efficacy or affecting its activity.

Phase 1 studies introduce the biological to a small number of humans (generally patients
rather than volunteers as is the case with drugs for ethical reasons) to provide information
on the product’s metabolism, pharmacology and safety with escalating doses. The
maximum tolerated dose and optimum therapeutic dose are established, and the bioactivity
assessed. Immunogenicity is also assessed in terms of antibody development after
administration, then again 28 days after administration to determine if there is a link to PK,
PD, or adverse events.18,19

Phase 2 studies in a few hundred patients are controlled and provide information on the
short-term adverse events and specific use for the product as well as exposure and
response relationships, PK, PD and immunogenicity. This information aids decision making
regarding appropriate size, study population, and endpoints for the Phase 3 studies

Phase 3 studies are typically large, randomized, double-blind, controlled, multi-center trials.
Placebo controls are used if considered ethical. These studies are the main source of
information for the risk benefit assessment for the product and its label claims. The patient
population needs to represent those for which the sponsor will be seeking approval. The
endpoint selected should be an established clinical outcome measure to demonstrate a
clinical benefit in that patient population. Data from these clinical studies will form the
majority of the BLA and MAA packages.

Biologics are sensitive to changes in the manufacturing process, such as scaling up from
pilot production to full scale manufacturing, changes to improve efficiency or a change in
production facility. The manufacturer must assess the effects of these changes using
appropriate analytical testing, functional assays and, in some cases, animal or clinical
studies to prove that the change does not affect product safety and efficacy.20,21 The
manufacturer also may need to perform additional tests on the released product and FDA
may request samples from each lot to perform their own tests.

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What is a biosimilar product?

FDA defines a biosimilar product as a biological product shown to be highly similar to an

existing FDA-approved reference biological product. The high similarity is demonstrated
using analytical animal and clinical studies and allowing for minor differences in clinically
inactive components, providing there are no clinically meaningful differences in safety,
purity and potency.22-24

EMA defines a biosimilar product as one similar to a biological medicinal product which has
already been authorized in the EU. Similarity must be in terms of structure, bioactivity,
safety, efficacy and immunogenicity based on comprehensive comparability studies. These
studies provide evidence that the biosimilar is highly similar, notwithstanding natural
variations inherent to all biological medicines and with no clinically meaningful differences.

The biosimilar approach is more likely to be applied successfully for biotechnology-derived

products, which are highly purified and can be more thoroughly characterized using state-
of-the-art analytical methods. It is more difficult to apply a biosimilar approach to other
types of biological products, such as those extracted from biological sources, as they are
more difficult to characterize.

If the active substance is a protein, the biosimilar is expected to contain the same amino
acid sequence (protein) and folding pattern (3D structure) as the reference product. These
factors determine biological activity. The biosimilar also must have the same posology and
route of administration as the reference product. In the US, if the indication or condition for
use corresponds to a particular presentation of the reference biological product, the
applicant must use the same presentation. However, not all presentations for which the
reference product has been approved are required for the biosimilar’s approval.

As biosimilars are types of biological products, the same natural variability seen in biologics
applies. The manufacturing process will be unique to each manufacturer and, as a result,
minor differences, ones not affecting safety and efficacy, may occur between the biosimilar
and the reference product, e.g., formulation (different excipients), presentation
(reconstituted powder rather than solution for injection) or administrative device.

Approval Process and Guidance on Biosimilars

The EU has been a pioneer in regulating biosimilar medicines since in 2006 when they
approved the first, which was a human growth hormone. By shaping their development
globally and establishing a framework for their approval, the EU has gathered considerable
experience over the last 10 years in showing how biosimilars, in their approved indications,
are as safe and efficacious as biologicals.

To improve patient access to biological medicines, FDA introduced the Biologics Price
Competition and Innovation Act (BPCI Act) in 2009. This act authorized FDA to create an
abbreviated licence approval pathway for biosimilar products. FDA did this to provide more
treatment options for patients, increase patient access to life saving medicines and lower
the cost of these types of medicines through competition.25

Both FDA and the EMA have similar guidelines.

The World Health Organization also has issued guidance for the development of biosimilars
following the same principles as those of the EU and FDA.26

The goal of a biosimilar development program is to confirm similarity with the reference
medicinal product based on PK and PD equivalence and a confirmatory comparative
clinical study in a representative indication evaluating safety, efficacy and immunogenicity.
The scientific principles for these comparability studies are based on ICH guidance for
evaluating the impact of changes in the manufacturing process for a biological medicinal

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product. It is not necessary to independently establish safety and effectiveness for the
proposed biosimilar product as this has already been done with the reference product. If
biosimilarity is proven through comparative studies, the manufacturer can rely on existing
scientific knowledge about safety and efficacy drawn from the reference product data, thus
avoiding repetition of completed clinical trials with the reference product.

If the product is proven to be highly similar, as well as safe and efficacious in one
therapeutic indication, the safety and efficacy data for other indications approved for the
reference product may be extrapolated. This allows the biosimilar product to be approved
for an indication without direct studies and also avoids unnecessary repetition of clinical
trials with the reference product.

Generally, in both the EU and US, comparability studies should be conducted with an
EU/US licensed product. However, both agencies have taken steps to facilitate global
development programs by allowing the use of non-licensed products in comparative clinical
studies if adequate scientific justification is provided to bridge the non-licensed product to
one that is licensed. The sponsor is invited to discuss such an approach with the agencies
to ensure other points for consideration are covered, such as whether the facility used to
produce the non-licensed product is up to agency standards.

In the US, determination of interchangeability is also a consideration. An interchangeable

biosimilar product is one expected to offer the same clinical result as the reference product.
There should not be a risk of increased safety or diminished efficacy if alternating during
repeat dosing between the biosimilar and the reference product. FDA has issued guidance
for this.

Data Requirements for a Biosimilar

Reproducing a biosimilar product is a challenge quite different from that for manufacturing a
small molecule generic drug. Biosimilars are not generics of the biological reference
product due to the natural variability of proteins and because their complicated
manufacturing processes do not allow for making an exact copy. Therefore, the data
package for biosimilars must be more extensive than for a generic to ensure any minor
differences in structure and function will not impact product safety, efficacy and
immunogenicity.

A generic product is produced by chemical synthesis and can be copied exactly from the
reference product, which is smaller and is easier to characterize. The manufacturer of a
generic product also must produce a full pharmaceutical quality dossier demonstrating
bioequivalence, meaning the active substance is released into the body at the same rate,
and to the same extent, under the same conditions. PK bioequivalence studies are the only
clinical data requirements as all indications can be approved based on bioequivalence.

By contrast, because a biosimilar product is obtained from a biological source, it can only
be reproduced to a high degree of similarity due to the natural variability and unique
manufacturing methods. Once more, biosimilars are made of structurally complex
molecules needing advanced technologies to characterize them. As a result, the biosimilar
manufacturer must demonstrate biosimilarity with robust pharmaceutical quality data as
well as comprehensive comparison studies (both nonclinical and clinical) with the reference
product to show that structure, biological function, PK and PD, efficacy, safety and
immunogenicity are all highly similar. Efficacy and safety must be justified in each
indication; however, extrapolation of data to other indications may be justified if biosimilarity
is demonstrated.

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 Table 2. Comparison of Development and Characteristics Between a Generic and
Biosimilar
Generic Drug Product Biosimilar Product
Chemical synthesis From natural sources
Exact copy can be obtained Can only reproduce to a high degree of
similarity due to natural variability and
unique manufacturing processes
Small and easy to characterize Large and complex. Advanced analytical
technologies required for characterization
Full quality data package required Full quality data package required with
additional process and product
characterization plus comparison with
reference product
Demonstrate bioequivalence Demonstrate biosimilarity using
comparability studies assessing chemical
structure, biofunction, efficacy, safety and
immunogenicity
N/A Abbreviated preclinical program based on
complexity and residual uncertainty from
quality
Clinical PK bioequivalence studies Comparative PK and PD equivalence
studies (plus safety and efficacy if
complex)
All indications approved based on Efficacy and safety in at least one
bioequivalence indication if mechanism of action is the
same. Extrapolation to other indications if
there is scientific knowledge available

A totality-of-evidence approach is recommended in the guidance for biosimilars, along with

a step-wise development program focusing on demonstrating similarity in structure and
functional equivalence. This analytical data will form the foundation of the development
program to include animal studies, a human PK/PD equivalence study and a clinical study
in a sensitive population with appropriate endpoints to confirm similar efficacy. Safety and
immunogenicity must be confirmed as well as allowing any clinically meaningful differences
to be detected. A robust manufacturing process also must be established to ensure a high-
quality biosimilar product is consistently produced.

Advances in analytical technologies, such as mass spectrometry, have meant that some
protein products can be extensively characterized in terms of their physicochemical and
biological properties, which include higher order structures and functional characteristics.
This ability has greatly improved identification and characterization of the drug substance of
a protein product as well as excipients and impurities.

Comparability studies are used to demonstrate the physiochemical properties and

biological activity of the biosimilar and the reference product are highly similar. This is
achieved in a step-wise process.

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 Table 3. The Stepwise Process for Biosimilar Development
Stepwise Process for Biosimilar Development
STEP 1
Demonstrate analytical similarity
Compare all predicted functions and confirm no enhanced function
STEP 2
Nonclinical PK/PD and toxicology as required
STEP 3
Human PK and PD
Additional clinical data as required

Step 1: Comparative Quality Studies

The main part of a biosimilar application is the direct comparison demonstrating analytical
similarity between a reference product and the proposed biosimilar product.

First, using state of the art technology, an in-depth analysis of the structure and function of
both the reference biological product and the biosimilar is carried out. This serves to
establish a target profile and to define, through analytical characterization, the Critical
Quality Attributes (CQAs) impacting the PK, safety or efficacy. Analysis includes aspects
such as primary structure (amino acid sequence), higher order structure (receptor binding),
biological properties (mechanism of action), impurities, particle and aggregates and stability
profiles.27, 28

In vitro studies compare protein structure and biological function of both products using
sensitive methods to identify minor differences in clinical relevance between the biosimilar
and the reference product. The amino acid sequence should be the same as the reference
product, but there may be variations due to mutation or modification occurring during
manufacture. These studies are much more accurate than clinical trials because of the
variability among human subjects. Any differences discovered during this analysis must be
carefully evaluated and their relationship to function assessed. Even subtle differences in
structure can significantly impact the product’s pharmacokinetics (PK), efficacy, safety and
immunogenicity. The clinical significance of these differences can be investigated through a
series of PK (exposure) and PD (response) studies, and by assessing clinical
immunogenicity.29

Step 2 - Comparative Nonclinical Studies

In vitro PD studies can confirm whether the biosimilar matches the reference product in
terms of its action within the body, such as antigen binding and activation (or inhibition) of
physiological targets and the immediate physiological effects in cells. This is accomplished
through a variety of activity-relevant assays.30

In vivo disease models can be used to compare dose response efficacy and demonstrate
equivalence in activity. They also can be used to compare PK, PD, toxicology and immune
response.

If there is enough confidence in the analytical and in vitro pharmacological similarity, the
need for testing in animals can be reduced or eliminated. In vivo PD studies using animal
models are only performed if there is no suitable in vitro model (cell based bioactivity
models) or if toxicological studies are required, such as the biosimilar is produced in a new
type of cell or organism or there are differences in formulation (new excipients not used
before), which may affect efficacy or raise potential toxicity concerns.

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A PK/PD comparative single dose study or toxicity study may be required if there is
uncertainty regarding similarity. Immunogenicity studies to detect differences between the
reference and the biosimilar may be performed, but these will not predict similarity in
clinical immunogenicity.31

Step 3 - Comparative Clinical Trials

Clinical studies are not designed to demonstrate safety and efficacy in patients, per-se, but
to confirm biosimilarity and address any questions from the analytical or functional studies
to exclude clinically meaningful differences.

The extent of differences will be determined by the degree of similarity demonstrated during
the analytical and preclinical studies. This could include PK, PD, efficacy, safety and
immunogenicity studies. At the very least, it will likely require one sufficiently large
randomized PD study to demonstrate clinical equivalence, comparable safety and
immunogenicity in an informative population.

A PK study must first be carried out in either healthy subjects or in patients within the study
population needing to be scientifically justified. If equivalence exposure can be
demonstrated in the PK study, the pivotal clinical study can be conducted using the same
therapeutic dose as used for the reference product, thereby eliminating the need for phase
II studies. A PD study should be conducted if there is a marker relevant to the mechanism
of action available to provide information on efficacy. In addition, a safety, efficacy and
immunogenicity study should be carried out in a sensitive population to allow detection of
any clinically meaningful differences. Study populations should represent the indication for
which approval is being sought. However, regulators generally allow extrapolation between
indications if efficacy relies on a similar mechanism of action and equivalence has been
demonstrated in one of them.

Totality-of-Evidence

The agency may determine that not all of the above studies are required; however, they
may request companies to meet with them to discuss their proposed biosimilar product
development plan and to establish a schedule of milestones to serve as “landmarks” for
future discussions with the agency. Each product is assessed on a case-by-case basis.

Use of a non-EU or US Licenced Product in the Comparative Clinical Studies

In both the EU and US, comparability studies for biosimilars should, ideally, be conducted
with a locally approved reference medicinal product. For approval in the US, the
manufacturer should prove biosimilarity to a US licence reference medicinal product; the
same applies in the EU. However, both agencies will accept the use of foreign sourced
comparators in the comparability studies if an adequate scientific justification or rationale
can be provided to “bridge” the foreign product to one that is licenced in either the US or
the EU. This scientific bridge will include a comprehensive analytical assessment (structural
and functional) comparing all three products: the biosimilar, the licensed product and the
non-licensed product. It is also likely to include a clinical PK and, if appropriate, a PD study
for all three products to establish bioequivalence unless justification can be provided as to
why such a study is not required. It is recommended to discuss the acceptability of such an
approach with the agencies in advance.

Interchangeability

For a biosimilar product expected to be administered to a patient more than once, a

“switching study” to determine interchangeability is required. This requirement is unique to
the US. The risk, in terms of safety or diminished efficacy of switching or alternating

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between the biosimilar and the reference medicinal product, should not be greater than if
only the reference medicinal product is used without switching.

The study should evaluate changes in treatment resulting from two or more alternating
exposures (switch intervals) between the biosimilar and the reference product to
demonstrate the same clinical result as the reference medicinal product would be expected
to provide for all indications of use in any given patient. The study should be carried out in
an appropriate patient population with endpoints assessing PK (and PD if a suitable market
is available) as PK (and PD) are expected to be more sensitive to potential changes in
immunogenicity. Postmarketing data is important for monitoring the safety of
interchangeable products.32

For biological products not administered more than once, switching studies are generally
not needed, although a justification for why they are not needed is expected. There are no
specific EU guidelines on interchangeability as individual member states make substitution
policies.

How and why Data Requirements for Biological and Biosimilar Medicines
Differ

In both the US and the EU, biological products undergo a rigorous evaluation to ensure
safety, efficacy and quality. However, a biosimilar product has an abbreviated approval
process and different data requirements. For example, the manufacturer of the reference
product must produce a “stand-alone” application containing all data and information
needed to affirm efficacy and safety have been demonstrated through extensive clinical
trials for the disease indications being sought.

By contrast, the development of a biosimilar product focuses only on demonstrating its high
similarity to the reference product. It is not necessary to establish safety and efficacy with a
full clinical package, as this has already been done for the reference product. Biosimilarity
is proven first with detailed comparative analysis of structure and function of the reference
and biosimilar products, and then through animal studies and comparative clinical studies if
there are differences needing to be assessed for clinical significance. Once biosimilarity is
demonstrated, the manufacturer can rely on the scientific knowledge from the reference
product regarding safety and efficacy in the therapeutic indications.

Table 4. Comparison of Data Requirements for a Biological Reference Product and

a Biosimilar Product
Biological Reference Product Biosimilar Product
Pharmaceutical quality studies – full Pharmaceutical quality studies – full
process and product characterization process and product characterization
N/A Comparative quality studies with reference
product
Full preclinical program Comparative nonclinical studies –
abbreviated program based on complexity
and residual uncertainty from quality
Clinical studies Comparative clinical studies
Phase I PK equivalence
PD equivalence (dose response) if marker
available
Phase 2 N/A
Phase 3 in all indications Phase 3 in at least one indication (if
mechanism of action is the same across all
indications)
Risk management plan (EU only) Risk management plan (EU only)
Pharmacovigilance Pharmacovigilance

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For a biosimilar product, there are more detailed Chemistry, Manufacturing and Controls
(CMC) and analytical (comparative) requirements, but less clinical data is expected. Once
analytical and nonclinical similarity is confirmed, the clinical studies are only required to
answer questions about minor differences between the biosimilar and the reference
product.

Summary and Conclusion

Biological medicines are large, complex molecules with inherent variability. These
molecules are difficult to characterize in the laboratory and are sensitive to minor changes
in manufacturing processes, storage and handling conditions.

The difference between a biological medicine and a biosimilar is that biologics are
developed in living organisms, whereas biosimilars are pharmaceutical drugs synthesized
outside of the living organism. Biosimilars mimic the biological medicine, but they are not
identical in nature.

Biological products must undergo a rigorous evaluation to ensure safety, efficacy and
quality. By contrast, the development of a biosimilar product focuses on demonstrating its
high similarity to the reference product through comparative studies. In other words, it is not
necessary to establish safety and efficacy with a full clinical package. However, any
differences emerging between the biosimilar and the reference product must be assessed
for clinical significance.

Biosimilars are likely to have a great impact on the pharmaceutical industry, an impact
similar to how generic drugs have impacted the industry by making more medicines
affordable and available to patients. In addition, the cost of developing a biosimilar is much
lower the developing biologics due to the abbreviated clinical trial program. Risk of failure is
also much lower than for a biosimilar’s reference product. Reduced cost should broaden
the availability of such drugs to patients. Because they are better characterized than their
reference product due to the extensive analytical studies required for regulatory approval,
there is a more complete picture of the drug and how it will affect the patient. However, one
disadvantage to biosimilars is the risk of differences due to structure, which can impact
clinical and safety profiles. If there is enough justification to provide totality of evidence,
agencies are likely to be open to many different approaches in development. However,
sponsors are advised to request scientific advice to discuss their proposed development
program. Finally, the truncated clinical development program and exposure in fewer
patients means that companies must be extra vigilant in their postmarketing surveillance.

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proteins as Active Substance: Quality Issues (EMA/CHMP/BWP/247713/2012). EMA website.
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biotechnology-derived-proteins-active_en-0.pdf. Accessed 9 July 2019.
29. Kay J, Issacs JD. “Clinical Trials Of Biosimilars Should Become More Similar.” Ann Rheum Dis. 2017:76;4-6.
30. Issacs J, et al. “The Biosimilar Approval Process: how Different is it?” Consideration Med. 2017:1;3-6.
31. US Food and Drug Administration. Guidance for Industry: Clinical Pharmacology Data to Support a Demonstration of
Biosimilarity to a Reference Product. Rockville. MD. 2014. FDA website.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM397017.pdf.
Accessed 9 July 2019.
32. FDA Considerations in Demonstrating Interchangeability With a Reference Product. FDA website.
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf.
Accessed 9 July 2019.

About the Author

Olivia McBride is a senior regulatory affairs consultant at Parexel. She can be contacted at [email protected].

Cite as: McBride O. “Comparison of Data Requirements for the Approval of a Biosimilar Versus the Reference Medicine.”
Regulatory Focus. July 2019. Regulatory Affairs Professionals Society.

© 2019 by the Regulatory Affairs Professionals Society. All rights reserved.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 58

 REGULATORY FOCUS

Protecting the Healthcare Infrastructure: Global

Cybersecurity Compliance

By Suzanne Schwartz, MD, MBA and Michelle Jump, MS, MSRS, RAC

This article reviews past and current efforts to protect medical devices and other connected
healthcare infrastructure from security breaches. The authors cover recent regulatory
efforts in Australia, Canada, China, Europe, Japan and the US aimed at enhancing
cybersecurity and industry’s efforts in cybersecurity regulatory compliance to protect
patients as well as healthcare infrastructure.

Introduction

What are the Issues?

The US healthcare and public health critical infrastructure sector represents a significantly
large cyberattack surface. Intrusions and breaches occur through weaknesses and
vulnerabilities in the system’s architecture and medical devices. As with all other computer
systems, medical devices that use software are vulnerable to cyberattacks and hospital
network operations using software and the Internet are also subject to disruption. If
vulnerabilities are not addressed and remediated, they can serve as points of access and
entry into medical devices, hospital and other healthcare networks, resulting in
compromised data confidentiality as well as compromised patient safety.

Strengthening healthcare cybersecurity and the critical infrastructure within and across
sectors is imperative. Doing so requires fostering an incentivized culture that encourages
proactive behavior, especially with regard to information sharing, as well as developing a
framework to strengthen cybersecurity and critical infrastructure.

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Australia

In the fall of 2018, the Australian government’s Therapeutic Goods Administration (TGA)
announced cybersecurity consultation through The Commonwealth Scientific and Industrial
Research Organisation (CSIRO), an independent Australian federal government agency
responsible for scientific research, in the areas of Software as a Medical Device (SaMD)
and Cybersecurity for Medical Devices (CSfMD).1 The collaboration aims at generating
reports for both SaMD and CSfMD that can help move regulation forward.2 According to
CSRIO, TGA engaged CSIRO to conduct research to build an understanding of Australia’s
Software as a Medical Device innovators and learn how and when TGA can support them
in demonstrating the safety of their products. To accomplish this, CSIRO conducted
research into medical device cybersecurity in an effort to support the development of a
TGA guidance document to assist the medical devices ecosystem implement best practices
for cybersecurity. On 20 December 2018, CSRIO posted draft regulatory guidance and
other informational materials on their website and invited comments from interested parties
on the applicability and usefulness of the content contained in the draft regulatory guidance
and information materials.3 The comment period deadline was 14 February 2019.

The Australian guidance stresses a Total Lifecycle (TPLC) approach, similar to the
Canadian guidance and also refers to AAMI TIR57 and UL 2900, as well as ISO 27799,
ISO/IEC 290147, ISO/IEC 30111 and others. It also focuses on the importance of
information sharing, vulnerability disclosure and supply chain assessment. Cybersecurity-
specific considerations have been added for each essential principle.

Canada

In the fall of 2018, Health Canada sought “input” on its approach to medical device
cybersecurity from the Scientific Advisory Committee on Digital Health Technologies. That
input was published on 7 December 2018 on the Health Canada website as a draft
guidance document on the premarket requirements for cybersecurity of medical devices. 4,5
The draft guidance6 outlines a set of high level goals, including security design and risk
control activities, as well as specific license application requirements such as an SBOM, list
of recalls related to cybersecurity, risk management reports and evidence of a cyber
framework as part of device development. It also references the NIST cybersecurity
framework and references standards such as AAMI TIR57 and UL 2900.

China

China’s National Medical Product Administration (NMPA)), founded on the basis of the
former China Food and Drug Administration (CFDA) was rebranded and restructured as the
China NMPA in 2018.7

Now, CFDA has new, codified medical device cybersecurity expectations prior to product
registration that include the expectation that companies will conduct a self-assessment of
cybersecurity standards and measures. The measures are not mandatory, but the new
cybersecurity law suggests that failure to do an assessment may delay product
registrations. The latest CFDA cybersecurity guidelines, published in 2018, covers devices
connected for data exchange, remote control or those devices used to store media for the
exchange of information.

NMPA’s medical device cybersecurity focus follows a three-part, CIA Model: Confidentiality,
Integrity and Availability.8 “Confidentiality” means data can only be accessed by authorized
users within an authorized time frame through authorized means. “Integrity” means data
must be accurate, comprehensive and cannot be altered without authorization. “Availability”
means data must be accessible and utilized as expected. Once more, the CIA model focus
must cover the entire process, from data generation through data usage and consider the
entire lifecycle. That data, says NMPA, is the patient’s personal information protected by
encryption and embedded software “controls” for monitoring, security and tracking capabilities.

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Europe

The European Union Agency for Network Information Security (ENISA), now a permanent
agency in the European Union (EU), is developing a Single Digital Market strategy as
proposed in the EU Cybersecurity Act on 29 May 2018. The Single Digital Market includes
the concept of the Internet of Things (IOT), which merges physical and virtual worlds,
creating smart environments.9 The European Commission actively cooperates with
industry, organizations and academic institutions to unleash the potential of the IOT
technology across EU Member States and beyond.

Baseline security recommendations have been crafted for IOT. The recommendations
include cybersecurity recommendations focused on critical information infrastructures
where their destruction or disruption that could bring about major consequences for the
health, safety and economic wellbeing of EU citizens. Section 4 of the EU IOT
recommendations focuses on security “best practices” in terms of policies, organizational,
people, process measures and technical measures. System safety and reliability
recommendations include designing systems with operational disruption in mind and
preventing the system from causing unacceptable risk of injury or physical damage. Also
included is the recommendation for a mechanism with the ability of “self-diagnosis” and
self-repair to recover from a failure, malfunction or compromised state. Ensuring a
“standalone” operation, in which essential features of the device should continue to work in
a loss of communications or negative impacts from compromised devices or cloud-based
systems is a goal.

Gap analysis is also recommended in the context of IOT design and development. In all,
IOT recommends the following 24 categories of detailed security measures:

1. security by design
2. privacy by design
3. asset management
4. risk and threat identification and assessment
5. hardware security
6. trust and integrity management
7. strong default security and privacy
8. data protection and compliance
9. system safety and reliability
10. secure software/firmware updates
11. authentication
12. authorization
13. access control
14. cryptography
15. secure and trusted communication
16. secure interfaces and network services
17. secure input and output handling
18. logging
19. monitoring and auditing
20. end-of-life support
21. proven solutions
22. management of security vulnerabilities and/or incidences
23. human resource security training and awareness
24. third party relationships

Japan

In July 2018, the Japanese Pharmaceuticals and Medical Devices Agency (PMDA)
published Guidance for Ensuring Cybersecurity in Medical Devices (Notification No. 0724-

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1).10 Since breaches of cybersecurity are now seen as a foreseeable hazard, the primary
focus of the guidance is on risk management and with a dual focus on both technical
controls and procedural protection.

Federal Efforts to Strengthen US Cybersecurity

Federal policy framework for cybersecurity and critical infrastructure resilience emphasizes
a collaborative approach among government, industry and other stakeholders. Executive
Order 13636, “Improving Critical Infrastructure Cybersecurity” 11 seeks partnerships with the
owners and operators of critical infrastructure to improve cybersecurity while Presidential
Policy Directive 21, “Critical Infrastructure Security Resilience” 12 promotes better security.
In addition, Executive Order 13691 promotes the establishment of Information Sharing and
Analysis Organizations (ISAOs)13 and Executive Order 13800 aims at strengthening the
cybersecurity of federal networks and critical infrastructure networks. 14

FDA’s Cybersecurity History and key Principles, Premarket and Postmarket

The US Food and Drug Administration’s (FDA) recent medical device cybersecurity efforts
include releasing the 2018 Medical Device Safety Action Plan,15 issuing safety
communications and cybersecurity guidances, convening several public workshops (2014,
2016 and 2017),16 partnering with the Health ISAC, supporting ISAO efforts and organizing
independent security researchers, medical device manufacturers and the Department of
Homeland Security for coordinated vulnerability disclosure, among other activities. These
efforts continue to enhance multi-stakeholder engagements for cybersecurity initiatives
including cooperation and collaboration with the following groups and agencies:

• Medical Device Innovation Consortium (MDIC)

• National Telecommunications and Information Administration (NTIA): US
Department of Commerce
• Healthcare and Public Health Sector Coordinating Council (HSCC) Cybersecurity
Working Group

Key principles of FDA’s premarket cybersecurity guidance have emphasized shared

responsibility between stakeholders (including healthcare facilities, patients, healthcare
providers and manufacturers of medical devices), addressing cybersecurity during the
design and development of medical devices, establishing design inputs for devices related
to cybersecurity and establishing a cybersecurity vulnerability and management approach
as part of software validation and risk analysis as required by 21 CFR 820.30 (g). 17

FDA is also driving efforts to improve the postmarket management of cybersecurity in

medical devices by incentivizing “right behavior.” For example, FDA advocates for a risk-
based framework to assure risks to public health are addressed in a continual and timely
fashion. The emphasis articulates manufacturer responsibilities by leveraging existing
Quality System Regulation and postmarket authorities. FDA also continues to foster a
collaborative and coordinated approach to information sharing and risk management while
aligning with Presidential executive orders and National Institute of Standards and
Technology (NIST) frameworks.

Over the years, there have been many cybersecurity lessons learned. Accordingly, FDA’s
thinking with regard to cybersecurity in the healthcare space has evolved. For example,
when investigating device vulnerabilities it is necessary to get to “ground truth” as quickly
as possible so that mitigations can be proactively communicated and executed. FDA has
observed that non-coordinated disclosure of vulnerabilities may result in delayed
assessments. In addition, the impact of cyberattacks, such as WannaCry, on critical
infrastructure has the potential to disrupt critical patient care and can therefore result in
delayed treatment and patient harm.

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These lessons have led to efforts to further advance medical device cybersecurity. FDA’s
“Medical Device Safety Action Plan” considers the need for the Agency to seek additional
premarket and post-market authorities, including to require:

1. companies to build and update security capabilities into a product’s design and to
include appropriate data supporting these design capabilities into premarket
submissions to FDA
2. manufacturers to develop a Software Bill of Materials (SBOM) to be shared with
customers and as part of regulatory submissions
3. firms adopt policies and procedures for coordinating disclosures about
vulnerabilities as they are identified

FDA’s Current and Future Efforts: Medical Device Safety Action Plan

FDA released an updated draft Medical Device Cybersecurity Premarket Guidance in

October 2018. The new draft guidance outlines tiers that separate products into two
categories, dependent on their potential risk to patients.
In addition, MITRE, in collaboration with FDA, has developed a cybersecurity preparedness
and incident response playbook which involves using testing scenarios for medical devices
in the clinical environment to help foster regional and national preparedness. To enhance
information sharing of medical device vulnerabilities across the ecosystem, FDA has
executed Memorandums of Understanding with emerging ISAOs emphasizing information
sharing relevant to patient safety and treatment.

Also, with MITRE’s expert support and guidance, efforts to develop a clinical rubric for
Common Vulnerability Scoring System as a Medical Device Development Tool (MDDT)
continue to progress with active multi-stakeholder engagement. Finally, the Medical Device
Innovation Consortium (MDIC)—a public private partnership with FDA—published a white
paper in late 2018 that provided a compelling analysis for adoption of coordinated
vulnerability disclosure policies and processes.18

Summary and Conclusion

A Common Cybersecurity Thread

Around the globe and across regulators, four consistent themes are emerging with regard
to medical device cybersecurity: risk management, security by design, standardization and
documentation. Cybersecurity risk management starts with an understanding of risk and its
control, which means “security-by-design” or designing technical controls to ensure
comprehensive and robust medical device protection for patient health and their personal
data. As standards are being developed, assessed and implemented, methods and rules
for manufacturers to show they are doing “the right things” are also being incorporated.
However, global medical device cybersecurity will depend on three expectations of
industry—that there will be enhanced collaboration, greater transparency and increased
awareness of the security risks inherent in medical devices.

References

1. Research: Software as a Medical Device and Cybersecurity for Medical Devices. February 2019. Australia’s
Therapeutic Goods Administration (TGA) website. https://www.tga.gov.au/research-software-medical-device-and-
cyber-security-medical-devices.Accessed 16 May 2019.
2. Understanding the Emerging Medical Devices Landscape and the Associated Regulatory Environment.
https://research.csiro.au/tga/. Accessed 16 May 2019.
3. Consultation: Medical Device Cybersecurity. Draft Regulatory Guidance and Information Materials. December
2018. TGA website. https://www.tga.gov.au/consultation/consultation-medical-device-cyber-security. Accessed
16 May 2019.
4. Notice: Medical Device Cybersecurity. August 2018. Health Canada website. https://www.canada.ca/en/health-
canada/services/drugs-health-products/medical-devices/activities/announcements/notice-cybersecurity.html.
Accessed 16 May 2019.
5. Scientific Advisory Committee on Digital Health Technologies (SAC-DHT). Meeting Announcement. Ottawa,
Ontario. 7 June 2018. Health Canada website. https://www.canada.ca/en/health-canada/services/drugs-health-

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 63

 products/medical-devices/activities/scientific-expert-advisory-committees/digital-health-technologies/meeting-
announcement.html. Accessed 16 May 2019.
6. Draft Guidance Document: Premarket Requirements for Medical Device Cybersecurity. Health Canada website.
https://www.canada.ca/en/health-canada/services/drugs-health-products/public-involvement-
consultations/medical-devices/consutation-premarket-cybersecurity-profile/draft-guidance-premarket-
cybersecurity.html. Accessed 16 May 2019.
7. Yang B. “Bye Bye CFDA, Hello NMPA: China Regulatory Express.” September 2018. Pink Sheet Pharmaceutical
Intelligence. https://pink.pharmaintelligence.informa.com/PS123796/Bye-Bye-CFDA-Hello-NMPA-China-
Regulatory-Express. Accessed 16 May 2019.
8. CYBER EDU. What is the CIA Triad? The CIA Triad Defined, Explained, and Explored. Forcepoint website.
https://www.forcepoint.com/cyber-edu/cia-triad. Accessed 16 May 2019.
9. Digital Single Market. Policy. The Internet of Things. https://ec.europa.eu/digital-single-market/en/internet-of-
things. Accessed 16 May 2019.
10. Cybersecurity Compliance: Global Considerations for Healthcare. Presentation by Michelle Jump. Nova Leah.
http://www.hl7.org/documentcenter/public_temp_939DF9D5-1C23-BA17-
0CF935B999187742/wg/healthcaredevices/Global%20Cybersecurity%20Trends_and%20Standards.pdf.
Accessed 16 May 2019.
11. Fact Sheet: Executive Order (EO) 13636 Improving Critical Infrastructure Cybersecurity and Presidential Policy
Directive (PPD) 21 Critical Infrastructure Security and Resilience. https://www.dhs.gov/publication/eo-13636-ppd-
21-fact-sheet Accessed 16 May 2019.
12. Presidential Policy Directive/PPD-21 Subject: Critical Infrastructure Security and Resilience. 12 February 2013.
https://fas.org/irp/offdocs/ppd/ppd-21.pdf. Accessed 16 May 2019.
13. 3 CFR 13691: Executive Order 13691 of 13 February 2015. Promoting Private Sector Cybersecurity Information
Sharing. https://www.govinfo.gov/app/details/CFR-2016-title3-vol1/CFR-2016-title3-vol1-eo13691/context.
Accessed 16 May 2019.
14. Executive Order on Strengthening the Cybersecurity of Federal Networks and Critical Infrastructure.
https://www.dhs.gov/executive-order-strengthening-cybersecurity-federal-networks-and-critical-infrastructure.
Accessed 16 May 2019.
15. Medical Device Safety Action Plan: Protecting Patients, Promoting Public Health. FDA website.
https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHRe
ports/UCM604690.pdf. Accessed 16 May 2019.
16. Cybersecurity. FDA website. https://www.fda.gov/medical-devices/digital-health/cybersecurity#workshops.
Accessed 16 May 2019.
17. 21 CRR Part 820.30: Quality System Regulation. Subpart C—Design Controls. FDA website.
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=820.30. Accessed 16 May 2019.
18. Medical Device Cybersecurity Report. Advancing Coordinated Vulnerability Disclosure. Medical Device
Innovation Consortium (MDIC) website. http://mdic.org/wp-content/uploads/2018/10/MDIC-
CybersecurityReport.pdf. Accessed 20 May 2019.

About the Authors

Suzanne Schwartz, MD, MBA, is FDA’s CDRH associate director for science and strategic partnerships. She can be contacted at
[email protected].

Michelle Jump, MS, MSRS, RAC, is vice president of the Cyber Program Initiatives at Nova Leah. She can be contacted at
[email protected].

Cite as: Schwartz S and Jump M. “Protecting the Healthcare Infrastructure: Global Cybersecurity Compliance.” Regulatory Focus.
May 2019. Regulatory Affairs Professionals Society.

© 2019 by the Regulatory Affairs Professionals Society. All rights reserved.

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 64

 REGULATORY FOCUS

Regulatory Strategist Toolbox: 2018 FDA Regulatory

Intelligence Briefing

By Meredith Brown-Tuttle, RAC, FRAPS

If you thought 2017 had a lot of changes, 2018 was even busier (and 2019 seems to be
shaping up just the same if not busier). This article explores the major changes during 2018
including guidance documents drafted and finalized, new legislation, other areas of interest
and some tools to help you explore additional areas.

Strategic Policy Areas (Drug/Biologic Specific Only) Summary

The following four priority areas were identified in FDA’s 2018 Strategic Policy Roadmap
issued in January 2018:

1. reduce the burden of addiction crises threatening US families

2. leverage innovation and competition to improve healthcare, broaden access and
advance public health goals
3. empower consumers to make better and more informed decisions about their diets
and health and expanding the opportunities to use nutrition to reduce morbidity and
mortality from disease
4. strengthen FDA’s scientific workforce and its tools for efficient risk management

Number 2 impacts industry and #4 is internal to FDA but will ultimately affect/help industry.
Within the document, specifics are given to support these goals including:

• improve product development and strengthen FDA’s Gold Standard (#2) which was
implemented through the Advanced Manufacturing Strategy Roadmap (assure the
availability of safe and effective medicines by modernizing the drug manufacturing
methods to make the processes more reliable, efficient and high quality)

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 65

 • promote Generic Drug Competition (#2) implemented through the Drug
Competition Action Plan and Biosimilar Innovation Plan
• modernize FDA’s Regulatory Toolbox (#4) started through both the Building a
Strong FDA and Scientific Computing Work Plan (internal to FDA)

Major Legislation/Regulations

What major legislation was passed this year and will be implemented through the passage
of regulations? While new bills/laws were scarce, there were a few new regulations (Table
1) and many guidance documents recapped below (Table 2).

Right to Try

On 30 May, President Trump signed the “Right to Try” bill into law. This law is another way
for patients who have been diagnosed with life-threatening diseases or conditions who
have tried all approved treatment options and who are unable to participate in a clinical
trial to access certain unapproved treatments. FDA encourages companies to
accommodate these patients’ requests; watch for more action to follow about this.

Table 1. 2018 Proposed and Implemented Changes in Regulations

Regulation Title
21 CFR Part 600 Removal of Certain Time of Inspection and Duties of Inspector Regulations for
Biological Products
Proposed Rule
21 CFR Part 3 Modification of Product Jurisdiction
Proposed Rule
Update
21 CFR 345 Nonprescription Drug Product With an Additional Condition for Nonprescription
use
21 CFR 310 Repeal of Regulation Requiring an Approved new Drug Application for Drugs
Sterilized by Irradiation
21 CFR Parts 20 Public Information - Amend Regulations (FOI)
and 720
21 CFR Parts FDA takes steps to allow greater flexibility for clinical investigators about
50, 312 and 812 informed consent in minimal risk situations.
FDA is proposing to amend its regulations to implement section 3024 of the
add § 50.22 to 21st Century Cures Act.
part 50 (21 CFR
part 50)
21 CFR Parts Supplemental Applications Proposing Labeling Changes for Approved Drugs
314 and 601 and Biological Products; Withdrawal

Guidance Documents

In 2018, FDA published a number of draft and final guidance documents in the Federal
Register (Table 2). Also included in Table 2 is the Federal Register notice or press release
associated with each guidance document, when available (and the newly designed FDA
website captures information like this as well….great minds think alike). Why would a link to
the Federal Register notice be important? Often the background of the guidance document,
definitions used in the guidance document, rationale for why needed and comments
received on a previous draft are included in the Federal Register notice. Below are some
helpful links to help you explore this critical body of knowledge:

• new guidance documents posted by FDA

• search guidance documents
• 2018-2019 guidance document agenda
• withdrawn guidances (Table 3)

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 66

 Table 2. 2018 Guidance Documents
Category Title Type Date
Bioresearch Monitoring Technical Conformance Revision Feb
Guide 1 2018
Institutional Review Board (IRB) Written Final May
Procedures: Guidance for Institutions and IRBs 2018

Summary of Guidance
Civil Money Penalties Relating to the Draft Sept
ClinicalTrials.gov Data Bank 2018

Summary of Guidance
Advertising Presenting Quantitative Efficacy and Risk Draft Oct
Information in Direct-to-Consumer Promotional 2018
Labeling and Advertisements
Biopharmaceutics Bioanalytical Method Validation Final May
2018
Summary of Guidance
Biopharmaceutics Dissolution Testing and Acceptance Criteria for Final Aug
Immediate-Release Solid Oral Dosage Form 2018
Drug Products Containing High Solubility Drug
Substances

Summary of Guidance
Biosimilars Questions and Answers on Biosimilar Final Dec
Development and the BPCI Act Revision 2018
1
Summary of Guidance
Biosimilars New and Revised Draft Q&As on Biosimilar Draft Dec
Development and the BPCI Act (Revision 2) Revision 2018
2
Summary of Guidance
CBER Submitting Study Datasets for Vaccines to the Final April
Office of Vaccines Research and Review 2018
CBER Donor Screening Recommendations to Reduce Revision May
the Risk of Transmission of Zika Virus by 2018
Human Cells, Tissues, and Cellular and Tissue-
Based Products
CBER Revised Recommendations for Reducing the Final July
Risk of Zika Virus Transmission by Blood and 2018
Blood Components
CBER Recommendations for Reducing the Risk of Draft July
Transfusion-Transmitted Babesiosis 2018

Summary of Guidance
CBER Further Testing of Donations That are Reactive Draft Sept
on a Licensed Donor Screening Test for 2018
Antibodies to Hepatitis C Virus

Summary of Guidance
CBER Recommendations for Requalification of Blood Draft Sept
Donors Deferred Because of Reactive Test 2018
Results for Antibodies to Human T-
Lymphotropic Virus Types I and II (Anti-HTLV-
I/II)

Summary of Guidance
CBER Considerations for the Development of Dried Draft Oct
Plasma Products Intended for Transfusion 2018

Summary of Guidance
CBER Bacterial Risk Control Strategies for Blood Draft Dec
Collection Establishments and Transfusion 2018

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 Services to Enhance the Safety and Availability
of Platelets for Transfusion

Summary of Guidance
CBER Labeling of Red Blood Cell Units with Historical Final Dec
Antigen Typing Results 2018

Summary of Guidance
CBER/Gene Therapy Human Gene Therapy for Hemophilia Draft July
2018
Summary of Guidance
CBER/Gene Therapy Human Gene Therapy for Retinal Disorders Draft July
2018
Summary of Guidance
CBER/Gene Therapy Human Gene Therapy for Rare Diseases Draft July
2018
Summary of Guidance
CBER/Gene Therapy Chemistry, Manufacturing and Control (CMC) Draft July
Information for Human Gene Therapy 2018
Investigational New Drug Applications (INDs)

Summary of Guidance
CBER/Gene Therapy Testing of Retroviral Vector-Based Gene Draft July
Therapy Products for Replication Competent 2018
Retrovirus (RCR) During Product Manufacture
and Patient Follow-up

Summary of Guidance
CBER/Gene Therapy Long Term Follow-up After Administration of Draft July
Human Gene Therapy Products 2018

Summary of Guidance

Statement from FDA Commissioner Scott

Gottlieb on Agency’s Efforts to Advance
Development of Gene Therapies
Clinical Maximal Usage Trials for Topical Active Draft May
Pharmacology/Over-the- Ingredients Being Considered for Inclusion in an 2018
Counter (OTC) Over-the-Counter Monograph: Study Elements
and Consideration

Summary of Guidance
Clinical/Antimicrobial Microbiology Data for Systemic Antibacterial Revision Feb
Drugs—Development, Analysis and 2 2018
Presentation
Clinical/Antimicrobial Uncomplicated Urinary Tract Infections; Draft May
Developing Drugs for Treatment 2018

Summary of Guidance
Clinical/Antimicrobial Complicated Urinary Tract Infections: Revision June
Developing Drugs for Treatment 1 2018
Clinical/Antimicrobial Cytomegalovirus in Transplantation: Developing Draft May
Drugs to Treat or Prevent Disease 2018

Summary of Guidance
Clinical/Antimicrobial Anthrax: Developing Drugs for Prophylaxis of Final May
Inhalational Anthrax 2018

Summary of Guidance
Clinical/Antimicrobial Complicated Intra-Abdominal Infections: Revision May
Developing Drugs for Treatment 1 2018

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 Clinical/Antimicrobial Human Immunodeficiency Virus-1 Infection: Draft June
Developing Systemic Drug Products for pre- Final 2018
Exposure Prophylaxis
Mar
Summary of Guidance 2019
Clinical/Antimicrobial Smallpox (Variola Virus) Infection: Developing Draft July
Drugs for Treatment or Prevention Revision 2018
1
Summary of Guidance
Clinical/Antimicrobial Chronic Hepatitis B Virus Infection: Developing Draft Oct
Drugs for Treatment 2018

Summary of Guidance
Clinical/Clinical Drugs for Treatment of Partial Onset Seizures: Draft Feb
Pharmacology Full Extrapolation of Efficacy From Adults to 2018
Pediatric Patients 4 Years of age and Older

Summary of Guidance
Clinical/Medical Establishing Effectiveness for Drugs Intended to Guidance May
Treat Male Hypogonadotropic Hypogonadism 2018
Attributed to Nonstructural Disorders
Clinical/Medical Hypertension: Developing Fixed-Combination Final Nov
Drug Products for Treatment 2018

Summary of Guidance
Clinical/Medical Bacillus Calmette-Gu[eacute]rin (BCG)- Final Feb
Unresponsive Nonmuscle Invasive Bladder 2018
Cancer: Developing Drugs and Biologics for
Treatment

Summary of Guidance
Clinical/Medical Early Alzheimer’s Disease: Developing Drugs Revision Feb
for Treatment 1 2018

Summary of Guidance
Clinical/Medical Amyotrophic Lateral Sclerosis: Developing Draft Feb
Drugs for Treatment 2018

Summary of Guidance
Clinical/Medical Duchenne Muscular Dystrophy and Related Final Feb
Dystrophinopathies: Developing Drugs for 2018
Treatment

Summary of Guidance
Clinical/Medical Migraine: Developing Drugs for Acute Final Feb
Treatment 2018

Summary of Guidance
Clinical/Medical Chronic Obstructive Pulmonary Disease: Use of Final Mar
the St. George’s Respiratory Questionnaire as a 2018
PRO Assessment Tool

Clinical/Medical Atopic Dermatitis: Timing of Pediatric Studies Final Oct

During Development of Systemic Drugs 2018
Summary of Guidance

Final
Clinical/Medical Pregnant Women: Scientific and Ethical Draft April
Considerations for Inclusion in Clinical Trials 2018

Summary of Guidance
Clinical/Medical Opioid Use Disorder: Developing Depot Final April
Buprenorphine Products for Treatment 2018

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 Summary of Guidance
Clinical/Medical Clinical Trial Imaging Endpoint Process Final April
Standards 2018

Summary of Guidance
Clinical/Medical Pediatric HIV Infection: Drug Development for Draft May
Treatment 2018

Summary of Guidance
Clinical/Medical Acne Vulgaris: Establishing Effectiveness of Final May
Drugs Intended for Treatment 2018

Summary of Guidance
Clinical/Medical Establishing Effectiveness for Drugs Intended to Final May
Treat Male Hypogonadotropic Hypogonadism 2018
Attributed to Nonstructural Disorders

Summary of Guidance
Clinical/Medical Assessment of Pressor Effects of Drugs Draft May
2018
Summary of Guidance
Clinical/Medical Considerations for the Inclusion of Adolescent Draft June
Patients in Adult Oncology Clinical Trials 2018

Summary of Guidance Final Mar

2019
Clinical/Medical Epidermolysis Bullosa: Developing Drugs for Draft June
Treatment of Cutaneous Manifestations 2018

Summary of Guidance
Clinical/Medical Major Depressive Disorder: Developing Drugs Draft June
for Treatment 2018

Summary of Guidance
Clinical/Medical Hypertension: Conducting Studies of Drugs to Draft July
Treat Patients on Background of Multiple 2018
Antihypertensive Drugs

Summary of Guidance
Clinical/Medical Smallpox (Variola Virus) Infection: Developing Revision July
Drugs for Treatment or Prevention 1 2018
Clinical/Medical Inborn Errors of Metabolism That Use Dietary Draft July
Management: Considerations for Optimizing 2018
and Standardizing Diet in Clinical Trials for Drug
Product Development

Summary of Guidance
Clinical/Medical Opioid Use Disorder: Endpoints for Draft Aug
Demonstrating Effectiveness of Drugs for 2018
Medication-Assisted Treatment: Draft Guidance
for Industry

Summary of Guidance
Clinical/Medical Osteoarthritis: Structural Endpoints for the Draft Aug
Development of Drugs, Devices and Biological 2018
Products for Treatment

Summary of Guidance
Clinical/Medical Hematologic Malignancy and Oncologic Draft Aug
Disease: Considerations for Use of Placebos 2018
and Blinding in Randomized Controlled Clinical
Trials for Drug Product Development

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 Summary of Guidance
Clinical/Medical Physiologically Based Pharmacokinetic Final Aug
Analyses Format and Content 2018

Summary of Guidance
Clinical/Medical Allergic Rhinitis: Developing Drug Products for Final Sept
Treatment 2018

Summary of Guidance
Clinical/Medical Nonallergic Rhinitis: Developing Drug Products Final Sept
for Treatment 2018

Summary of Guidance
Clinical/Medical Adaptive Design for Clinical Trials of Drugs and Draft Sept
Biologics 2018

Summary of Guidance
Clinical/Medical Hematologic Malignancies: Regulatory Draft Oct
Considerations for use of Minimal Residual 2018
Disease in Development of Drug and Biologic
Products for Treatment

Summary of Guidance
Clinical/Medical Nonmetastatic, Castration-Resistant Prostate Draft Nov
Cancer: Considerations for Metastasis-Free 2018
Survival Endpoint in Clinical Trials

Summary of Guidance
Clinical/Medical Noncirrhotic Nonalcoholic Steatohepatitis with Draft Dec
Liver Fibrosis: Developing Drugs for Treatment 2018

Summary of Guidance
Clinical/Medical Clinical Trial Endpoints for the Approval of Final Dec
Cancer Drugs and Biologics 2018

Summary of Guidance
Clinical/Medical Testicular Toxicity: Evaluation During Drug Final Oct
Pharmacology/Toxicology Development 2018

Summary of Guidance
Clinical/Pharmacology Developing Targeted Therapies in Low- Final Oct
Frequency Molecular Subsets of a Disease 2018

Summary of Guidance
CMC Policy Regarding Certain Entities Subject to the Draft Jan
Current Good Manufacturing Practice and 2018
Preventive Controls, Produce Safety and/or
Foreign Supplier Verification Programs

Summary of Guidance
Combination How to Prepare a Pre-Request for Designation Final Feb
2018
Summary of Guidance
Combination Postmarketing Safety Reporting for Draft Mar
Combination Products Guidance for Industry 2018
and FDA Staff
Combination Compliance Policy for Combination Product Draft Mar
Postmarketing Safety Reporting 2018

Summary of Guidance
Drug Development Tools Biomarker Qualification: Evidentiary Framework Draft Dec
2018

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 Summary of Guidance
Drug Safety Development of a Shared System REMS Draft June
2018
Summary of Guidance
Drug Safety Waivers of the Single, Shared System REMS Draft June
Requirement 2018

Summary of Guidance
Drug Safety Meta-Analyses of Randomized Controlled Draft Nov
Clinical Trials to Evaluate the Safety of Human 2018
Drugs or Biologic Product

Summary of Guidance
Electronic Submissions Standardized Format for Electronic Submission Draft Feb
of NDA and BLA Content for the Planning of 2018
Bioresearch Monitoring (BIMO) Inspections for
CDER Submissions

Summary of Guidance
Generic Good ANDA Submission Practices Draft Jan
2018
Summary of Guidance

FDA Targets Multiple Review Cycles With New

Draft Guidance, MAPP
Generics Product-Specific Guidances for Generic Drug Revised Feb
Development Draft 2018

Generics ANDA Submissions—Amendments to Final July

Abbreviated New Drug Applications Under 2018
GDUFA

Summary of Guidance

Webinar
Generics Technical Specifications—Comparative Clinical Final Sept
Endpoint Bioequivalence Study Analysis 2018
Datasets for Abbreviated New Drug
Applications
Generics ANDA Submissions—Content and Format Final Sept
2018
Generics Post-Complete Response Letter Meetings Final Dec
Between FDA and ANDA Applicants Under 2018
GDUFA

Summary of Guidance
Generics Abbreviated New Drug Application Submissions Final Sept
Content and Format 2018

Summary of Guidance
ICH Q11 Development and Manufacture of Drug Final Feb
Substances—Questions and Answers 2018
(Chemical Entities and
Biotechnological/Biological Entities)
ICH E18 Genomic Sampling and Management of Final Mar
Genomic Data 2018
ICH E11(R1) Addendum: Clinical Investigation of Revision April
Medicinal Products in Pediatric Population 1 2018

Summary of Guidance
ICH M7(R1) Assessment and Control of DNA Revision Mar
Reactive (Mutagenic) Impurities in 1 2018

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 Pharmaceuticals to Limit Potential Carcinogenic
Risk

ICH Q7 Good Manufacturing Practice Guidance for Final April

Active Pharmaceutical Ingredients: Questions 2018
and Answers

Summary of Guidance
ICH S3A Guidance: Note for Guidance on Final May
Toxicokinetics: The Assessment of Systemic 2018
Exposure in Toxicity Studies: Focus on
Microsampling: Questions and Answers

Summary of Guidance
ICH Q12 Technical and Regulatory Considerations Draft May
for Pharmaceutical Product Lifecycle 2018
Management

Summary of Guidance
ICH Q12 Technical and Regulatory Considerations Draft June
for Pharmaceutical Product Lifecycle 2018
Management: Annex
ICH S9 Nonclinical Evaluation for Anticancer Final June
Pharmaceuticals: Questions and Answers 2018

Summary of Guidance
ICH Q3D(R1) Elemental Impurities Final July
2018
Summary of Guidance
ICH E17 General Principles for Planning and Design Final July
of Multiregional Clinical Trials 2018

Summary of Guidance
ICH M9 Biopharmaceutics Classification System- Draft Oct
Based Biowaiver 2018

Summary of Guidance
Labeling Systemic Antibacterial and Antifungal Drugs: Draft Dec
Susceptibility Test Interpretive Criteria Labeling 2017
for NDAs and ANDAs

Summary of Guidance
Labeling Indications and Usage Section of Labeling for Draft July
Human Prescription Drug and Biological 2018
Products: Content and Format

Summary of Guidance
Labeling Labeling for Biosimilar Products Final July
2018
Summary of Guidance
Labeling Product Identifiers Under the Drug Supply Draft Sept
Chain Security Act: Questions and Answers 2018
Summary of Guidance
Orphan Clarification of Orphan Designation of Drugs Draft/ July
and Biologics for Pediatric Subpopulations of Final 2018
Common Diseases

Summary of Guidance

Final Guidance
OTC Innovative Approaches for Nonprescription Draft July
Drug Products 2018

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 Summary of Guidance
OTC Guidance for Industry on Postmarketing Updated June
Adverse Event Reporting for Nonprescription 2018
Human Drug Products Marketed Without an
Approved Application

Summary of Guidance
Pharmaceutical Elemental Impurities in Drug Products Final Aug
Quality/CMC 2018
Summary of Guidance
Pharmaceutical Regulatory Classification of Pharmaceutical Co- Revision Feb
Quality/CMC Crystals Guidance for Industry 1 2018

Summary of Guidance
Pharmaceutical Liposome Drug Products Chemistry, Final April
Quality/CMC Manufacturing and Controls: Human 2018
Pharmacokinetics and Bioavailability: and
Labeling Documentation

Summary of Guidance
Pharmaceutical Metered Dose Inhaler (MDI) and Dry Powder Revision April
Quality/CMC Inhaler (DPI) Products: Quality Considerations 1 2018

Summary of Guidance

Comment Period Extended

Pharmaceutical Use of Liquids and/or Soft Foods as Vehicles Draft July
Quality/CMC for Drug Administration: General 2018
Considerations for Selection and In Vitro
Methods for Product Quality Assessments

Summary of Guidance
Pharmaceutical Quality Attribute Considerations for Chewable Final Aug
Quality/CMC Tablets 2019

Summary of Guidance
Pharmaceutical Postapproval Changes to Drug Substances Draft Sept
Quality/CMC 2018
Summary of Guidance
Pharmaceutical Selection of the Appropriate Package Type Final Oct
Quality/CMC Terms and Recommendations for Labeling 2018
Injectable Medical Products Packaged in
Multiple-Dose, Single-Dose and Single-Patient-
Use Containers for Human Use

Summary of Guidance
Pharmaceutical Field Alert Report Submission: Questions and Draft July
Quality/Manufacturing Answers 2018
Standards (CGMP)
Summary of Guidance
Pharmaceutical Data Integrity and Compliance With Drug Final Dec
Quality/Manufacturing CGMP Questions and Answers 2018
Standards (CGMP)
Summary of Guidance

Statement from FDA Commissioner Scott

Gottlieb the Agency’s Efforts to Improve Drug
Quality Through Vigilant Oversight of Data
Integrity and Good Manufacturing Practice

Pharmacology/Toxicology Severely Debilitating or Life-Threatening Final April

Hematologic Disorders: Nonclinical 3/2019 2018
Development of Pharmaceuticals

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 Summary of Guidance
Pharmacology/Toxicology Oncology Therapeutic Radiopharmaceuticals: Draft Jun
Nonclinical Studies and Labeling 2018
Recommendations

Summary of Guidance
Pharmacology/Toxicology Microdose Radiopharmaceutical Diagnostic Final Aug
Drugs: Nonclinical Study Recommendations 2019

Summary of Guidance
Procedural Material Threat Medical Countermeasure Draft Jan
Priority Review Vouchers 2018

Summary of Guidance
Procedural Qualified Infectious Disease Product Draft Jan
Designation Questions and Answers 2018

Summary of Guidance
Procedural Definitions of Suspect Product and Illegitimate Draft Mar
Product for Verification Obligations Under the 2018
Drug Supply Chain Security Act
Procedural Standardization of Data and Documentation Draft Feb
Practices for Product Tracing Guidance for 2018
Industry
Procedural E6(R2) Good Clinical Practice: Integrated Revision Feb
Addendum to ICH E6(R1) 2 2018
Procedural Investigational In Vitro Diagnostics in Oncology Draft Mar
Trials: Streamlined Submission Process for 2018
Study Risk Determination
Procedural Special Protocol Assessment Revision April
1 2018
Summary of Guidance
Procedural Waivers, Exceptions and Exemptions from the Final May
Requirements of Section 582 of the Federal 2018
Food, Drug, and Cosmetic Act

Summary of Guidance
Procedural Formal Meetings Between the FDA and Draft June
Sponsors or Applicants of BsUFA Products 2018

Summary of Guidance
Procedural Patient-Focused Drug Development: Collecting Draft June
Comprehensive and Representative Input 2018

Summary of Guidance

Statement from FDA Commissioner Scott

Gottlieb on Agency Efforts to Advance the
Patient Voice In Medical Product Development

FDA Patient-Focused Drug Development

Guidance Series for Enhancing the
Incorporation of the Patient’s Voice in Medical
Product Development

Public Meeting
Procedural Limited Population Pathway for Antibacterial Draft June
and Antifungal Drugs 2018

Summary of Guidance
Procedural Drug and Device Manufacturer Final June
Communications With Payors, Formulary 2018

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 Committees and Similar Entities Questions and
Answers

Summary of Guidance
Procedural Medical Product Communications That Are Final June
Consistent with Food and Drug Administration- 2018
Required Labeling Questions and Answers

Summary of Guidance
Procedural Use of Electronic Health Record Data in Clinical Final July
Investigations 2018

Summary of Guidance
Procedural Expansion Cohorts: Use in First-In-Human Draft Aug
Clinical Trials to Expedite Development of 2018
Oncology Drugs and Biologics

Summary of Guidance
Procedural Guidance for Industry: Drug Supply Chain Date
Security Act Implementation: Identification of update,
Suspect Product and Notification expired
31 Dec
Summary of Guidance 2018
Presentation
Procedural Product Identifier Requirements Under the Drug Final Sept
Supply Chain Security Act—Compliance Policy 2018

Summary of Guidance
Procedural Grandfathering Policy for Packages and Final Sept
Homogenous Cases of Product Without a 2018
Product Identifier

Summary of Guidance
Procedural Good Review Management Principles and Revision Sept
Practices for New Drug Applications and 1 2018
Biologics License Applications

Summary of Guidance
Procedural Master Protocols- Efficient Clinical Trial Design Draft Sept
Strategies to Expedite Development of Cancer 2018
Drugs and Biologics

Summary of Guidance
Procedural Contents of a Complete Submission for Draft Sept
Threshold Analyses and Human Factors 2018
Submissions to Drug and Biologic Applications

Summary of Guidance
Procedural Citizen Petitions and Petitions for Stay of Action Draft, Oct
Subject to Section 505(q) of the Federal Food, Revision 2018
Drug, and Cosmetic Act 2

Summary of Guidance
Procedural Verification Systems Under Drug Supply Chain Draft Oct
Security Act for Certain Prescription Drugs 2018

Summary of Guidance
Procedural Developing and Labeling In vitro Companion Draft Dec
Diagnostic Devices for a Specific Group or 2018
Class of Oncology Therapeutic Products

Summary of Guidance

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 Procedural Interpretation of the “Deemed to be a License” Final Dec
Provision of the Biologics Price Competition and 2018
Innovation Act of 2009

Summary of Guidance
Procedural The “Deemed to be a License” Provision of the Draft Dec
BPCI Act Questions and Answers 2018

Summary of Guidance
Procedural Developing and Submitting Proposed Draft Draft Dec
Guidance Relating to Patient Experience Data 2018

Summary of Guidance
Rare Diseases Slowly Progressive, Low-Prevalence Rare Draft July
Diseases with Substrate Deposition That 2018
Results From Single Enzyme Defects: Providing
Evidence of Effectiveness for Replacement or
Corrective Therapies

Summary of Guidance
Rare Diseases Rare Diseases: Early Drug Development and Draft Oct
the Role of Pre-Investigational New Drug 2018
Application Meetings
Recalls Public Warning and Notification of Recalls Draft Jan
Under 21 CFR Part 7, Subpart C 2018

Summary of Guidance
User Fees Assessing User Fees Under the Prescription Final May
Drug User Fee Amendments of 2017 2018

Summary of Guidance
User Fees Prescription Drug User Fee Act Waivers for Draft June
Fixed-Combination Antiretroviral Drugs for the 2018
President’s Emergency Plan for AIDS Relief

Summary of Guidance
User Fees Prescription Drug User Fee Act Waivers, Draft June
Reductions and Refunds for Drug and 2018
Biological Products

Summary of Guidance
User Fees Assessing User Fees Under Biosimilar User Final June
Fee Amendments of 2017 2018

Summary of Guidance

Table 3. 2018 Withdrawn Guidance Documents

Title Date Issued Date
Withdrawn
Chronic Obstructive Pulmonary Disease: Developing 19 May 2016 26 March
Drugs for Treatment (Revised Draft) 2018
Clinical Development Programs for Drugs, Devices and 15 July 1999 22 Aug 2018
Biological Products Intended for the Treatment of
Osteoarthritis
Formal Meetings Between the FDA and Biosimilar 17 Nov 2015 4 June 2018
Biological Product Sponsors or Applicants
Pediatric Oncology Studies In Response to a Written 21 June 2000 30 June 2018
Request
Sinusitis: Designing Clinical Development Programs of 11 Jan 2006 19 April 2018
Nonantimicrobial Drugs for Treatment
Statistical Approaches to Evaluate Analytical Similarity 21 Sept 2017 21 June 2018
Guidance for Industry

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Action Plans and Related New Programs

While Action Plans are not technically legislation or regulations, they lay out FDA’s plans
for how they plan to modify functions, processes and structure to meet the challenges
posed by scientific innovation, globalization, the increasing breadth and complexity of the
products that FDA regulates and new legal authorities. While the Action Plan process was
technically rolled out in 2014, there were quite a few issued during 2018 or progress made
on those issued in years past.

Drug Competition Action Plan (DCAP): Generic Drug Review Enhancement

Technically, this is from 2017 but a lot of work was accomplished on this during 2018 (see
below). FDA took two new, important steps to increase competition in the market for
prescription drugs and facilitate entry of lower-cost alternatives. The agency published a list
of off-patent, off-exclusivity branded drugs without approved generics and also
implemented, for the first time, a new policy to expedite the review of generic drug
applications where competition is limited. To encourage generic drug development, FDA
posted a list of branded drugs that have no listed patents or exclusivities and for which the
agency has yet to approve a generic drug application (known as an Abbreviated New Drug
Application [ANDA]). The agency also intends to expedite the review of any generic drug
application for a product on this list to ensure they come to market as expeditiously as
possible. FDA will continue to refine and update the list periodically to ensure continued
transparency around drug categories where increased competition has the potential to
provide significant benefit to patients.

FDA is also announcing a change to its policy on how the agency prioritizes its review of
generic drug applications and will expedite the review of generic drug applications until
there are three approved generics for a given drug product. The agency is revising the
policy based on data that indicate that consumers see significant price reductions when
there are multiple FDA-approved generics available.

• Statement from FDA Commissioner Scott Gottlieb on new Steps to Facilitate

Efficient Generic Drug Review to Enhance Competition, Promote Access and
Lower Drug Prices
• Advancing Toward the Goal of Global Approval for Generic Drugs: FDA Proposes
Critical First Steps to Harmonize the Global Scientific and Technical Standards for
Generic Drugs
• FDA Tackles Drug Competition to Improve Patient Access
• Statement from FDA Commissioner Scott Gottlieb Responding to Report From
GAO and Updating on FDA’s Ongoing Efforts to Increase Access to Complex
Generic Drugs
• Statement from FDA Commissioner Scott Gottlieb on new Agency Actions to
Further Deter ‘Gaming’ of the Generic Drug Approval Process by the use of Citizen
Petitions

Competitive Generic Therapy (CGT) Designation

Under new authorities provided to the agency in the FDA Reauthorization Act of 2017
(FDARA), a drug can be designated as a Competitive Generic Therapy (CGT) if there is
inadequate generic competition for that drug, meaning there is not more than one approved
drug in the active section of the Orange Book. Applicants for drugs that receive a CGT
designation may receive review enhancements and expedited review of their ANDA.
Applicants for drugs that receive a CGT designation are also eligible for a 180-day period of
marketing exclusivity if they are the first approved applicant for that CGT and meet certain
other conditions. Under a special forfeiture rule for CGTs, the applicant must commercially
market the CGT within 75 days after the date of approval of its ANDA or it will forfeit its

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exclusivity. FDA approved several strengths of potassium chloride oral solution as the first
generic drugs to receive a Competitive Generic Therapy (CGT) designation.

• FDA Approves First Generic Drug Under new Pathway Aimed at Enhancing Market
Competition for Sole Source Drugs

ANDA Suitability Petitions

Certain differences between a Reference Listed Drug (RLD) and a proposed generic drug
product may be permitted in an ANDA if these differences are the subject of an
approved suitability petition. An applicant may submit a suitability petition to the FDA under
section 505(j)(2)(C) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and pursuant
to 21 CFR 314.93 requesting permission to submit an ANDA for a generic drug product that
differs from an RLD in its route of administration, dosage form, strength or that has one
different active ingredient in a fixed-combination drug. An ANDA citing a suitability petition
that has not been approved will be refused for receipt because the application lacks a legal
basis for the submission. FDA issued a MAPP establishing the policies and procedures of
the OGD for responding to suitability petitions submitted to it by or on behalf of prospective
abbreviated new drug application (ANDA) applicants.

• Manual of Policies and Procedures (MAPP)

• Patent Certifications and Suitability Petitions

ANDA New Guidance Documents Issued

• FDA provides scientific and regulatory clarity for generic drug developers through
the issuance of 43 new or revised product-specific guidance documents, including
hard-to-copy complex generics and abuse-deterrent formulations of opioids.
• Product-Specific Guidances for Generic Drug Development
• Product-Specific Guidances: Draft and Revised Draft Guidances for Industry:
Availability

FDA Disallows use of REMS to Block Generics

Sponsors have sometimes been able to use their Risk Evaluation and Mitigation Strategy
(REMS) requirements to block timely generic entry. FDA feels the REMS requirements has
been exploited in two ways. One occurs at the front end of the drug development process,
when generic drugs are being developed. The other occurs at the back end of the process,
after necessary testing has been completed, when a generic drug seeks approval and
market entry. On the front end, brand drug makers sometimes use REMS as a way to
restrict the sale of their drugs, keeping the drug out of the hands of generic firms. The
generic drug makers typically need up to 5,000 doses of a brand drug in order to run
bioequivalence and bioavailability studies to prove the generic medicine is the same as its
brand drug. The other obstacle occurs at the back end, after a generic drug seeks FDA
approval and market entry because brand and generic drug makers are required to develop
a single shared REMS program—the generic drug maker has to negotiate with the brand
firm to enter into a shared REMS programs before the generic drug can be approved and
these negotiations can be protracted for the branded manufacturers advantage and bar
entry of the generic. Through a new policy, supported by a draft guidance document, FDA’s
aim is to help generic drug makers get their products through the development and
approval processes efficiently while maintaining the safety controls sought by the REMS.
The first draft guidance, Development of a Shared System REMS, describes general
principles and recommendations to assist sponsors with developing these programs. The
goal is to improve the clarity and efficiency for developing shared system REMS, which will
enable timelier market entry for products that are part of these REMS.

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 • Statement from FDA Commissioner Scott Gottlieb on new Policies to Reduce the
Ability of Brand Drug Makers to use REMS Programs as a way to Block Timely
Generic Drug Entry, Helping Promote Competition and Access

FDA’s Proposal to Harmonize Standards for Generic Drugs (ICH Involvement)

FDA has submitted a proposal to ICH recommending the development of internationally

harmonized guidelines on scientific and technical standards for generic drugs. ICH is the
global venue for harmonization of standards for pharmaceutical products, including both
new drugs and generic drugs. Although many existing ICH guidelines are applicable to
generic drugs, historically ICH has focused on standards for new drugs. As a result, there
are areas specific to generic drugs where harmonized guidance is lacking.

Citizen Petition Modifications

Further to support generic competition and market entry, FDA issued a revised draft
guidance, Citizen Petitions and Petitions for Stay of Action Subject to Section 505(q) of the
Federal Food, Drug, and Cosmetic Act, designed to allow for a more efficient approach to
505(q) petitions and allow them to focus more reviewer resources on scientific reviews
instead of Citizen’s Petitions and stop manufactures from gaming the system and stopping
generics market entry.

• Statement from FDA Commissioner Scott Gottlieb new Agency Actions to Further
Deter ‘Gaming’ of the Generic Drug Approval Process by the use of Citizen
Petitions

Biosimilars Action Plan

FDA released the Biosimilars Action Plan (BAP) to provide information about the key
actions the agency was taking to encourage innovation and competition among biologics
and the development of biosimilars. The BAP is focused on four key areas:

• improving the efficiency of the biosimilar and interchangeable product development

and approval process
• maximizing scientific and regulatory clarity for the biosimilar product development
community
• developing effective communications to improve understanding of biosimilars
among patients, clinicians and payors
• supporting market competition by reducing gaming of FDA requirements or other
attempts to unfairly delay competition

The BPCI Act requires a marketing application for a “biological product” (that previously
could have been submitted under section 505 of the Federal Food, Drug, and Cosmetic Act
(FD&C Act)) must be submitted as a Biologics License Application (BLA) under section 351
of the Public Health Service Act (PHS Act). Certain biologic products regulated by CDER
were previously approved as drugs and need to be reclassified as biologics (i.e., insulin
and other proteins) and this reclassification will take place over a 10-year transition period
ending on 23 March 2020. On 23 March 2020, the BPCI Act requires an approved
marketing application for a “biological product” under section 505 of the FD&C Act shall be
deemed to be a license for the biological product (i.e., an approved BLA) under section 351
of the PHS Act. To support the BPA, FDA released the following documents related to the
“Deemed to be a License” Provision of the BPCI Act:

• Draft Guidance for Industry: The “Deemed to be a License” Provision of the BPCI
Act: Questions and Answers
• Proposed Rule on “Definition of the Term Biological Product”

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 • MAPP on Responsibility in the Office of Pharmaceutical Quality (OPQ) for the
Integrated Quality Assessment of Products Containing Drug Substances
Composed of Amino Acid Polymers
• Preliminary List of Approved NDAs for Biological Products That Will be Deemed to
be BLAs on March 23, 2020
• A new webpage that contains information and resources related to the ‘Deemed to
be a License’ Provision of the BPCI Act
• Federal Register Notice of Availability and Request for Comments

“Deemed to be a License” Provision of the BPCI Act

• Remarks from FDA Commissioner Scott Gottlieb as Prepared for Delivery at the
Brookings Institution on the Release of the FDA’s Biosimilars Action Plan
• Biosimilars Action Plan: Balancing Innovation and Competition

Biosimilar Pay-For-Delay Reporting Bill Introduced in House

The Biosimilars Competition Act of 2018, introduced in the House by Rep. John Sarbanes,
D-Md., would require reporting of pay-for-delay agreements by biologic and biosimilar drug
manufacturers. Biosimilar makers are not currently required to report these agreements, in
which biosimilar companies agree to pay generic drug manufacturers to delay product
releases, to the Justice Department and the Federal Trade Commission.

Drug Supply Chain Security Act (DSCSA): 2018 Updates

The Drug Quality and Security Act (DQSA), was enacted by Congress on 27 November
2013. Title II of DQSA, the Drug Supply Chain Security Act (DSCSA), outlines steps to
build an electronic, interoperable system to identify and trace certain prescription drugs as
they are distributed in the US. This will enhance FDA’s ability to help protect consumers
from exposure to drugs that may be counterfeit, stolen, contaminated or otherwise harmful.
The system also will improve detection and removal of potentially dangerous drugs from
the drug supply chain to protect US consumers.

Additionally, the DSCSA directs FDA to establish national licensure standards for
wholesale distributors and third-party logistics providers, and requires these entities report
licensure and other information to FDA annually

In May 2018, FDA announced a new Drug Supply Chain Security Act (DSCSA) Pilot
Project Program

Additionally, five new guidance documents were issued this year to support the DSCSA.

FDA's Predictive Toxicology Roadmap

The Predictive Toxicology Roadmap is a six-part framework for integrating new predictive
toxicology methods into safety and risk assessments of FDA products. FDA’s collaborative
efforts to advance toxicology toward a more predictive science with NIH, EPA and other
federal agencies through programs like Tox21 and ICCVAM.

During the past decade, FDA scientists have taken significant steps to upgrade their
toxicology toolboxes. However, a comprehensive strategy is needed to evaluate new
methodologies and technologies for their potential to expand FDA’s toxicology predictive
capabilities and to potentially reduce the use of animal testing. Acceptance of any new
toxicology methods will require sufficient convincing data as well as continuous dialogue

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and feedback among all relevant stakeholders from development to implementation,
including qualification and acceptance by regulatory authorities.
To ensure FDA continues to employ cutting-edge science to assess the safety and
effectiveness of its regulated products and to leverage advances being made in toxicology,
the FDA Commissioner tasked the Agency’s Toxicology Working Group with developing a
roadmap for integrating predictive toxicology methods into safety and risk assessments.
• FDA’S Predictive Toxicology Roadmap

Tools to Turbo Charge Drug Development

Real World Evidence Action Plan

Framework for FDA’s Real-World Evidence Program Framework

While this is from the 21st Century Cures Act of 2016, the process of implementation is a
continuum and there were strides to further define how to implement this clinical
development option with issuing a framework document for evaluating the potential use of
Real-World Evidence (RWE). The goal of the framework was to:

• help support the approval of a new indication for an already approved drug or
• help support or satisfy drug post-approval study requirements

This framework applies to drug and biological products approved under section 505(c) of
the FD&C and biological products licensed under the Public Health Service Act. The
framework does not cover medical devices.
The RWE Program outlined will evaluate the potential use of RWE to support changes to
labeling about drug product effectiveness. This includes adding or modifying an indication,
such as a change in dose, dose regimen or route of administration, adding a new
population or adding comparative effectiveness or safety information. The RWE Program
will establish demonstration projects, engage stakeholders, get input from FDA senior
leadership when evaluating RWE and promote shared learning and consistency in applying
the framework. FDA also will develop guidance documents to assist sponsors interested in
using RWE to support drug development.

In the framework, FDA identifies a three-part approach for assessing whether the use of
Real-World Data (RWD) to generate RWE is appropriate to answer a regulatory question:

• Are the RWD fit for use?

• Can the trial or study design used to generate RWE provide adequate scientific
evidence to answer or help answer the regulatory question?
• Does the study conducted meet FDA regulatory requirements (e.g., for study
monitoring and data collection)?

FDA RWE Framework Issued in December 2018

• FDA’s New Efforts to Advance Biotechnology Innovation

• Real-World Evidence
• Framework for a Real-World Evidence Program: Availability
• FDA Budget Matters: A Cross-Cutting Data Enterprise for Real World Evidence
• FDA’s Real World Evidence and Data Page

Master Protocols

Master protocols might be the way of the future for all fast track and breakthrough products;
but for now, the guidance document was issued just for oncology products. A Master
Protocol is used for oncology drugs and biologics regarding the design and conduct of
clinical trials, other than First-In-Human (FIH) trials, intended to simultaneously evaluate
more than one investigational drug and/or more than one cancer type within the same

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overall trial structure (master protocols) in adult and pediatric cancers. In contrast to
traditional trial designs, where a single drug is tested in a single disease population in one
clinical trial, master protocols use a single infrastructure, trial design and protocol to
simultaneously evaluate multiple drugs and/or disease populations in multiple sub studies,
allowing for efficient and accelerated drug development. Master Protocols have been used
by both Keytruda and Opdivo to rapidly test and expand labeled indications.

Complex Innovative Designs (CID) Pilot

FDA launched a pilot meeting program for Complex Innovative Designs (CID) to facilitate
the advancement and use of novel clinical trial designs. The pilot meeting program offers
sponsors who are selected an opportunity to engage with FDA experts from CDER and/or
CBER to discuss CID approaches and analyses in medical product development. The pilot
program period will run through fiscal year 2022 and is being conducted to fulfill FDA’s
performance commitment under PDUFA VI, incorporated as part of the FDA
Reauthorization Act of 2017. During the pilot, FDA has committed to accepting up to two
meeting requests quarterly, about 120 days apart, to offer feedback on the proposed CID
approach within a specific drug development program and to providing regulatory advice.
FDA is exploring the use of CIDs to inform regulatory decision-making and to enhance the
understanding and review capacity of CID.

• Complex Innovative Designs Pilot Meeting Program

• Promoting the Use of Complex Innovative Designs in Clinical Trials

Pilot Meetings Program for Model-Informed Drug Development (MIDD)

Approaches

MIDD approaches use a variety of quantitative methods to help balance the risks and
benefits of drug products in development and when successfully applied, can improve
clinical trial efficiency, increase the probability of regulatory success and optimize drug
dosing/therapeutic individualization in the absence of dedicated trials. The pilot program
provides sponsors or applicants who are selected to participate the opportunity to meet with
agency staff to discuss MIDD approaches in medical product development.

The program period will run from fiscal years 2018 to 2022. FDA subject matter experts
from relevant fields such as clinical pharmacology will lead the meetings. Experts from
CDER and/or CBER will participate as needed. The pilot program is being conducted to
fulfill a performance goal under PDUFA VI, incorporated as part of the FDA Reauthorization
Act of 2017. Under the pilot, FDA has committed to accepting two to four paired-meeting
requests quarterly each fiscal year.

Increased Transparency on Clinical Data: CSR Pilot Program

For this program, FDA will include the study report body, the protocol and amendments and
the statistical analysis plan for each of the participating product’s pivotal studies. Once the
clinical trial transparency pilot program is complete, FDA will seek public feedback through
a Federal Register notice and docket for public comments. Please note that some larger
companies already post these in full or redacted on their company website or are included
in New England Journal of Medicine (and other scientific journals) articles about pivotal
trials in the supplemental section.

• FDA Commissioner Scott Gottlieb on new Steps FDA is Taking to Enhance

Transparency of Clinical Trial Information to Support Innovation and Scientific
Inquiry Related to new Drugs

Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure

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FDA’s surrogate endpoint table provides valuable information for drug developers on
endpoints that may be considered and discussed with FDA for individual development
programs. This table also fulfills a 21st Century Cures Act requirement to publish a list of
“surrogate endpoints which were the basis of approval or licensure (as applicable) of a drug
or a biological product” under both accelerated and traditional approval pathways.

According to section 507(e)(9) of the FD&C Act “[t]he term ‘surrogate endpoint’ means a
marker, such as a laboratory measurement, radiographic image, physical sign, or other
measure, that is not itself a direct measurement of clinical benefit, and—
‘‘(A) is known to predict clinical benefit and could be used to support traditional approval of
a drug or biological product; or
‘‘(B) is reasonably likely to predict clinical benefit and could be used to support the
accelerated approval of a drug or biological product in accordance with section 506(c).’’

This surrogate endpoint table includes surrogate endpoints that sponsors have used as
primary efficacy clinical trial endpoints for approval of New Drug Applications (NDAs) or
Biologics License Applications (BLAs). The table also includes surrogate endpoints that
may be appropriate for use as a primary efficacy clinical trial endpoint for drug or biologic
approval, although they have not yet been used to support an approved NDA or BLA. FDA
believes this list should facilitate consideration of potential surrogate endpoints when
developers are designing their drug development programs.

Division Musical Chairs

FDA has proposed an important series of new steps to modernize the organization and
functions of CDER’s Office of New Drugs. These changes are intended to free up
resources so that reviewers have more time to focus on drug development, particularly for
unmet medical needs, and on the multiple collaborations needed to make sure candidate
drugs are developed and assessed properly, with appropriate input from external scientists,
expert physicians and patient communities. The proposals include regulatory and review
process changes, as well as organizational restructuring. FDA also intend to strengthen the
support structures, including personnel and Information Technology (IT), that underpin the
regulatory process. So what this means to companies is that if you go to the GI Division to
talk about Nonalcoholic steatohepatitis (NASH), you will get NASH or hepatic experts to aid
in the development process and not an oncologist.

• Advancing Toward the Goal of Global Approval for Generic Drugs: FDA Proposes
Critical First Steps to Harmonize the Global Scientific and Technical Standards for
Generic Drugs
• FDA’s Comprehensive Effort to Advance New Innovations: Initiatives to Modernize
for Innovation
• Statement from FDA Commissioner Scott Gottlieb on Proposed Modernization of
FDA’s Drug Review Office

Military Breakthrough Designation

• FDA and DoD Launch Program to Expedite Availability of Medical Products for the
Emergency Care of American Military Personnel

FDA’s Department of Defense’s (DoD) Office of Health Affairs announced the launch of a
joint program to prioritize the efficient development of safe and effective medical products
intended to save the lives of American military personnel. The framework for the program
was put in place through H.R.4374, which authorized DoD to request, and FDA to provide,
assistance to expedite development and FDA’s review of products to diagnose, treat or
prevent serious or life-threatening diseases or conditions facing American military
personnel. Utilizing this law’s expanded authorities, FDA will work closely with Health
Affairs to better understand the military’s medical needs for deployed personnel, give the

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highest level of attention to and expedite its review of priority DoD medical products in a
manner similar to products under the breakthrough designation program, provide ongoing
technical advice to Health Affairs to aid in the rapid development and manufacturing of
medical products for use by the military and take a closer look at products currently under
development to determine opportunities to expedite their availability.

Material Threat Medical Countermeasure Priority Review Vouchers

Per the provision of the 21st Century Cures Act that added a new section to the FD&C on
priority review vouchers, the first voucher for material threat medical countermeasure
applications was issued for TPOXX. The program was put in place through the 21st
Century Cures Act (Cures Act) that adds a new section to the FD&C Act on priority review
vouchers for material threat medical countermeasure applications. This program was
designed to encourage development of medical countermeasures by offering additional
incentives for obtaining approval of new drug or biological medical products for the
prevention and treatment of harm from a biological, chemical, radiological, or nuclear agent
identified as a material threat.

• Material Threat Medical Countermeasure Priority Review Vouchers: Draft

Guidance for Industry: Availability
• 21st Century Cures Act: MCM-Related Cures Provisions
• Material Threat Medical Countermeasure Priority Review Vouchers - Draft
Guidance for Industry
• Fee for Using a Material Threat Medical Countermeasure Priority Review Voucher
in Fiscal Year 2019
• FDA Approves the First Drug With an Indication for Treatment of Smallpox

Tropical Diseases Added to Voucher Program

FDA added four tropical diseases to priority review voucher program to encourage drug
development in areas of unmet need, the addition included: Lassa fever, chikungunya virus
disease, rabies and cryptococcal meningitis. Applicants who submit applications for drug or
biological products to prevent or treat these diseases may qualify for a tropical disease
Priority Review Voucher (PRV). A tropical disease PRV can be used to obtain priority
review of a subsequent drug application that does not itself qualify for priority review.

• Tropical Disease Priority Review Vouchers

Patient Engagement

There has been strides forward by FDA to include patients in the drug development
process; so now besides a dedicated Advisory Committee meeting, patients can now ask
for meetings and suggest draft guidances.

Request a Meeting on Drugs: Stakeholder Engagement

FDA now allows patients to submit a request for a meeting on drug-related topics which will
be handled by the Professional Affairs and Stakeholder Engagement (PASE) Staff; this is
not an option for industry stakeholders. These meetings are not intended to establish
binding agreements pertaining to drug development programs or to discuss proprietary
information pertaining to specific drug development programs under FDA review. To
support this process FDA launched a new External Stakeholder Meeting Request (ESMR)
system. This system will help external, non-industry stakeholders more easily request
meetings with CDER on drug development and drug safety matters. The ESMR system will
ensure these requests are managed appropriately and consistently.

• Request a Meeting on Drugs

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Submitting Drafts of Proposed Guidance Documents Electronically

Under FDA’s good guidance practices regulations at 21 CFR 10.115(f)(3), external parties
can submit drafts of proposed guidance documents for FDA to consider. All proposed draft
guidance documents should be marked “Guidance Document Submission” and be
submitted either in paper to the address found on the Dockets Management page or
electronically.

• Instructions for Submitting Drafts of Proposed Guidance Documents Electronically

Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank

History of clinicaltrials.gov Legislation Includes:

• 1997: Congress Passes Law (FDAMA) Requiring Trial Registration

• 2000: NIH Releases ClinicalTrials.gov Web Site
• 2000–2004: FDA Issues Guidance for Industry Documents
• 2004: ClinicalTrials.gov Wins the Innovations in American Government Award
• 2005: International Committee of Medical Journal Editors Requires Trial
Registration
• 2005: State of Maine Passes Clinical Studies Registration Law (Repealed in 2011)
• 2006: World Health Organization Establishes Trial Registration Policy
• 2007: Congress Passes Law (FDAAA) Expanding ClinicalTrials.gov Submission
Requirements
• 2008: ClinicalTrials.gov Releases Results Database
• 2008: Declaration of Helsinki Revision Promotes Trial Registration and Results
Dissemination
• 2009: Public Meeting Held at the National Institutes of Health
• 2013: European Medicines Agency Expands Clinical Trial Database to Include
Summary Results
• 2014: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 Issued for Public
Comment
• 2014: NIH Draft Policy on Registration and Results Submission of NIH-Funded
Clinical Trials Issued for Public Comment
• 2015: National Cancer Institute Issues Clinical Trial Access Policy
• 2016: Final Rule for FDAAA 801 Issued
• 2016: Final NIH Policy on the Dissemination of NIH-Funded Clinical Trial
Information Issued
• 2017: Revised Common Rule (45 CFR 46) Issued

There has been an issue with Sponsors not posting the initial trial or the subsequent results
on clinicaltrials.gov even though the International Committee of Medical Journal Editors
won’t allow the publication of the trial results in a major journal if the trial is not posted with
21 days after the first patient was dosed.

The ClinicalTrials.gov registration requirements were expanded with FDA Amendments Act
of 2007 (FDAAA); section 801 specifically requires more types of trials to be registered,
results information to be submitted and the submission of FDA Form 3674 to show
compliance. FDAAA 801 also established penalties for failing to register or submit the
results of trials. To date, penalties, which could have been levied at a rate of $10,000/day
for failure to comply, have not been enforced. The guidance document addresses the
following questions:

• How do the Centers intend to identify whether responsible parties have failed to
submit required clinical trial registration and/or results information to the

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 ClinicalTrials.gov data bank or submitted false or misleading information to the data
bank, or whether submitters have failed to submit to FDA the certification required
by section 402(j)(5)(B) of the Public Health Service Act (PHS Act) or knowingly
submitted a false certification to FDA?
• Under what circumstances may a Center decide to seek civil money penalties
against a responsible party or submitter?
• What procedures apply when a Center seeks civil money penalties?
• What civil money penalty amounts may be assessed for:
o failing to submit required clinical trial registration and/or results information
to the ClinicalTrials.gov data bank
o submitting false or misleading information to the data bank
o failing to submit the required certification to FDA
o knowingly submitting a false certification to FDA

Bottom line: FDA is getting ready to implement its ability to levy fines and has given
industry 12 years to comply with the requirements.

FDA Collaborations

Biotech Working Group

In early May, FDA formed a new Biotech Working Group. This Working Group is comprised
of representatives from multiple FDA centers and offices. The Biotech Working group will
develop an Action Plan that lays out the steps they intend to take to ensure FDA has a
flexible regulatory framework for evaluating the safety of products that also supports plant
and animal biotechnology innovation.

Clinical Trials Transformation Initiative

FDA announced a collaboration with the Clinical Trials Transformation Initiative (CTTI) and
are cohosting a Patient Engagement Collaborative (PEC) (Federal Register 60749 / Vol.
82, No. 245/Friday, 22 December 2017). The PEC will be an ongoing, collaborative forum
coordinated through the Patient Affairs Staff, Office of Medical Products and Tobacco
(OMPT), Office of the Commissioner and will be hosted by CTTI. Through the PEC, the
patient community and regulators will be able to discuss an array of topics regarding
increasing meaningful patient engagement in medical product development and regulatory
discussions at FDA. The activities of the PEC may include, but are not limited to:

• providing diverse perspectives on topics such as systematic patient engagement,

transparency, and communication
• providing considerations for implementing new strategies to enhance patient
engagement at FDA
• proposing new models of collaboration in which patients and patient advocates are
partners in certain aspects of the medical product development and FDA: review
process

Manufacturing

Quality Metrics for Drug Manufacturing

FDA announced two new programs to gather feedback on the use of quality metrics to
modernize pharmaceutical quality systems and advance innovation. These efforts, the
Quality Metrics Feedback Program and the Quality Metrics Site Visit Program, build on
stakeholder comments requesting continued dialogue on quality metrics and provide ways
for industry to engage the agency and inform FDA’s use of quality metrics. Feedback from
early adopters, manufacturers who implemented quality metrics programs to address

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significant manufacturing problems, and independent academic research indicates that
manufacturers’ overall quality programs benefit from an establishment’s quality metrics
program. The new programs provide an opportunity for FDA to continue learning about the
advantages and challenges companies have experienced in implementing quality metrics
programs.

FDA is encouraging new drug application holders to request Type C Formal Meetings and
Abbreviated New Drug Application (ANDA) holders to submit pre-ANDA meeting requests
to FDA to initiate discussions on quality metrics for specific products.

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The Quality Metrics Site Visit Program

This voluntary site visit program is designed to offer experiential and firsthand learning
opportunities to FDA staff involved in development of FDA’s Quality Metrics Program.

Staff will gain exposure to robust quality metrics programs through on-site visits, tours of
operations, and discussions with establishments to assist staff in further developing FDA’s
Quality Metrics Program. FDA staff also will observe how quality metrics data are gathered,
collected, and reported to management.

Continuous Manufacturing Progress

• FDA Supports Critical Research to Spur Innovation for Continuous Manufacturing

Technology to Support and Advance Drug and Biologics Development

For more than 50 years, pharmaceuticals have been produced using a method known as
“batch manufacturing,” a multi-step, lengthy process that involves the use of ungainly,
large-scale equipment. However, recent advances in manufacturing technology have
prompted the pharmaceutical industry to consider moving away from batch manufacturing
to a faster, more efficient process known as continuous manufacturing. FDA is taking
proactive steps to facilitate the drug industry’s implementation of emerging technologies,
including continuous manufacturing to improve product quality and address many of the
underlying causes of drug shortages and recalls.

The continuous manufacturing process has been discussed for years, but now FDA has
awarded three grants, using its authority under the 21st Century Cures Act to institutions of
higher education and non-profit organizations to study and recommend improvements for
the continuous manufacturing of drugs and biological products, as well as similar innovative
monitoring and control techniques.

Emerging Technology Program (ETP)

The ETP was created to promote the adoption of innovative approaches to pharmaceutical
product design and manufacturing. Through the program, industry representatives can
meet with Emerging Technology Team (ETT) members to discuss, identify and resolve
potential technical and regulatory issues regarding the development and implementation of
a novel technology prior to filing a regulatory submission.

New Inspection Protocol Project (NIPP)

This New Inspection Protocol Project (NIPP) uses standardized electronic inspection
protocols to collect data in a structured manner for more consistent oversight of facilities
and faster and more efficient analysis of FDA findings. The protocols also include additional
questions related to quality culture observed in facilities. The new tool is being applied to
FDA inspectional work related to sterile injectable drugs, which have been the subject of
sterility problems and shortages in the past. The primary focus of this new tool is to ensure
a more streamlined and consistent coverage and reporting of FDA inspectional activities.

Approvals

Division Specific Approvals

• Hematology/Oncology (Cancer) Approvals and Safety Notifications

• 2019 FDA Approved Drugs

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Novel Drug Approvals

• Center for Drug Evaluation and Research Advancing Health Through Innovation
2017 New Drug Therapy Approvals

• Novel Drug Approvals for 2017

• Novel Drug Approvals for 2018

Why is this report so cool? It gives a breakdown of all drugs approved and what
accelerated approval options they carried with them in a graphic, no longer do you need to
hunt and peck through recent approvals to pull this information together—FDA gives it to
you in their annual report.

Figure 1. Novel Drug Report Breakdown

New Class of Drugs Fulfills Promise of RNA-Based Medicine

The approval of a new drug to treat polyneuropathy caused by a rare and frequently fatal
disease called hereditary transthyretin-mediated amyloidosis (hATTR) marks the arrival of
a game-changing new class of therapeutics. The new drug, called patisiran (Onpattro), is a
small interfering RNA (siRNA) that is part of a class of therapeutics that can target
hereditary diseases by affecting gene function. With this ability to target specific RNA
“messages,” there is the potential to design therapeutics for a wide range of diseases.
Patisiran is the first drug approved to treat hATTR. Why are these drugs unique? This class
of drugs is unique because the drugs work at the RNA level to specifically silence the
production of a disease-causing protein. siRNAs can be designed to interfere with the
production of abnormal proteins throughout the body, and are often chemically modified to
ensure they are not destroyed by enzymes in the body.

New Class of Drugs Fulfills Promise of RNA-Based Medicine

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Just Interesting

FDA created and made Bayer use a “Patient Decision Checklist” to make sure patients
were informed about the use of the device “Essure” (postmarketing).

About the Author

Meredith Brown-Tuttle, RAC, FRAPS, is the principal consultant for Regulatorium a company specializing in regulatory
intelligence, writing and strategy. She is the author of IND Submissions: A Primer, published by Barnett, Regulatory Intelligence
101, published by RAPS, numerous articles and currently serves as the chair of RAPS Editorial Advisory Committee. She can be
reached at [email protected].

Cite as: Brown-Tuttle M. “Regulatory Strategist Toolbox: 2018 FDA Regulatory Intelligence Briefing.” Regulatory Focus. May
2019. Regulatory Affairs Professionals Society.

All the website links in this article were verified as of 26 April 2019. Subsequently, the US Food and Drug Administration (FDA)
relaunched its website, which changed or deactivated many of the links connecting to agency information. Due to this article’s
publication schedule, it was not possible to update all the URLs referenced, so some FDA links may not be accessible. RAPS
apologizes for any inconvenience this may cause.

© 2019 by the Regulatory Affairs Professionals Society. All rights reserved.

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 REGULATORY FOCUS

The Value of Engagement With Trade Associations

in Policymaking, Regulation and Standardization

By Léa Coulet

This article presents an argument for the value that trade associations bring to healthcare
in terms of promoting best practices, policies, regulations and standards. The author
defines trade associations and lays out their functions and the value of those functions for
regulators and policy makers and also presents defining characteristics of good regulations
and good policies. The focus is on foods for special medical purposes and the author
shares examples from the work of the Medical Nutrition International Industry (MNI) in
these areas.

Introduction

Trade associations play an important role in promoting best practice, informing public
policies and regulations and developing standards. In the complex and fast-moving
healthcare area, which is driven by innovation, data technologies, patient demand and
budget constraints, policymakers and regulators face tremendous challenges to formulate
effective, evidence-based and future-proof policies that serve the public interest. Productive
engagement with stakeholders and trade associations is increasingly necessary. This
article aims to present the value that trade associations bring to the debate, based on the
experience of the Medical Nutrition International Industry (MNI).

Several questions can be posed regarding the role of trade associations in developing good
policies, regulations and standards. Why is their involvement necessary, and how do they
bring value?

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 What is a trade association?

There are many standard definitions for ‘trade association.’ Wikipedia proposes a definition
that emphasizes the activities of a trade association:

“A trade association, also known as an industry trade group, business association, sector
association or industry body, is an organization founded and funded by businesses that
operate in a specific industry. An industry trade association participates in public relations
activities such as advertising, education, lobbying and publishing, but its focus is
collaboration between companies. Associations may offer other services, such as
producing conferences, networking or charitable events or offering classes or educational
materials. Many associations are non-profit organizations governed by bylaws and directed
by officers who are also members.”1

By contrast, the Cambridge English dictionary definition emphasizes the objective of the
trade association:

“An organization that supports companies and employers of a particular type of industry
and protects their rights.2

These definitions focus on the services trade associations provide to their industry.
However, in the regulatory context, it is also important to look at the services that trade
associations offer to the community and their stakeholders, including policymakers and
regulators.

The Value of Trade Associations for Regulators and Policymakers

Although every trade association is different, they have similar characteristics enabling
them to serve the community and bring value to their stakeholders.

Trade associations represent the “voice” of their sector.

Trade associations act as a main point of contact, thereby facilitating dialogue with industry.
Regulators find it easier talking to a trade association, rather than to every company active
in the sector. It is the role of the trade association to consolidate the industry viewpoint and
make the link between industry and regulator and, by doing so, allow a structured,
representative and transparent dialogue.

Trade associations provide access to a vast pool of expertise and

information.

Trade associations have an extensive knowledge of their sector and a strong culture of
knowledge sharing, which can be quickly passed on to regulators and policymakers.

Trade associations are well equipped to assess the impact of policy/regulatory measures
on their sector and are, therefore, essential interlocutors for ensuring government action
achieves its desired purpose. They can also provide access to a vast pool of experts and
expertise. In the area of medical nutrition, for example, companies are well-connected and
work with doctors, scientists, nutritionists, researchers and patient advocacy groups.

Trade associations guarantee a dialogue with respectable and trustworthy

industry partners to regulators.

Trade associations have membership criteria to ensure their members are reputable and
trustworthy businesses. Engaging with a trade association is a guarantee for regulators to
deal with respected and committed partners.

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MNI, for example, has detailed membership criteria to ensure its members are
representative of the sector, respectable businesses, and committed to providing better
care through better nutrition to all patients, across all care settings and age groups.

Trade associations facilitate multi-stakeholder cooperation.

Trade associations are part of a broader community and an “eco-system” that consolidates
industry, regulators and citizens who are willing to work cooperatively with them to find
solutions. They are generally able to support multi-stakeholders’ platforms, organize forums
and conferences and develop joint positions on questions submitted by authorities. Rather
than cultivating diverging and competing interests, trade associations are great allies with
whom to work towards convergence and reach consensus.

Shaping an Adequate Environment: Key Principles

All sectors, including the medical nutritional sector, need a stable environment, one shaped
through policies, regulations and standards.

What makes a good regulation?

According to Wikipedia, a regulation is “an abstract concept of management of complex

systems according to a set of rules and trends.”3

The European Union defines a regulation as “a binding legislative act. It must be applied in
its entirety across the EU.”4

The Cambridge English dictionary defines regulation as “an official rule or the act of
controlling something.”5

The term regulation is, rightly or wrongly, associated with a negative connotation. One often
hears about too much regulation, rigid regulation, red-tape, administrative burden, brake on
innovation, etc.

The fact is that regulation is necessary in open market economies, including:

• to protect the rights and the safety of citizens/patients

• to create trust in the market, provide certainty and a level-playing field for business
• for the state’s control over the market players
• to translate legislation and policy into practical implementation

Getting regulation right is important; therefore, it is critical to understand what makes a

good regulation.

The immediate response is very simple: a good regulation serves the public interest.
Beyond this principle statement, a few key subordinate principles are essential to make a
good regulation.6 The principles outlined below are particularly important in the area of
healthcare.

Evidence-Based

Regulations should be evidence-based. They should be based on science, rooted in proven

facts and data, looking at health technology assessments and patient outcomes.

Necessity

The regulation should respond to a need, and the measures should be targeted to
responding to that specific need, while avoiding side effects. The triangle (the regulators,

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the regulated community and the beneficiaries of the regulation) need to cooperate to
agree on the need and on how to respond to it via a mix of binding rules and general
principles.

Transparency

The regulation should bring confidence to the regulated system. This can be achieved by
consulting all relevant stakeholders in a transparent and documented manner, following a
public consultation framework.

Proportionality

A regulation should provide measures and rules proportionate with the risks of the issue at
stake. The advantages of the regulation should outweigh the potential disadvantages of the
regulation and avoid unnecessarily stringent measures. Compliance costs should be
examined and minimized as much as possible.

Effectiveness

A regulation needs to work in practice. Consultation with the parties implementing the
regulation is absolutely crucial to ensure legal instruments adopted can be easily
understood, implemented and followed, without creating additional cost or burden. The
regulated community should be given time and support to comply.

Flexibility (or Future-Proof)

Regulations should be flexible enough to allow for future developments. This is particularly
important in the area of healthcare where regulation should allow and support innovation.

What makes a good policy?

The quick answer is a policy is good if it reaches its objectives.

However, policy is one of these “buzzwords” very commonly used without a clear
understanding of its meaning. For instance, policy and regulation are often mixed up. This
article will focus on public policies initiated and driven by government.

Wikipedia defines public policy as “the principled guide to action taken by the administrative
executive branches of the state with regard to a class of issues, in a manner consistent
with law and institutional customs.”7

The Cambridge dictionary uses the following definition:

“A government policy that affects everyone in a country or state, or these policies in

general.”8

A major difference between a public policy and a regulation lies in the fact that policies are
general, country-wide frameworks based on principles which affect the entire country
through a set of principles, measures, actions and budget. A regulation aims to implement
a policy by providing a frame to a given domain.

A good policy – as for a good regulation, includes:

• serves public interest

• has well-defined objectives
• benefits from a budget in line with its ambition
• has an implementation plan

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 • has evaluated its impact

What makes a good standard?

A quick answer to the question is: a standard is good if it is adopted. In healthcare, one
would argue that a standard is good if it secures patient safety.

Other elements define a successful standard:

• clarity
• practicality
• ease of implementation
• consensus-based
• improve performance
• reduce risk

CEN, the European Committee for Standardisation, defines a standard:

“A technical document designed to be used as a rule, guideline or definition. It is a

consensus-built, repeatable way of doing something.”9

Others define it as “an agreed way of doing something. It could be about making a product,
managing a process, delivering a service or supplying materials—standards can cover a
huge range of activities undertaken by organizations and used by their customers.”10

Typically, industry produces standards in order to create agreement on technical

specifications for health, safety and the environment and to achieve interoperability.

Trade associations are key role players in standards development. They help to develop
standards based on consensus among their members, ensure the standards reflect the
reality of the market, and encourage and facilitate adoption by industry.

Why Trade Associations can Help Getting Policies and Regulations Right

When developing a regulation in the health sector, regulators must “tick” all the above
boxes. To be successful, they have a vested interest in consulting all relevant stakeholders
including industry.

Trade associations, such as the MNI, can help them define the need, run the sanity checks,
run impact assessments, anticipate future developments, assess costs and risks, and help
in crafting robust , fit-for-purpose, future-proof policies and regulations that will provide
long-term benefits to patients and the healthcare system.

The Role of Trade Associations in Informing Policies, Regulations and

Standardization: MNI Example

In the previous section, insights have been shared on what makes a good public
policy/regulation or standard and how trade associations are equipped to inform these
processes meaningfully.

This section will focus on the healthcare area and share examples of how the MNI, the
trade association federating the medical nutrition industry at a global level, can bring value
to the policy, regulatory and standardization process.

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MNI Introduction

The Medical Nutrition International Industry (MNI) association11 was created in 2005 to
represent the voice of the medical nutrition industry at an international level.

MNI represents companies providing solutions for nutritional therapy, including oral
nutritional supplements, enteral tube feeding (enteral nutrition via the gastrointestinal tract)
and parenteral nutrition (intravenous feeding) as well as other actors operating in the
medical nutrition market.

MNI works to achieve better care through better nutrition, across all ages and healthcare
settings, and supports multi-stakeholder cooperation to improve the quality of nutritional
interventions for patients.

Defining the EU Regulatory Framework for Medical Nutrition

The development of the regulatory framework covering medical nutrition, also called Food
for Special Medical Purposes (FSMPs) in the EU, is an excellent example of consultation of
the industry and its trade association (MNI).

Defining FSMPs: A Headache for Regulators

FSMPs are foods for special medical purposes. They are foods for helping patients meet
their disease-related nutritional requirements when these cannot be met via the normal
diet. FSMPs can take different forms, such as liquids, thickening powders, sip-feeds or
naso-gastric solutions and must be used under medical supervision.

The first commercial products reached the market in the 1950s, yet their regulatory
category status typically evolved from being put under drug law, then Food for Special
Dietary Uses (FSDUs). Ultimately, by the 1980s and 1990s, they were properly defined as
Foods for Special Medical Purposes (Codex Stan 180-1991)12 supporting among other
objectives their development as products for patients. Still, these ‘food products for
patients’ often did not lose their “drug-like” characteristics or image.13

When the first products were commercialized, there was no understanding of these
products and how they could support malnourished patients. It was, therefore, necessary to
define the regulatory category with a clear definition.

However, defining such specialized products is not a simple task for those not involved in
their development. MNI, as the association of manufacturers providing FSMPs contributed
to the discussion and helped define the key characteristics of FSMPs. The definition for
FSMPs is today enshrined in the so-called FSG regulation (EU)609/2013:14

“…food specially processed or formulated and intended for the dietary management of
patients, including infants, to be used under medical supervision; it is intended for the
exclusive or partial feeding of patients with a limited, impaired or disturbed capacity to take,
digest, absorb, metabolise or excrete ordinary food or certain nutrients contained therein, or
metabolites, or with other medically-determined nutrient requirements, whose dietary
management cannot be achieved by modification of the normal diet alone.”

In addition, FSMPs are also classified in three categories in the European Commission
Delegated Regulation (EU) 2016/128:15

• Nutritionally complete food with a standard nutrient formulation which, used in

accordance with the manufacturer's instructions, may constitute the sole source of
nourishment for the persons for whom it is intended.

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 • Nutritionally complete food with a nutrient-adapted formulation specific for a
disease, disorder or medical condition which, used in accordance with the
manufacturer's instructions, may constitute the sole source of nourishment for the
persons for whom it is intended.
• Nutritionally incomplete food with a standard formulation or a nutrient-adapted
formulation specific for a disease, disorder or medical condition which is not
suitable to be used as the sole source of nourishment.

The article “Revising the EU FSMP Regulatory Framework: Laying the Foundation for
Future Nutritional Patient Care”16 provides an excellent summary of the provisions covering
FSMPs in the EU.

While the regulatory framework for FSMPs is now adopted and implemented in the EU,
many countries and regions are looking to the EU for inspiration to build their own
regulation on FSMPs.

MNI is regularly invited to share its expertise on medical foods in countries and regions
where regulation is being considered, initiated or reviewed.

Industry also can add value by information sharing and promoting good practice and
regulatory convergence across the globe.

Malnutrition and the Value of Medical Nutrition: Creating Awareness

Today, there is still very limited knowledge of medical nutrition among regulators and the
general public. There is also little awareness of the burden of malnutrition, also called
disease-related-malnutrition. It is MNI’s responsibility to inform and educate regulators and
the general public to fill the knowledge gap.

The prevalence of malnutrition is very high across the globe. In Europe, malnutrition—or
the risk of malnutrition—affects 25% of hospitalized patients17-19 and one third of people
living in the community.20

In Europe alone, an estimated 33 million people are malnourished21 or at risk of

malnutrition. The additional cost of managing the malnutrition of these patients is estimated
to cost healthcare systems 170 billion Euros ($191.2 billion) per year.22

Malnutrition is a serious public health issue. It is crucial that health authorities (government,
policymakers, regulatory authorities) take measures to manage malnutrition effectively.
These measures should prevent malnutrition and provide access to nutritional therapies,
including FSMPs.

MNI has developed case studies to help authorities and the general public understand
medical nutrition, the indications for using such products, the different forms that they can
take to fit healthcare professional and patient needs, why they should be used under
medical supervision, and the science behind these products.

More recently, MNI has published a comprehensive dossier entitled Better Care through
Better Nutrition: Value and Effects of Medical Nutrition. 23 The Dossier is a unique and
comprehensive summary of the evidence base on the prevalence of malnutrition and the
value and effects of medical nutrition. Data are presented by age group, healthcare setting,
and, where possible, by patient group. With forewords from key stakeholders, it is a
credible and valuable resource to address malnutrition and the health and economic
benefits of nutritional care. The dossier is also available in a summarized booklet for a lay
audience - Figure 1.

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Figure 1. Medical Nutrition Dossier

To date, no one else has provided such an extensive and documented summary on the
burden of malnutrition. MNI believes much more needs to be done to support malnourished
patients and is committed to supporting health authorities in articulating effective nutritional
care policies.

Supporting the Nutritional Care Community and Fostering Multi-Stakeholder

Dialogue to Inform Nutritional Care Policies

As mentioned in the first part of this article, trade associations are willing to work with other
stakeholders. MNI takes multi-stakeholder cooperation very seriously and supports
activities building a vibrant and empowered nutritional care community.

• In 2008, MNI launched the MNI Grant to raise awareness on malnutrition and to
reward initiatives tackling malnutrition at national level. Over the years, the MNI
Grant has supported and stimulated ambitious initiatives which have contributed to
improving nutritional care policies at national levels.

• MNI is an active member of the Optimal Nutritional Care for All (ONCA) campaign,
a European public-private partnership that promotes screening for malnutrition and

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 good nutritional care. The campaign started in eight countries in 2014 and is now
rolling out in eighteen countries. In each country, stakeholders with an interest and
expertise in nutritional care (including the academic world, authorities, patient
groups and manufacturers) work together to drive and enhance nutritional care
policies and provide access to quality nutritional care for patients. This campaign
was described in this review in the article Innovating Patient Driven Nutritional Care
Across Europe: The Optimal Nutritional Care for All (ONCA) Multi-Stakeholder
Initiative.24

• MNI also cooperates with the clinical and academic worlds. For instance, MNI has
a long-standing cooperation with the European Society for Clinical Nutrition and
Metabolism (ESPEN). The cooperation focuses on initiatives to improve clinical
practice, such as the dissemination of ESPEN guidelines or initiatives aiming at
strengthening the education of medical students on nutrition. Every year for the last
ten years, MNI, ONCA and ESPEN have joined forces to bridge the gap between
the academic/clinical worlds, and health decision-makers by inviting senior officials
to the ESPEN Congress in a spirit of knowledge sharing.

Promoting Adoption of International Standards That Reflect Common

Practice and Ensure Patient Safety: Case Study

Background

Enteral feeding therapies rely on devices to administer nutrition solutions to patients. These
include giving sets, feeding tubes, syringes, pumps, connectors, etc. known as enteral
feeding systems – Figure 2.

Figure 2. Overview of an Enteral Feeding System

The design and the testing of enteral feeding systems will be described by an international
standard: ISO 20695.25 The draft ISO20695 standard reflects current practice in the market
and it is being increasingly adopted around the globe with a proven track record of
guaranteeing the safety of patients on enteral feeding by minimizing risks linked to
misconnections between various devices for different medical applications.

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Threat

The standard was under review as part of the regular ISO standards creation process, and
there were calls to change the design of certain devices. MNI analyzed the situation and
anticipated how a modification to the design of devices would create confusion among
users:

• Users would need to be trained to the new design.

• Users would need to phase two or more different designs, which might not be
interconnectable with each other. This might result in the impossibility to start a
feeding therapy; or in the need to replace parts of the enteral feeding system or to
use adapters to facilitate a connection.
• Using adapters should be avoided as this might cause confusion or even distress
and again opens the possibility for accidental misconnections again between
systems for different medical applications leading to potential safety risks for the
patients.

Action

MNI and the Global Enteral Device Supplier Association (GEDSA)26 joined forces to
support the adoption of ISO 20695 and developed a joint position paper. 27

The adoption of the standard will be an important and much-needed milestone to provide a
unique set of rules at the global level for enteral feeding devices. It will provide clarity and
certainty for uses and will strengthen safety of patients on enteral nutrition.

Outcomes

As this article goes to press, it is not possible to share a clear outcome as the review
process for ISO 20695 is ongoing. However, it is important to note that the active
involvement of trade associations such as MNI and GEDSA have been instrumental to
federate industry around an international standard, providing for a single design for enteral
feeding devices worldwide.

Conclusion

Trade associations are key actors on consultations to have a balanced and future proof
policies, regulations and standards. Cooperation between industry associations and
government is very important for the policy making process. In the healthcare sector, there
are many ways that trade associations can make an impactful and beneficial contribution to
their community including patients and healthcare professionals.

In turn, trade associations can gain government’s and stakeholders’ trust and respect by
following a few basic guidelines:

• act as a consolidate, co-ordinated voice of the sector

• provide evidence-based information
• share commercially neutral positions that reflect the consensus views of the sector
• work towards convergence
• be trustworthy, patient and transparent
• support the community
Trade associations should continuously ask themselves: How can we participate to make
the process better and ensure my input helps to reach the objectives set by the
community?

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References

1. Wikipedia. Trade Association. https://en.wikipedia.org/wiki/Trade_association. Accessed 5 June 2019.

2. Cambridge Dictionary. Trade Association. https://dictionary.cambridge.org/dictionary/english/trade-association.
Accessed 5 June 2019.
3. Wikipedia. Regulation. https://en.wikipedia.org/wiki/Regulation. Accessed 5 June 2019.
4. Regulations, Directives and Other Acts. https://europa.eu/european-union/eu-law/legal-acts_en. Accessed 5 June
2019.
5. Cambridge Dictionary. Regulation. https://dictionary.cambridge.org/dictionary/english/regulation. Accessed 5 June
2019.
6. OECD Council Recommendation of the Council on Regulatory Policy and Governance – 2012.
https://www.oecd.org/governance/regulatory-policy/49990817.pdf. Accessed 5 June 2019.
7. Wikipedia. Public Policy. https://en.wikipedia.org/wiki/Public_policy. Accessed 5 June 2019.
8. Cambridge Dictionary. Public Policy. https://dictionary.cambridge.org/dictionary/english/public-policy. Accessed 5 June
2019.
9. European Committee for Standardization. What is a Standard.
https://www.cen.eu/work/ENdev/whatisEN/Pages/default.aspx. Accessed 5 June 2019.
10. About BSI. Business Standards Company (BSI) website. https://www.bsigroup.com/en-GB/about-bsi/. Accessed 5
June 2019.
11. Medical Nutrition International Industry Association website. https://medicalnutritionindustry.com/. Accessed 5 June
2019.
12. Codex Standard for the Labelling of and Claims for Foods for Special Medical Purposes.
file:///Users/leacoulet/Downloads/CXS_180e%20(1).pdf. Accessed 5 June 2019.
13. Binzak Blumenfeld B. “A Long-Awaited Update to the FDA Draft Medical Food Guidance.” November/December 2013.
www.fdli.org. Accessed 5 June 2019.
14. Regulation (EU) No 609/2013 of the European Parliament and of the Council of 12 June 2013 on food intended for
infants and young children, food for special medical purposes, and total diet replacement for weight control and
repealing Council Directive 92/52/EEC, Commission Directives 96/8/EC, 1999/21/EC, 2006/125/EC and 2006/141/EC,
Directive 2009/39/EC of the European Parliament and of the Council and Commission Regulations (EC) No 41/2009
and (EC) No 953/2009.
https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32013R0609&from=EN. Accessed 5 June 2019.
15. Commission Delegated Regulation (EU) 2016/128 of 25 September 2015 supplementing Regulation (EU) No 609/2013
of the European Parliament and of the Council as regards the specific compositional and information requirements for
food for special medical purposes.
https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32016R0128&rid=1. Accessed 5 June 2019.
16. Bushell C and Ruthsatz M. “Revising the EU FSMP Regulatory Framework: Laying the Foundation for Future
Nutritional Patient Care.” Regulatory Focus. July 2018. Regulatory Affairs Professionals Society.
17. Russell C and Elia M. “Nutrition Screening Week in the UK and Republic of Ireland in 2011. Hospitals, Care Homes
and Mental Health Units.” Redditch, BAPEN. 2012.
18. Schindler K, Pernicka E, Laviano A, Howard P, Schutz T, Bauer P, et al. “How Nutritional Risk is Assessed and
Managed in European Hospitals: A Survey of 21,007 Patients Findings from the 2007-2008 Cross-Sectional Nutrition
day Survey.” Clin Nutr. 2010;29(5):552-559.
19. Meijers JM, Schols JM, van Bokhorst-de van der Schueren MA, Dassen T, Janssen MA and Halfens RJ. “Malnutrition
Prevalence in the Netherlands: Results of the Annual Dutch National Prevalence Measurement of Care Problems.” Br J
Nutr. 2009;101(3):417-423.
20. Kaiser MJ, Bauer JM, Ramsch C, Uter W, Guigoz Y, Cederholm T, et al. “Frequency of Malnutrition in Older Adults: A
Multinational Perspective Using the Mini Nutritional Assessment.” J Am Geriatr Soc. 2010;58(9):1734-1738.
21. Ljungqvist O and de Man F. “Under Nutrition: Major Health Problem in Europe.” Nutr Hosp. 2009;24(3):368-370.
22. Ibid.
23. Better Care Through Better Nutrition: Value and Effects of Medical Nutrition. A Summary of the Evidence Base. 2018
Edition.
https://medicalnutritionindustry.com/files/user_upload/documents/medical_nutrition/2018_MNI_Dossier_Final_web.pdf.
Accessed 5 June 2019.
24. De Man F, Smit C and Ruthsatz M. “Innovating Patient Driven Nutritional Care Across Europe: The Optimal Nutritional
Care for All (ONCA) Multistakeholder Initiative.” Regulatory Focus. October 2017. Regulatory Affairs Professionals
Society.
25. ISO/DIS 20695.2. Enteral Feeding Systems: Design and Testing. International Organization for Standardization (ISO)
website. https://www.iso.org/standard/68853.html. Accessed 5 June 2019.
26. Global Enteral Device Supplier Association (GEDSA) website. http://gedsa.org/. Accessed 5 June 2019.
27. Joint MNI GEDSA Position Paper on ISO 20695 Standard. 15 April 2019.
https://medicalnutritionindustry.com/files/user_upload/intranet/position_papers/Joint_MNI_GEDSA_position_paper_ISO
_20695.pdf. Accessed 5 June 2019.

Disclaimer

This article reflects the personal opinion and experience of the author. It should not be construed as an official position by any
organization with which the author is affiliated.

About the Author

Léa Coulet is executive director at the Medical Nutrition International Industry, the trade association for the medical nutrition
industry, based in Brussels. Coulet has more than 15 years of experience in policy and regulatory affairs in a wide range of health
issues, including nutrition, public health, pharmaceutical policy, market access, global health, standardization and medical
technology. She can be contacted at [email protected].

Cite as: Coulet L. “The Value of Engagement with Trade Associations in Policy-Making, Regulation and Standardization.”
Regulatory Focus. June 2019. Regulatory Affairs Professionals Society.

© 2019 by the Regulatory Affairs Professionals Society. All rights reserved.

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 REGULATORY FOCUS

The Botanical Safety Consortium (BSC): The Development

of a 21st Century Framework for Assessing the Safety of
Botanical Dietary Supplements
By Daniel S. Marsman, DVM, PhD, Joseph T. Dever, PhD, Stefan Gafner, PhD,
Cynthia Rider, PhD, Sibyl Swift, PhD and James C. Griffiths, PhD

This article discusses steps to improve the safety of botanicals in dietary supplements. The
authors discuss several US legislative initiatives and efforts by several nongovernmental
organizations, such as the Council for Responsible Nutrition and the American Botanical
Council, to track patterns of botanical use, and the Congress of the European Societies of
Toxicology’s efforts to approach safety issues, including its establishment of the Botanical
Safety Consortium and its working groups.

Introduction

Natural health products, often considered a safe and natural alternative to conventional
medicine, have exhibited a resurgence in Western society. In the US, since the introduction
of the Dietary Supplement Health and Education Act of 1994 (DSHEA),1 the dietary
supplement market has flourished. Concomitantly, the dietary supplement market has
further morphed into various product streams, a most rapidly expanding one being products
containing one or more botanical/herbal ingredients. In parallel with this market expansion,
substantial advancements in analytical methodologies have led to a better understanding of
the complexity and diversity of botanical chemistry and botanical preparations. This
increased knowledge has led to a growing awareness of the potential safety concerns
associated with botanicals, especially their impurities, and contaminants.

Tracking use of Botanical Dietary Supplement Products

Because of the success of the dietary supplement industry and the pursuit of an ever-
broadening array of products, it is not surprising the industry needed to turn greater focus
toward assuring the safety of these products. For the botanical dietary supplement

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products, a plethora of botanical compounds are currently “in vogue” and an increasing
number and diversity of botanical preparations have been incorporated into innovative
multi-botanical products continually entering the market. To track their success, the Council
for Responsible Nutrition (CRN) conducts an annual survey of consumer activity. Their data
clearly indicate how the use of botanicals continues to grow year-by-year. For example, in
2018, their survey indicated that 75% of Americans take supplements and of those, 41%
have used herbals/botanicals during the previous year. 2 This represents a 13% increase for
herbals/botanicals use over the last five years. Similarly, the American Botanical Council
tracks consumer use patterns and has published data indicating interest in and use of
herbal and other natural products has continued to rise at a substantial rate, with US sales
in 2017 exceeding $8 billion dollars.3 This increased use, and the entrance into the market
of newer and more ethnically focused botanicals from emerging regions and countries,
such as India, China and Latin America, should be a focus of attention for those in the
scientific and regulatory community charged with product stewardship and consumer
safety.

Safety and Testing Revisions

To establish the reasonable expectation of safety, companies have had to rely on outdated
botanical safety frameworks. These frameworks employ the same methodologies used for
discrete and pure drug compounds and other chemical moieties, and they primarily depend
upon a significant number of animal toxicity tests. From a global regulatory perspective,
there are essentially no specific safety tests required, allowing each manufacturer to use
their own best judgment on which testing approach is needed for the New Dietary
Ingredient (NDI) variant in question. Traditional premarket safety testing, with reliance on in
vivo animal test methods, has become increasingly difficult for addressing botanical safety,
both due to the complexity and variability of the ingredients as well as the combination of a
multitude of discrete botanical ingredients into ever-increasing combinations and co-use
scenarios. These concerns for testing botanicals in traditional animal studies is in addition
to the many criticisms of these studies. These concerns include high-dose, non-physiologic
dosing regimens, additional uncertainty factors for extrapolation to humans, significant
financial and labor costs, time consumption (often in years) and the questionable ethics
associated with the use of animal models. In addition to direct challenges to use of
traditional pre-clinical studies, another confounding factor is the large number of potential
variants of each potential botanical material due to seasonal variations, harvesting
practices, processing and manufacturing differences, among others.

Innovation within the dietary supplement sector often focuses on subtle—and not so
subtle—“tweaks” to currently popular botanical ingredients so that different levels of marker
compounds, active moieties and changes in Absorption, Distribution, Metabolism and
Elimination (ADME), may be realized. When higher concentrations of marker
compounds/putative actives are achieved, safety studies may focus solely on these
substances. However, it is often unclear, or unlikely, that the active constituent for
nutritional efficacy is the most toxic constituent. Therefore, the traditional toxicological
challenges with complex mixtures apply to botanicals. These uncertainties may include
questions around synergistic or antagonistic action between botanical constituents, or
actions with other botanical constituents in the mixture.

New Approaches for Safety Assessment

Given the continued interest in botanicals in a variety of consumer care products, coupled
with a strong desire to minimize or eliminate animal testing and the recent developments
regarding in vitro and in silico safety testing methods, the time is ripe to consider new
approaches for the safety assessment of botanicals intended for use in food/dietary
supplements. These approaches could include capturing adverse event data from clinical
studies and postmarket surveillance, but this should be carried out by relying on new
methodologies to assess specific safety endpoints. Human use data can be used as a filter
to assist in the decision-making for further testing. In addition, modern analytical

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characterization of a botanical ingredient can be potentially coupled with a suite of endpoint
evaluations to create a tiered approach to assessing toxicity based on existing data as well
as new data generated specifically for safety assurance.4

In order to expand on the topic of botanical safety assessments, representatives from

industry, academia and the regulatory community participated in a scientific session,
“Botanical Safety Evaluation in the era of Alternatives” at the 53rd Congress of the
European Societies of Toxicology (Eurotox 2017). This session was followed by a
roundtable building on the elements shared by presenters during the scientific session. The
roundtable panel and participants discussed—and provided perspective on—a “decision
tree” approach (i.e., is there general alignment to the key elements that are needed to build
a robust botanical safety evaluation) and inherent vulnerabilities of such an approach. 5 Key
elements discussed and carefully considered included the accurate identification and
advanced multi-detector analytical characterization of botanical raw materials and the in
silico approaches potentially used to address safety data gaps and inform the need for
further studies. Other topics discussed included a discussion of scientific proof necessary
to conduct similarity comparisons to commonly consumed foods or botanicals (i.e., with a
well-established safety profile and a systematic evaluation of relevant toxicity data of
botanical constituents utilizing structure-activity relationships. Included as well was the
application of established Threshold of Toxicologic Concern (TTC) principles to botanical
constituents, in the absence of data and where safety endpoint gaps are identified which
cannot be resolved without in vitro or in vivo studies, and the botanical compositional data
that essential to inform study design. The 2017 Eurotox session was used as a
“springboard” to add these perspectives to the public discourse and the scientific literature,
as evidenced by the 2018 Society of Toxicology poster presentation6 and the 2019
Toxicology Letters manuscript.7

The Botanical Safety Consortium

The scientific discourse begun at Eurotox 2017 continued at the International Conference
on the Science of Botanicals (ICSB 2018). At this meeting, interested parties from industry,
academia, science-based trade associations and the regulatory community came together
to propose the inauguration of a pragmatic strategy to explore scientific solutions through a
multifunctional collaborative, later referred to as the Botanical Safety Consortium (BSC).8,9

The objective of the BSC is to provide a sound scientific basis for integrating existing
botanical safety/toxicity data with the latest toxicological tools, including, but not limited to,
in silico and in vitro methodologies to more thoroughly evaluate botanical safety.

Some of the key areas the BSC will explore include the chemical characterization of
complex botanical mixtures and fit-for-purpose assays and models for evaluating
genotoxicity, hepatotoxicity, developmental and reproductive toxicity, cardiotoxicity and
systemic toxicity. In addition, attention also will focus on in vitro ADME and herb-drug and
herb-herb interactions.

A botanical library containing ingredients with known in vivo toxicity gained from animal
studies or reports of adverse events in humans, will be created and evaluated in the
recommended battery of assays. Results from the consortium will be shared through a
publicly available database and along with findings and recommendations published in
peer-reviewed literature.

BSC Working Groups (WGs) will address analytical characterization and key safety
endpoints. The two co-chairs of each BSC WG will be technical representatives from
industry and from government or academia to maintain balance. A BSC Steering Team will
provide oversight and guidance to the BSC WGs. The Steering Team includes
representation from a variety of dietary supplement stakeholder segments including the
Federal Government as FDA’s Office of Dietary Supplement Program (ODSP), National

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Institute of Environmental Health Sciences (NIEHS), dietary supplement manufacturers,
trade associations and other non-governmental organizations.

Conclusion

At this writing, the BSC is still in the early stages of coalescing and establishing its
processes and procedures. In addition to this administrative work, the steering committee is
working with the BSC WG co-chairs to identify additional scientists with specific expertise in
the above-mentioned toxicologic endpoints. WG membership will be based on a capacity to
carry out the work, interest, expertise and willingness to share internal data and experience
in the design of future work. Active participation is an expectation in this ‘roll-up-your-
sleeves’ exercise, including specific expertise in tests, assays and models to address the
endpoints outlined above. The BSC WGs will be expected to provide input on the selection
of candidate ingredients to be placed in the BSC’s assays and modeling exercises. There
are plans to create a mechanism for stakeholder and scientific peer feedback, as well as an
annual scientific meeting where information will be openly shared. Results from work
undertaken by the BSC (via the targeted working group activities and data generation) will
be published in the peer-reviewed literature.

The goal of the BSC will be to enhance the botanical safety toolkit and bring clarity to
botanical safety assessments for manufacturers and regulators. With broad representation
by interested and affected parties, the BSC Steering Committee and Working Groups will
be designed to ensure collaborative and cooperative scientific recommendations.

References

1. US Congress. United States Code: Federal Food, Drug, and Cosmetic Act, 21 USC §§ 301-392 Suppl. 5. 1934.
https://www.loc.gov/item/uscode1934-006021009/. Accessed 17 June 2019.
2. Council for Responsible Nutrition (CRN). Annual Survey on Dietary Supplements. 2018. Washington, DC.
https://www.crnusa.org/CRNConsumerSurvey. Accessed 17 June 2019.
3. American Botanical Council (ABC). Herbal Gram. The Journal of the American Botanical Council. 2017. Issue 119.
http://cms.herbalgram.org/herbalgram/issue119/hg119-
herbmktrpt.html?ts=1556561855&signature=8dfe62c7ff406bc90d9dac1d2306e361. Accessed 17 June 2019.
4. Little JG, Marsman DS, Baker TR and Mahony C. “In silico Approach to Safety of Botanical Dietary Supplement
Ingredients Utilizing Constituent-Level Characterization.” Food Chem. Toxicol. September 2017; 107 (Part A), 418-429.
https://www.ncbi.nlm.nih.gov/pubmed/28698155. Accessed 17 June 2019.
5. Ibid.
6. Griffiths JC, Edwards J, Fitzpatrick, et al. “Development of a Consensus Approach for Botanical Safety Evaluation.”
The Toxicologist. 2018.
7. Galli CL, Walker NJ, Oberlies NH, Roe AL, Edwards J, Fitzpatrick S, Griffiths JC, Hayes AW, Mahony C, Marsman DS
and O’Keeffe L. “Development of a Consensus Approach for Botanical Safety Evaluation – A Roundtable Report.”
Toxicology Letters. 2019. https://www.ncbi.nlm.nih.gov/pubmed/31082523. Accessed 17 June 2019.
8. Statement from FDA Commissioner Scott Gottlieb, MD, on the agency’s new efforts to strengthen regulation of dietary
supplements by modernizing and reforming FDA’s oversight. 2019. FDA website. https://www.fda.gov/news-
events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-agencys-new-efforts-strengthen-
regulation-dietary. Accessed 17 June 2019.
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About the Authors

Daniel S. Marsman, DVM, PhD, is head of product safety for P&G Health Care. In his role at P&G as a veterinary scientist and
board-certified toxicologist, he has led global safety and regulatory initiatives for an array of natural health products, medicines and
consumer goods. He can be contacted at [email protected].

Joseph T. Dever, PhD, is a board-certified toxicologist and manager of product safety at Amway Corporation. He oversees a
global safety program for all nutrition and cosmetic products including the NutriliteTM and ArtistryTM brands. He can be contacted at
[email protected].

Stefan Gafner, PhD, is currently chief science officer of the American Botanical Council (ABC), an independent, nonprofit
research and education organization. He is also technical director of the ABC-AHP-NCNPR Botanical Adulterants Program, a
large-scale collaborative program initiated by the American Botanical Council (ABC), the American Herbal Pharmacopoeia (AHP)
and the National Center for Natural Product Research (NCNPR) at the University of Mississippi to educate members of the herbal
and dietary supplement industry about ingredient and product adulteration. He can be contacted at [email protected].

Cynthia Rider, PhD, is a toxicologist with the National Toxicology Program (NTP), National Institute of Environmental Health
Sciences (NIEHS), where she serves as a project leader for testing programs including botanical dietary supplements. Her
research focuses on evaluating and refining methods to predict mixture toxicity based on data from components or whole
reference mixtures. She can be contacted at [email protected].

regulatoryfocus.org Regulatory Intelligence and Policy, Vol. 2, No. 4, 2019 106

Sibyl Swift, PhD, is a special assistant within the US Food and Drug Administration’s (FDA’s) Office of Dietary Supplement
Programs (ODSP). In this role, Swift works on special projects related to dietary supplements, including directing the Office’s
research agenda and reviewing dietary ingredient safety. She can be contacted at [email protected].

James C. Griffiths, PhD, is senior vice president of International and Scientific Affairs at the Council for Responsible Nutrition
(CRN). He is a board-certified toxicologist and has been active in product safety, nutrition and international issues throughout a
thirty-year scientific career. He can be contacted at [email protected].

Cite as: Marsman, DS, Dever, JT, Gafner, S, Rider, C, Swift, S and Griffiths, JC. “The Botanical Safety Consortium (BSC): The
Development of a 21st Century Framework for Assessing the Safety of Botanical Dietary Supplements.” Regulatory Focus. June
2019. Regulatory Affairs Professionals Society.

© 2019 by the Regulatory Affairs Professionals Society. All rights reserved.

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