DRUG

DEVELOPMENT
PROCESS AADHIRA.J
PHARM.D 5 TH YEAR – CLINICAL RESEARCH - 18.06.2025
Drug development is an exceptionally long, complex, and high-risk endeavor, typically spanning 10–15 years and
costing over $1–2 billion per approved drug.
The process is characterized by a high attrition rate, with approximately 90% of candidates entering human trials
failing to reach the market.
 This pipeline is a systematically phased process—encompassing Discovery, Preclinical Research, Clinical Trials
(Phases I-IV), and Regulatory Review—that has been rigorously shaped by historical public health crises to
prioritize patient safety and therapeutic efficacy.
 SCOPE, SCALE, AND ATTRITION
Bringing a new drug to market is a monumental undertaking defined by significant
investment and a low probability of success.
 Timeline: The process typically takes 10 to 15 years from initial discovery to market
approval.
Cost: Estimates for developing a single new drug range from $1–2 billion to as high as
$2.6 billion when accounting for the cost of failed candidates.
Attrition Funnel: The pipeline is marked by a dramatic attrition rate. For every 5,000–
10,000 compounds screened during discovery, approximately 250 advance to preclinical
testing, 5–10 enter human clinical trials, and only one is ultimately approved.
Clinical Failure Rate: Approximately 90% of drug candidates that enter clinical trials fail
to be approved. The leading causes of failure include lack of efficacy (~40–50%),
unforeseen toxicity (~30%), and poor drug-like properties (~10–15%). Phase II is a
notorious bottleneck where many candidates fail to demonstrate proof-of-concept.
 TYPICAL
DEVELOPMENT STAGE OR POPULATION REGULATORY AND MARKET
CATEGORY PHASE PRIMARY OBJECTIVE SIZE KEY CHALLENGES IMPACT
Small Molecules Pre-approval / Chemically synthesized low molecular Not in source Optimizing chemical properties, Well-established regulatory
Discovery weight drugs designed to diffuse across cell (Preclinical) managing off-target effects, drug pathways with clear guidelines for
membranes and bind to specific protein resistance, and enhancing oral safety and efficacy; lower
sites. bioavailability. manufacturing costs compared to
biologics.

Biologics Pre-approval / Large, complex molecules produced in Not in source Immunogenicity, manufacturing Requires specialized regulatory
Discovery living cells to target extracellular molecules (Preclinical) variability/sensitivity, high development considerations (e.g., biosimilars);
or cell surface receptors. costs, and complex mechanisms of often granted longer market
action. exclusivity and premium pricing.

Clinical Trial Phase Pre-approval Assess safety, tolerability, and 20-100 (healthy Managing acute side effects and ensuring Supports initial safety assessment;
I pharmacokinetics; determine safe dosage volunteers or safe starting doses based on animal data results determine if a drug proceeds
range and Maximum Tolerated Dose specific patients) (Human Equivalent Dose). to patient studies.
(MTD).

Clinical Trial Phase Pre-approval Assess preliminary efficacy (proof of 100-300 patients High attrition rates due to lack of efficacy Informs dosing and design for
II concept) and further explore safety and (approximately 40-50% of failures) and larger pivotal trials; critical "go/no-
optimal dosing in patients. unforeseen human toxicity. go" decision point.

Clinical Trial Phase Pre-approval Confirm efficacy and monitor adverse 1,000-3,000+ Managing high costs (averaging $255M- Provides the primary evidence for
III reactions in large-scale pivotal trials to patients $345M) and late-stage failures due to NDA/BLA submission and
establish benefit-risk ratio. efficacy or rare safety issues. marketing authorization.

Clinical Trial Phase Post-approval Evaluate real-world effectiveness, long-term Thousands of Patient diversity, adherence issues, long- Supports post-approval
IV safety, and identify rare adverse events in diverse, real- term monitoring, and data heterogeneity commitments; can lead to label
general populations. world participants in real-world settings. changes, new indications, or
regulatory withdrawals.
 HISTORICAL CONTEXT AND REGULATORY
FOUNDATIONS
The rigorous, phase-based structure of today's drug development pipeline is a direct result of historical public
health disasters that mandated stricter government oversight.
 1937 Elixir Sulfanilamide Disaster: A toxic solvent used in an antibiotic formulation killed over 100
people, leading to the 1938 U.S. Federal Food, Drug, and Cosmetic (FD&C) Act. This landmark
legislation required manufacturers to provide scientific proof of a drug's safety before marketing.
 1960s Thalidomide Tragedy: A sedative marketed to pregnant women caused thousands of severe birth
defects globally. This catastrophe prompted the 1962 Kefauver-Harris Amendments, which required
manufacturers to provide "substantial evidence" of both safety and efficacy through "adequate and well-
controlled investigations," establishing the modern paradigm of phased clinical trials.
 1980s HIV/AIDS Crisis: Patient activism and urgent medical need led to the creation of expedited
regulatory pathways by the FDA, such as Accelerated Approval (1992), to speed the availability of drugs
for serious or life-threatening conditions based on surrogate endpoints.
 1992 PDUFA: The Prescription Drug User Fee Act (PDUFA) allowed the FDA to collect fees from
manufacturers to fund review staff, significantly shortening NDA review times from over two years to
around one year or less.
 STAGE 1: DISCOVERY AND PRECLINICAL RESEARCH
This foundational stage aims to identify a therapeutic target and develop a lead compound with a suitable safety profile for human testing.
1. Target Identification and Validation: Researchers identify a biological molecule (e.g., a protein, enzyme) implicated in a disease and
validate that modulating it can produce a therapeutic benefit. This involves pathway analysis, genetic insights, and pharmacological
validation.
2. Hit Identification: Using techniques like High-Throughput Screening (HTS)—which leverages automation and miniaturization to test
millions of compounds—researchers identify initial "hits" that interact with the target. Other methods include fragment-based and virtual
screening.
3. Lead Optimization: Medicinal chemists iteratively modify "hit" compounds to create "leads" with improved properties, including potency
(strength of effect), selectivity (avoiding off-targets), and favorable ADME characteristics (Absorption, Distribution, Metabolism,
Excretion).
4. Preclinical Testing: The selected lead candidate undergoes extensive laboratory (in vitro) and animal (in vivo) testing under Good
Laboratory Practice (GLP) regulations. Key studies include safety pharmacology (effects on vital organ systems), repeat-dose toxicology in
two animal species (one rodent, one non-rodent), and genotoxicity assays. These data are used to determine a safe starting dose for human
trials and are compiled into an Investigational New Drug (IND) application submitted to regulators like the FDA.
A. Target Selection
◦ Before a drug can be discovered, a biological target must be chosen. This process involves a deep understanding
of the disease to be treated to identify its "underlying cause." Studying the disease mechanism allows researchers
to formulate a possible approach to slow or reverse the disease's progress.
 Therapeutic Targets: Potential targets for intervention include:
o Receptors
o Proteins
o Enzymes
o DNA
o RNA
o Ribosomal targets
 Identification Methods:
o Classical Methods: Cellular biology, Molecular biology
◦ Newer Methods: Genomics, Proteomics
B. Target Validation
Once a potential target is identified, it must be validated. Validation is the process of proving that
the identified molecular target is directly involved in the disease process and that binding a drug
to this target produces a curative effect.
 Validation Process: The process involves an In Vitro phase followed by an In vivo phase to
define the clinical potential of the target.
 Druggability: A key consideration in validation is determining the "druggability of the
target," which is defined as the ability of a target to bind to a drug.
C. Lead Identification
In this stage, the objective is to identify compounds that interact with the validated target protein.
These initial compounds are known as "hits."
 Sources of Compounds:
o Natural Products: Derived from microbes, plants, or animals.
o Compound Libraries: Large collections of synthetic chemical compounds.
 Screening Process:
o Primary Screening: Compound libraries are screened to identify initial "Hits."
o Hit Retesting: The identified Hits are retested.
o Independent Retesting: The retest is conducted again independently, often on a different day,
using the initial assay.
o Confirmation: A compound that exhibits statistically significant activity is termed a
"confirmed Hit" and proceeds to the next stage.
D. Lead Optimization
◦ Lead optimization takes a "confirmed hit" and refines its chemical structure to
improve its characteristics. The goal is to produce a preclinical drug candidate with an
optimal profile.
 Key Optimization Studies: This phase involves a series of studies to understand the
compound's behavior:
 Kinetic studies
 Dynamic studies
 Absorption studies
 Distribution studies
 Metabolism studies
 Excretion studies
STAGE 2 :PRECLINICAL EVALUATION

The primary aim of preclinical testing is to obtain basic information on the effects of a drug to
predict its safe and effective use in humans. Due to species differences, data from animals cannot
be completely extrapolated to humans, making eventual human testing essential. Preclinical
testing is divided into two broad categories.
◦ A. Pharmacological Testing

◦ B. Toxicological Testing
A. Pharmacological Testing
 These tests are conducted to determine if a substance possesses both effectiveness and a reasonable safety profile.
Key Components of Pharmacological Testing:
 Selectivity Testing: Assesses the compound's selectivity for its chosen molecular target, which determines the drug's potency. This involves
screening of selectivity and binding assays (to determine affinity for the receptor).
 Pharmacological Profiling: Determines the pharmaco-dynamic effects of the new compound using invitro models (on isolated tissues) and
invivo models (on normal animals).
 Testing in Animal Models of Disease: These models are used to evaluate the drug's efficacy in a disease context.
 Acute Models: Mimic certain aspects of a clinical disorder (e.g., hot plate for pain, induced seizures for epilepsy).
 Chronic Models: Use drugs or physical interventions to induce an ongoing abnormality that resembles a clinical condition (e.g., self-
administration of opiates as a model for drug dependence).
 Genetic Models: Use transgenic animals with gene overexpression or deletion to replicate human diseases.
 Safety Pharmacology: Evaluates potentially life-threatening pharmacological effects that are unrelated to the desired therapeutic effect. It
seeks to identify unanticipated effects on major organ functions and detect undesirable or dangerous effects.
Levels of Pharmacological Study:
 Molecular Level: Studies the drug's selectivity for various receptors and its activity against selective enzyme systems.
 Cellular Level: Uses cell/tissue culture and computer programs to assess pharmacological action on isolated tissues like blood vessels,
heart, and lungs.
 Whole Animal Level: Determines the effect of the drug on organ systems and disease models (e.g., anti-hypertensive effects in
hypertensive rats).
B. Toxicological Testing
Toxicological evaluation is crucial because all drugs are toxic at some dose. These studies determine a drug's potential for
toxicity with both short-term and long-term use at various dose levels. Regulatory authorities recommend a range of
studies.

Study Type Description

The drug is given daily for a minimum of two weeks. This data supports the initial single-
Sub-acute Toxicity dose administration in human trials. The initial human dose is typically 1/10th of the
highest non-toxic dose in animals (mg/kg).
Required for drugs intended for extended use. Animal studies of 3-6 months are needed
Chronic Toxicity for drugs used for over a week in humans; studies of one year or longer are required for
drugs treating chronic illness.
Assess effects on fertility, mating performance, and evaluate maternal parents, fetuses,
Reproduction Studies
and offspring for anatomical abnormalities and developmental issues.

Carried out in rats and mice to assess tumor incidence. Studies use the minimum tolerated
Carcinogenicity Studies
dose to avoid signs of minimal toxicity.
Genotoxicity (Mutagenicity) Determine the drug's effects on genetic stability and mutations in bacteria or mammalian
Studies cells.
 STAGE 3: CLINICAL TRIALS IN HUMANS
After an IND is approved, the drug is tested in humans through a series of progressively larger and more rigorous
clinical trial phases.
 Phase 0 (Optional): Also known as exploratory or microdosing studies, these involve giving sub-therapeutic doses
to a small number of volunteers (~10-15) to gather preliminary human pharmacokinetic (PK) data.
 Phase I: The primary goal is safety. Healthy volunteers (or patients in diseases like cancer) receive single and
multiple ascending doses to determine a safe dosage range, characterize how the body processes the drug (PK), and
identify common, short-term side effects.
 Phase II: This is the first test of efficacy. The drug is given to a moderately sized group of patients (e.g., 50-300)
to establish "proof-of-concept," explore the relationship between dose and response, and further evaluate safety in
the target population. A high percentage of drugs fail at this stage due to a lack of efficacy.
 Phase III: These are large-scale, pivotal trials involving hundreds to thousands of patients, often conducted
globally at multiple centers. The goal is to definitively confirm the drug's effectiveness and safety against a placebo
or standard-of-care treatment. Successful Phase III trials provide the primary evidence for regulatory approval.
 STAGE 4: REGULATORY REVIEW AND POST-
MARKETING
If Phase III trials are successful, the developer submits a comprehensive data package to regulatory authorities.
 New Drug Application (NDA) / Biologics License Application (BLA): The sponsor submits a formal application
containing all preclinical and clinical data, manufacturing details, and proposed labeling.
 FDA Review: Regulatory teams of physicians, statisticians, chemists, and other experts conduct a thorough review
to assess whether the drug's benefits outweigh its risks for the intended population.
 Phase IV (Post-Marketing Surveillance): After a drug is approved, Phase IV studies are conducted to monitor its
long-term safety and effectiveness in the general population. These studies rely on Real-World Data (RWD) from
sources like electronic health records and patient registries to identify rare or delayed adverse events and assess
performance across diverse demographics. This ongoing safety monitoring is known as pharmacovigilance.
DRUG DEVELOPMENT PROCESS
-Brief Recap-
DISCOVERY AND DEVELOPMENT
PRE-CLINICAL RESEARCH
CLINICAL RESEARCH
REGULATORY REVIEW
POST MARKETING MONITORING
FINACIAL AND RISKS
THANK YOU