Introduction to Drug Research and Development (R&D)

 Why R&D is Hard: Developing a new drug is complex, risky, and expensive. On average,
thousands of chemical compounds must be tested before one is approved.
 Cost: Developing a single drug costs around $800 million or more.
 Return on Investment: Only 30% of drugs that reach the market generate enough
revenue to cover development costs.
2. Role of the FDA
 Purpose: The FDA’s role is to ensure that all drugs available in the U.S. are safe and
effective.
 Establishment: The FDA was created because of tragic events where unsafe drugs
caused multiple deaths.
FDA’s Background and Creation
 Sulfanilamide Tragedy (1937):
o Incident: A sulfanilamide antibiotic was dissolved in a toxic solvent called
diethylene glycol (found in antifreeze), which led to many deaths.
o Result: Congress passed the Food, Drug, and Cosmetic Act of 1938 to regulate
drugs, requiring drug manufacturers to:
 Share ingredients, formulations, animal test data, and human testing
data with the FDA before selling any drug.
 Thalidomide Tragedy (1960s):
o Incident: Thalidomide, a sedative sold in Europe, caused severe birth defects
when used by pregnant women.
o Outcome: Led to the Kefauver-Harris Amendments (1962), which:
 Required drug manufacturers to prove both safety and effectiveness.
 Mandated Investigational New Drug (IND) Applications before testing
any drug in humans.
3. FDA’s Structure and Responsibilities
 FDA Centers: The FDA has different centers to monitor specific types of products:
o Center for Drug Evaluation and Research (CDER): Oversees prescription and
over-the-counter drugs.
 o Center for Biologics Evaluation and Research (CBER): Supervises biologic
products like vaccines and blood products.
o Center for Food Safety and Applied Nutrition: Ensures food and cosmetics are
safe.
o Center for Veterinary Medicine: Handles animal drugs and feed.
o Center for Devices and Radiological Health: Manages medical devices and
radiation-emitting devices like X-rays.
 CDER’s Role: This center:
o Reviews drug safety and efficacy before and after marketing.
o Can withdraw drugs from the market if they pose risks.
o Provides public and healthcare professionals with accurate drug information.
o Ensures ads for drugs are truthful and balanced.
4. Stages of the Drug Development and Approval Process
 Overview: Developing a new drug takes years of testing and strict review by the FDA.
 Phases:
1. Preclinical Testing:
 Purpose: Conducted in labs and on animals to assess safety and
determine if the drug works.
 Goal: Identify the best “lead compound” that shows promise for further
testing.
2. Clinical Testing (Human Trials):
 Involves testing the drug in humans to assess its effects, proper dosage,
and potential side effects.
o Schematic Overview: The drug approval process is divided into two main parts:

 Preclinical Testing: Focuses on lab and animal tests.

 Clinical Testing: Focuses on testing in human volunteers.
5. Clinical Trial Phases
 Clinical testing in humans goes through several phases to ensure safety and efficacy:
1. Phase 1: Tests the drug in a small group of healthy volunteers to assess safety.
 2. Phase 2: Involves more people and focuses on both safety and effectiveness.
3. Phase 3: Large-scale testing on patients to confirm effectiveness, monitor side
effects, and compare the drug to other treatments.
4. Phase 4 (Post-Marketing): After approval, the drug continues to be monitored in
the general population for any long-term or rare side effects.
6. Drug Application and Approval
 New Drug Application (NDA): If clinical trials show the drug is safe and effective, the
manufacturer submits an NDA to the FDA.
 FDA Review: FDA experts review all data on safety, effectiveness, and manufacturing
quality.
 Outcome: The FDA can approve, request further information, or reject the drug
application.
7. Post-Market Surveillance
 Importance: After a drug is on the market, monitoring continues to ensure safety in a
larger, more diverse population.
 Responsibilities of CDER: CDER oversees this phase, tracking adverse events and can
take action if safety concerns arise.
 Actions: If issues are detected, the FDA may:
o Update drug labels to warn of new risks.
o Restrict drug use or, in rare cases, withdraw the drug from the market.

Summary
The FDA’s drug approval process is designed to protect public health by:
 Ensuring thorough testing of all new drugs.
 Verifying safety and effectiveness before approval.
 Continuing safety checks even after a drug is marketed.
1. Drug Discovery Process
 Objective: Pharmaceutical companies begin by selecting a broad disease category (e.g.,
cancer) or a specific disease (e.g., breast cancer) to develop treatments.
 Lead Compound: A promising chemical, called a lead compound, is identified as a
potential treatment.
Techniques to Find Lead Compounds
1. Random Screening:
o Testing a variety of chemicals from existing libraries to find a lead compound with
biological activity.
o Low upfront cost but often requires testing thousands of compounds.
2. Targeted Synthesis:
o Focuses on a specific step in the disease’s mechanism, which may increase the
likelihood of finding an effective lead compound.
3. Combinatorial Chemistry:
o Starts with one base compound and adds different groups to create variations
and improve activity.
o This method is more expensive and complex.
4. Drug Modeling:
o Uses computer simulations to design molecules that may fit specific protein
targets.
o High initial cost, but it shows promise as a future technique with ongoing
research.
Future Prospects
 Future drug discovery may focus more on functional proteomics—studying proteins
coded by genes to understand biological roles and target specific disease pathways.
2. Preclinical Testing
 Purpose: To gather data about the lead compound's properties and ensure it is safe for
further testing.
 Multidisciplinary Team: Scientists from various fields work together to evaluate the
compound’s properties.
Key Components of Preclinical Testing
1. Discovery Testing: Confirms the biological activity in living organisms.
2. Chemical Synthesis: Produces the compound in high purity.
3. Formulation and Stability Testing: Determines how to deliver the drug, its stability, and
various chemical characteristics.
4. Animal Safety Testing:
o Involves testing the compound’s absorption, distribution, metabolism, and
excretion (ADME).
o Toxicity is tested in at least two species (one rodent and one non-rodent) to
cover different biological responses.
Regulatory Standards
 Good Laboratory Practices (GLPs): Standards specified in Title 21 CFR Section 58 govern
preclinical study conduct, personnel qualifications, and Standard Operating Procedures
(SOPs).
Important Preclinical Tests
 ADME and Toxicity: Determines the drug’s movement and potential side effects in
animals.
 Safety Dose Determination: Identifies the highest dose without harmful effects (no-
effect dose).
 Impurities Testing: Impurities over 0.1% are characterized and tested for toxicity.
3. Pre-IND Meetings
 Purpose: These are optional but can be helpful to clarify testing plans and data
requirements with the FDA before submitting the Investigational New Drug (IND)
application.
 Usefulness: Especially beneficial for drugs developed overseas, where substantial data
may already exist, and the FDA can agree on suitable testing phases.
 FDA Guidance: Sponsors can consult FDA guidance documents for requesting formal
meetings.
4. Investigational New Drug (IND) Application
 Objective: Required before testing a new drug in humans.
 Contents of the IND:
o Chemical Description: Detailed information on the active ingredient and other
components.
o Manufacturing and Dosage: Specifies preparation methods and dosage forms.
 o Preclinical Data: All data from animal studies to show the drug’s safety.
o Investigators’ Information: Lists the investigators and clinical trial locations.
 FDA Review Timeline: The FDA has 30 days to decide if the clinical trial can proceed. If
they don’t respond within this timeframe, the trial may move forward.
 Clinical Holds: The FDA can pause trials if there’s a significant safety concern or if
information is incomplete.
Exemptions from IND Requirements
 INDs aren’t required if:
o The trial does not intend to support new labeling or advertising.
o The trial does not involve significant changes in administration, dose, or patient
population.
o The drug is already FDA-approved and used in standard doses and populations.
5. Clinical Investigations
 Purpose: Administering the drug to humans, which requires extensive resources and
involves multiple phases, each with specific goals.
 Cost: Clinical trials are the most expensive part of drug development.
Phases of Clinical Trials
 Phase 1: Tests for basic safety in a small group of healthy volunteers.
 Phase 2: Tests effectiveness and further assesses safety in a larger group.
 Phase 3: Involves large-scale testing on diverse patients to confirm effectiveness and
identify side effects.
 Phase 4: Post-approval monitoring for rare or long-term side effects in the general
population.

Phase I Clinical Trials

 Objective: To assess the basic safety of a new drug.
 Participants: Small group of 20-80 healthy volunteers (except for life-threatening
diseases, where patients with the disease may be included, e.g., cancer).
 Starting Dose: Typically begins at 1/10th of the highest safe dose found in animal tests.
 Process:
 o Initial low doses are tested; if safe, doses are gradually increased.
o Researchers monitor for maximum dose tolerated without significant side
effects.
 Data Collected:
o Preliminary ADME (Absorption, Distribution, Metabolism, Excretion) data.
o Pharmacokinetic (drug behavior in the body) and pharmacodynamic (drug effects
on the body) data.
o This data informs the design of Phase II trials.

Phase II Clinical Trials

 Objective: To determine efficacy and further evaluate safety.
 Participants: Larger group of 100-300 patients with the target illness.
 Process:
o Focuses on the drug’s effectiveness in treating the illness.
o Side effects and safety are also closely monitored.
 Common Outcome:
o Many drugs fail in Phase II as real-life human responses are often more complex
than lab models.
 Regulatory Requirements:
o Clinical protocols for Phase II trials must be submitted to the FDA as
amendments to the IND before beginning the trial.

Phase III Clinical Trials

 Objective: To thoroughly test efficacy and safety on a large scale.
 Participants: 1,000-3,000 patients with the target illness.
 Design:
o Conducted in multiple major hospitals or clinics, often nationally or
internationally.
 o Involves randomization and control (may compare with a placebo or standard
treatments).
o Final drug formulation should be ready before starting.
 Meeting with FDA:
o Before starting Phase III, sponsors meet with FDA to review:
 Trial design, inclusion/exclusion criteria, dosing, data collection, and
follow-up methods.
 Plans for maintaining the blinding (ensuring neither patients nor
researchers know which patients receive the drug or placebo).
o Addressing these points aims to reduce trial bias.
 Outcomes and Approval:
o Successfully completing Phase III gives the drug a 95% chance of FDA approval.
o Another meeting with the FDA is encouraged before filing the New Drug
Application (NDA) to ensure all data and formats meet review standards
Phase IV Clinical Trials
 Objective: Post-approval trials to monitor long-term safety, efficacy, and potential side
effects.
 Purpose:
o FDA may mandate these to further assess drug effects in specific populations.
o Sponsors may conduct additional trials to compare the new drug with other
available treatments.
o Used to monitor long-term safety due to limited exposure time in earlier phases.

New Drug Application (NDA)

 Objective: Compiling all data (preclinical + clinical) to request FDA approval for
marketing.
 Contents of NDA:
o Drug safety and efficacy data.
o Details on drug components, manufacturing, and quality control
o Proposed labeling and packaging.
 Submission Process:
o FDA assigns NDAs a status within 60 days of submission.
o Priority Review (P) for drugs with enhanced therapeutic benefits; Standard
Review (S) for others.
 Review Process:
o FDA reviewers analyze and submit recommendations within 180 days.
o If issues arise, they notify the sponsor to make corrections.
o NDA can receive approval, conditional approval, or disapproval based on safety,
efficacy, and quality control.
 Pre-Approval Inspections:
o FDA inspects the sponsor’s facilities to ensure compliance with current Good
Manufacturing Practices (cGMPs).
o If deficiencies are found, companies receive FDA Form 483 and must correct
issues before final approval.

Abbreviated New Drug Application (ANDA)

 Objective: Approval pathway for generic drugs.
 Focus: Bioequivalence testing (rate and extent of absorption) rather than safety and
efficacy.
 Requirements:
o In vivo bioequivalence testing is needed for most tablets/capsules.
o In some cases, bioavailability can be established through comparative
dissolution or formulation comparison.
 Outcome:
o If the generic is bioequivalent, ANDA may be approved.
o Tentative approval is possible if patent/exclusivity restrictions prevent immediate
market release.
Rapid Access to New Drug Products
 Purpose: Allows quicker access to drugs for diseases that are life-threatening or cause
severe disability.
 Regulations for Faster Approval:
o Subpart E (21 CFR 312.80-.88): Fast-tracks the development and approval
process for critical conditions.
o Subpart H (21 CFR 314.500-.550): Lets the FDA approve drugs based on a
surrogate endpoint (an early indicator like a lab result or symptom that may
predict real benefits) instead of waiting for full clinical results.
 Special Access Programs:
o Treatment INDs (Investigational New Drug Applications, 21 CFR 312.34): Allows
seriously ill patients to use drugs still in testing, usually in Phase III trials.
o Parallel Track: Gives HIV patients early access to drugs even if they can’t join
regular trials (e.g., they’re too sick or don’t meet criteria for the trial).

Orphan Drug Approval

 What Are Orphan Drugs?: These are drugs made to treat rare diseases (affecting fewer
than 200,000 people in the U.S.).
 Approval Process: Orphan drugs go through the usual FDA review, often faster due to
the critical need.
 Support and Incentives:
o Orphan Drug Act of 1983: To encourage companies to develop these drugs, this
Act provides:
 Tax Incentives: Helps reduce the cost burden on the company.
 Reduced Fees: Lowers application and regulatory fees.
 Exclusivity: Protects the drug from competition for a set time, allowing
companies to recoup costs.
o Funding: FDA grants are available to support research on orphan drugs,
announced yearly in the Federal Register.
 Results: By 1995, the Act had helped bring 121 new orphan drugs to market.

Over-the-Counter (OTC) Drug Approval

 Approval Process:
 o Advisory Panel: A group of scientists reviews data from manufacturers and
published studies to decide if the drug is safe and effective for OTC use.
o FDA Review: The FDA publishes a tentative final monograph (draft rule)
summarizing findings in the Federal Register. This document sets safety and
effectiveness standards for the OTC drug.
o Public Feedback: The public and interested parties can comment on the
monograph.
 Finalization of the Monograph:
o After reviewing all comments, the FDA publishes the final monograph in the
Federal Register.
o The monograph becomes effective one year after publication, establishing
guidelines for labeling and claims.
 Additional Claims: If a company wants to make claims not covered by the monograph,
they must either:
o Submit more data to the FDA to revise the monograph.
o Submit a New Drug Application (NDA) for approval of those claims.

Post-Approval Activities
 Safety Monitoring:
o Adverse Event Reporting: Companies must report any adverse events (side
effects) related to the drug:
 Quarterly reports: Filed every three months for the first three years after
the drug is approved.
 Annual reports: Filed once a year after the initial three years.
o Serious Side Effects: Any severe, unexpected side effects (e.g., death,
hospitalization) must be reported within 15 days to the FDA.
o MedWatch Program: Allows healthcare providers to report any serious side
effects to the FDA directly, which then issues safety alerts to healthcare
professionals if needed.
 Labeling Changes and Withdrawals:
o Labeling Updates: If new safety concerns arise, the label may be updated with
added warnings or precautions.
 o NDA Withdrawal: The FDA may decide to withdraw a drug if new data shows it’s
unsafe, following a review by an Advisory Committee. Sometimes, companies
voluntarily withdraw drugs before this happens.
 Changes to Approved Products (SUPAC - Scale-Up and Post-Approval Changes):
o Types of Changes: Any change to the drug's composition, manufacturing, batch
size, or labeling must be reported.
o Notification Types:
 Annual Reports: For minor changes.
 Supplemental New Drug Applications (SNDA): For significant changes
that may impact drug quality and require FDA approval.
Clinical Trial Planning and Design
Before Starting Clinical Trials:
 After completing pre-clinical testing (lab and animal studies), a company decides
whether to continue developing a drug. This decision is based on:
1. Therapeutic Potential: The drug should be equal to or better than existing
treatments.
2. Unmet Medical Need: The drug should address an unmet need or improve
therapy for a specific condition.
3. Market Potential: There must be enough potential users to make the drug
profitable.
4. Risk Assessment: Risks like efficacy (effectiveness) and toxicity (safety) are
considered.
5. Development Costs: The company considers how much it will cost to bring the
drug to market.
6. Market Success: They estimate how successful the drug could be, based on
competition and the drug’s unique features.
Once these factors look favorable, the company begins clinical trials to study the
drug's effects on people.

Selecting Trial Objectives

Trial objectives vary by trial phase:
 Phase I: Focuses on testing the drug's safety and toxicity at different doses.
o For life-threatening diseases, some efficacy (effectiveness) assessments may also
be included.
 Phase II and III: Focus on clinical efficacy (how well the drug works) in larger groups.
 Phase IV: Conducted after approval, focusing on efficacy and side effects in specific
populations.
Setting Objectives:
 Each clinical trial should have a clear objective, stating:
o What will be studied (e.g., comparing drugs or assessing side effects).
o The specific disease, type of patients, and drug therapy.
o Purpose of the study (e.g., safety, efficacy, pharmacokinetics).
o Endpoints: What outcome measures will be used (e.g., cure rate, safety markers,
cost-effectiveness).
Primary vs. Secondary Objectives:
 Primary Objective: The main question of the study, essential for determining the sample
size and data analysis methods.
 Secondary Objectives: Other questions of interest. Even if the primary outcome doesn’t
show significant results, the secondary outcomes might, making them valuable.

Trial Designs
Types of Trial Designs:
 Open-Label (Unblinded): Used in Phase I; everyone knows the treatment since the focus
is on initial safety data.
 Parallel Design: Most common in Phase II and III trials.
o Patients are divided into groups to receive either the test drug or a comparison
treatment (e.g., placebo or another therapy).
o Patients stick with their assigned treatment throughout the trial.
o Factorial Design: A type of parallel design used to compare different drugs or
drug combinations. Useful for answering multiple questions but needs a larger
sample size. For example, a study might compare Drug A, Drug B, both together,
and a placebo.
 Crossover Design: Patients receive more than one treatment or dose over different trial
periods.
o Washout Period: Between treatments, there’s a break (often placebo) to avoid
lingering drug effects (carryover).
o Suitable only when the drug has no lasting effects after discontinuation.
Postmarketing (Phase IV) Studies:
 Nonexperimental Designs: Usually observational studies (no assigned treatments), such
as:
o Case-Control Studies: Compares patients with a condition to those without to
identify risk factors.
o Cohort Studies: Follows a group over time to see how different treatments affect
outcomes.
Controlling for Bias
A crucial part of clinical trials is controlling the intervention (the treatment being
tested). Control occurs at three main levels:
1. Assignment of Patients to Interventions
o Randomization: Patients are randomly assigned to different treatment groups to
eliminate bias and confounding factors.
 Computer Programs: Used to generate random assignment to ensure
fairness.
 Imbalanced Assignment: Sometimes, more patients may be assigned to a
treatment believed to be superior (e.g., 2:1 ratio).
 Stratified Randomization: Ensures equal distribution of key
characteristics (e.g., age, gender) across treatment groups by randomizing
patients within these groups.
 Block Randomization: Ensures equal numbers of patients are assigned to
each treatment at regular intervals to avoid imbalances as the trial
progresses. Block sizes can vary randomly (e.g., 4, 8, 12) to prevent
guessing.
2. Application of Interventions
 o Protocol: A detailed plan that outlines how the intervention should be
administered to all patients. It includes dosing, timing, and adjustments based on
patient conditions.
o Monitoring: Compliance with the protocol is monitored. Any deviations are
documented, and staff may need retraining to adhere to the protocol.
3. Measurement of Trial Outcomes
o Standardized Measurements: All personnel receive training on measurement
tools to ensure consistency.
o Centralized Analysis: Using a centralized laboratory or endpoints committee
helps reduce variability in outcome assessment. This committee reviews data to
ensure accurate outcome determination.

Selecting the Trial Population

Inclusion and Exclusion Criteria:
 Phase I Trials: Usually involve healthy volunteers (except for trials targeting life-
threatening diseases).
 Phase II and III Trials: Involve patients who have the condition being treated.
o Inclusion Criteria: Define which patients are eligible based on the trial's
objectives.
o Exclusion Criteria: Identify patients who should not participate due to potential
harm, inability to complete the trial, or contraindications (e.g., allergies or other
health issues).

Sample Size
Determining the sample size is vital to the design of a clinical trial and is influenced
by four main factors:
1. Expected Difference in Outcomes: The size of the effect considered clinically important,
based on previous research.
o This helps to answer: What difference in results would make a clinician switch to
the new treatment?
2. Level of Error in Measurement: The variability in how outcomes are measured, usually
expressed as standard deviation or standard error.
3. Alpha Level (Type I Error): The probability of incorrectly concluding that there is a
difference when there isn't one, commonly set at 0.05 (5% chance of error).
4. Power (Type II Error): The probability of correctly finding a difference when one exists.
Power levels between 80% and 90% are typical, meaning there’s a 10-20% chance of
missing a true effect.
Interrelationships:
 Clinically Important Difference: Increasing this will decrease the required sample size.
 Inherent Error: Increasing measurement error will require a larger sample size.
 Alpha Level: Lowering the alpha level (making it stricter) will increase the sample size
needed.
 Desired Power: Increasing desired power will also increase the sample size.

Importance of Sample Size Planning

 An adequate sample size ensures the trial has enough power to detect meaningful
differences.
 Too small a sample size can lead to false negatives (missing a real effect).
 A sample size that's too large wastes resources and exposes more patients to potential
risks.
Feasibility of Conducting the Trial
Feasibility Factors:
 Purpose of the Trial: The trial's goal affects its feasibility. A broad goal may require a
large sample size, which can increase cost and duration.
 Observation Period: Longer observation periods are needed for trials focusing on
preventing disease events or measuring mortality, which increases time and costs.
 Trial Population: If the target population changes frequently, following patients over
time can be challenging.
 Outcome Type: Generalizable outcomes require broad inclusion criteria to ensure a
diverse patient representation.
 Data Requirements: The nature of the outcomes affects the amount and type of data
needed for the trial.
Patient Access:
 Estimating available patients and their eligibility before starting helps determine
recruitment needs.
 Increasing trial sites can improve patient access but may increase costs. Many
companies hire contract research organizations (CROs) to assist in patient recruitment.
Drug Product Design and Blinding
Blinding:
 Purpose: Blinding prevents bias by disguising which treatment the patient or healthcare
provider is receiving.
 Types of Blinding:
o Single Blinding: Only the patient doesn’t know the treatment.
o Double Blinding: Both the patient and the healthcare provider are unaware.
o Triple Blinding: Involves the patient, healthcare provider, and additional
personnel like biostatisticians.
Techniques for Blinding:
 Drug forms (like tablets or capsules) are modified to be indistinguishable in appearance
(size, shape, color, etc.).
 A "double dummy" approach is sometimes used for trials with multiple treatments,
where patients take placebos along with active drugs to maintain blinding.
Trial Drug Packaging
Packaging Requirements:
 Packages must keep blinding intact, reduce dosing errors, promote patient adherence,
and ensure drug stability.
 Package sizes must align with trial requirements (e.g., dosage adjustments).
Examples:
 In a trial, patients taking different amounts of a drug might receive bottles with varying
quantities to match their dosing schedule.
 Special designs like blister cards can simplify complex dosing regimens and enhance
patient adherence.
Regulations Governing Clinical Trials
Approval Process:
 Before starting, trials must be approved by an institutional review board (IRB) to ensure
patient safety and scientific validity.
 Annual renewals of IRB approval are necessary.
Informed Consent:
 Participants must understand the trial's purpose, risks, and benefits before consenting.
 Consent documents should be clear and comprehensible, and participants have the right
to withdraw at any time.
HIPAA Regulations:
 Protects patients' privacy and requires informed consent for accessing medical records.
Good Clinical Practice Monitoring
GCP Regulations:
 Governed by FDA regulations to ensure patient safety and data integrity.
 Involves monitoring by outside reviewers to detect fraud or data falsification.
Post-Trial Record Keeping:
 Records must be maintained for a minimum of two years after trial completion or drug
approval.
Monitoring and Reporting Adverse Events
Adverse Event Reporting:
 Serious adverse events (SAEs) must be reported to the FDA within seven days. These
include events leading to death, hospitalization, or requiring extensive treatment.
 Other adverse events are regularly collected and coded for analysis.
Statistical Analysis of Clinical Trial Data
Intention to Treat Analysis:
 Includes data from all participants, regardless of whether they completed the study or
adhered to the treatment.
Multiple Comparisons Adjustment:
 Adjusts for the increased risk of finding false positives when conducting multiple
statistical tests.
Subgroup Analysis:
 Involves examining data from specific groups within the study to identify trends or
differences.