This document summarizes the process of drug development from discovery through clinical trials and approval. It discusses the main goals and requirements of each phase of clinical trials: Phase I focuses on safety and dosing in healthy volunteers, Phase II evaluates efficacy and side effects in patients, Phase III tests efficacy versus existing treatments in hundreds to thousands of patients, and Phase IV monitors long-term safety and efficacy after approval and marketing. The overall process from discovery to approval takes 10-15 years and costs over $2 billion on average.

1. By:- Dr. Sameer Khasbage

2. Introduction
• Discovering and developing new treatments for diseases and other medical
conditions is a lengthy and expensive process. Millions of dollars and years of
work is involved in getting a therapeutic product manufactured, tested,
approved and marketed for use of patients. The process of drug development
undergoes following phases:
• Drug discovery: This step involves identification of the compound which have
the potential to be converted into a therapeutic product.
• Preclinical testing: This step validates the safety and biological activity of a
therapeutic compound through in vitro and animal studies.
• Clinical trials: Clinical studies, follow preclinical studies and are designed to
determine the safe and most effective dosages, route of administration,
efficacy (how well the therapeutic compound works) and patient outcomes.

3. Drug discovery
• Identification of targeted chemical moiety. The targeted chemical moiety can be a
receptor, enzyme, gene etc.; which if modified can help to achieve the therapeutic
effect in a given pathology.
• To explore the potential drug candidates which can act on the targeted chemical
moiety and find the lead compound (i.e. the best possible compound out of the
given potential candidates).
• After the identification of lead compound next step is lead compound
optimization, which means altering the chemical structure of lead compound to
increase its stability, selectivity and potency; to produce favorable changes in
pharmacokinetics, and decreasing the adverse effects.

4. Pre-Clinical Development
• It is important to use the right animal model and study design.
Minimum requirements for Preclinical Development are as follows:
• Develop a pharmacological profile of the drug.
• Determine the acute toxicity of the drug in at least two species of animals –
1 rodent & 1 non rodent.
• Conduct short-term toxicity studies ranging from 2 weeks to 3 months,
depending on the proposed duration of use of the therapeutic compound in
the proposed clinical studies.
• Researcher creates this pharmacological and toxicology profile of
drug from:
• in vitro functional assays.
• in vivo PK and PD analysis.

5. Clinical Trials
• According to Sir Austin Bradford Hill Clinical Trials are: carefully and ethically
designed human experimentation with the aim of answering some precisely
framed questions.
• A clinical trial is a prospective biomedical or behavioral research study of human
subjects that is designed to answer specific questions about biomedical or
behavioral interventions (vaccines, drugs, treatments devices, or new ways of
using known drugs treatments or devices).
• Interventional trial is defined as a prospectively planned biomedical or health-
related experiment in humans.

6. • Clinical trial is a systematic investigation in human subjects for evaluating
the safety & efficacy of any new drug.
• Clinical trials are a set of tests in medical research and drug development
that generate safety and efficacy data for health interventions in human
beings.
• Research studies involving people and try to answer scientific questions and
find better ways to prevent, diagnose, or treat disease.

7. Core components of clinical trials
• Involve human subjects.
• Move forward in time.
• Must have a comparison CONTROL group.
• Must have method to measure intervention.
• Focus on unknowns: effect of medication.
• Must be done before medication is part of standard of care.
• Conducted early in the development of therapies.
• Must review existing scientific data & build on that knowledge.
• Test a certain hypothesis.
• Study protocol must be built on sound & ethical science.
• Control for any potential biases – RANDOMIZATION/BLINDING.

8. Various phases of Clinical Trials
• In Phase I trials, small group of healthy people (20-80) the first time to evaluate
its safety, determine a safe dosage range.
• In Phase II trials, group of patients (80 – 300) effective and evaluate its safety.
• In Phase III trials, large group of patients ( 300– 3000) effectiveness, monitor
side effects, compare it to commonly used treatments, and used safely.
• In Phase IV trials, post marketing studies drug’s risks, benefits and optimal
use.

10. Microdosing / Phase 0 study
• Early studies of the pharmacodynamic and pharmacokinetic properties of a
potential drug in humans.
• Microdosing approach could 'accelerate’ drug development without
compromising clinical safety.
• Microdosing helps researchers select better drug candidates for clinical trials
by providing early human PK and bioavailability data.

11. • Advantages
• Less chances of adverse effects , Short duration.
• Less no. of volunteers.
• Reduced cost of development.
• Reduced drug development time.
• Limitations:
• Study mainly based on PK parameters - not efficacy and safety based.
• Agents having different kinetic characteristics between micro dose and full
dose are not evaluated by phase 0 trials.
• Of Limited use for agents having Non linear PKs.
• The laboratory parameters are very limited and expensive, researchers
have to depend on BA/BE labs.

12. Phase I
• First stage of testing in human subjects.
• Designed to assess the safety, tolerability, PK and PD of drug.
• 20-80 healthy volunteers.
• Patients: Anticancer drugs, AIDS therapy.
• Duration: 6-12 months
• No blinding / Open labelled

13. Phase I: Reasons for Using Healthy
Volunteers
• Large numbers available (vs. Patients).
• Rapid recruitment rate.
• Potential risks are considerably reduced.
• Results not confounded by presence of disease variables.
• More homogenous group.
• Greater compliance with Protocol.
• In case of ADR’s Chances of Speedy and Complete recovery are
better Advantages > Disadvantages.

14. Phase I studies: Need
• To make reliable and rapid Prediction of human response, from Preclinical
Data (PD, PK,Toxicity).
• Involves Extrapolation from Animal data to first human exposure.
• Phase I serves as an interface between Preclinical Research and Clinical
Drug development.
• Once Phase I is complete, Human beings become first-choice test species
(Human Guinea- pigs).

15. Phase 1 Basic pre-requisites
• Preclinical data.
• IND application approval by the regulatory authority.
• Protocol approval by the Ethics Committee.
• Informed consent.
• Adherence to Declaration of Helsinki /ICH-GCP guidelines, at the
start as well as from time to time, during the study.

16. Phase I Study/ Clinical trial
• The aim of a Phase I trial is to determine the maximum tolerated
dose (MTD) of the new treatment.
• The MTD is found by escalating the treatment dose until the dose-
limiting toxicity (DLT) is reached.
• Kinds of Phase I
• SAD: single ascending dose studies.
• MAD: multiple ascending dose studies.
• Food Effect: investigates differences in absorption caused by food.

18. Phase II
• Therapeutic ExploratoryTrial.
• 80-300 Subjects.
• To confirm effectiveness, monitor side effects, & further evaluate
safety.
• First in patients (who have the disease that the drug is expected to
treat).
• Duration: 6 months to several years.

19. Phase II: Objectives
• Efficacy in patients (primary objective).
• Safety issues (secondary objective).
• Optimum dose finding.
• Dose efficacy relationship :
• Therapeutic dose regimen
• Duration of therapy
• Frequency of administration
• Therapeutic window

20. Phase II Study/ Clinical trial
• Phase IITypes:
• Phase IIA: Designed to assess dosing requirements.
• Phases IIB: Designed to study efficacy.

21. Phase III
• Therapeutic confirmatory trials.
• Large scale, multicentre, Randomised, Controlled trials .
• Target population: several 100’s to 3000 patients.
• Takes a long time: up to 5 years.
• To establish efficacy of the drug against existing therapy in larger
number of patients, method of usage & to collect safety data.

22. Phase III: Objectives
• To assess overall and relative therapeutic value of the new drug Efficacy,
Safety and Special Properties.
• To determine optimal dosage schedule for use in general.
• The dosage schedule in C.T.’s should be as close as possible to its
anticipated clinical use.

23. Phase III : Prerequisites
• Efficacy and dose schedule defined in Phase II studies.
• No gross ADR’s.
• Long term preclinical safety studies completed.
• ChronicToxicity
• Reproductive toxicity
• Carcinogenicity
• Marketing inputs favorable
• IRB and DCGI approval obtained

24. Phase III studies
• Subtypes
• Phase IIIA: To get sufficient and significant data.
• Prior to NDA
• Generates data on safety and efficacy.
• Phase IIIB: Allows patients to continue the treatment, Label
expansion, additional safety data.
• Phase III B studies are known as "label expansion” to show the drug
works for additional types of patients/diseases beyond the original use
for which the drug was approved for marketing.
• After the NDA but prior to the approval and launch.
• These may supplement or complete the earlier trials or may be directed
to Phase IV trials.

25. NDA: New Drug Application
• NDA Refers to New Drug Application.
• Formal proposal for the FDA/DCGI to approve a new drug for sale.
• Sufficient evidences provided to FDA/DCGI to establish:
• Drug is safe and effective.
• Benefits outweigh the risks.
• Proposed labeling is appropriate.
• NDA contains all of the information gathered during preclinical to
phase III.
• NDA can be thousands of pages long so it can take 1-2 years for FDA to
review.

26. Phase IV Study / Clinical trial
• Harmful effects discovered may result in a drug being no longer sold, or
restricted to certain uses.
• On September 30, 2004, Merck withdraw rofecoxib from the market
because of concerns about increased risk of heart attack and stroke
associated with long-term, high-dosage use.

27. Phase IV: Objectives
• Confirm the efficacy and safety profile in large populations during practice.
• Detect the unknown/rare adverse drug reactions.
• Evaluation of over-dosage.
• Identifications of new indications.
• Dose refinement: Evaluation of new formulations, dosages, durations of
treatment.
• Evaluation in different age groups / types of patients.
• Comparative Benefit-Risk assessment.
• Benefit-Cost assessment (Pharmaco- economics).
• Drug usage in the community.
• Quality Of Life assessment.

28. • Phase IV studies are also known as post marketing surveillance studies.
• Conducted after a product has been marketed.
• Undertaken by the sponsor company and can provide new information
regarding the drug such as:
• A new use for the drug.
• New drug- drug or drug- food interactions.
• Any rare or long-term side effects over a much larger patient population and longer
time period than was possible during the Phase I-III clinical studies.
• Affects produced in specific subgroup of patients (e.g., pregnant women).

29. Primary causes of failure of potential drug
candidate
• Adverse or suboptimal Pharmacokinetic profile, 39%.
• Lack of efficacy, 30%.
• Studies demonstrating animal toxicity, 11%.
• Adverse effects in humans, 10%.
• Commercial reasons, 5%.
• Miscellaneous, 5%.

30. Types of Trials
• Open Label Trial – Both Investigator and Patients knows the full details
of the treatment.
• Single Blind- Investigator knows the details of the treatment but patient
does not.
• Double Blind- Neither investigator nor patients is aware of the
treatment details.
• Triple Blind- Investigator, Patients and statistician are blinded

31. Randomized Controlled Trials (RCT)
• Randomization
• Participants are allocated at random .
• Control
• It may be standard practice (an active comparator), placebo or
no interventions.
• The RCT is one of the simplest and most powerful tools in
clinical research

32. An Overview: Drug Development Timeline

33. Questions:
• Draw the flowchart of whole Drug development process.
• What is clinical trial? And What are objectives of clinical trial?
• Write the difference between Phase-I and Phase-II of Clinical trial?
• Write in brief about Phase-III and types of Phase-III.
• What is post marketing surveillance? And It’s importance in drug
development?

34. Thank you