This document provides an overview of the different phases of clinical trials and drug approval processes. It discusses the key phases of clinical trials (Phase 0-IV), the purpose and objectives of each phase, and common trial types. It also explains the IND, NDA and ANDA processes. The IND allows testing in humans, the NDA seeks approval to market a new drug, and the ANDA provides a streamlined approval path for generic drugs that are equivalent to an existing approved drug. Overall, the document provides a high-level introduction to the clinical trial and drug approval framework.

1. Different Phases
of Clinical Trial,
IND, NDA and
ANDA
Prepared By:
Azad Singh
(Medical writer)

2. Table of Contents:
– Definitions
– Types of Clinical trials
– IND (Investigation New Drug )
– Phases of Clinical Trial
– NDA (New Drug Application)
– ANDA (Abbreviated New Drug Application)

3. Clinical trial
– Clinical Trial “clinical trial” in relation to a new drug or investigational new
drug.
– Any systematic study of such new drug or investigational new drug in human
subjects to generate data for discovering or verifying its,-
– (i) Clinical
– (ii) pharmacological, including pharmacodynamics, pharmacokinetics
– (iii) adverse effects, with the objective of determining the safety, efficacy or
tolerance of such new drug or investigational new drug;

4. Schedule Y (122-DAA):
– Systematic study of new drug(s) in human subject(s) to generate data
for discovering and/or verifying the clinical, pharmacological (Incl.
PK & PD) and/or adverse effects with the objective of determining
safety and/or efficacy of the new drug.
– The World Health Organization:
Any research study that prospectively assigns human participants or
groups of humans to one or more health-related interventions to
evaluate the effects on health outcomes.

5. Types of Clinical Trials:
 Treatment Trials - test new treatments, new combination of drugs
or new approaches to surgery or radiation.
 Prevention Trials - look for better ways to prevent diseases.
 Clinical Observational study:-The investigators observe the
subjects and measure their outcomes. They don't actively
manage the study.
 Diagnostic Trials - determine better tests or procedures for
diagnosing a particular disease or condition.
 Screening Trials - test the best way to detect or treat diseases.
 Quality of Life Trials (Supportive care trials) - explore and
measure ways to improve the comfort and quality of life of
people with a chronic illness.

6. Three important key words
– Experimental Unit
Subject from a targeted population under study. The intended population could be
patients with certain diseases at certain stages or healthy human subjects.
– Treatment
It can be a placebo, a drug, a new diet, a surgical procedure, a diagnostic test, a
medial device, a health education program, or no treatment. Other examples
include surgical excision, radiotherapy, and chemotherapy as a combination of
surgical procedure and drug therapy for breast cancer; magnetic resonance imaging
(MRI) with a contrast imaging agent as a combination of diagnostic test and a drug
for enhancement of the efficacy of a diagnostic test.
– Evaluation
Effectiveness and safety of a test treatment.

7. – Investigation New Drug (IND) Program is the means by
which a Pharmaceutical company (sponsor) obtains
Permission to start human clinical trials and to ship an
experimental drug across state lines before a marketing
application for the drug has been approved.
– An investigational new drug (IND) application is to
provide the data showing that is reasonable to begin
tests of a new drug on humans.

9. CDER (Center for Drug Evaluation and Research) to foster early
communications between sponsors and new drug review divisions in order to
provide guidance on the data necessary to warrant IND submission.
Guidance Documents for INDs
Documents are prepared for FDA review staff and applicants/sponsors to provide
guidelines to the processing, content, and evaluation/approval of applications and
also to the design, production, manufacturing, and testing of regulated products.
Form1571 and Form 1572

11. CDSCO (Central Drug Standard
Control Organisation)
– The CDSCO of India is main regulatory body for
regulation of pharmaceutical, medical devices and
Clinical Trials.
– Head office of CDSCO is located in NEW DELHI and
functioning under the control of Directorate General of
Health Services, ministry of health and family welfare
Government of India.

12. Drugs Controller General of India
[DCGI]
• He/she is a responsible for approval of New Drugs, Medical
devices and Clinical Trails to be conducted in India.
• He is appointed by the central government under the DCGI
the State drug control organization will be functioning.
• The DCGI is advised by the Drug Technical Advisory Board
{DTAB} and the Drug Consultative Committed {DCC}.

14. Time frame and Sample size

15. Phase 0 Clinical trials
– Exploring if and how a new drug may work
– Done in humans
– Exploratory studies
– Few small doses of a new drug in a few patients only for a short time/limited
duration (=≤ 7 days)
– Non-toxic doses
– Sample size: Fewer than 15 people
– Designed mainly for selected investigational agents
– Anticancer agents (success rate is about 5%)
– Conducted under an US FDA ExpIND guidance
– Pilot clinical studies
– Rational transition from preclinical to clinical development

16. Phase 0 Clinical trials
Successful example
ABT-888 (veliparib)
A PARP inhibitor
Fewer than 14 patients
Determined Dose-range and Time-course.
Goal of Phase 0 studies
 To assess whether the mechanism of action defined in pre
clinical studies is achieved or not
 Define specific biomarkers or targets in human studies
 Determine special methods to assess the pharmacokinetics
of the drug

17. For permission of such clinical trials in india the documents
required to be submitted are as follows:
 Form CT-04 (in place of Form 44) with revised application fee as per Sixth Schedule.
 Challan/fees
 Sources of bulk drug/raw material.
FEES & FORMS A hiked fee structure has been implemented.
 3 lakh INR (aprox 3800 Euro/4500 USD) for Phase I.
 2 lakh INR (aprox 2500 Euro/2900 USD) for Phase II, III, IV & BA/BE study.
 5 lakh INR (aprox 6500 Euro/7200 USD) for pre submission meeting.
 50,000 INR (aprox 650 Euro/720 USD) for post submission meeting.
 5 lakh INR (aprox 6500 Euro/7200 USD) for registration of BA / BE study centre.
 5 lakh INR (aprox 6500 Euro/7200 USD) for new drug permission / Finished
formulation or API [import].

18. FORMS
 Form CT04 – Clinical Trial Application Form (Replaces Form 44)
 Form CT 04 A- Automatic Approval Information to CDSCO
 Form CT 06 - Permission to Conduct CTs by CDSCO
 Form CT 16- Application to grant of License to Import of New Drug for Clinical Trials
(Replaces Form 12).

19. Phase I Clinical trials
– Primary Objective:
 Estimation of Safety and Tolerability
Safety - Determine the most significant adverse events in human subjects.
Tolerability – The safe dose range is determined by dose escalations and
corresponding serial lab tests.
 Maximum tolerated dose (MTD)
 Non-therapeutic objectives
 Healthy volunteers subjects
Drug - drug interaction
 Certain types of patients (Cytotoxic drugs)
 Pharmacokinetics (Characterization of ADME)
Pharmacogenomics study
 Pharmacodynamics -
Guide the dosage and dose regimen to be applied in later studies.

20. Types of Phase I trials:
– Single ascending dose
Food effect
Multiple ascending dose

21. Phase I/II Clinical Trials (In Patients)
– Test drug is too toxic to be tested in healthy volunteers
e.g anticancer drugs, HIV
– Dose in patient > Normal Volunteers can tolerate.
(e.g. Neuroleptics)

22. Phase II(Therapeutic exploratory studies)
– Primary Objectives:
 Evaluate the effectiveness of a drug for a particular indication.
 Determine the common short-term side-effects and risks.
 Relatively homogeneous population.
 Determine the dose(s) and regimen for Phase III trials.
 Doses are usually less than highest dose used in Phase I.
 Phase II trials are performed on larger groups (100-300).
 Confirm the hypothesis conceptualised
 Placebos and fixed treatment regimens
 Tight inclusion and exclusion criteria
– Additional objectives:
 Evaluation of potential study endpoints.
 Therapeutic regimens (including concomitant medications).
 Target populations (e.g. mild versus severe disease) for further study in Phase II or III.
 Long washout” period is required between treatments.

23. Phase II (Therapeutic exploratory trials)
– Types of Phase II trials:
Phase IIA/Phase 2A
Specifically designed to assess dosing requirements (how
much drug should be given).
Phase IIB/Phase 2B
Specifically designed to study efficacy (how well the drug
works at the prescribed dose)

24. Difference between Phase IIa and IIb
Clinical trial
Phase IIa Phase IIb
Early phase Late Phase
Pilot Clinical trials Pivotal Clinical trials
20-200 Patients 50-300 Patients
Non multicentric Multicentric
Single Blind Compraison with standard drug Double Blind Compared with a placebo or
standard drug

25. Phase III clinical trials
– To obtain sufficient evidence about the efficacy and safety
of the drug in a larger no. of patients in comparison with
standard drug or placebo as Appropriate.
 large patient groups (300–3,000 or more depending upon the
disease/medical condition studied)
 assessment of how effective the drug is, in comparison with current
'gold standard' treatment.

26. Phase III clinical trials
– Primary Objectives:
 Confirmation of therapeutic benefit(s)
 Provide an adequate basis for marketing approval (NDA application)
 Dose-response relationships
 Use of the drug in wider populations
 Different stages of disease
 Safety and efficacy of the drug in combination with other drug(s).
 Drugs intended to be administered for long periods
To assess overall and relative therapeutic value of the new drug Efficacy, Safety
and special properties.
 New drugs approved outside India
 Generate evidence of efficacy and safety of the drug in Indian patients

27. Phase III Clinical trial
– Randomized controlled
– Multicenter trials
– Safety ,drug interactions are accessed on a larger scale
– Additional pharmacokinetic data may be obtained.
– Phase III trials are the most expensive
– Time-consuming
– Difficult trials to design
– Especially in therapies for chronic medical conditions

28. Types of Phase III Trials
Phase IIIA/Phase 3A
 Trials carried out on a large number or in a special category –
Regulatory requirement for NDA
Phase IIIB/Phase 3B
 Extended trials of IIIa after applying for approval but before
launch.
 Phase 3B 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), to
obtain additional safety data, or to support marketing claims for the
drug.

29. Phase IV (Post Marketing Trials)
– Objectives of Phase IV:
– Confirm the efficacy and safety profile in large
Population during practice.
– Detect the unknown/rare adverse drug reaction/s.
 Regulators gather additional information about a
products safety efficacy, or optimal use.
 Agreed with regulators at the time of approval of
 drug Identifications of new indication.
– Dose refinement: Evaluation of new formulations,
dosages, duration of treatment.

30. REPORTING OF ADR:
The ADR can be reported to a formal reporting system such as:
 WHO international System
 USFDA- Medwatch
 UK- Yellow card system
 INDIA-National Pharmacovigilance Programme (CDSCO)

31. NDA (NEW DRUG APPLICATION)
The NDA is an application submitted to USFDA for permission to
market a new drug product in the united states.
The goals of the NDA are to provide enough information to permit
FDA reviewers to establish the followings:
 Whether the drug is safe and effective in its proposed use(s) and
whether the benefits of the drug outweigh the risks?
 Whether the drug’s proposed labelling appropriate and what should
it contain?
 Are the methods used in manufacturing (GMP) of the drug and the
control used to maintain the drug’s quality adequate to preserve the
drug’s identity, strength, quality and purity?

32. All NDA’S must contain the following
information
 Index
 Summary
 Chemistry, Manufacturing and Control
 Samples, Methods Validation Package and Labeling
 Non clinical Pharmacology and Toxicology
 Human Pharmacokinetics and
Bioavailability

33. Microbiology (For anti-microbial drug only)
Clinical data
Safety Update report
Statistical
Case Report Tabulation
Case report Forms
Patent Information
Patent Certification
Other Information

34. 3 copies of the application are required:
Archival copy
Review copy
Field copy
Archival copy:
It is a complete copy of the application
FORMAT OFAPPLICATION:

35. Review copy
Include the information needed by each review discipline
for its evaluation.
 Quality
 Non clinical
 Clinical – safety & efficacy documents for clinical reviewer
 Clinical – safety & efficacy documents for statistical reviewer
 Clinical – clinical pharmacology & pharmacokinetics documents
 Clinical – clinical microbiology documents

36. Field copy:
– Separately bound copy of the quality section. It is
directly send to the appropriate field office.
– FDA will maintain guidance documents on the format &
content of applications to assist applicants in their
preparation.

37. NDA Review Process

38. At the end of that, The FDA is
Required with an action letter.
Three action letters
– Anapproval letter
– Anapprovable letter
– Annon approvable letter
In the case of Approvable letter Sponsor have to respond
with 10 days

39. ANDA (Abbreviated New Drug Application)
– An Abbreviated New Drug Application (ANDA) contains data
which when submitted to FDA's CDER, Office of Generic Drugs,
provides for the review and ultimate approval of a generic drug
product.
– Once approved, an applicant may manufacture and market the
generic drug product to provide a safe, effective, low cost
alternative to the public.
– All approved products, both innovator and generic, are listed in
FDA's Approved Drug
– Products with Therapeutic Equivalence Evaluations (Orange
Book).

40. Goal of ANDA
– To reduce the price of the drug.
– To reduce the time development.
– Increase the bioavailability of the drug in comparison to
references list drug.

41. Generic Drug Approval
In 1970 FDA established the ANDA as a mechanism for the
review and approval of generic versions.
Before 1978, generic product applicants were required to
submit complete safety and efficacy through clinical trials.
Post 1978, applicants were required to submit published
reports of such trials documenting safety and efficacy.
Neither of these approaches was considered satisfactory and
so originated Hatch Waxman Act on 1984.

42. Hatch-Waxman Act
Commonly known as “Drug Price Competition & Patent Term
Restoration Act” of 1984.
“The Hatch-Waxman Act is an act dealing with the approval of
generic drugs and associated conditions for getting their approval
from FDA, market exclusivity, rights of exclusivity, patent term
extension and Orange Book Listing.” Necessitated By :
1. Absence of Generic drug manufacturing. 2. Cumbersome
regulatory procedures. 3. Patients were denied the option of
cheaper drugs

44. ANDA Review/Approval process

45. References
– New Drugs and Clinical Trials Rules, 2019.
– https://www.fda.gov
- Clinicaltrials.gov
- http://fda.gov/cder/guideline
- https://www.nlm.nih.gov/services /ctphases.html