This document discusses the process of new drug evaluation, which involves 3 phases - drug discovery, preclinical testing, and clinical trials. In the drug discovery phase, candidate molecules are selected. Preclinical testing involves animal studies to evaluate safety. Clinical trials with human subjects are then conducted in 3 phases to evaluate efficacy, safety, and adverse effects. The clinical trials process is highly regulated to ensure safety and data integrity. If successful, a New Drug Application is filed with regulatory authorities for approval to market the new drug.

1. NEW DRUG EVALUATION
Dr. Bijoy Bakal

2. INTRODUCTION:
• Drug development -Scientific endeavor
• Highly regulated
•Complex & time-consuming process

3. DRUG DISCOVERY:
 Challenging & Expensive
 With technology advance-
 Time taken for drug discovery
 Cost of drug discovery

4. AIM:
 Develop clinically efficacious & safer drug
 Economically viable
 Discover entirely new class of drug
 Discover new use of old drugs
 Explore mechanism/ pharmacodynamics property

5. BROADLY DIVIDED INTO 3 PHASES:
1. Drug discovery phase
Candidate molecules are chosen
2. Preclinical phase
Animal studies are performed
3. Clinical trial phase
Evaluated for efficacy, safety and adverse effects

7. METHODS OF DRUG DISCOVERY:
1. Random/nontargeted screening
2. Serendipity (by chance)
3. Rational drug designing (High throughput
screening)
4. Mechanism-based drug design

8. PRECLINICAL EVALUATION
PHASE (ANIMAL STUDIES):
• Performed according to GLP
• Major areas:
 Pharmacodynamic studies.
 Toxicological studies -OECD-425 Guidelines.
 Pharmacokinetic studies.
 Assessment of safety index.

9. TYPES OF ANIMAL TEST:
 General Screening for Pharmacological effects
 Hepatic & Renal Function monitoring
 Blood and Urine Tests
 Gross & HPE of tissues
 Tests of Teratogenicity
 Mutagenesis
 Carcinogenecity

10. TRANSGENIC & KNOCKOUT ANIMAL MODELS:
 Powerful tool for Drug Discovery, Gene Therapy
 Knock-ins & floxP system - manipulate gene
functions in particular tissues
 Extensive use in cancer, obesity (ob/ob knock out
mice), heart disease, arthritis, Substance abuse.
Eg. OncoMouse/ Harvard mouse

11. CLINICAL TRIAL PHASE
(HUMAN TRIALS):
• Biomedical/behavioral research study in human
subjects
• Generate data for clinical claims
• Finding adverse effects
• After preclinical screening -IND application filed.

12. OBJECTIVES OF CLINICAL TRIALS:
 Identify the relationship between dose and
plasma concentration(PK)
 Define the shape and location of
dose/concentration/response curves for both
desired and undesired effects
 Identify the range of dosage/concentration
producing maximum benefit with fewest
undesirable effects

13. THE KEY PLAYERS IN A CLINICAL TRIAL:
Internal:
Sponsors
Contact research organization(CRO)
Medical writing team
Statistician
Clinical research associate
Principal investigator
Clinical research coordinator
Data management team
External:
 Ethics Committee (IRB/IEC)
 Regulatory/ licensing authority
 Data safety monitoring boards
 Central laboratories

14. CLINICAL TRIAL DESIGN:
i. Research design and protocol
ii. Types of control
iii. Volunteer and subject selection
iv. Number of subjects

15. v. Influence of the disease indication on trial design
*Acute condition *Chronic condition
vi. Randomization-simple or stratified
vii. Duration of dosing
viii. Methods of clinical measurement-must be
standardized.

16. GOOD CLINICAL PRACTICES (GCP)
Aim:
i) To ensure that the studies are scientifically and
ethically sound
ii)To document the clinical properties of the
pharmaceutical substance
Two cardinal principles:
i) Protection of the rights of human subjects
ii) Authenticity of biomedical data generated

17. INVESTIGATIONAL NEW DRUG(IND)
APPLICATION:
• Provides the data showing that it is reasonable
to begin tests of a new drug in humans
• It is a result of successful preclinical
development program
• It is a vehicle through which a sponsor advances
to the stage of clinical trials

18. IND INCLUDES:
 Information on the composition of Drug.
 Source of Drug.
 Chemical & Manufacturing information.
 All data from animal studies.
 Proposed clinical plans & protocol.
 Names & Credentials of Physicians conducting
trial.
 Compilation of Key Data made available to
investigators & Institutional Review Boards.

19. IND APPLICATION TYPES:
1.Investigator IND
2.Emergency use IND
3.Treatment IND

20. ETHICS COMMITTEE AND ITS
RESPONSIBILITIES:
 Review and accord its approval to a clinical
trial according to the protocol
 Safeguard the rights, safety and well being of
the trial subjects
 Periodical review of the ongoing trial and to
ensure SOPs are being followed

21. ETHICS COMMITTEE:
• The ethics committee should have at least 7
members
 Chairperson(from outside the institute)
 Member secretary(from the clinical department)
 Medical scientists (Preferably a pharmacologist)
 Clinicians from various disciplines.
 One legal expert.
 One social scientist
 One lay person

22. PHASES
OF
CLINICAL TRIALS

23. 1. Is the data from Animal Studies Adequate?
2. What is the probable risk involved in giving the drug
to humans? Is it worth the risk?
3. Is there any need for a new drug in the disease under
consideration and if so does the new remedy seem
promising?

24. MICRODOSING [PHASE 0]:
• Primary application of exploratory IND
studies.
• Permit collection of human pharmacokinetics
and bioavailability data.
• MICRODOSE is 1/100th
of the dose calculated
to yield a pharmacological effect of a test
substance and a maximum dose of 100µg.

25. MICRODOSING [PHASE 0]:
 Can be initiated with less preclinical safety data.
 Requires very less number of subjects
 Requires fewer resources for selecting promising
drug
 Techniques applied:
* Accelerated Mass Spectrometry
* PET

26. MICRODOSING [PHASE 0]:
Human PK data can be used to:
 Assist in the candidate selection process
 Determine the 1st
dose in phase I
 Establish the likely pharmacological dose
Advantages:
 Select the best lead compound
 Save time
 Save money

27. PHASE-I HUMAN TESTING:
(1ST
IN HUMAN)
 Phase I clinical studies sit at the interface between the end
of preclinical testing and the start of human exploration
 Assess the safety of the drug in humans
 Efficacy of the drug
 Pharmacokinetic and pharmacodynamic parameters
 Comprises of 20-80 healthy volunteers

28. PHASE-I HUMAN TESTING: DESIGN
 Type of control- Generally placebo
 Subject selection - Inclusion and exclusion criteria
 Randomization- Blinding
 Type of trial design- Parallel or crossover
 Dosing- Estimation of the 1st
dose is done using
preclinical studies

29. PHASE-I HUMAN TESTING:
PROCEDURE

30. PHASE-I HUMAN TESTING: OUTCOME
 Safe dose range is established
 Bioavailability data depending on Cmax, Tmax, AUC, t1/2,
metabolic pathway, route and rate of excretion
 Nature of ADR
 Secondary objectives like drug activity, potential
therapeutic benefits etc.

31. PHASE-I HUMAN TESTING: In India
Schedule Y requirements:
• Phase I trials are done to determine the maximum
tolerated dose in humans, pharmacodynamic
effects, adverse effects, if any, with their nature
and intensity as well as the pharmacokinetic
properties of the drug
• At least two subjects should be used for each dose.

32. Challenges:
 Ethical issues arise due to the inclusion of
healthy volunteers as study subjects
 Stringent monitoring of the subject is
required, as it is a first in human study.
PHASE-I HUMAN TESTING:

33. PHASE-II THERAPEUTIC
EXPLORATION (1ST
IN PATIENT)
• Comprises of 20-300 patient volunteers
• Done to assess-how well the drug works(efficacy) and
continues the phase I safety assessments
• When development process fails it is usually in this
phase:
 Failure due to toxic effects
 Failure due to decreased efficacy

34. PHASE-II THERAPEUTIC EXPLORATION:
Objectives:
 To explore the therapeutic efficacy and safety
 Identify common side effects
 Provide essential risk benefit assessment
Prerequisites:
 Preclinical safety data
 Early phase clinical trial data
 Regulatory authority and ethics committee approval

35. PHASE-II THERAPEUTIC
EXPLORATION
 Types of phase II
 IIa-In these studies, dosage which was safe in phase
I is used
 IIb- Done to establish a safe dose range in patients
 Site:
 IIa- Single site
 IIb- Multiple centers
 Players
 Investigators
 Patient volunteers

36. PHASE-II. TRIAL DESIGN:

37. PHASE-II THERAPEUTIC
EXPLORATION
• Phase II studies are comparative studies with either
placebo or gold standard treatment as the
comparator
• Outcomes:
 Safe dosage schedule
 Characterization of Dose Response Curve
 Clinical benefit
 Pharmacokinetic characteristics
 Nature of Adverse Drug Reactions

38. PHASE-II THERAPEUTIC EXPLORATION:
In India:
Schedule Y requirements:
• To determine possible therapeutic use,
effective dose ,safety and pharmacokinetics
• 10-12 patients should be studied at each
dose level. Studies limited to 3-4 centers.
• In case of multinational trial number of sites,
patients and justification for undertaking
such trials should be provided

39. PHASE-II THERAPEUTIC
EXPLORATION
• Advantages: Efficacy of test drug is determined
• Challenges: If positive results are not obtained
during this phase, dosage schedules for phase III
cannot be determined

40. PHASE-III THERAPEUTIC CONFIRMATORY
TRIALS:
• Comprises of several hundreds to thousand
patients
• Most expensive, time consuming, difficult trials to
design and conduct
• Major component of New Drug Application(NDA)

41. PHASE-III THERAPEUTIC CONFIRMATORY
TRIALS:
• Additional information about effectiveness and
safety to evaluate benefit-risk relationship
• Provide an adequate basis for extrapolating
results
• It excludes many real world patients. Eg: those
with other serious medical conditions, women
of child bearing age etc

42. PHASE-III THERAPEUTIC CONFIRMATORY TRIALS:
 Objectives:
 Primary objective- Confirm the therapeutic benefit
 Confirm the preliminary evidence accumulated in
phase II
• Site:
 Multispecialty hospitals
• Subjects:
 Patient population of around 250-1000

43. PHASE-III THERAPEUTIC CONFIRMATORY TRIALS:
• Prerequisites:
 Preclinical safety data.
 Early phase clinical trial data.
 Regulatory authority and ethics committee approval.
• Types of phase III:
 IIIa- Compulsory regulatory requirement for
submission of NDA
 IIIb- Extended trials of IIIa after NDA submission,
done before launch and are a marketing need.

44. PHASE-III THERAPEUTIC CONFIRMATORY TRIALS:
TRIAL DESIGN:
 Control types: placebo, gold standard, different doses
of the drug
 Patient population should be representative of the
general population
 Influence of disease indication
 Randomization and blinding (usually double blinding
is preferable)

45. PHASE-III THERAPEUTIC CONFIRMATORY
TRIALS:
• Types of trial design: Either parallel, crossover
or factorial
• Outcomes:
 Efficacy confirmed in a Realistic Population
 Efficacy assessed in Special Population
 Tolerability And Safety
 Advantages and Disadvantages over standard
treatment

46. PHASE-III THERAPEUTIC CONFIRMATORY
TRIALS: In INDIA
Schedule Y requirement:
• Data on at least 500 patients over 10-15 centers and
post marketing surveillance for ADR must.
• For new drug approved outside India there should
be data on 100 patients over 3-4 centers.
• PK studies to be undertaken to verify that the data
generated on Indian population is in conformity
with that generated abroad.

47. PHASE-III THERAPEUTIC CONFIRMATORY
TRIALS:
Advantages:
 Therapeutic confirmation
 Less stringent inclusion/exclusion criteria
 Simultaneous generation of large data
 Results are generalizable

48. PHASE-III THERAPEUTIC CONFIRMATORY
TRIALS: CHALLENGES
 Approval from IEC/IRB.
 Patient recruitment should be large and heterogenous
 Training of staff and monitoring the trial
 Central laboratory & Clinical trial supplies
 Central data management and analysis
 Different study outcomes, difficult to interpret
 Drafting of a common final report and public issues

49. NEW DRUG APPLICATION(NDA)
• NDA - Formally propose that the FDA approve a
new drug for sale & marketing
• Data gathered during animal studies and human
clinical trials of an IND becomes part of the NDA
• Can be filed on completion of phase IIIa in the
form of a dossier

50. NEW DRUG APPLICATION: GOALS
To provide FDA enough information to permit the reviewer
to reach the key decisions:
•Whether the drug is safe and effective
•Whether the drug’s proposed labeling is appropriate and
what it should contain
•Whether the methods used in manufacturing the drug and
the controls used to maintain the drug’s quality are adequate

51. NEW DRUG APPLICATION:
• After review of NDA, 3 possible action to the
sponsor:
 Not approvable letter- Lists the deficiencies
 Approvable letter - Signals that, ultimately, the
drug can be approved after minor deficiencies
corrected
 Approval letter - States that the drug is
approved

52. ABBREVIATED NEW DRUG APPLICATION (ANDA):
• Provides for the review & approval of a generic
drug product
• Once approved, the applicant may manufacture
and market the generic drug product to provide
a safe, effective, low cost alternative to the
public
• “Abbreviated” because they are generally not
required to include preclinical and clinical data
to establish safety and efficacy.

53. POST MARKETING SURVEILLANCE
• Systematic detection and evaluation of adverse reactions
• Periodic Safety Update Reports (PSUR) to be submitted
every 6 monthly for 1st
two years and thereafter, yearly for
two years to DCGI
• Ascertain whether further investigation needs to be
carried out
• Changes to the marketing authorization and product
information

54. PHASE-IV MARKETING
STUDIES/EXPERIENCE STUDIES
Purpose:
 To extend knowledge about drug efficacy
 To confirm safety in a wider patient population
Involves comparison with available treatment:
Example:
 Compare different chemical entities eg:
methyldopa versus propranolol for
hypertension

55. PHASE-IV MARKETING
STUDIES/EXPERIENCE STUDIES:
• These can also explore:
 New indication for a product.
 New dosage regimen.
 New formulations.
• These mark the introduction of the drug into clinical
practice.
• Randomization: Crucial aspect of phase IV trials is that
they should be based on a sound statistical design.

56. PHASE V:
Phase V is a growing term used in the literature
of translational research to refer to comparative
effectiveness research and community-based
research; it is used to signify the integration of a
new clinical treatment into widespread public
health practice.

57. SPECIAL
CONSIDERATIONS

58. TRIALS FOR VACCINES:
 Given to healthy individuals mostly children & infants
 Given to prevent disease
 Biological products i.e., Highly complex substances
derived from living materials/ living organisms.
 Require specialized assays & testing to assure their
quality and safety.

59. CANCER DRUG DEVELOPMENT-
PHASE 0 TRIALS:
• Patients with the disease participate in Phase I
studies
• Types of phase 0 trials:
 Imaging studies or measurement of agent
pharmacokinetic parameters
 Comparison of analogs to select a lead agent for
further evaluation
 Assessment for modulation of a molecular target in
a tumor

60. ORPHAN DRUGS:
• To treat a rare medical condition, the condition itself
being referred to as “Orphan disease.”
• Developing of Orphan drugs is not only challenging but
involves many disincentives, which include career
disincentives, lack of funding, and the multiple areas of
expertise that are required.
Advantages of developing an Orphan Drug:
 The time from Phase II to market is often shorter.
 Once a compound has been granted orphan
designation, the odds for approval are high (82%).

61. BIOLOGICS:
 Biologicals or “biologics” can be defined as products of
which the active substance is produced by or extracted
from a biological source.
Eg: Vaccines, Blood or components, Somatic cells, Gene
therapies etc.
 Challenges in Development:
 The production and purification process is complex.
 Huge risks with regards to the safety profile.
 The predictability data of animals to humans is limited.

62. ROLE OF REGULATORY BODIES:
• In order to license or register a new chemical
entity a pharmaceutical company should
develop a dossier that describes the
pharmaceutical quality, safety and efficacy of
the product for a specified indication.
• Eg: USFDA, Drugs Controller General of India
(DCGI)

63. DRUGS CONTROLLER GENERAL OF
INDIA (DCGI):
 The pharmaceutical industry in India is governed by
Drugs and Cosmetics Act 1940.
 The legislation is enforced by the Central Govt
 2 drug organizations exercise control over drugs:
 CDSCO.
 State Drug Control Organizations

64. FUTURE TRENDS IN NEW DRUG
DISCOVERY:
 High-throughput screening has undoubtedly
emerged as a powerful lead-finding technology.
 A new trend is the growing of biopharmaceuticals,
particularly monoclonal antibodies e.g.
Development of Secukinumab .
 Genotyping to individualize drug treatments.

65. CONCLUSION:
• Drug discovery revolutionized due to changes in
technology.
• Careful decision making during drug development is
essential to avoid costly failures.
• Novel initiatives include partnering between
governmental organizations and industry.
• In 2004, the FDA created the “Critical Path Initiative”
(CPI) project to guide the new drug development process

66. REFERENCE:
1. Goodman & Gilman’s : The Pharmaceutical
Basis of Therapeutics. 12th
Edition.
2. Kulkarni SK. Handbook of Experimental
Pharmacology. 4th
Edition.
3. Satoskar RS, Bhandarkar SD, Rege NN.
Pharmacology and Pharmacotherapeutics.
4. Various Internet Sources.