Regulatory perspective of clinical trials, phases of clinical trials,ICH-GCP Principles

1. PRESENTATION ON
REGULATORY PERSPECTIVES OF
CLINICAL TRIALS: ORIGIN AND
PRINCIPLES OF (ICH-GCP)
GUIDELINES
SUBMITTED BY-
AARTI PAL
ROLL NO:13
M. PHARM
(PHARMACOLOGY)
2nd SEMESTER
SUBMITTED TO-
DR. MANJUSHA CHAUDHARY
ASSISTANT PROFESSOR
INSTITUTE OF PHARMACEUTICAL SCIENCES,KUK

2. CONTENTS :
1) Introduction
i) clinical trial
ii) Drug review steps
iii) phases of clinical trial
iv) Drug development phases
v) Drug development process
2) Clinical Research Regulations
3) Clinical Research Regulation in India
4) Regulatory bodies
5) ICH (International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use
7) GCP (Good Clinical Practices)
8) Principles of ICH-GCP Guidelines

3. • 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.
Clinical trials are conducted only when:
• satisfactory information has been gathered on the quality of the nonclinical
safety
• health authority/ethics committee approval is granted in the country where
approval of the drug is sought.
• Clinical Trial is the mainstay for bringing out New Drugs to the Market.
INTRODUCTION:

4. • Clinical trial is a human experiment designed to study the efficacy
and safety of a new drug/intervention
• Involves Phase 1-4 with specific objectives and end results
• Application to Regulatory authority:
IND - Permission to conduct CT
NDA - Permission to Market New drug
• Well designed and effectively executed clinical trials form the
base of therapeutic decisions
• CT must follow guidelines & protocol to ensure well-being of
participants

5. 1. Preclinical (animal) testing.
2. An investigational new drug application (IND): outlines what the sponsor of a new
drug proposes for human testing in clinical trials.
3. Phase 1 studies
4. Phase 2 studies
5. Phase 3 studies
6. Submission of New Drug Application (NDA) is the formal step asking the FDA to
consider a drug for marketing approval.
7. FDA reviewers will approve the application or find it either "approvable" or "not
approvable."
8. Phase 4 studies
Drug Review Steps:

6. Clinical Drug Development Phase

7. Phases of clinical trial

8. Drug Development Process

9. • Study of new drug in microdoses to derive PK information in human before
undertaking phase I studies is called PHASE O
• Microdose: Less than 1/100 of the dose of a test substance calculated to produce
pharmacological effect with a max dose ≤100 micrograms
• Objective: To obtain preliminary Pharmacokinetic data.
• Preclinical Data: Subacute toxicity study in one species by two routes of
administration.
• These are very 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.
Phase 0 study / Microdosing

10. • First stage of testing in human subjects
• Designed to assess the safety, tolerability, PK and PD of drug.
• 20-100 healthy volunteers
• Patients: Anticancer drugs, AIDS therapy
• Duration: 6-12 months
• No blinding / Open labelled
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
Phase 1

11. • 1. Primary i. Tolerability and Safety
ii. Pharmacokinetics
• 2. Secondary iii. Pharmacodynamics
Phase 1 study: objectives

12. • Therapeutic Exploratory Trial
• 20-300 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
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
Phase II:

13. • 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 etc.
• 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
Phase III
Objectives

14. • 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
• Can take 2-3 years for FDA to review
NDA : New Drug Application

15. Harmful effects discovered may result in a drug being no longer sold, or restricted to certain uses.
On September 30, 2004, Merck withdrew rofecoxib from the market because of concerns about
increased risk of heart attack and stroke associated with long-term, high-dosage use
 Done after drug has been marketed
 Post Marketing Surveillance (PMS).
 No fixed duration / patient population
 studies continue to collect data about effects in various populations & side effects from long term use.
 These are primarily observational or non- experimental in nature.
Phase IV

16.  Confirm the efficacy and safety profile in large populations during practice
 Detect the unknown/rare adverse drug reaction/s
 Evaluation of over-dosage
 Identifications of new indications
 Dose refinement: Evaluation of new formulations, dosages, durations of
treatment
Phase IV : Objectives

17. Why are Regulation important to clinical Research?
 Regulations has been set to Ensure integrity of data collected from clinical trials which
assure the safety, right and welfare of the subject.
 Clinical trials are the only way of establishing the safety and efficacy of any new drug
before its introduction in the market for human use. Clinical trials (with safeguards) are
necessary for introduction of new drugs for a country like India, considering its disease
burden and emergence of new variants of disease.
 The regulatory bodies need to frame guidelines and regulatory approval processes on a par
with international standards. Many of the new laws, guidance documents, notifications and
initiatives for regulating pharmaceutical industry were in the charts for quite a long time.
Indian regulatory authorities have started looking into speedy implementation and providing
support in terms of necessary infrastructure and investment.
CDSCO which comes under the Ministry of health and family welfare Is the main body
which works On development of regulatory Procedures And standard for drugs, cosmetics,
diagnostics and devices. It lays down regulatory guidance by amending acts and rules; and
regulate new drugs approvals. Its main objective is to standardize clinical research and bring
safer drugs to market.
Clinical Research Regulations

18. • Schedule y allows Clinical trials to be carried out in India.
• India has appropriate provisions to ensure the human subjects used for the trails are
informed Well and their participation is voluntary.
• CDSCOs priorities to enhance the current mechanism
• Establish single window clearance for approvals.
• Fix timelines for each application(2-6 weeks).
• Subject experts-reviewers - internal/external.
• Staff and infrastructure at one site.
• Continuous training for the officers.
Clinical Research Regulations in India

20.  Central Drugs Regulatory body Standard Control controlled and Organization governed by
 (CDSCO) drug directorate General of Health Services of Ministry of Health and Family
Welfare which regulates drugs in India
 Drugs Controller Regulatory agency General India (DCGI): Under the government of India
whose function is to assess the quality, safety and efficacy of a drug.
 Indian Council of Medical Research (ICMR);
Apex body in India that formulates, co-ordinates and promotes biomedical research
 Drugs consultative committee (DCC);
Provides technical guidance to the central drug standard control organization
 Central Drugs Laboratory (CDL);
National statutory laboratory of the Indian government for quality control of drugs.
 Drugs Technical Advisory Board (DTAB)
Provides technical guidance to the CDSCO
Regulatory bodies in India

21. 1. USA : United States food and drug administration(USFDA)
2. INDIA : Central drug standard control organization(CDSCO)
3. CANADA : Health Canada – sante canada
4. AUSTRALIA : Therapeutic goods administration( TDA)
5. UK : Medicine and health care products and regulatory Agencies (MHRA).
6. EUROPE : European medicines agency(EMEA)
7. SWITZERLAND : Swissmedic
8. JAPAN : Ministry of health and labour welfare(MHLW)
The world wide Regulations

26. • The Central Government constitute a Board
(to be called the Drugs Technical Advisory
Board) to advise the Central Government
and the State Governments on technical
matters arising out of the administration of
D&C, Act 1940
Drug Technical Advisory Board (DTAB)

27. • ICH is a joint initiative involving both the regulators and the industry as equal partners in the
scientific and technical discussions of the testing procedures which are required to ensure
and assess the safety, quality and efficacy of medicines.
What is ICH
How did it evolve?
The need to harmonize
 Public disasters, serious fraud and abuse of human rights.
 Trials of War criminals-Nuremberg code 1949
 Thalidomide- Declaration of Helsinki 1964
 Belmont report 1978( Ethical Principles and guidelines for the protection of human subjects of
research)-Tuskegee syphilis study

28. The thalidomide disaster

30.  To discuss and define the minimum standards for the development and registration of investigational
products
• 6 parties
 EU
 EFPIA : European federation of pharmaceutical industries' associations
 MHLW : Ministry of health, Labor and welfare, Japan
 JPMA: Japan Pharmaceuticals manufacturers Association
 US FDA
 PhRMA
Observers: WHO, TPP (canada)
International federation of Pharmaceutical manufacturer's association
Key objective
ICH parties

31.  Efficacy: clinical trials etc
 Safety: pharmacovigilance, adverse drug reaction reporting
 Quality: raw materials, impurities, residual solvents etc
 Multidisciplinary: common technical document, electronic submission, coding
systems
ICH Guidelines: examples

32. • A standard for the design, conduct, performance,
monitoring ,auditing , recording, analyses and
reporting of clinical trials that provide assurance
that the data and the reported results are credible,
accurate and that the rights, integrity and
confidentiality of trial subjects are protected
Why is it needed?
 To ensure the rights, safety and well being of the
trial subjects are protected
 Ensure the credibility of clinical trial data
GCP (Good Clinical Practices) :

36. • Good clinical practice (GCP) is an international ethical &
scientific standard for conducting clinical trials that involve the
participation of human subjects
• Compliance with this standard provides public assurance that the
rights, safety & well-being of trial subjects are protected, which is
consistent with the principles outlined in the declaration of
Helsinki .
• GCP also ensures the credibility of clinical trial data.
ROLE OF GCP

37. • 1. Glossary
Common language for investigators/sponsors/ethics committees
• 2. Principles of Good Clinical Practice : 13 tenets of ICH GCP
• 3. Requirements for IRB/IEC : Roles responsibility and composition
• 4. Responsibilities of the investigator
• 5. Responsibilities of the sponsor
• 6. Requirements for clinical trial protocol and protocol amendments
• 7. Responsibility of the sponsor in the development of investigator's brochure.
• 8. Essential documents
ICH GCP guideline

39. 1. Clinical trials should be conducted in accordance with the ethical principles that have their
origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable
regulatory requirement(s)
2. Before a trial is initiated, foreseeable risks and inconveniences should be weighed against
the anticipated benefit for the individual trial subject and society. A trial should be initiated and
continued only if the anticipated benefits justify the risks.
3. The rights, safety, and well-being of the trial subjects are the most important considerations
and should prevail over interests of science and society.
Principles of ICH- GCP

40. 4. The available nonclinical and clinical information on an investigational product should be
adequate to support the proposed clinical trial.
5. Clinical trials should be scientifically sound, and described in a clear, detailed protocol.
6. A trial should be conducted in compliance with the protocol that has received prior
institutional review board (IRB)/independent ethics committee (IEC) approval/favorable
opinion.
7. The medical care given to, and medical decisions made on behalf of, subjects should
always be the responsibility of a qualified physician or, when appropriate, of a qualified
dentist.

41. 8. Each individual involved in conducting a trial should be qualified by education, training, and experience to
perform his or her respective task
9. Freely given informed consent should be obtained from every subject prior to clinical trial participation.
10. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate
reporting, interpretation and verification.
11. The confidentiality of records that could identify subjects should be protected, respecting the privacy and
confidentiality rules in accordance with the applicable regulatory requirement(s).
12. Investigational products should be manufactured, handled, and stored in accordance with applicable good
manufacturing practice (GMP). They should be used in accordance with the approved protocol.
13. Systems with procedures that assure the quality of every aspect of the trial should be implemented.

42. • SAFEGUARD PUBLIC HEALTH
• ASSURE CONSUMER PROTECTION STANDARDS
• FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
• ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
• FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS

43. 1. Clinicaltrials.gov
2. Wikipedia
3. WWW.cancerresearchuk.org
4. WWW.centrewatch.com > home > clinical trials
5. Images: Google Images
6. https://www.slideshare.net/VharshiniManoharan/phases-of-clinical-
trials
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