Ethical standards to protect people have been around for over 60 years
Clinical Trials regulations
Dr Urmila M. Aswar
Department of Pharmacology, SIOP, Narhe
Investigational New Drug Application
• Current Federal law requires that a drug be
approved for marketing application before it is
transported or distributed across state lines.
• But in case of investigational drug, it is
required by clinical investigators in many
• IND is an exemption.
• FDA's role in the development of a new drug
begins when the drug's sponsor (usually the
manufacturer or potential marketer) having
screened the new molecule for
pharmacological activity and acute toxicity
potential in animals, wants to test its
diagnostic or therapeutic potential in
humans. At that point, the molecule changes
in legal status under the Federal Food, Drug,
and Cosmetic Act and becomes a new drug
subject to specific requirements of the drug
Composition, manufacturer, stability, and
controls used for manufacturing the drug
substance and the drug product.
This information is assessed to ensure that the
company can adequately produce and supply
consistent batches of the drug.
Lic form-29 is taken for mfg of new drug
Clinical Protocols and Investigator
• Detailed protocols for proposed clinical studies to
assess whether the initial-phase trials will expose
subjects to unnecessary risks.
• Information on the qualifications of clinical trial
• Informed consent from the research subjects,
• to obtain review of the study by an institutional
review board (IRB),
• Adherence to the investigational new drug
Review by FDA
• Once the IND is submitted, the sponsor must
wait 30 calendar days before initiating any
clinical trials. During this time, FDA
(DCGI/CDSCO) has an opportunity to review
the IND for safety to assure that research
subjects will not be subjected to unreasonable
• An application to conduct clinical trials in India
should be submitted along with the data of
chemistry, manufacturing, control and animal
studies to DCGI. The date regarding the trial
protocol, investigator's brochures, and informed
consent documents should also be attached. A
copy of the application must be submitted to the
ethical committee and the clinical trials are
conducted only after approval of DCGI and ethical
committee. To determine the maximum tolerated
dose in humans, adverse reactions, etc.
New Drug Application
• The new drug registration (using form no. 44 along with full
pre-clinical and clinical testing information) is applied after
the completion of clinical trials.
• The comprehensive information on the marketing status of
the drug in other countries is also required other than the
information on safety and efficacy.
• The information regarding the prescription, samples and
protocols, product monograph, labels, and cartons must also
• Schedule Y of D&C act, provides the guidelines and
requirements for clinical trials.
• The application can be reviewed in a range of about 12- 18
Regulatory bodies in World
• USA: FDA, Dept of health and human services
• Canada: Health Canada
• UK: Medicines and Healthcare products
regulatory agency (MHRA)
• EU: European Medicines Agency (EMEA)
• Japan: Pharmaceutical and Medical Devices
Regulating bodies in India
• The Drug and Cosmetic Act 1940 and Rules
1945 were passed by the India's parliament to
regulate the import, manufacture, distribution
and sale of drugs and cosmetics.
• The Central Drugs Standard Control
• The Drugs Controller General (India) [DCGI]
Regulatory requirements for clinical
Before starting trial
• Consent of investigator
• Approval by IRB..approval of protocol, site,
• Approval from ICMR in case of new molecules
developed in India
• Informed consent
• Insurance cover for trial related injury
During the conduct
• Compliance with the trial protocol
• Reporting protocol violations to EC
• Seek approval for protocol amendments
• Adherence to GCP
• Record all adverse effects
• Record of all serious adverse effects to sponsor in
• Notification of fatal adv effect to RB
• Review the progress of results of study
• Send periodic status of study.
Post trial requirement
• Site close out
• Check investigational product utilization
• Analyze the data using statistical softwares
• Forward the report from investigator to EC
• Seek new drug approval.
• Prepare and submit the prescribing
information for ND to the authorities
Newly approved drugs
• Gilotrif (afatinib) Tablets: for lung cancer
Boehringer Ingelheim Pharmaceuticals
• Khedezla (desvenlafaxine): for depression
Osmotica Pharmaceutical Corp.
• Clinical trials: World wide
• Follow ICH/WHO, GCP provides universal
• US, Canada, EU, Japan, Australia and India
USFDA: Achievements in Clinical
• Ethical Principles and Infrastructure (IRBs)
• Evidence-Based Decision-Making
– Safety; Efficacy
• Standards of Research Conduct (GCP)
• International Harmonization
• Quality Improvement
Why so much strict: A Change in
• More clinical investigators
• More studies
• More participation of vulnerable populations
– Children, Elderly, Ethnic Groups, etc.
• More “outsourcing” (CRO’s, SMO’s)
• New technologies
• Global expansion
– Countries/areas new to GCP
CT Disasters in history: A lesson
• May 1999: NY Times, “Research for Hire. A
Doctor’s Drug Studies Turn into Fraud”
• September 1999: Death in gene therapy trial
• December 2000: Washington Post series “The
• June 2001: Death in lung physiology trial
• FDA has a broad public protection mission
Ensure the safe use of regulated products that are
themselves safe and efficacious
Approvals: Based on complete and accurate
information from well-designed, ethically-
conducted, and well-monitored clinical research
FDA’s Mission in Clinical Research
• Ensure Implementation of Good Clinical Practice
– GCP is an international ethical and scientific
quality standard for designing, conducting,
recording, and reporting trials that involve the
participation of human subjects
– GCP embraces trial objectives, trial design, study
oversight, data collection and quality assurance,
study analysis, as well as human subject
protection in studies that support product
Good Clinical Practice
• GCP is most fundamentally a System of Shared
–Institutions/Institutional Review Boards
• Federal food, drug and cosmetic act, 1938
• Orphan drug act 1983,
• Prescription drug user fee act, 1992 (PDUFA).
• Food and drug modernization act 1997,
3 approaches for treating serious
• Fast track: to get important new drug to the patient ealier.
• For no therapy/ superior new drug.
• Accelerated approval: allows earlier approvals of drugs to
treat serious diseases or fills an unmet medical need based on
a surrogate endpoint.
• S.endpoint means a lab test or a physical sign or survival.
• Post marketing trials become important.
• Continue or remove
• Priority review: the drugs that offer major advantage in the
treatment or provide a treatment where no adequate therapy
• Review time is reduced.
Federal food, drug and cosmetic
• Basic food and drug law in the US
• Food are pure and safe to eat
• Drugs and devices are safe to use
• Cosmetics are safe and made from
Code for federal regulations (CFR)
• The CFR is divided into 50 titles
• SECTION 21 OF CFR –regulations related to
food and drugs.
• Part of CFR 21 give details of IND (312), NDA
(314), orphan drugs (316)
Center for Biologics Evaluation and
• Section 505 of FD & C provide that no person can
market a drug without filling IND.
• Dept of health and human services of FDA protects the
rights of human in Clinical Trial.
• The CBER is one of six main centers for the U.S. Food
and Drug Administration, which is a part of the U.S.
Department of Health and Human Services.
• CBER is responsible for assuring the safety, purity,
potency, and effectiveness of biologics and related
products (such as vaccines live biotherapeutics
(probiotics), blood products, and cell, tissue,
and gene therapies).
Center for Drugs Evaluation and
• The center reviews applications for new and generic
pharmaceuticals, manages US current Good
Manufacturing Practice (cGMP) regulations for
pharmaceutical manufacturing, determines which
medications require a medical prescription, monitors
advertising of approved medications, and collects
and analyzes safety data about pharmaceuticals that
are already on the market.
• CDER reviews New Drug Applications to ensure that
the drugs are safe and effective. Its primary objective
is to ensure that all prescription and OTC medications
are safe and effective when used as directed.
Bioresearch Monitoring Program
• FDA's Bioresearch Monitoring (BIMO) program is a
comprehensive program of on-site inspections and data
audits designed to monitor all aspects of the conduct and
reporting of FDA regulated research.
• It assure the quality and integrity of data submitted to the
agency in support of new product approvals.
• It provide for protection of the rights and welfare of the
thousands of human subjects involved in FDA regulated
• It has become a cornerstone of the FDA preapproval
process for new medicines, medical devices, food and color
additives and veterinary products introduced to the U.S.
• Post Ranbaxy, Wockhardt faces a hit as US FDA
bans imports over quality concerns
ET Bureau May 24, 2013
• The U.S. Department of Agriculture’s (USDA)
Animal and Plant Health Inspection Service
• Drugs are licensed for use in the UK with a
European license or a national license. They
are licensed through European Medicines
Agency (EMEA) for Europe wide license and
from Medicine and healthcare products
regulatory agency (MHRA) for UK license.
EMEA, Committee for orphan medicinal
products (COMP): orphan drugs: 5/10,000
Centralized system in EMEA
• Drugs for AIDS
• NEURODEGENRATIVE DISEASES
• ORPHAN DRUGS
Decentralized system in EMEA
• Other than the listed
• Apply for more than one country of EU
• With review of 1 country can be licensed in
• Prior to 2004 the standards were guidelines and dual
• For the first time ethical and scientific standards for the
set up, and conduct of clinical research involving
human subjects receiving investigational medicinal
products, became subject to law
CLINICAL TRIAL REGULATIONS
• EU Directives are legislation issued by the European Union defining
an outcome or change that is binding for each member state
• EU Directives must be transposed into law for each member state
to become law in that country
• In the UK this is achieved by the introduction of a Statutory
Instrument named within an Act of Parliament, which then becomes
European Directives & UK Laws
EU Clinical Trials Directive
EU GCP Directive
EU Legislation UK Legislation
Medicines for Human Use
(Clinical Trials) Regulations
2004 (SI 1031)
Medicines for Human Use
(Clinical Trials) Amendment
Regulations 2006 (SI 1928)
Amendment 2006 (SI 2964)
Amendment 2008 (SI 941)
Amendment 2009 (SI 1164)
Eudralex – Volume 10 Clinical
ICH GCP Topic E6 – Good
Framework for Health and
• Amendment 2010 (SI 1882)
• Introduced to ensure that everyone follows the same GCP
• Clarified and standardised practice for the safety of the subject and
the quality of the data.
• Major areas of change included:
• - The ethics review system came under the law
• - Each member state had to appoint a Competent Authority
(MHRA in UK)
• - Strengthened consent for vulnerable groups
• - Amendments required to follow a process
• - Additional safety reporting requirements
• - All results have to be made available even if negative findings
European Clinical Trials Directive 2001/20/EC
GCP principles are a standard for the design, conduct,
performance, monitoring, auditing, recording, analyses and
reporting of clinical trials that provides assurance that the
data and reported results are credible and accurate, and that
the rights, integrity and confidentiality of trial subjects are
GCP elements : MHRA inspection areas
• Trial initiation, approvals and completion
• Responsibilities of organisations and
• Recruitment and informed consent
• Documentation and data quality
• Safety reporting /pharmacovigilance
• Statutory Instrument 2004/1031
• Transposed European Clinical Trials Directive
2001/20/EC into UK Law from 1 May 2004
• Made amendments to the Medicines Act 1968 which
regulated the supply of medicines for a clinical trial, but
did not cover standards of conduct on a clinical trial SI
2004/1031 regulates the commencement and conduct of
a clinical trial and the manufacture of medicinal products
to be used (including placebo)
Legislation: Medicines for Human Use (Clinical
• The second EU Directive clarified and extends the first
• Major areas of change included:
• - Duties can be delegated, but not responsibilities
• - New requirements on sponsor and investigators in relation to Trial
• - Notification of serious breaches
• Statutory Instrument 2006/1928
• Transposed European Clinical Trials Directive 2005/28/EC into UK Law
from 29 August 2006
• Makes amendments to the Medicines for Human Use (Clinical Trials)
European Clinical Trials Directive 2005/28/EC
• There have also been subsequent Statutory Instruments which
govern the conduct of clinical research in the UK.
• The Statutory Instruments are:
• 2004/1031 (1 May 2004) – EU Directive 2001/20/EC transposed into law
• 2006/1928 (29 August 2006) – EU Directive 2005/28/EC transposed into law
• 2006/2984 (12 December 2006) – A&E trials without consent for adults without
• 2008/941 (1 May 2008) – Research Ethics Committee membership and approval
• 2009/1164 (8 May 2009) – Urgent safety measures
• 2010/1882 (19 August 2010) – Advanced Therapy Medicinal Products
• All are available on the MHRA website
Other UK Regulations
• Researchers work within other guidelines and laws, including
• Data Protection Act (1998)
• Protection of Children Act (1999)
• Mental Capacity Act (2005)
• Human Tissue Act (2004)
• Equality and Diversity Legislation
• Freedom of Information Act (2000)
• Welsh Language Act 1993/ 2011
• Health Board Policies
In addition …
Drugs and Health is in concurrent list of Indian Constitution It is
governed by both Centre and State Governments under the Drugs
& Cosmetics Act, 1940.
Central Drug Standard Control Organization (CDSCO)
Ministry Of Health & Family Welfare (MHFW)
Indian Council Of Medical Research (ICMR)
Indian Pharmaceutical Association (IPA)
Drug Technical Advisory Board (DTAB)
Central Drug Testing Laboratory (CDTL)
Indian Pharmacopoeia Commission (IPC)
National Pharmaceutical Pricing Authority (NPPA)
Functions undertaken by
1. Laying down standards of drugs, cosmetics, diagnostics and devices.
2. Laying down regulatory measures, amendments to Acts and Rules.
3. To regulate market authorization of new drugs.
4. To regulate clinical research in India
5. To approve licenses to manufacture certain categories of drugs as
Central Licence Approving Authority i.e. for Blood Banks, Large Volume
Parenterals and Vaccines & Sera.
6. To regulate the standards of imported drugs.
7. Work relating to the Drugs Technical Advisory Board (DTAB) and Drugs
Consultative Committee (DCC).
8. Testing of drugs by Central Drugs Labs.
9. Publication of Indian Pharmacopoeia.
Regulations: For conducting CT in India
• Permission is required from the DCGI for conducting CT
• Also for BABE studies
• DD with in India/outside India
• The application for permission to initiate a specific phase of
• Investigators Brochure
• Proposed trial protocol, case report form, informed
consents, investigator undertaking, investigators CV
• Regulatory status in other countries.
• If drug is developed in India, approval by ICMR
is also required.
• Guidelines for CT in India are based on ICH-
• Lab used for studies sd be GMP and GLP
• Ministry of Health and Family Welfare
DGHS (Directorate General of Health Services)
INDIA – WELL DEFINED DRUG
REGULATORY SYSTEM Govt. of India
Enforcement & GMP audit Div
Quality Control Division – CDTL
New Drug Div
Central Drugs Standard Control
• Organization Directorate General of Health
Ministry of Health and Family Welfare,
Government of India, FDA Bhavan, ITO, Kotla
Road, New Delhi -110002
Phone: 91-11-23236975 / 23236971Fax: 91-
Dr. Gyanendra Nath Singh
M. Pharm., Ph.D., M.B.A. (U K)
Drug Controller General of India
Approval of Biologics
• CDSCO AND DCGI
• Other than that
Genetic engineering approval council
Recombinant DNA advisory committee
Review committee on genetic manipulation
Institutional biosafety committee
State biosafety coordination committee
District level committee
• National Biotechnology ACT 2008
Approval of medical devices
• By notification SO1468 (2005).
• The notification declares 10 categories of
sterile devices to be considered as drugs
under section 3 (b) of D&C act. These are
cardiac stents, catherters, bone cement, heart
valves, scalp vein sets, orthopaedic implants,
cannulae intraocular lenses.
• Separate committees for evaluation of these..
Regulation of Clinical trials
• Schedule Y of D&C act
• Guidelines for biomedical research on human
participants, ICMR, 2006.
• Guidance on clinical trial inspection, CDSCO
• Guidance on submission of CT Applications for
evaluating safety and efficacy.
• Guidelines on BABE studies, CDESCO
• Guidelines on GCLP
Data Monitoring Committee
• Sponsorer must establish a data monitoring
committee or data safety committee.
• They assess the progress of a CT, data safety,
efficacy endpoints at predetermined
endpoints. They also recommend whether to
continue/modify or stop the trial.
• Contains registered clinical trials in India
Regulation regarding transport
• Committee on the transport of dangerous
• Committee of the United Nations Economic
and Social council.
• In india, ICMR has issued the guidelines on
transfer of human development of
National Institute of Health and Family Welfare
NIHFW is an Apex Technical Institute, funded by Ministry of
Health and Family Welfare, for promotion of health and family
welfare programmers in the country through
education, training, research, evaluation, consultancy and specialized
The NIHFW was established on March 9, 1977 by a merger of the
National Institute of Health Administration and Education (NIHAE)
with the National Institute of Family Planning (NIFP).
DRUG TECHNICALADVISORY BOARD
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
The Board shall consist of the following members,
10 ex-officio Members
5 Nominated Members
5 Elected Members
CENTRAL DRUG TESTING LABORATORY
The central drug laboratory, Kolkata is national statutory
laboratory of the government of India for quality control of
drug and cosmetic and established under the D&C act ,1940.
Oldest quality control laboratory of the drug control authorities
Function under the director general of Health Services in the
Ministry of Health and Family Welfare.