ROLE OF REGULATORY BODIES

IN THE APPROVAL OF CLINICAL TRIALS

US-FDA, EU, CANADA & PAKISTAN

Dr Laiq Ahmed Siddiqui

MBBS, MBA, CRCP, Dip. Diabetes
03121127860
 Prior to penicillin and medical research, death was an
everyday occurrence. It was intimate.
Katherine Dunn

Modern medical advances have helped millions of people

live longer, healthier lives. We owe these improvements
to decades of investment in medical research. Ike Skelton
 REGULATORY PROFESSIONALS

Regulatory professionals should know Laboratory and manufacturing deviations, Pre-approval

inspections, GMP, Maintenance and update of PMF, Internal Compliance of Documentation,
CTD/eCTD, Quality systems, Quality Assurance, Method Validations, Process Validations,
Master Validation Plan, Protocols, Standard Operating Procedures (SOPs), Auditing and
Compliance Functions, Regulatory strategies, legislation and documentation required for
USFDA, EU, Pak, UKMCA/UKMHRA, MCC, WHO etc., FDA/UKMHRA queries & submission,
application requirements and guidelines, medical device regulations, stability as per ICH
guidelines & MBRs, International harmonization, practice of regulatory affairs, Clinical Trial
Information, Documents Design, Role of the International Business Operations of the
Pharmaceutical MNCs, Clinical Pharmacy, Drug Trials and Vaccine Trials Guidelines, Drug Laws,
Investigational New Drug Applications, Formatting, assembling and submitting the New Drug
Applications, Human Genetic Research, Clinical Trials, Role and existence of Ethics Committee,
GCP, Pharmaco-vigilance and Adverse Drug Reactions reporting, Clinical Trial Regulation,
Intellectual Property Rights, Basis of Patentability, Patent Application Procedure, Compulsory
License, Infringement of Patents, Product Registration for Regulated and Non Regulated
Markets.
QUOTE OF THE DAY
ALL DRUG SUBMISSIONS MUST UNDERGO RIGOROUS
SCRUTINY AND FULLY SATISFY ALL SCIENTIFIC
REQUIREMENTS UNDER THE REGULATIONS BEFORE
ANY DRUG CAN BE MARKETED.
WHY REGULATORY BODIES

https://www.youtube.com/watch?v=cOwf45eDzfI
 A History of Clinical Research - 
YouTube
https://www.youtube.com/watch?
v=cOwf45eDzfIMay 1, 2013 ... Dr. Dennis
Gillings, founder and Executive Chairman
of Quintiles, gives a brief overview on
the history of clinical research.
https://youtu.be/cOwf45eDzfI

https://www.youtube.com/watch?v=RGK3VKkyVxs
 ROLE OF REGULATORY BODIES

The pharmaceutical, biotechnology and medical devices are

among the most highly regulated industries in the world.

The regulation of medical products has been expanding since

early 20th century. Regulatory agencies are being established
in an ever increasing number of countries across the globe.
https://www.fda.gov/science-research Updated Oct 2020
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-focused-d
rug-development-methods-identify-what-important-patients-guidance-industry-food-and

Updated Oct 2020

https://www.fda.gov/news-events/fda-voices/fda-voices-medical-products
https://www.fda.gov/drugs
Updated Oct 2020
 DRUG APPROVAL PROCESS INFOGRAPHIC

http://www.fda.gov/drugs/resourcesforyou/consumers/ucm295473.htm
 DRUG APPROVAL PROCESS INFOGRAPHIC

http://www.fda.gov/drugs/resourcesforyou/consumers/ucm295473.htm
 FDA’s ROLE: CLINICAL TRIAL

FDA's Role: ClinicalTrials.gov Information

 
Portions of the Food and Drug Administration Amendments Act of 2007 (FDAAA)
require that the “Responsible Party” for certain clinical trials register with, and
submit the results of some trials to, the ClinicalTrials.gov databank (
www.ClinicalTrials.gov).

FDA has been given certain implementation and compliance/enforcement

responsibilities related to Title VIII of FDAAA. These responsibilities include:
1. Requiring a certification regarding compliance with ClinicalTrials.gov
requirements to accompany certain human drug, biological product, and
device applications and submissions to FDA.
2. Requiring the inclusion of a particular statement in the informed consent
documents for "applicable clinical trials" (trials that will be entered into the
ClinicalTrials.gov databank as required by FDAAA).
3. Compliance and enforcement activities related to the failure to submit required
clinical trial information to ClinicalTrials.gov.
REQUIREMENTS OF FDA REGARDING CERTIFICATION

In general, FDA recommends that a Form FDA 3674 accompany the following

applications and submissions to FDA:
Investigational New Drug Application (IND)
New Clinical Protocol Submitted to an IND
New Drug Application (NDA)
Efficacy Supplement to an Approved NDA
Biologics License Application (BLA)
Efficacy Supplement to an Approved BLA
Abbreviated New Drug Application (ANDA)
Premarket Approval Application (PMA)
PMA Panel Track Supplement
Humanitarian Device Exemption (HDE)

Note – FDA does not require the submission of a Form FDA 3674 with an
Investigational Device Exemption (IDE) application as this was not required by
FDAAA.
 Investigational New Drug Application (IND) is filed
with the Food and Drug Administration’s (FDA) CDER
& CBER.
A drug be the subject of an approved marketing
application before it is transported or distributed across
state lines. Because a sponsor will probably want to ship
US-FDA the investigational drug to clinical investigators in many
states, it must seek an exemption from that legal
requirement. The IND is the means through which the
sponsor technically obtains this exemption from the FDA.

Since 1938
4 Kinds of drugs registration application: IND, NDA,
ANDA, OTC & BLA
3 Types of IND: Investigator IND, Emergency use IND
& Treatment IND
2 Categories of IND: Commercial IND & Non-commercial
IND
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalAppli
cations/InvestigationalNewDrugINDApplication/default.htm
 ABBREVIATIONS/ DEFINITIONS

IND: Investigational New Drugs application for clinical investigation.

NDA: New Drugs Application is for a new drug when sponsor believes that enough
evidence on the drug's safety and effectiveness has been obtained to meet FDA's
requirements for marketing approval. If the NDA is approved, the product may be
marketed in the United States.
ANDA: An Abbreviated New Drug Application contains data that, when submitted
to FDA's CDE&R, Office of GD, provides for the review and ultimate approval of a
generic drug product. Generic drug applications are called "abbreviated" because
they are generally not required to include preclinical (animal) and clinical (human)
data to establish safety and effectiveness. 
OTC: Over-the-counter drugs play an increasingly vital role in America's health
care system. OTC drug products are those drugs that are available to consumers
without a prescription.
BLA: A Biologics License Application is a submission that contains specific
information on the manufacturing processes, chemistry, pharmacology, clinical
pharmacology and the medical affects of the biologic product.
 TYPES OF IND (Investigational New Drug
Application)
Investigator IND: Submitted by a physician who both initiates and
conducts an investigation, and under whose immediate direction
the investigational drug is administered or dispensed.  A physician
might submit a research IND to propose studying an unapproved
drug, or an approved product for a new indication or in a new
patient population.
Emergency Use IND: Allows the FDA to authorize use of an
experimental drug in an emergency situation that does not allow
time for submission of an IND in accordance with  21CFR , It is
also used for patients who do not meet the criteria of an existing
study protocol, or if an approved study protocol does not exist.
Treatment IND: Submitted for experimental drugs showing
promise in clinical testing for serious or immediately life-threatening
conditions while the final clinical work is conducted and the FDA
review takes place.
 INFORMATION REQUIRED FOR IND

• Animal Pharmacology and Toxicology Studies: Preclinical data to permit an

assessment as to whether the product is reasonably safe for initial testing in
humans.  Also included are any previous experience with the drug in humans.
• Manufacturing Information: Information pertaining to the 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.
• Clinical Protocols and Investigator Information:
i. Detailed protocols for proposed clinical studies to assess whether the initial-
phase trials will expose subjects to unnecessary risks. 
ii. Also, information on the qualifications of clinical investigators/professionals; who
oversee the administration of the experimental compound. 
iii. Finally, commitments to obtain informed consent from the research subjects, to
obtain review of the study by an institutional review board (IRB), and to adhere
to the investigational new drug regulations.
 TIMELINES
TIMELINES &
& RESOURCES
RESOURCES
30 calendar days before initiating any clinical trials. 
Pre-IND Consultation Program will foster early communications between
sponsors and new drug review divisions to provide guidance on the data necessary
to warrant IND submission (Pre-IND consultation list).
Guidance Documents for IND
•Represent the Agency's current thinking on a particular subject.
•These documents provide FDA review staff and applicants/sponsors with
guidelines to the processing, content, and evaluation/approval of applications and
also to the design, production, manufacturing, and testing of regulated products.
•They also establish policies intended to achieve consistency in the Agency's
regulatory approach and establish inspection and enforcement procedures.
•For complete list of CDER guidance, review guidance index. e.g. Safety reporting
requirements for INDs and BE/BA studies, cGMP for Phase 1 investigational drugs,
Exploratory IND studies, Content and format of INDs for Phase 1 studies of drugs,
including well characterized therapeutics, biotechnology-derived products etc.
 REGULATIONS FOR IND
• The Federal Food, Drug and Cosmetic Act is the basic food and drug law of
the U.S.
• Code of Federal Regulations (CFR) are final regulations published in the
Federal Register. The CFR is divided into 50 titles that represent broad areas
subject to Federal regulations.  Section 21 of the CFR contains most regulations
pertaining to food and drugs. The regulations document all actions of all drug
sponsors that are required under Federal law.
The following regulations apply to the IND application process:
• 21CFR Part 312 Investigational New Drugs.
• 21CFR Part 314 INDA & NDA for FDA Approval to market a New Drug.
• 21CFR Part 316 Orphan Drugs.
• 21CFR Part 58 GLP for nonclinical laboratory studies.
• 21CFR Part 50 Protection of Human Subjects.
• 21CFR Part 56 Institutional Review Boards.
• 21CFR Part 201 Drug Labeling.
• 21CFR Part 54 Financial Disclosure by Clinical Investigators.
• Two final rules.
FORMS & INSTRUCTIONS
http://ec.europa.eu/health/documents/eudralex/vol-10/index_en.htm Oct 2020
http://ec.europa.eu/health/documents/eudralex/vol-10/index_en.htm Oct 2020
 Investigational Medicinal Product
Application (IMP) filed with EU directorate
or member state regulatory body.
Clinical trials are investigations in humans
intended to discover or verify the effects of
one or more investigational medicinal
EU products ("IMPs").

Requirements for the conduct of clinical trials in the EU are provided in

“Directive 2001/20/EC of the European Parliament and of the Council of
4 April 2001 on the approximation of the laws, regulations and
administrative provisions of the Member States relating to the
implementation of good clinical practice in the conduct of clinical
trials on medicinal products for human use”.
It is further concertized by “ commission Directive 2005/28/EC of 8 April
2005 laying down principles and detailed guidelines for good clinical
practice as regards investigational medicinal products for human use,
as well as the requirements for authorization of the manufacturing or
importation of such products”.

http://ec.europa.eu/health/documents/eudralex/vol-10/index_en.htm
 CT APPROVALS

• Clinical trials performed in the EU are required to be conducted

in accordance with the Clinical Trials Directive.
• Clinical trials are conducted outside the EU, but submitted in an
application for marketing authorization in EU, they have to follow
the principles which are equivalent to the provisions of the
Clinical Trials Directive (cf. Annex I, point 8 of the Directive
2001/83/EC of the European Parliament and of the Council of 6
November 2001 on the Community code relating to medicinal
products for human use”.
 CT GUIDELINES

• Guidelines further specifying various aspects of clinical

trials are information to be submitted to the competent
authorities and to the ethics committees, requirements
on safety monitoring and the reporting of adverse
reactions, requirements regarding GCP including the
documentation of the clinical trials, requirements
regarding the products and the clinical trials &
inspections of competent authorities and the applicable
procedures. These are published by EC, EMA & CTFG.
 APPROVAL PROCESS
• Submission of Application and allocation of EudraCT
number.
• Approval from Ethics Committee.
• Article 9(4) of Directive 2001/20/EC, consideration of a valid
request for authorization by the national competent authority
shall be carried out in 60 calendar days.
• Authorization of a CT by the national competent authority is
valid for a clinical trial conducted in that Member State.
• In case of invalid application, national competent authority
should inform the applicant of this within the first 10 calendar
days with reason.
• Amendments, notification and related measures.
• Declaration of the end of clinical trial.
 INFORMATION REQUIRED IN IMP
APPLICATION

• Application Form
• CT Protocol
• Investigator’s Brochure
• Investigational Medicine Product (IMP) Dossier
• Non-investigational medicinal products used in the trial
• Other documents to be submitted,
• Overview
• Amendments and notifications
 CLINICAL TRIAL APPLICATION

•The Clinical Trials Directive harmonizes the rules in the EU

for the approval of a clinical trial conducted in a Member
State. As regards national competent authorities, the details
are set out in the 'Commission Detailed guidance on the
request to the competent authorities for authorization of a
clinical trial on a medicinal product for human use, the
notification of substantial amendments and the declaration of
the end of the trial (CT-1)' published in EudraLex Volume 10.
•Application Form for Approval of Clinical Trial

EU Clinical Trials EU Guidance on

Application Form IMPs
 CANADA

http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/ctdcta_ctddec-eng.pdf
 New Drug Submission (NDS) filed with
Therapeutics Product Directorate of
Health Canada.
Sponsors seeking authorization to conduct a
clinical trial in Canada with guidance to
support the protection of clinical trial subjects
CANADA and contributes to the high standards of
excellence in research and development in
Canada.

The Food and Drugs Act and the Food and Drug Regulations govern
the sale and importation of drugs for use in human clinical trials in
Canada. It is regulated under the regulatory obligations pursuant to
Part C, Division 5 of the Regulations, Drugs for Clinical Trials Involving
Human Subjects.

http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/ctdcta_ctddec-eng.pdf
 W&W TO DO

• Except Phase IV studies, clinical trial sponsors must submit a

clinical trial application
• REBs oversight of the conduct of clinical trials and site
according to C.05.006(1)(c)
• Regulations follow principles, definitions & standards of ICH
Guidance on CT
• Clinical Trial Application Amendments by (CTA-A) [C.05.008]
and Notifications (CTA-N) [C.05.007]
• Pre-Clinical Trial Application Consultation Meeting by PCTA
with information. 30 & 14 days
• CTA Submission [C.05.005]. 30, 7 & 2 days
• CTA-A submission. 15 days
• Post-authorization requirement, Site closure, study completion
 PRECONSULTATION MEETING
PRE-CONSULTATION MEETING

• Brief synopsis of proposed study

• Sufficient information for HC for utility of meeting with
identification of appropriate staff
• Proposed agenda and complete list of attendees
• Scope of the intended CTA, including:
 Drug information including summary of method of manufacture for drug
substance & dosage form.
 Listing of all production site(s) - only for biologics &
radiopharmaceuticals.
 PROCEDURE & APPLICATION

• Administrative and Product Information

Including cover letter, meeting information, administrative
Information, application forms, certification & attestation,
compliance & site information, clinical trial site information
form, authorization for sharing information, international
information, product information, IB, HC summaries, PSEAT-
CTA, CT information, Protocol, IC forms, Canadian REB
refusals & information on prior-related applications.
• CTD summaries including QOS
• Quality including table of contents of module 3 & literature
references
 REVIEW PROCESS

• Sponsor is responsible for resolving issues identified by

HC. Information provision within 2 calendar days
[C.05.009].
• Unable to provide requested information application
withdrawn & resubmitted without prejudice.
• A Not Satisfactory Notice (NSN) issued if significant
deficiencies are identified.
• If the CTA or CTA-A is deemed acceptable, a No Objection
Letter (NOL) will be issued.

Guidance for CT
by HC
 Application for CT filed with QA & Laboratory
Testing Division of Drugs Regulatory
Authority Pakistan (DRAP).
Research in drugs shall be conducted at such
place or places and by such person or persons
PAKISTAN as may be approved by the Federal Government
and shall be categorized as other than clinical
trials and clinical trials.

Drugs (Research) Rules, 1978 was implemented by

S.R.O. 1047(I)/78, dated 15th July, 1978 under Section
43 of the Drugs Act, 1976 (XXXI of 1976), the same
having been previously published as required by sub-
section (3) of the said section

http://www.dra.gov.pk/gop/index.php?q=aHR0cDovLzE5Mi4xNjguNzAuMTM2L2RyYXAvZGVmYXVsdC5hc3B4
https://dra.gov.pk/Home/DownloadsAllDocs#gsc.tab=0
Updated Oct 2020
DRUG REGULATORY AUHTORITY OF PAKISTAN

Updated Oct 2020

 DRAP ORGANOGRAM
Saira Afzal Tarrar M. Ayub Sheikh
Minister of State Secretary NHSRC

NHSRC
Dr. M. Aslam
CEO DRAP

Dr. Noor M. Shah

Mr. Amanullah Mr. G. R. Dutani Mr. Sh. Ansaar Saleem khan
Mr. Arshad Khan Sheikh Faqir Mohd. Director, Medical
Director, Director, Ph. Director, Biologicals Director, MIS and
Director , Legal Director Licensing + devices and
Budget/Acc. and evaluation/Reg./ & Pharmacy Natural
Affairs Director QC & QA medicated
Costing/Pricing controlled drugs services medicines/OTC
cosmetics

Mr. Fakharuddin Mrs. Tehreem

Mr. Abdul Dr. Obaidullah Amir Sara DDC Dr. Masud ur
Dr. Obaid Ali Medical
Ghaffar DDC DDG R-1/ DDC R II DDG L&A Rehman DDG
DDC Biologicals Devices
Pricing AM
Mr. Khalid
Mr. Ammad Mr. Asif Jalil
Mehmood
ADC R-II Mr. Abdullah DDC ADC Medical Mr. Abdul
DDC L&A
Ms. Sara Awan RRR Devices Sattar Sohrani
ADC Pricing DDC AM
Mr. M. Arif
Ms. Quratul Ain
DDC R I
ADC L&A
Mr. Akhtar Abbas
DDG R II/DDC R Mr. Manzoor Ali Mr. Zaheeruddin
Ms. Sara V Bozdar DDC M Baber
Mehreen I&E DDC Q&A
ADC R-I Mr. Baber Khan
DDC R III Mr. Faisal Shehzad
FID I
Mr. Muneeb
Dr. Tariq ADC I&E
Siddique DDC R Mr. Zeeshan Bajar
IV FID II
GUIDELINES FOR CLINICAL TRIAL

https://dra.gov.pk/docs/Guidelines%20for
%20Conduct%20of%20Clinical%20Trial-
Final.pdf

Updated Oct 2020

CONDITIONS FOR CLINICAL TRIAL
CONDITIONS FOR CLINICAL TRIAL
CONDITIONS FOR CLINICAL TRIAL
CONDITIONS FOR CLINICAL TRIAL
CONDITIONS FOR CLINICAL TRIAL
 CONDITIONS FOR CLINICAL TRIAL
• Rule 6, Characterized research in drugs & CT as:
(i) Stage I: single & short term multiple dosing for tolerance, side effects, toxicity,
metabolism, preferred routes of administration, safe dosage range & other
pharmacological actions of the drug in small number of subjects.
(ii) Stage II: safety & effectiveness, effective dose range, side effects of the drug
on clinical and laboratory parameters, level of drug in biological fluids in relation
to therapeutic response. Subject to satisfactory results of Stage I & shall be
administered to carefully supervised patients. Concurrent animal study also
require for safety.
(iii) Stage III: expand knowledge of potential use & hazards subject to
satisfactory results of stages I & II
• Hazards communicated and further pre-clinical studies
• Studies on children risk benefit and adult studies available
• ADR shall be sent immediately to the Federal Government
• Recording of studies in respect of every drug and retain it for at least ten years
after registration of that drug
 CLINICAL TRIAL APPROVAL PROCESS

Application & Protocol submission to the Clinical Trial Section

Application & Protocol checked by ADC (CT)

Complete Incomplete

Sponsor informed about

New molecule Registered deficiencies

Expert Evaluation

Rejected Approved

Rejection letter ADC (CT)

License issued
Issued With for the import
Observations of Drugs to conduct the
File sent to DDG (R&D)
of the Expert Clinical Trial
Drugs Controller (R&D)
Director General (Health)
 DRAP – PV ONLINE SYSTEM

https://primaryreporting.who-umc.org/Reporting/Reporter?
OrganizationID=PK
https://oprs.usc.edu/files/2017/05/SoCRA-v-ACRP.pdf
ANY QUESTIONS
QUIZ TIME
 QUESTION 1

1. What are the core responsibilities of FDA?

a. Protecting the public health by assuring safety and

efficacy of drugs.
b. Ensuring proper monitoring of the trial.
c. Conduct the clinical study in accordance with IRB
approved protocol.
d. Advancing the public health that makes foods and
medicines less effective and safe.
e. Help public in getting accurate, science-based
information which is needed to use medicines.
 QUESTION 2

2. Information required for Sponsors-Investigators

submitting Investigational New Drug Application
(INDs), includes:
a. Mailing addresses.
b. Instruction for forms.
c. FDA’s receipt of IND.
d. Application form.
e. Investigator’s Brochure.
 QUESTION 3

3. Information required for IND (Investigational New Drug

Application):

a. Product is reasonably safe for initial testing in human.

b. Information about composition, manufacture, stability and
control used.
c. Information on the qualification of clinical professionals.
d. Information on the qualification of sponsors.
e. To ensure the company produce batches of the drug.
 QUESTION 4

4. E.U guidelines for C.T (Clinical Trial) approval are:

a. Required to be conducted in accordance with the Clinical
Trial Directive 2001.
b. Required safety monitoring and reporting of adverse
reaction.
c. Brief synopsis of proposed study.
d. Published by EC (European Commission), EMA
(European Medicines Agency) and CTFG (Clinical Trial
Facilitation Group).
e. Certification of compliance.
 QUESTION 5

5. Information required for IMP (Investigational

Medicinal Product Application):
a. Investigator’s Brochure.
b. CT protocol.
c. Information on the qualification of sponsors.
d. Certification of compliance.
e. Application form.
THANK YOU FOR YOUR ATTENTION