Presented by :- Kapil
M. Pharmacy 1st year (DRA)
Roll No. 180000802001
Regulations Governing Clinical Trials

• Content
 India: Clinical Research Regulation in India
 Medical Device Regulation in India
 USA: Regulations to conduct drug studies in USA (FDA)
 NDA505(b)(1) of the FD&C Act (Application for approval of a
new drug)
 NDA 505(b)(2) of the FD&C Act (Application for approval of a
new drug that relies, at least in part, on data not developed by the
applicant)
 ANDA 505(j) of the FD&C Act (Application for approval of a
generic drug product)
 FDA Guidance for Industry - Acceptance of Foreign Clinical
Studies
 FDA Clinical Trials Guidance Document: Good Clinical Practice
 EU: Clinical Research Regulations in European Union (EMA)
 References

• Clinical Research Regulation in India:
 Schedule Y allows clinical trials to be carried out in India.
 India has appropriate provisions to ensure that human subjects used for
the trials are informed well and their participation is voluntary.
 CDSCO’s priorities to enhance the current mechanism:-
 Establish single window clearance for approvals.
 Fix timelines for each application (2-6 Weeks).
 New drug application status on the web –update fortnightly.
 Subject experts-reviewers –internal / external.
 Staff & infrastructure at one site.
 Continuous training for the officers.

• Medical Device Regulation in India:-
 Medical Devices are notified as Drugs under Drugs & Cosmetics Act.
 Section 3 (b) (iv) defines, Medical Devices as:-
 Devices intended for internal or external use in the diagnosis, treatment,
mitigation or prevention of disease or disorder in human beings or
animals”.
 GMP Requirements are specified under Schedule M-III
 Rule 109-A Labeling of Medical Devices.
 Rule 125-A Standards for Medical Devices.
 Currently, 14 medical devices have been notified as Drugs. Some
examples are disposable hypodermic syringes, disposable hypodermic
needles & disposable perfusion sets etc.

• Register Process of Medical Device in India –
1. Product Requires Registration.
2. Appoint an Authorized Indian Agent.
3. Submit the Regulatory Dossier under Form
40.
4. Obtain Registration Certificate in Form 41.
5. Obtain Issue license in Form 10.
6. Marketing in India.

1. Product Requires Registration: Medical devices which require
registration in India include spinal needles, cochlear implants,
syringes and needle, dental implants, heart valves, cardiac stents,
among others. These devices should undergo registration process with
the CDSCO. In some cases the DCGI will review certain product
information and provide an exemption on registration process of a
medical device in the form of an NOC. This process takes anywhere
between 4 to 12 weeks.
2. Appoint an Authorized Indian Agent: A manufacturer can appoint
an authorized Indian agent to register with the CDSCO on their
behalf. The authorized Indian agent should have a wholesale drug
license in from 20B and 21B. The manufacturer will be the holder of
the registration certificate and freely appoint multiple distributors in
the country.
3. Submit the Regulatory Dossier under Form 40:A dossier with the
required list of documents to start the registration process are below.
a) Form 40

b) TR6 Challan
c) Power of Attorney
d) Schedule D(I)
e) ISO 13485 Certificate
f) Full Quality Assurance Certificate
g) CE Design Certificate
h) Declaration of Conformity
i) Free Sale Certificate
j) Certificate of Marketability from GHTF countries
k) Other Regulatory Approvals
l) PMS report
m) Plant Master File
n) Device Master File
 The CDSCO fee is US$1500 and US $1000 for a single device family.
The time for registration process can take anywhere between 6 to 9
months

4. Obtain Registration Certificate in Form 41: After the document
submission the CDSCO will get back to the Indian Agent with
first query letter in about 3 months time. Upon receiving the
answers for the query the CDSCO will either issue a subsequent
query letter or grant license. The registration certificate is valid for
3 years.
5. Obtain Issue license in Form 10:The Form-10 has to be applied
at the CDSCO by distributor directly. An application has to be
made in Form 8 along with Form 9 which mentions the
registration certificate number. This process takes 4 to 12 weeks.
6. Marketing in India: Once the registration certificate and the
import license are issued the product can enter the Indian market.
The authorized Indian agent should report any change, adverse
events, recalls in other countries etc to the CDSCO as and when
they happen.

USA: Regulation to Conduct Drug Studies in USA
(FDA)
 NDA 505(b)(1) of the FD&C Act (Application for approval of new
drug) :-The NDA application is the vehicle through which drug
sponsors formally propose that the FDA approve a new pharmaceutical
for sale and marketing in the U.S.
 Application used for approval of a new drug (for clinical use) whose
active ingredient has not previously been approved.
 Goals of the NDA:-To provide enough information to permit FDA
reviewer to reach the following key decisions:
 Drug should be safe and effective.
 Drug’s proposed labeling should be appropriate.
 The methods used to preserve the drug's identity, strength, quality,
and purity are adequate.

• NDA Forms:-
Form FDA-356h: Application to market a new a drug,
biologic, or an antibiotic drug for human use.
Form FDA-356h instructions.
Form FDA-3397 User Fee cover sheet.
Form FDA-3331 New drug application field report.

• Steps involved in Developing a New Drug:-
1. Preclinical
Research
2. Investigational New
Drug Application3. Phase I
trials
4. Phase II trials
5. Phase III trails
6. New Drug
Application
7. Approval

1. Preclinical Research:- The first place researches start is in the lab.
Preclinical research is the process where researches & scientist
determine what germs, virus or bacteria cause a specific disease.
Once this is accomplished researchers & scientists will work to
breakdown the different component that make up a disease to find
out what abnormal event or process are taking place in the body.
Then scientist work to develop a drug that will treat these
abnormalities by conducting experiments in test tubes. The entire
process of preclinical research can take up to three & half years.
2. Investigational New Drug Application:- IND becomes effective if
FDA approves it within 30 days. At this time pharmaceutical
company can begin to test the potential new drug in humans. The
process includes three phases of clinical trials.
3. Phase-I Trials:- A new drug is administered to approx. 20-80
human volunteers. To study the activity & monitor potential toxicity
in people. This process takes one years and if successful will led to
phase-II clinical trials.

4. Phase-II Trials:- During phase II drug is given to 100-300 volunteers
with the disease being studied to determine drug effectiveness. This
process can take about two years to complete before moving to phase
III clinical trails.
5. Phase-III Trials:- It involves 1000-3000 volunteers with the specific
disease that are in hospitals. Physicians will monitor these patients
closely to determine the effects of drugs and determine any side
effects involved. This phase confirms if the drug is effective & safe
and takes about three years.
6. New Drug Application:- After all three phases of clinical trials have
been completed successfully a pharmaceutical company must file
NDA with FDA. The pharmaceutical company must be able to clearly
determine the effectiveness & safety of the drug and must provide all
of the scientific information company has collected on the specific
drug.
7. Approval:- If FDA approves the drug it is then made available for
physicians to prescribe to patients. The Pharmaceutical company still
responsible for submitting periodic reports to the FDA regarding any
unknown side effects.

• NDA 505(b)(2)of the FD&C Act (Application for
approval of a new drug that relies, at least in part, on data
not developed by the applicant):-
 This is application for approval of a new drug that relies, at least in
part, on data not developed by the applicant.
 Must provide information to establish:
 Safety and effectiveness of the drug.
 Findings of safety and effectiveness for already approved products.
 Production methods are adequate to ensure identity, strength, quality,
purity of the drug.
 Proposed labeling for the drug is appropriate and contains all necessary
information.

• Advantages of NDA505(b)(2):-
Provide a
shorter drug
development
program.
It is less
expensive.
Faster new
drug
development
pathway.
Attractive to
manufacturer
with
experience in
developing
generic
products.
Bring a
profitable
drug to
market more
rapidly.

• NDA Submission Checklist:-
 The checklist is intended for use in the preparation and submission of
505(b)(2) NDAs.
 The checklist was developed through discussions with consultants and
Quality Assurance directors and has been field – tested in final form
with three successful submissions.
 Form 1571 completed
 Cover letter
 Name and Address of sponsor
 Name, address, title, telephone, and e-mail of contact person
 Generic and trade name of drug or drug product
 FDA code number
 Form 3674 “certification of compliance with requirement of Clinical-
Trails.gov Data Bank” completed.

• Application for approval of a New Drug:

• Abbreviated New Drug Application(ANDA)505(j) of
FD&C act(Application for approval of a generic drug
product):-
 ANDA contains data which is submitted to FDA for the review and
potential approval of a generic drug product.
 Once approved, an applicant may manufacture and market the generic
drug product to provide a safe, effective, lower cost alternative to the
brand-name drug.
 A generic drug product is one that is comparable to an innovator drug
product in dosage form, strength, route of administration, quality,
performance characteristics, and intended use.
 Goal of ANDA:- To reduce the price of the drug.
 To reduce the time development.
 Increased the bioavailability of the drug in comparison to reference list
of drug.

ANDA Forms
1. In order to submit a complete ANDA, applicants should review
the following forms and prepare all that are required for your
specific application.
2. Filing Review of ANDA’s MAP including filing checklist.
3. Form FDA-356h: Application to Market a New Drug, Biologic,
or Antibiotic drug for human use.
4. Instructions for using Form FDA-356h.
5. Form FDA-3794: GDUFA Cover Sheet.
6. Instructions for creating a GDUFA Cover Sheet.
7. Form FDA-3674: Certification of Compliance.
8. Instructions for completion of Form FDA-367.
9. Generic Drug User Fee Payment Information.
10. Drug Master Files (DMF).

• Application for approval of a Generic Drug Product:

• FDA Guidance for Industry-Acceptance of
Foreign Clinical Studies:
 FDA regulations permit the acceptance of foreign clinical studies in
support of an application for marketing approval of a human drug,
biological product, or device.
 Foreign studies performed under an-
i. Investigational new drug application (IND).
ii. Investigational device exemption (IDE).
iii. And must meet the same requirements of 21 CFR Part 312 or 21
CFR Part 812.
 FDA will accept a foreign clinical study not conducted under an IND
only if the study confirms to the ethical principles contained in the
Declaration of Helsinki (Declaration).
 FDA will accept a foreign clinical study involving a medical device that
is not subject to an IDE only if the study conforms to the ethical
principles contained in the Declaration.

DECLARATION OF HELSINKI
 The World Medical Association first adopted the Declaration in 1964
and, subsequently, has revised the document five times. It is FDA's
responsibility to define the conditions under which it will consider
foreign clinical studies to be acceptable under the standards imposed
by the United States laws and regulations. In carrying out that
responsibility, in 1975 FDA incorporated the 1964 Declaration in its
regulation governing investigational drug trials conducted in non-
U.S. countries.
 Amendments:-
• The agency amended the regulation in 1981 to replace the 1964
Declaration with the 1975 version.
• Then in 1991 to replace the 1975 Declaration with the 1989 version.

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 FDA has repeatedly considered amendments to its regulations
governing foreign clinical studies not conducted under an IND. Each
time, FDA has incorporated amendments only after carefully
considering the impact of the amendment and revising its
regulations.
 FDA is currently reviewing its regulations pertaining to the
acceptance of foreign clinical studies, to determine if it should revise
those regulations to incorporate new or modified standards or
requirements.

• FDA Clinical Trials Guidance Documents:-
 Guidance documents represent the agency's current thinking on
protection of human subjects in research.
 Draft guidance documents have been proposed and are issued for
public comment.
 Draft Guidance Documents:-
1. Civil money penalties relating to the clinical trials
2. Pregnant women
3. Use of Electronic records and Electronic signatures in Clinical
Investigation
4. Informed Consent
5. Charging for Investigational Drugs
6. Humanitarian Device Exemption (HDE)

1. Civil Money Penalties Relating to the Clinical Trials: The Food and
Drug Administration has issued the draft guidance titled "Civil Money
Penalties Relating to the ClinicalTrials.gov Data Bank." The guidance
is intended for FDA staff, responsible parties, and submitters of certain
applications and submissions to FDA. This guidance document is
intended to describe the current thinking of FDA regarding civil
money penalties. That section authorizes FDA to assess civil money
penalties against responsible parties and/or submitters of certain
applications and submissions to FDA regarding drug products,
biological products, and device products.
2. Pregnant Women: This draft guidance discusses the ethical and
scientific issues when considering the inclusion of pregnant women in
clinical trials of drugs and biological products. This draft guidance is
intended to advance scientific research in pregnant women, and
discusses issues that should be considered within the framework of
human subject protection regulations.

3. Use of Electronic records and Electronic signatures in
Clinical Investigation: The goals of the draft guidance are to
clarify and update recommendations for applying and
implementing part 11 requirements in the current environment
of electronic systems used in clinical investigations and to
encourage and facilitates the use of electronic records and
systems to improve the quality and efficiency of clinical
investigations. The guidance discusses the procedures that may
be followed to help ensure that electronic records and electronic
signatures meet FDA requirements
4. Informed Consent: This draft guidance is intended to assist
IRBs, clinical investigators, and sponsors involved in clinical
investigations of FDA-regulated products in carrying out their
responsibilities related to informed consent. The guidance
provides the Agency’s recommendations and requirements for
informed consent to assure the protection of the rights and
welfare of human subjects in clinical investigations.

5. Charging for Investigational Drugs: This draft guidance is
intended to provide information for industry, researchers, and
physicians about the implementation of FDA’s regulation on
charging for investigational drugs under an Investigational New
Drug Application (IND) (21 CFR 312.8). It includes information
concerning charging for investigational drugs made available
under expanded access programs.
6. Humanitarian Device Exemption (HDE): This draft guidance
answers commonly asked questions about Humanitarian Use
Devices (HUDs) and the Humanitarian Device Exemption (HDE)
authorized under section 520(m) of the Federal Food, Drug, and
Cosmetic Act (the FD&C Act).

• EU: Clinical Research Regulation in European
Union (EMA):-
 Goal of Clinical Trial Regulation:- To create an environment that is
favorable to conducting clinical trials in the EU with high standards of
safety for participants and increased transparency of trials information.
 Regulation Requirements:-
1. Consistent rules for conducting clinical trials throughout the EU.
2. Information on the authorization, conduct and results of each clinical
trial carried out in the EU to be publicly available.
 Advantages:-
 Increase the efficiency of all trials in Europe with the greatest benefit.
 It aims to foster innovation and research.
 Avoid unnecessary duplication of clinical trials or repetition of
unsuccessful trials.

• The Main Characteristics of the Regulations
are:-
• Application procedure via a single entry point, the EU portal.
• A single set of documents to be prepared and submitted for the
application defined in Annexure I of the Regulation.
• Strictly defined deadlines for the assessment of clinical trial application.
• A harmonized procedure for the assessment of applications for clinical
trials
• Increased transparency as regards clinical trials and their outcomes.
• The involvement of the ethics committees in the assessment procedure
in accordance with the national law of the Member state.

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• Extension of the agreement principle to the whole authorization
process which, without compromising safety, will give sponsors, in
particular SMEs and academics, increased legal certainty.
• Simplified reporting procedures which will spare sponsors from
submitting broadly identical information separately to various bodies
and different Member States.
• Clinical trials conducted outside the EU, but referred to in a clinical
trial application within the EU, will have to comply with regulatory
requirements that are at least equivalent to those applicable in the EU.
• Union controls in Member states and third countries to ensure
that clinical trials rules are being properly supervised and
enforced.

• References:-
 Sharma H, Parekh S. Pharmaceutical Regulatory Affairs: Open Access
[Internet]. 2012 [cited 09 November 2018]. Available from:
https://www.omicsonline.org/open-access/clinical-trials-regulations-in-
india-2167-7689.1000e118.pdf
 Pamadi S. Medical device regulations in India [Internet].
Slideshare.net. 2015 [cited 09 November 2018]. Available from:
https://www.slideshare.net/surajpamadi/medical-device-regulations-in-
india
 Step by Step: Registration Process of Medical Devices in India
[Internet]. Morulaa.com. 2018 [cited 09 November 2018]. Available
from: http://www.morulaa.com/medical-device/step-by-step-process-to-
register-your-medical-device-in-india/
 Tiwari G, Tiwari R. INTELLECTUAL PROPERTY RIGHTS AND
DRUG REGULATORY AFFAIRS. NIRALI PRAKASHAN; 2016,
Page No. 8.9, 8.18-8.20, 8.23-8.24, 8.30 & 8.33.

• Continue…
 Guidance for Industry-Acceptance of Foreign Clinical Studies
[Internet]. Fda.gov. 2001 [cited 10 November 2018]. Available from:
https://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm
124939.pdf
 Proposed Regulations and Draft Guidances [Internet]. Fda.gov. 2018
[cited 12 November 2018]. Available from:
https://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalT
rials/ProposedRegulationsandDraftGuidances/default.htm
 Clinical Trial Regulation | European Medicines Agency [Internet].
Ema.europa.eu. 2018 [cited 12 November 2018]. Available from:
https://www.ema.europa.eu/en/human-regulatory/research-
development/clinical-trials/clinical-trial-regulation
 New drug application [Internet]. Slideshare.net. 2013 [cited 10
November 2018]. Available from:
https://www.slideshare.net/VKEkbote/new-drug-application