Subject Name: Clinical Research Regulations

Subject code : MRA103T

Chapter 5 : USA & EU Guidance

Q:1 Explain FDA approval to market a new drug.

• U.S Pharmacopoeia In 1906, Congress passed the original Food and Drugs Act, which requires that
drugs must meet official standards of strength and purity. However, in 1937, due to sulphanilamide
tragedy, the Federal Food, Drug and Cosmetic Act (of 1938) was enacted and added new provisions
that new drugs must be shown safe before marketing. Further, in 1962, the Kefauver-Harris
Amendment Act was passed which require that manufacturers must prove that drug is safe and effective
(for the claims made in labeling. The United States has perhaps the world’s most stringent standards
for approving new drugs. Drug approval standards in the United States are considered by many to be
the most demanding in the world. The Food and Drug Administration (FDA) is responsible for
protecting and promoting public health. Like general drug approval process, FDA's new drug approval
process is also accomplished in two phases: clinical trials (CT) and new drug application (NDA)
approval. FDA approval process begins only after submission of investigational new drug (IND)
application.
• The United States has perhaps the world’s most stringent standards for approving new drugs. Drug
approval standards in the United States are considered by many to be the most demanding in the world.
The Food and Drug Administration (FDA) is responsible for protecting and promoting public health.
Like general drug approval process, FDA's new drug approval process is also accomplished in two
phases: clinical trials (CT) and new drug application (NDA) approval. FDA approval process begins
only after submission of investigational new drug (IND) application.
• New drug application (NDA) A new drug application (NDA) can be filed only when the drug
successfully passes all three phases of clinical trials and includes all animal and human data, data
analyses, pharmacokinetics of drug and its manufacturing and proposed labeling. The preclinical,
clinical reports and risk- benefit analysis (product's beneficial effects outweigh its possible harmful
effects) is reviewed at the Centre for Drug Evaluation and Research by a team of scientists. If clinical
studies confirm that a new drug is relatively safe and effective, and will not pose unreasonable risks to
patients, the manufacturer files a New Drug Application (NDA), the actual request to manufacture and
sell the drug in the United States.
• Generally, approval of an NDA is granted within two years (on an average); however, this process can
be completed from two months to several years. The innovating company is allowed to market the drug
after the approval of an NDA and is considered to be in Phase IV trials. In this phase, new areas, uses
or new populations, long-term effects, and how participants respond to different dosages are explored.
FIGURE 2 describes the drug approval process in USA.
Administration process:
Requirements US
Agency One agency USFDA
Registration process One registration process
Application ANDA/NDA
Debarment classification Required
Number of copies 3
Approval timeline 18 months
Fees Under $2 million – NDA application
$1520 – ANDA application
Braille code Braille code is not required
on labeling
Post approval changes Post approval changes in approved
drug:
• Minor
• Moderate
• Major
Presentation eCTD and paper
 Fig: - Drug approval process in US

NEW DRUG APPLICATION (NDA):

If clinical studies confirm that a new drug is relatively safe and effective, and will not pose unreasonable risks
to patients, the manufacturer files a New Drug Application (NDA), the actual request to manufacture and sell
the drug in the United States. The process of NDA has been illustrated in figure
Figure: The Basic Regulation
Bioequivalence requirements

Requirements US
CRO Audited by FDA
(Audits)
Reserve sample 5 times the sample required for analysis
Fasted / Fed Must be as per OGD recommendation
Retention of sample 5 years from the date of filing
the application
BE study of generic drug SS Against US RLD in any country.
To refer “to be recommendations” in
FDA site for guidance.

Q:2 Define bioavailability & bioequivalence requirements with suitable

example.

See que 14.

Q:3 Explain FDA safety reporting requirements for INDs.

• Sponsors investigating a drug under an IND were required to notify FDA and all
participating investigators, in a written IND safety report, of any adverse experience
associated with the use of the drug that was both serious and unexpected, and any finding
from tests in laboratory animals that suggested a significant risk for human subjects.
• The phrase associated with the use of the drug was defined as “there is a reasonable
possibility that the experience may have been caused by the drug”.
• Notwithstanding this definition, sponsors frequently reported, as individual cases, serious
adverse experiences for which there were little reason to believe that the drug caused the
event. For example, sponsors often reported:
• Serious adverse experiences (e.g., mortality or major morbidity) that were likely to have been
manifestations of the underlying disease
• Serious adverse experiences that commonly occurred in the study population independent of drug
exposure (e.g., strokes or acute myocardial infarctions in an elderly population)
• Serious adverse experiences that were study endpoints (i.e., the study was evaluating whether the drug
reduced the rate of these events)
 • These types of reports are generally uninformative when reported as single events (i.e., without a
comparison of the incidence of the event in treated and untreated subjects), and they do not contribute
meaningfully to the developing safety profile of an investigational drug or to human subject protection.
• Attempting to review and evaluate these reports without the necessary context was also a drain on
resources for FDA, investigators, and institutional review boards (IRBs), diverting them from other
activities.
• The tendency for sponsors to report such uninformative individual cases seems to have been primarily
related to interpretation of the reasonable possibility standard in the definition of associated with the
use of the drug.
• For an individual case of the types of adverse events described above, there would generally not be
enough evidence to suggest that there was a reasonable possibility that the drug caused the adverse
event.
• Such events would therefore not meet the definition of “associated with the use of the drug” and should
not have been reported as IND safety reports.
• Amended requirements revise the definitions used for safety reporting and make clear when to submit
expedited safety reports.
• The requirements distinguish circumstances in which it is appropriate to submit individual cases and
circumstances in which cases should be aggregated and compared to cases in a control group and
submitted only if the event occurs more frequently in the drug treatment group.
• Compliance with these requirements will increase the likelihood that submitted information will be
interpretable and will meaningfully contribute to the developing safety profile of the investigational
drug and improve the overall quality of safety reporting.
• In addition, reducing the number of uninformative individual reports will enhance the ability of
sponsors, FDA, investigators, and IRBs to focus on safety issues that affect public health.
• Because the regulations require reporting certain adverse events in the aggregate rather than as
individual cases, it is important for sponsors to collect and evaluate safety data systematically during
product development, including accumulating safety data.

Q:4 S .N on pharmacovigilance for medicinal products for human use.

Introduction

• Pharmacovigilance has been defined by the World Health Organization as the science and activities relating
to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related
problem.

• This guidance is required to include technical requirements for the electronic exchange of pharmacovigilance
information in accordance with internationally agreed formats.
• In addition, the European Commission is also required to publish a reference to an internationally agreed
medical terminology.

• This Volume 9A has therefore been prepared by the European Commission in close consultation with the
Agency, Member States and interested parties and is specifically related to human pharmacovigilance.

• It brings together general guidance on the requirements, procedures, roles and activities in this field, for both
Marketing Authorization Holders and Competent Authorities of medicinal products for human use; it
incorporates international agreements reached within the framework of the International Conference on
Harmonisation (ICH).

• Volume 9A is presented in four parts: Part I deals with Guidelines for Marketing Authorization Holders. Part
II deals with Guidelines for Competent Authorities and the Agency. Part III provides the Guidelines for the
electronic exchange of pharmacovigilance in the EU. Part IV provides Guidelines on pharmacovigilance
communication. Part 1 – Guidelines for marketing authorization holders

• The Marketing Authorization Holder should ensure that he has an appropriate system of pharmacovigilance
in place in order to assume responsibility and liability for his products on the market and to ensure that
appropriate action may be taken when necessary.

• The Marketing Authorization Holder should therefore ensure that all information relevant to the risk-benefit
balance of a medicinal product is reported to the Competent Authorities and the Agency fully and promptly in
accordance with the legislation.

• The QPPV(Qualified Personnel Responsible for Pharmacovigilance) is responsible for Establishing and
maintaining/managing the Marketing Authorization Holder’s pharmacovigilance system. Having an overview
of the safety profiles and any emerging safety concerns in relation to the medicinal products for which the
Marketing Authorization Holder holds authorizations; Acting as a single contact point for the Competent
Authorities on a 24-hour basis.

• It is recognized that this important role of the QPPV may impose extensive tasks on the QPPV, depending
on the size and nature of the pharmacovigilance system and the number and type of medicinal products for
which the company holds authorizations.

• The QPPV may therefore delegate specific tasks, under supervision, to appropriately qualified and trained
individuals, e.g. acting as safety experts for certain products, provided that the QPPV maintains system
oversight and overview of the safety profiles of all products.

• Such delegation should be documented.

• The Marketing Authorization Holder should adequately support the QPPV and ensure that there are
appropriate processes, resources, communication mechanisms and access to all sources of relevant information
in place for the fulfillment of the QPPV’s responsibilities and tasks.
• The Marketing Authorization Holder should ensure that there is full documentation covering all procedures
and activities of the QPPV and that mechanisms are in place to ensure that the QPPV may receive or seek all
relevant information.

• The Marketing Authorization Holder should also implement mechanisms for the QPPV to be kept informed
of emerging safety concerns and any other information relating to the evaluation of the risk-benefit balance.

• This should include information from ongoing or completed clinical trials and other studies the Marketing
Authorization Holder is aware of and which may be relevant to the safety of the medicinal product, as well as
information from sources other than the specific Marketing Authorization Holder, e.g. from those with whom
the Marketing Authorization Holder has contractual arrangements. Part 2 – Guidelines for competent
authorities and the agency

• For centrally authorized products, the European Commission is the Competent Authority.

• As the Agency co-ordinates some of the pharmacovigilance activities on behalf of the European Commission,
the Agency should be understood as included in the term “Competent Authorities” for the purposes of this
guidance.

• To meet their legal requirements, Member States should undertake all appropriate activities, including the
following:

➢ To encourage reporting of suspected adverse reactions by Healthcare Professionals To facilitate

reporting of adverse reactions by Patients either directly to national Competent Authorities, or via
patient organizations, or via Healthcare Professionals, as appropriate in accordance with the national
system
➢ To maintain awareness of relevant pharmacovigilance publications through regular monitoring of the
scientific literature To initiate, as appropriate investigation and assessment of safety concerns
➢ To oblige Marketing Authorization Holders to systematically collect information on risks related to
their medicinal products and to transmit this information to the Competent Authorities and the Agency.
To ensure that Marketing Authorization Holders implement appropriate Risk Management Plans to
effectively monitor and manage risks associated with the safety of their products
➢ To monitor the impact and effectiveness of such Risk Management Plans and regulatory action taken
to enhance safe and appropriate use of medicinal products.
➢ To monitor the compliance of Marketing Authorization Holders in relation to the pharmacovigilance
activities.
➢ To implement conditions and restrictions with regard to the safe and effective use of centrally
authorized products, or products subject to referral procedures, on the basis of Commission Decisions.
➢ To interact with relevant international organizations, particularly the World Health Organization
(WHO), in accordance with agreed guidance and procedures.
➢ To communicate the outcome of evaluation of safety concerns as appropriate to Healthcare
 Professionals and as necessary to the public, through timely and appropriate methods of
communication and to assess the impact of such communications.
➢ To make Individual Case Safety Reports (ICSRs) available to the agency, competent Authorities of
other Member States and to the concerned Marketing Authorization Holders according to the criteria
laid down in legislation.
➢ To record electronic data and paper based ICSRs in a data base managed by National Competent
Authority.
• Each Member State should have in place systems for receipt and evaluation of all pharmacovigilance
data and to ensure that appropriate regulatory action may be taken.
• Such systems, whether involving distribution of activities through regional centre or operated fully
by a single national centre, within the Competent Authority, should ensure that pharmacovigilance data
are managed in a way that is compatible with the procedures undertaken in other Member States and
the Agency in order that pertinent data may be shared between Member States and the Agency. Part 3-
Guidelines for the electronic exchange of pharmacovigilance in the EU.
• Part 3 9A refers to the electronic exchange of pharmacovigilance information and provides a reference
to the preparation and electronic transmission of Individual Case Safety Reports (ICSRs).
• It applies to the national competent authorities, the European medicines agency and Marketing
authorization holders in EU.
• The standards to support the electronic transmission of ICSRs on an expedited and periodic basis are
defined in the frame of International Conference on Harmonisation of Technical requirements for
registration of pharmaceuticals for human use. • Taking into account the international dimension of
adverse reaction reporting and the need to achieve uniformity and high quality with regard to content
and format of ICSRs between all involved parties it is of utmost importance that all parties follow the
applicable ICH and EU guidelines.
• This applies in particular to electronic reporting, which requires strict adherence to uniform standards.
• The electronic re-transmission of cases refers to the electronic transmission of ICSRs between
multiple senders and receivers, e.g. where a case was first reported by the Marketing Authorization
Holder to the competent authorities in Member states as well as Iceland, Liechtenstein and Norway
and from there to the agency.
• Based on the reporting obligations in pharmacovigilance, ICSRs are re-transmitted between different
senders and receivers.
• During this re-transmission process, information on the case should not be omitted or changed if no
new information on the case is available to the re-transmitting sender.
• Exceptions are the following: Sender’s (case) safety report unique identifier Date of this transmission
Date report was first received from source for initial reports Date of receipt of the most recent
information for this report Sender and receiver details Relativeness of drug to reaction or events.
Senders diagnosis/syndrome and reclassification of reaction/event. Sender’s comments English
 translation of the free text fields in the ICSRs. Part 4 - Guidelines on pharmacovigilance
communication.
• In addition to the guideline “Direct Healthcare Professional Communications” it is anticipated that
further guidance for marketing authorization holders and competent authorities on pharmacovigilance
communication will be developed.
• Any new guideline will be subject to public consultation. • The aim of this guidance is to establish
principles for the content and format of Direct Healthcare Professional Communications (DHPCs)
(commonly called “Dear Doctor-letters” (DDL)), as well as describing situations where dissemination
of DHPCs should be considered.
• The guidance also aims to describe the main requirements and procedures for such communications
on the safe and effective use of medicinal products for human use. CLINICAL
• DHPCs relating to quality defects with medicinal products are outside the scope of this guidance.
• A Direct Healthcare Professional Communication (DHPC) is defined as information aimed at
ensuring safe and effective use of medicinal products which is delivered directly to individual
Healthcare Professionals by a Marketing Authorization Holder, or by a Competent Authority (this
excludes direct personal replies to requests from individual Health care Professional).
• Such DHPCs should not include any material or statement which might constitute advertising within
the scope of Title VIII of Directive 2001/83/EC, or which is considered to be promotional or
commercial by the Competent Authority.

Q:5 Discuss format used for IND application.

Introduction:-
• • There are 8 subparts of CFR 21 Part 312. They are:-

• 1. Subpart A- General Provisions

• 2. Subpart B- IND(Investigational New Drug Application)

• 3. Subpart C- Administrative actions

• 4. Subpart D- Responsibilities of sponsors and investigators

• 5. Subpart E- Drugs intended to life threatening and severely debilitating illness

• 6. Subpart F- Miscellaneous

• 7. Subpart G- Drugs for investigational use in laboratory research animals or in-vitro tests.

• 8. Subpart H- Expanded access to investigational drugs for treatment use.

1. Subpart A- General Provisions

▪ Scope:-

• This part contains procedures and requirements governing the use of investigational new drugs, including
procedures and requirements for the submission to, and review by, the Food and Drug Administration of
investigational new drug applications (IND's).
• An investigational new drug for which an IND is in effect in accordance with this part is exempt from the
premarketing approval requirements that are otherwise applicable and may be shipped lawfully for the purpose
of conducting clinical investigations of that drug.
▪ Applicability:-
• Except as provided in this section, this part applies to all clinical investigations of products that are subject
of the Federal Food, Drug, and Cosmetic Act or to the licensing provisions of the Public Health Service Act.
▪ Labeling of an investigational new drug:-
• The immediate package of an investigational new drug intended for human use shall bear a label with the
statement “Caution: New Drug - Limited by Federal (or United States) law to investigational use.”
• The label or labeling of an investigational new drug shall not bear any statement that is false or misleading
in any particular and shall not represent that the investigational new drug is safe or effective for the purposes
for which it is being investigated.
▪ Promotion of investigational drugs:-
• A sponsor or investigator, or any person acting on behalf of a sponsor or investigator, shall not represent in
a promotional context that an investigational new drug is safe or effective for the purposes for which it is under
investigation or otherwise promote the drug.
• This provision is not intended to restrict the full exchange of scientific information concerning the drug,
including dissemination of scientific findings in scientific or lay media.
• Rather, its intent is to restrict promotional claims of safety or effectiveness of the drug for a use for which it
is under investigation and to preclude commercialization of the drug before it is approved for commercial
distribution.
2. Subpart B- Investigational New Drug Application (IND)
▪ Requirement for IND:-
• A sponsor shall submit an IND to FDA if the sponsor intends to conduct a clinical investigation with an
investigational new drug.
• A sponsor shall not begin a clinical investigation until the investigation is subject to an IND.

• A sponsor shall submit a separate IND for any clinical investigation involving an exception from informed
consent.
• Such a clinical investigation is not permitted to proceed without the prior written authorization from FDA.
• FDA shall provide a written determination 30 days after FDA receives the IND or earlier.
▪ Phases of Investigation:-
• There are 3 phases of an investigation.
• They are:-

❖ Phase 1:- Phase 1 includes the initial introduction of an investigational new drug into humans.

❖ Phase 2:- Phase 2 includes the controlled clinical studies conducted to evaluate the effectiveness of the
drug for a particular indication or indications in patients with the disease or condition under study and to
determine the common short-term side effects and risks associated with the drug.

❖ Phase 3:- Phase 3 studies are expanded controlled and uncontrolled trials.

▪ IND content and format:-

• A sponsor who intends to conduct a clinical investigation subject to this part shall submit an “Investigational
New Drug Application” (IND) including, in the following order:

❖ Cover sheet

❖ A table of contents

❖ Introductory statement and general investigational plan

❖ Investigator’s brochure

❖ Protocol

❖ Chemistry, manufacturing and control information

❖ Pharmacology and Toxicology information

❖ Previous human experience with the investigational drug.

❖ Relevant information.

▪ Withdrawal of an IND:-
• At any time a sponsor may withdraw an effective IND without prejudice.
• If an IND is withdrawn, FDA shall be so notified, all clinical investigations conducted under the IND shall
be ended, all current investigators notified, and all stocks of the drug returned to the sponsor or otherwise
disposed of at the request of the sponsor.
• • If an IND is withdrawn because of a safety reason, the sponsor shall promptly so inform FDA, all
participating investigators, and all reviewing Institutional Review Boards, together with the reasons
for such withdrawal.
3. Administrative actions:-
▪ Comment and advice on IND:-
• FDA may at any time during the course of the investigation communicate with the sponsor orally or in writing
about deficiencies in the IND or about FDA's need for more data or information.
• On the sponsor's request, FDA will provide advice on specific matters relating to an IND.
• Examples of such advice may include advice on the adequacy of technical data to support an investigational
plan, on the design of a clinical trial, and on whether proposed investigations are likely to produce the data
and information that is needed to meet requirements for a marketing application.
• Unless the communication is accompanied by a clinical hold order, FDA communications with a sponsor
under this section are solely advisory and do not require any modification in the planned or ongoing clinical
investigations or response to the agency.
▪ Clinical holds and requests for modification:-
• A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical investigation or to
suspend an ongoing investigation.
• The clinical hold order may apply to one or more of the investigations covered by an IND.
• When a proposed study is placed on clinical hold, subjects may not be given the investigational drug.
• When an ongoing study is placed on clinical hold, no new subjects may be recruited to the study and placed
on the investigational drug; patients already in the study should be taken off therapy involving the
investigational drug unless specifically permitted by FDA in the interest of patient safety.
▪ Termination:-
• This section describes the procedures under which FDA may terminate an IND.

• If an IND is terminated, the sponsor shall end all clinical investigations conducted under the IND and recall
or otherwise provide for the disposition of all unused supplies of the drug.
• A termination action may be based on deficiencies in the IND or in the conduct of an investigation under
an IND.
• A termination shall be preceded by a proposal to terminate by FDA and an opportunity for the sponsor
to respond.
• FDA will, in general, only initiate an action under this section after first attempting to resolve differences
informally or, when appropriate, through the clinical hold procedures.
▪ Meetings:-
• Meetings between a sponsor and the agency are frequently useful in resolving questions and issues raised
during the course of a clinical investigation.
• FDA encourages such meetings to the extent that they aid in the evaluation of the drug and in the solution
of scientific problems concerning the drug, to the extent that FDA's resources permit.
▪ Dispute resolution:-
• The Food and Drug Administration is committed to resolving differences between sponsors and FDA
reviewing divisions with respect to requirements for IND's as quickly and amicably as possible through
the cooperative exchange of information and views.
4. Subpart D- Responsibilities of sponsors and investigators
▪ Transfer of obligations to a contract research organization:-
 • A sponsor may transfer responsibility for any or all of the obligations set forth in this part to a contract
research organization. Any such transfer shall be described in writing. If not all obligations are transferred,
the writing is required to describe each of the obligations being assumed by the contract research
organization. If all obligations are transferred, a general statement that all obligations have been transferred
is acceptable. Any obligation not covered by the written description shall be deemed not to have been
transferred.
▪ Informing investigators:-
• Before the investigation begins, a sponsor shall give each participating clinical investigator an
investigator brochure containing the information.
▪ Disposition of unused supply of investigational drug:-

• The sponsor shall assure the return of all unused supplies of the investigational drug from each individual
investigator whose participation in the investigation is discontinued or terminated.

▪ General responsibilities of investigators:-

• An investigator is responsible for ensuring that an investigation is conducted according to the signed
investigator statement, the investigational plan, and applicable regulations; for protecting the rights,
safety, and welfare of subjects under the investigator's care; and for the control of drugs under
investigation.

▪ Control of the investigational drug:-

• An investigator shall administer the drug only to subjects under the investigator's personal supervision
or under the supervision of a sub-investigator responsible to the investigator.

• The investigator shall not supply the investigational drug to any person not authorized under this part to
receive it.

5. Drugs intended to treat life threatening and severely debilitating illness:-

▪ Early consultation:-

• For products intended to treat life-threatening or severely-debilitating illnesses, sponsors may request to meet
with FDA-reviewing officials early in the drug development process to review and reach agreement on the
design of necessary preclinical and clinical studies.

• Where appropriate, FDA will invite to such meetings one or more outside expert scientific consultants or
advisory committee members.

• To the extent FDA resources permit, agency reviewing officials will honor requests for such meetings.

▪ Treatment protocols:-
• If the preliminary analysis of phase 2 test results appears promising, FDA may ask the sponsor to submit a
treatment protocol to be reviewed under the procedures and criteria.

▪ Phase 4 studies:-

• Concurrent with marketing approval, FDA may seek agreement from the sponsor to conduct certain post-
marketing (phase 4) studies to delineate additional information about the drug's risks, benefits, and optimal
use.

▪ Focused FDA regulatory research:-

• At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting
aspects of the preclinical, chemical/manufacturing, and clinical phases of drug development and evaluation.

6. Miscellaneous:-

▪ Availability for public disclosure of data and information in an IND:-

• The existence of an investigational new drug application will not be disclosed by FDA unless it has
previously been publicly disclosed or acknowledged.

▪ Address for correspondence:-

• A sponsor must send an initial IND submission to the Center for Drug Evaluation and Research (CDER) or
to the Center for Biologics Evaluation and Research (CBER), depending on the Center responsible for
regulating the product as follows:

Drug products regulated by CDER

Biological products regulated by CDER

Biological products regulated by CBER

IND, the responsible Center will inform the sponsor which one of the divisions in CDER or CBER is
responsible for the IND.

7. Subpart G- Drugs for investigational use in laboratory research animals or in-vitro tests:-

• A person may ship a drug intended solely for tests in vitro or in animals used only for laboratory research
purposes if it is labeled as follows:

CAUTION: Contains a new drug for investigational use only in laboratory research animals or for tests in
vitro. Not for use in humans.
• A person shipping a drug shall use due diligence to assure that the consignee is regularly engaged in
conducting such tests and that the shipment of the new drug will actually be used for tests in vitro or in animals
used only for laboratory research.
• A person who ships a drug shall maintain adequate records showing the name and post office address of the
expert to whom the drug is shipped and the date, quantity, and batch or code mark of each shipment and
delivery.
• The person who ships the drug shall assure the return of all unused supplies of the drug from individual
investigators whenever the investigation discontinues or the investigation is terminated.
8. Subpart H- Expanded access to investigational drugs for treatment use:-
▪ Requirements for all expanded access uses:-

• The criteria, submission requirements, safeguards, and beginning treatment information set out in this section
apply to all expanded access uses described in this subpart.
• Additional criteria, submission requirements, and safeguards that apply to specific types of expanded access.
▪ Individual patients, including for emergency use:-
• Under this section, FDA may permit an investigational drug to be used for the treatment of an individual
patient by a licensed physician.
▪ Intermediate-size patient populations:-
Under this section, FDA may permit an investigational drug to be used for the treatment of a patient population
smaller than that typical of a treatment IND or treatment protocol.
FDA may ask a sponsor to consolidate expanded access under this section when the agency has received a
significant number of requests for individual patient expanded access to an investigational drug for the same
use.

Q:6 Note on : Pharmacovigilance. (CFR 21 Part 822 Post market

surveillance)

• The CFR is the codification of the general and permanent rules and regulations published in the Federal
Register by the executive departments and agencies of the federal government of the United States.
The CFR is divided into 50 titles that represent broad areas subject to federal regulation.
• Post marketing surveillance is the practice of monitoring the safety of a pharmaceutical drug or medical
device after it has been released on the market and is an important part of the science of
pharmacovigilance

➢ SUB PARTS:
 Sub part A - General provisions
Sub part B - Notification
Sub part C - Post market surveillance plan
Sub part D - FDA Reviews and action
Sub part E - Responsibilities of manufacturer’s
Sub part F - Waivers and Exemptions
Sub part G - Records and reports

Sub part A- General provisions

➢ What does this part cover?

• This part implements section 522 of the Federal Food, Drug, and Cosmetic Act (the act) by providing
procedures and requirements for post market surveillance.
➢ What is the purpose of this part?
• The purpose of this part is to implement our post market surveillance authority to maximize the
likelihood that PMS plans will result in the collection of useful data. These data can reveal unforeseen
adverse events, the actual rate of anticipated adverse events, or other information necessary to protect
the public health.

Sub part B - Notification

Sec. 822.5 How will I know if I must conduct post market surveillance?

• We will send you a letter notifying you of the requirement to conduct post market surveillance.

Sec. 822.6 When will you notify me that I am required to conduct post market surveillance?

• They will notify during the review of a marketing application for your device, as your device goes to
market, or after your device has been marketed for a period of time.

Sec. 822.7 What should I do if I do not agree that post market surveillance is appropriate?

• If you do not agree you may request review of our decision by requesting a meeting with the Director
Office of Surveillance and Biometrics, who generally issues the order for post market surveillance.

Sub part C - Post market surveillance plan (822.8 822.15)

Sec. 822.8 When I submit my post market surveillance plan?

• You must submit your plan within 30 days of the date you receive the post market surveillance order.

Sec. 822.9 What must I include in my submission?

• Your submission must include the following:

 - Organizational/administrative information.
- Post market surveillance plan.
- Designated person information.

Sec. 822.10 What must I include in my surveillance plan?

• It includes:
- The investigator agreement, if applicable;
- Sources of data, e.g., hospital records;
- The data collection plan and forms;
- Sample size and units of observation.

Sec. 822.11 What should I consider when designing my plan to conduct post market surveillance?

• If any, patient protection measures should be incorporated into your plan.

Sec. 822.12 Do you have any information that will help me prepare my submission or design my post market
surveillance plan?

• Guidance documents that discuss our current thinking on preparing a post market surveillance
submission and designing a post market surveillance plan are available.

Sec. 822.13 [Reserved].

Sec. 822.14 May I reference information previously submitted instead of submitting it again?

• Yes, you may reference information that you have submitted in premarket submissions as well as other
post market surveillance submissions.

Sec. 822.15 How long must I conduct post market surveillance of my device?

• The length of post market surveillance will depend on the post market surveillance question identified
in our order. We may order prospective surveillance for a period up to 36 months, longer periods
require your agreement.

Sub part D - FDA Reviews and action (822.16 -822.23)

Sec. 822.16 What will you consider in the review of my submission?

• First, we will determine that the submission is administratively complete. Then, in accordance with the
law whether the designated person has appropriate qualifications and experience

Sec. 822.17 How long will your review of my submission take?

• We will review your submission within 60 days of receipt

Sec. 822.18 How will I be notified of your decision?

 • We will send you a letter notifying you of our decision and identifying any action you must take.

Sec. 822.19 What kinds of decisions may you make?

If your plan: Then we will send you: And you must:

Should result in the An approval order, Conduct post market
collection of useful data identifying any specific surveillance of your
that will address the post requirements related to device in accordance with
market surveillance your post market the approved plan
question surveillance
Is not likely to result in the A letter disapproving your Revise your post market
collection of useful data plan and identifying the surveillance submission
that will address the post reasons for disapproval and submit it to us within
market surveillance the specified timeframe.
question We will determine the
timeframe case-by-case,
based on the types of
revisions or information
that you must submit

Sec. 822.20 What are the consequences if I fail to submit a post market surveillance plan?

• If fail to submit plan then failure to comply with section 522 of the act. Your failure would be a
prohibited act under section 301(q)(1)(C) of the act, and your device would be misbranded under
section 502(t)(3) of the act.

Sec. 822.21 What must I do if I want to make changes to my post market surveillance plan after you have
approved?

• You must submit three copies of the request to make the proposed change and revised post market
surveillance plan to the applicable address with making changes in your plan that will not affect the
nature or validity of the data.

Sec. 822.22 What recourse do I have if I do not agree with your decision?

• Requesting a meeting with the individual who issued the order for post market surveillance
• Seeking internal review of the order under part 10.75 of this chapter
• Requesting an informal hearing under part 16 of this chapter

Sec. 822.23 Is the information in my submission considered confidential?

 • We consider the content of your submission confidential until we have approved your post market
surveillance plan.

Sub part E - Responsibilities of manufacturer’s (822.4 – 822.8)

Sec. 822.24 What are my responsibilities once I am notified that I am required to conduct post market
surveillance?

• You must submit your plan to conduct post market surveillance to us within 30 days from receipt of
the order (letter) notifying you that you are required to conduct post market surveillance of a device.

Sec. 822.25 What are my responsibilities after my post market surveillance plan has been approved?

• After we have approved your plan, you must conduct the post market surveillance of your device in
accordance with your approved plan.

Sec. 822.26 If my company changes ownership, what must I do?

• You must notify us within 30 days of any change in ownership of your company.

Sec. 822.27 If I go out of business, what must I do?

• You must notify us within 30 days of the date of your decision to close your business. You should
provide the expected date of closure and discuss your plans to complete or terminate post market
surveillance of your device.

Sec. 822.28 If I stop marketing the device subject to post market surveillance, what must I do?

• You may request that we allow you to terminate post market surveillance or modify your post market
surveillance because you no longer market the device.

Sub part F - Waivers and Exemptions (822.29 – 822.30)

Sec. 822.29 May I request a waiver of a specific requirement of this part?

• You may request that we waive any specific requirement of this part. You may submit your request,
with supporting documentation, separately or as a part of your post market surveillance submission to
the address.

Sec. 822.30 May I request exemption from the requirement to conduct post market surveillance?

• You may request exemption from the requirement to conduct post market surveillance for your device
or any specific model of that device at any time.

Sub part G - Records and reports (822.31 – 822.38)

Sec. 822.31 What records am I required to keep?

 • You must keep copies of:
- All correspondence with your investigators or FDA, including required reports;
- Your approved post market surveillance plan, with documentation of the date and reason for any
deviation from the plan;
- All data collected and analyses conducted in support of your post market surveillance plan.

Sec. 822.32 What records are the investigators in my surveillance plan required to keep?

• Your investigator must keep copies of:

- All correspondence between investigators, FDA, the manufacturer, and the designated person,
including required reports.
- The approved post market surveillance plan, with documentation of the date and reason for any
deviation from the plan.
- All data collected and analyses conducted at that site for post market surveillance.

Sec. 822.33 How long must we keep the records?

• You, the designated person, and your investigators must keep all records for a period of 2 years after
we have accepted your final report.

Sec. 822.34 What must I do with the records if the sponsor of the plan or an investigator in the plan changes?

• you must ensure that all records related to the post market surveillance have been transferred to the
new sponsor or investigator and notify us within 10 working days of the effective date of the change.

Sec. 822.35 Can you inspect my manufacturing site or other sites involved in my post market surveillance
plan?

• We can review your post market surveillance programs during regularly scheduled inspections initiated
to investigate recalls or other similar actions, and inspections initiated specifically to review your post
market surveillance plan.

Sec. 822.36 Can you inspect and copy the records related to my post market surveillance plan?

• We may, at a reasonable time and in a reasonable manner, inspect and copy any records pertaining to
the conduct of post market surveillance that are required to be kept by this regulation.

Sec. 822.37 Under what circumstances would you inspect records identifying subjects?

• We are likely to be interested in such records if we have reason to believe that required reports have
not been submitted, or are incomplete, inaccurate, false, or misleading.

Sec. 822.38 What reports must I submit to you?

• You must submit interim and final reports as specified in your approved post market surveillance plan.
Q:7 Write in brief about the EMEA guidelines for medicinal products
containing GMOs.

Introduction:
• This guideline outlines the legislative framework governing the inclusion of Environmental Risk
Assessment particulars in applications for Marketing Authorisation (MA) for medicinal products
consisting of, or containing, a Genetically Modified Organism.
• The document also provides:
- An outline of the various special administrative and procedural details associated with the
applications involved.
- A description of the environmental risk assessment methodology and scientific issues and data
which applicants should address in the relevant parts of the application dossiers.
Scope:
• The application of the Centralised procedure to MA applications for medicinal products containing
GMO(s) as or in medicinal products constitutes the scope of this guideline. Although applications for
conducting clinical trials using such products fall outside the scope of the guideline, Section 4.2 of the
document may prove useful to the design and conduct of such trials, especially if conducted with a
view to submitting a future MA application for the product.

Overview of European legislation and guidance on the ERA of medicinal products and GMOs

Type Designation Scope and relevance for ERA

Directive 2001/83/EC community code relating to medical
products for human use
→ general requirement for evaluation of the
potential environmental risk posed by
medicinal products
Regulation (EC) No 726/2004 laying down procedures for the authorisation
and supervision of medicinal products for
human and veterinary use and establishing a
European Medicines Agency
→requirement for ERA performed in
accordance with the principles set out in
Annex II and based on information required
by Annex III and IV to Directive
2001/18/EC if medicinal product contains a
GMO
 Directive 2001/18/EC requirement for deliberate release into the
environment of GMOs
Commission 202/623/EC establishes guidance notes supplementing
Decision Annex II to Directive 2001/18/EC
Guideline(a) EMEA/CHMP/BWP provides guidance on the ERA for medicinal
/473191/06 Corr products containing GMOs
Guideline(b) EMEA/CHMP/GTW provides guidance on scientific requirements
P/125491/06 for the ERA of GTMPs containing GMOs
Guideline(c) EMEA/CHMP/SWP/ Provides guidance on the ERA for medicinal
4447/00 products for human use that do not contain
GMOs

CHMP: Committee For Medicinal Products For Human Use

EMEA: European Medicines Agency

MAIN GUIDELINE TEXT

➢ Procedures for the Evaluation of the ERA and its integration into the Centralised Procedure
1. Presentation of the GMO-ERA data in the MA application dossier
2. Appointment of assessor(s) for the Module 1.6.2 data
3. Consultation on the ERA with bodies established under Directive 2001/18/EC
4. Involvement of CHMP working parties in the ERA assessment
5. Centralised procedure steps integrating the evaluation of the ERA
6. Information to the public

➢ Information requirements for module 1.6.2, and the objectives and principles of the environmental risk
assessment to be performed
• Objective
Applicants are reminded that the objective of the ERA exercise is stated in Annex IIA of Directive
2001/18/EC, i.e. the objective of an ERA is, on a case by case basis, to identify and evaluate
potential adverse effects of the GMO, either direct or indirect, immediate or delayed, on human
health and the environment which the placing on the market of the GMO may exert; the ERA
should be conducted with a view to evaluating if there is a need for risk management, and if so, the
most appropriate methods to be used.
• General principles
Applicants are reminded that the general principles which should be followed when performing an
ERA are listed in Annex IIB of Directive 2001/18/EC, and include a comparison of the GMO with
 the non-GM organism, the application of a scientific case-by-case stepwise approach, and a
consideration of the possibilities for cumulative long term effects.
• Methodology
The Methodology section of Commission Decision 2002/623/EC begins with a statement that the
ERA has to take into account the relevant technical and scientific details regarding characteristics
of:

- The recipient or parental organism(s).

- The genetic modification(s), be it inclusion or deletion of genetic material, and relevant

information on the vector and the donor.

- The GMO.

- The intended release or use including its scale.

- The potential receiving environment.

- The interaction between these.

Steps in the ERA The following six steps should be addressed in sequence as the main topics in the ERA.

Step 1. Identification of characteristics which may cause adverse effects.

Step 2. Evaluation of the potential consequences of each adverse effect, if it occurs, and of the magnitude of
each identified consequence.

Step 3. Evaluation of the likelihood of the occurrence of each identified potential adverse effect.

Step 4. Estimation of the risk posed by each identified characteristic of the GMO.

Step 5. Application of management strategies for risks from the marketing of the GMO.

Step 6. Determination of the overall risk of the GMO.

Q:8 Highlight the requirements of safety reports for pharmacokinetic

studies as per USFDA.

• The person conducting a BA or BE study, including any contract research organization, must notify
FDA and all participating investigators of any serious adverse event observed during conduct of
the study, regardless of whether the event is considered drug related, as soon as possible but in no
case later than 15 calendar days after becoming aware of its occurrence.
 • This includes, for example, serious adverse events listed in the reference listed product’s approved
labeling, the investigator brochure, and protocol.
• Serious adverse events, whether observed in the investigational drug group or in the approved drug
group (e.g., reference listed drug), must be reported.
• If any information necessary to evaluate the serious adverse event is missing or unknown, the
person conducting the study should actively seek such information and maintain records of efforts
made to obtain additional information.
• Any relevant additional information that is obtained that pertains to a previously submitted safety
report must be submitted as a follow up Bioavailability/Bioequivalence Safety Report as soon as
the information is available, but should be submitted no later than 15 calendar days after the sponsor
receives the information.
• In addition, upon request from FDA, the person conducting the study must submit to FDA any
additional data or information that FDA deems necessary as soon as possible, but in no case later
than 15 calendar days after receiving the request (e.g., hospital record, autopsy report).
• If the adverse event is fatal or life-threatening, the person conducting the study must also notify the
Clinical Safety Coordinator in CDER’s Office of Generic Drugs as soon as possible but in no case
later than 7 calendar days after becoming aware of its occurrence.
• We recommend that these notifications be made by telephone, email, or facsimile transmission.

Q:9 Discuss the applicability of following in the healthcare industry :-

(i) ISO 14155:2011 (ii) EUDRALAX Vol. 9A(see que no 4)

(i) ISO 14155:2011

Introduction:

• ISO 14155 provides a detailed framework for the design, conduct and reporting of clinical
investigations involving human subjects for the purposes of assessing the safety or performance of
many types of medical devices (in-vitro diagnostic medical devices are excluded from the scope of the
standard).
• Originally published in 1996, the standard has been extensively revised over the past 20 years to more
effectively address the specific investigation requirements for medical devices, and to better align its
requirements with those of the Good Clinical Practice (GCP) guidelines developed by the International
Conference on Harmonization (ICH).
• The current version of the standard, ISO 14155:2011, which replaced ISO 14155:2003 Parts 1 and 2,
is now closely harmonized with GCP guidelines.
• These guidelines have served as the basis for regulatory requirements applicable to clinical
investigations of pharmaceutical products and medical devices in many jurisdictions around the world.
 • While some differences remain between GCP guidelines and ISO 14155 requirements (partially
explained by ISO 14155’s focus on clinical investigations with medical devices), data collected
through clinical investigations conducted in according with ISO 14155 is being more widely accepted
by regulators as part of the medical device pre-market approval application process.

Key elements of ISO 14155:

• ISO 14155:2011 consists of 6 separate clauses that provide specific requirements applicable to clinical
investigations for medical devices.
• The following sections provide details on each of the key clauses:

Clause 1:- Ethical considerations

• The essential ethical requirements of ISO 14155 are intended to protect the rights, safety and well-
being of the human subjects that are part of a clinical investigation.
• Adherence to these core principles outweighs any other commercial or scientific concerns.
• Specific ethical provisions include:-
- Improper influence or inducement: Both the study sponsor(s) and investigator(s) must avoid any
improper influence on, or the inducement of, any of the parties involved in the clinical
investigation.
- Compensation for human subjects: Compensation for subjects participating in clinical
investigation is permitted if allowable under applicable natural regulations.
- Oversight communications: An independent ethics committee must be appointed to protect the
rights, safety and wellbeing of investigational subjects.
- Vulnerable populations: The use of members as vulnerable populations as study subjects are not
permitted, except when an investigation cannot be otherwise conducted.
- Informed consent: ISO 14155 requires all study participants to give their informed consent in
writing prior to their involvement in the clinical investigation.

Clause 2:- Clinical Investigation Planning

• Prior planning to the clinical investigation is a key element of ISO 14155 requirements.
• The standard requires undertaking the following planning activities in advance of any clinical
investigation:-
- Risk analysis: A risk analysis consistent with the requirements of ISO 14971 must be conducted
to identify the potential risk and adverse effect to which investigation subjects must be exposed.
- Justification: A justification for the design of the clinical investigation must be prepared based on
evaluation of preclinical data and the result of clinical evaluation of the medical device.
- Clinical Investigation Plan: A clinical investigation plan (CIP) must be developed.
- Investigators brochure: The investigator’s brochure provides the investigator(s) with sufficient
device safety or performance data to justify human exposure during an investigation.
 - Case report form: Case report forms must be developed to collect and record data for each subject
during a clinical investigation.

Clause 3:- Clinical Investigation conduct

• Clinical investigations conducted under ISO 14155 cannot commence until written approval has been
provided by the investigation’s ethics committee and, if required, the relevant regulatory authorities
where the clinical investigation is being conducted.
• Subsequent to those approvals, clinical investigation sponsors and investigators must address the
following requirements:
- INVESTIGATION SITE INITIATION: An initiation meeting or visit is required for each
investigation site. A log of attendees, their functions and scope of authority must be created to
document the meeting.
- INVESTIGATION SITE MONITORING: Monitoring of investigation activities in accordance
with clinical investigation plan must be conducted, per the monitoring plan detailed above.
- ADVERSE EVENTS AND DEVICE DEFICIENCIES: All adverse events and deficiencies related
to the medical device under investigation must be documented as they occur and in a timely
manner. They then need to be reported, as per the requirements
- OTHER DOCUMENTS AND DOCUMENTATION: Amendments and changes to all required
forms and documents must be properly documented and include a statement justifying the change.
A log of subjects enrolled in the clinical investigation must be maintained.
- DOCUMENT AND DATA CONTROL: Documents and data generated during a clinical
investigation must be produced and maintained in a manner that assures their control and
traceability.
- DEVICE ACCOUNTABILITY: Access to medical devices that are the focus of a clinical
investigation must be controlled, and their use limited exclusively to the investigation in
accordance with the CIP.
- SUBJECT ACCOUNTABILITY: Human subjects enrolled in a clinical investigation must be
documented and accounted for during the course of the study. In cases where a subject withdraws
from a clinical investigation, the reason for their withdrawal must be recorded.
- AUDITING: When deemed appropriate by an investigation’s sponsor, an audit of the clinical
investigation may be conducted by the sponsor or an appointed third-party to assess compliance
with the CIP.

Clause 4:- Close-out of clinical investigation

• This clause of the standard addresses procedures for closing out a clinical investigation, including
instances in which an investigation is suspended or terminated for significant reasons.
• Specific provisions of this clause include:
 - SUSPENSION OR PREMATURE TERMINATION: A clinical investigation may be suspended
or prematurely terminated by the investigation sponsor, the principal investigator, the ethics
committee or a regulatory authority. Reasons for suspending or terminating an investigation
include unacceptable risks to study subjects, or serious or repeated deviations by the investigator
from the CIP. The party terminating an investigation must document in writing the reasons for its
action and report it as per the requirements.
- ROUTINE CLOSE-OUT OF INVESTIGATION: The standard stipulates a number of reporting
and notification actions to be conducted upon the completion of a clinical investigation. These
actions are intended to ensure that all records and documents are complete, that all open issues
related to the investigation have been resolved, and that any remaining clinical investigation
materials have been properly disposed of.
- CLINICAL INVESTIGATION REPORT: Upon the completion or termination of a clinical
investigation, a final written report must be prepared that identifies the medical device that was
evaluated in the investigation, a description of the methodology and the design of the investigation,
and an analysis of the data. A copy of the report should be provided to the ethics committee and
regulatory authorities.
- DOCUMENT RETENTION: Copies of the final clinical investigation report and all relevant
clinical investigation documents must be retained by the investigation sponsor and principal
investigator as required under applicable regulatory requirements.

Clause 5:- Responsibilities of the sponsor

• This clause enumerates the principle responsibilities of the sponsor of a clinical investigation.
• In general, these responsibilities include the planning and conduct of the clinical investigation within
prescribed quality assurance and quality control principles.
• The clause expressly permits a sponsor to contract with a CRO to perform the duties and functions
related to a clinical investigation.
• However, in such cases the sponsor must retain responsibility for the quality and integrity of the clinical
investigation data.

Clause 6:- Responsibilities of the principle investigator

• Clause 6 of ISO 14155 details the specific qualifications and responsibilities of the principal
investigator in a clinical investigation.
• These responsibilities include the implementation and management of the day-to-day activities of the
investigation in accordance with the CIP, ensuring the integrity of investigation data, and safeguarding
the rights, safety and well-being of the human subjects involved in the study

Q:10 Discuss the purpose , scope, recordkeeping in context of CFR 21 part

54.
Purpose:

• The Food and Drug Administration (FDA) evaluates clinical studies submitted in marketing
applications, required by law, for new human drugs and biological products and marketing applications
and reclassification petitions for medical devices.
• The agency reviews data generated in these clinical studies to determine whether the applications are
approvable under the statutory requirements.
• FDA may consider clinical studies inadequate and the data inadequate if, among other things,
appropriate steps have not been taken in the design, conduct, reporting, and analysis of the studies to
minimize bias.
• FDA will use this information, in conjunction with information about the design and purpose of the
study, as well as information obtained through on-site inspections, in the agency's assessment of the
reliability of the data.

Scope:

• The requirements in this part apply to any applicant who submits a marketing application for a human
drug, biological product, or device and who submits covered clinical studies.
• The applicant is responsible for making the appropriate certification or disclosure statement where the
applicant either contracted with one or more clinical investigators to conduct the studies or submitted
studies conducted by others not under contract to the applicant.

Recordkeeping and record retention:

(a) Financial records of clinical investigators to be retained.

• An applicant who has submitted a marketing application containing covered clinical studies shall keep
on file certain information pertaining to the financial interests of clinical investigators who conducted
studies on which the application relies and who are not full or part-time employees of the applicant, as
follows:
1. Complete records showing any financial interest or arrangement as described in § 54.4(a)(3)(i) paid to
such clinical investigators by the sponsor of the covered study.
2. Complete records showing significant payments of other sorts, as described in § 54.4(a)(3)(ii), made
by the sponsor of the covered clinical study to the clinical investigator.
3. Complete records showing any financial interests held by clinical investigators as set forth in §
54.4(a)(3)(iii) and (a)(3)(iv).

(b) Requirements for maintenance of clinical investigators' financial records.

1. For any application submitted for a covered product, an applicant shall retain records as described in
paragraph (a) of this section for 2 years after the date of approval of the application.
The person maintaining these records shall, upon request from any properly authorized officer or employee
of FDA, at reasonable times, permit such officer or employee to have access to and copy and verify these
records.

Q:11 Outline the main components of an IND application

➢ Requirement for IND:-

• A sponsor shall submit an IND to FDA if the sponsor intends to conduct a clinical investigation with
an investigational new drug.
• A sponsor shall not begin a clinical investigation until the investigation is subject to an IND.
• A sponsor shall submit a separate IND for any clinical investigation involving an exception from
informed consent.
• Such a clinical investigation is not permitted to proceed without the prior written authorization from
FDA.
• FDA shall provide a written determination 30 days after FDA receives the IND or earlier.
➢ Phases of Investigation:-
• There are 3 phases of an investigation.
• They are:-
❖ Phase 1:- Phase 1 includes the initial introduction of an investigational new drug into humans.
❖ Phase 2:- Phase 2 includes the controlled clinical studies conducted to evaluate the
effectiveness of the drug for a particular indication or indications in patients with the disease
or condition under study and to determine the common short term side effects and risks
associated with the drug.
❖ Phase 3:- Phase 3 studies are expanded controlled and uncontrolled trials.
➢ IND content and format:-
• A sponsor who intends to conduct a clinical investigation subject to this
part shall submit an “Investigational New Drug Application” (IND) including, in the following order:
❖ Cover sheet: it contains,
✓ The name, address, and telephone number of the sponsor,
✓ the date of the application, and the name of the investigational new drug.
✓ Identification of the phase or phases of the clinical investigation to be conducted.
✓ A commitment not to begin clinical investigations until an IND covering the investigations
is in effect.
✓ The name and title of the person responsible for monitoring the conduct and progress of the
clinical investigations.
✓ The signature of the sponsor or the sponsor's authorized representative.
 ✓ If the person signing the application does not reside or have a place of business within the
United States, the IND is required to contain the name and address of, and be countersigned
by, an attorney, agent, or other authorized official who resides or maintains a place of
business within the United States.
❖ A table of contents
❖ Introductory statement and general investigational plan:
✓ A brief introductory statement giving the name of the drug and all active ingredients, the
drug's pharmacological class, the structural formula of the drug (if known), the formulation
of the dosage form(s) to be used, the route of administration, and the broad objectives and
planned duration of the proposed clinical investigation(s).
✓ A brief summary of previous human experience with the drug, with reference to other IND's
if pertinent, and to investigational or marketing experience in other countries that may be
relevant to the safety of the proposed clinical investigation(s).
✓ If the drug has been withdrawn from investigation or marketing in any country for any
reason related to safety or effectiveness, identification of the country (ies) where the drug
was withdrawn and the reasons for the withdrawal.
❖ Investigator’s brochure: it contains,
(i) A brief description of the drug substance and the formulation, including the structural
formula, if known.
(ii) A summary of the pharmacological and toxicological effects of the drug in animals and, to
the extent known, in humans.
(iii) A summary of the pharmacokinetics and biological disposition of the drug in animals and, if
known, in humans
(iv) A summary of information relating to safety and effectiveness in humans obtained from
prior clinical studies
(v) A description of possible risks and side effects to be anticipated on the basis of prior
experience with the drug under investigation or with related drugs, and of precautions or special
monitoring to be done as part of the investigational use of the drug.
❖ Protocol:
✓ A protocol for each planned study,
✓ protocols for Phase 1 studies may be less detailed and more flexible than protocols for Phase
2 and 3 studies. Phase 1 protocols should be directed primarily at providing an outline of the
investigation - an estimate of the number of patients to be involved, a description of safety
exclusions, and a description of the dosing plan including duration, dose, or method to be
used in determining dose - and should specify in detail only those elements of the study that
are critical to safety, such as necessary monitoring of vital signs and blood chemistries.
✓ Modifications of the experimental design of Phase 1 studies that do not affect critical safety
assessments are required to be reported to FDA only in the annual report.
 ✓ In Phases 2 and 3, detailed protocols describing all aspects of the study should be submitted.
✓ A protocol for a Phase 2 or 3 investigation should be designed in such a way that, if the
sponsor anticipates that some deviation from the study design may become necessary as the
investigation progresses, alternatives or contingencies to provide for such deviation are built
into the protocols at the outset. For example, a protocol for a controlled short-term study
might include a plan for an early crossover of nonresponders to an alternative therapy.
❖ Chemistry, manufacturing and control information:
✓ As appropriate for the particular investigations covered by the IND, a section describing the
composition, manufacture, and control of the drug substance and the drug product.
✓ Although in each phase of the investigation sufficient information is required to be
submitted to assure the proper identification, quality, purity, and strength of the
investigational drug, the amount of information needed to make that assurance will vary
with the phase of the investigation, the proposed duration of the investigation, the dosage
form, and the amount of information otherwise available.
✓ FDA recognizes that modifications to the method of preparation of the new drug substance
and dosage form and changes in the dosage form itself are likely as the investigation
progresses.
✓ Therefore, the emphasis in an initial Phase 1 submission should generally be placed on the
identification and control of the raw materials and the new drug substance.
✓ Final specifications for the drug substance and drug product are not expected until the end of
the investigational process.
❖ Pharmacology and Toxicology information:
✓ Adequate information about pharmacological and toxicological studies of the drug involving
laboratory animals or in vitro, on the basis of which the sponsor has concluded that it is
reasonably safe to conduct the proposed clinical investigations.
✓ The kind, duration, and scope of animal and other tests required varies with the duration and
nature of the proposed clinical investigations.
✓ Guidance documents are available from FDA that describe ways in which these
requirements may be met.
✓ Such information is required to include the identification and qualifications of the
individuals who evaluated the results of such studies and concluded that it is reasonably safe
to begin the proposed investigations and a statement of where the investigations were
conducted and where the records are available for inspection.
✓ As drug development proceeds, the sponsor is required to submit informational
amendments, as appropriate, with additional information pertinent to safety.
❖ Previous human experience with the investigational drug:
✓ A summary of previous human experience known to the applicant, if any, with the
investigational drug. The information is required to include the following:
 ✓ if the investigational drug has been investigated or marketed previously, either in the United
States or other countries, detailed information about such experience that is relevant to the
safety of the proposed investigation or to the investigation's rationale.
✓ If the drug has been the subject of controlled trials, detailed information on such trials that is
relevant to an assessment of the drug's effectiveness for the proposed investigational use(s)
should also be provided.
✓ Any published material that is relevant to the safety of the proposed investigation or to an
assessment of the drug's effectiveness for its proposed investigational use should be
provided in full.
✓ Published material that is less directly relevant may be supplied by a bibliography.
✓ If the drug has been marketed outside the United States, a list of the countries in which the
drug has been marketed and a list of the countries in which the drug has been withdrawn
from marketing for reasons potentially related to safety or effectiveness.
❖ Relevant information: If requested by FDA, any other relevant information needed for review of the
application.
✓ Information previously submitted.
✓ Material in a foreign language.
✓ Number of copies.
✓ Numbering of IND submissions.
✓ Identification of exception from informed consent
➢ Withdrawal of an IND:-
• At any time a sponsor may withdraw an effective IND without prejudice.
• If an IND is withdrawn, FDA shall be so notified, all clinical investigations conducted under the IND
shall be ended, all current investigators notified, and all stocks of the drug returned to the sponsor or
otherwise disposed of at the request of the sponsor.
• If an IND is withdrawn because of a safety reason, the sponsor shall promptly so inform FDA, all
participating investigators, and all reviewing Institutional Review Boards, together with the reasons
for such withdrawal.

Q: 12 Note on: - Good pharmacovigilance practice.

• Background of good pharmacovigilance practices:

o New legislation for pharmacovigilance applies in the European Union (EU) since July 2012,
and to support its implementation, a set of guidelines for the conduct of pharmacovigilance in
the EU has been developed which, as they have been adopted, replaced the previous set in
Volume 9A of the Rules Governing Medicinal Products in the EU.
o This new guidance on good pharmacovigilance practices (GVP) is organized into two types of
chapters, namely Modules on pharmacovigilance processes and Product or Population Specific
Considerations.
• Objectives of Pharmacovigilance:

o Pharmacovigilance has been defined by the World Health Organization (WHO) as the science
and activities relating to the detection, assessment, understanding and prevention of adverse
effects or any other medicine related problem.
o In line with this general definition, underlying objectives of the applicable EU legislation for
pharmacovigilance are:
✓ Preventing harm from adverse reactions in humans arising from the use of authorized
medicinal products within or outside the terms of marketing authorisation or from
occupational exposure
✓ Promoting the safe and effective use of medicinal products, in particular through
providing timely information about the safety of medicinal products to patients,
healthcare professionals and the public.
o Pharmacovigilance is therefore an activity contributing to the protection of patients’ and public
health.
• Pharmacovigilance in EU: Roles of different actors:
o the EU, a regulatory network, consisting of the competent authorities in Member States, the
European Commission and the European Medicines Agency (in GVP referred to as “the
Agency”) is responsible for granting marketing authorizations and supervising medicinal
products, including the conduct of pharmacovigilance.
o The Agency has a core role in coordinating these activities for the network.
o In addition to the network’s responsibilities, EU legislation imposes responsibility for
pharmacovigilance, together with specific obligations (i.e. in terms of tasks and
responsibilities), on marketing authorisation holders.
o In the past, the role of healthcare professionals was mainly seen as contributing to
pharmacovigilance through spontaneous reporting of suspected adverse reaction cases and as
receiving, together with the patients, advice on minimizing risks through updated product
information or other information materials.
o However over time, participation of patients and healthcare professionals in EU regulatory
processes, including those for pharmacovigilance, has steadily increased.
o A large number of Member States have established, over the last years, schemes for reporting
of suspected adverse reactions by patients themselves.
o An EU legal framework for patient reporting in all Member States has now been introduced
through the new pharmacovigilance legislation.
o The new legislation further increases public participation by including patient and healthcare
professional representatives in the new Pharmacovigilance and Risk Assessment Committee
 (PRAC) and through public hearings on pharmacovigilance and benefit risk matters at the
Agency, involving all stakeholders.
• Structure of GVP:
o Pharmacovigilance activities are organized by distinct but connected processes, and each GVP
Module presents one major pharmacovigilance process.
o In addition, GVP provides guidance on the conduct of pharmacovigilance for specific product
types or specific populations in which medicines are used.
o These GVP Considerations apply in conjunction with the process related guidance in the
Modules.
o The following are the GVP modules:
✓ Module 1: Pharmacovigilance systems and their quality systems
✓ Module 2: Pharmacovigilance system master file
✓ Module 3: Pharmacovigilance inspections
✓ Module 4: Pharmacovigilance audits
✓ Module 5: Risk management systems
✓ Module 6: Collection, management and submission of reports of suspected adverse reactio
medicinal products
✓ Module 6 addendum 1: Duplicate management of suspected adverse
reaction reports
✓ Module 7: Periodic safety update report
✓ Module 8: Post authorization safety studies
✓ Module 8 addendum 1: Requirements and recommendations for submission
of information on non interventional post-authorization safety studies.
✓ Module 9: Signal management
✓ Module 9 addendum 1: Methodological aspects of signal detection from spontaneous repo
suspected adverse reactions
✓ Module 10: Additional monitoring
✓ Module 11: Safety communication
✓ Module 12: Risk minimization measures
✓ Module 12 addendum 1: Educational materials.
• Epidemiologic Assessment:-
• General aspects of study protocol:
o The study protocol is a core document of a study.
o A protocol should be drafted as one of the first steps in any research project
o The final version must precisely describe everything being done in the study so that the study
can be reproduced.
 o It should be amended and updated as needed.
o Amendments should be justified.
o The EU Guidance on the format and content of the protocol of non-interventional post-
authorization safety studies (PASS) provides a template which may be applied to all non-
interventional PASS, including meta-analyses and systematic reviews.
o Chapter II of the ISPE Guidelines for Good Pharmacoepidemiology Practices (GPP) provides
guidance on what is expected from a pharmacoepidemiology study protocol and on the different
aspects to be covered.
o It states that the protocol should include a description of the data quality and integrity, including
abstraction of original documents, extent of source data verification, and validation of
endpoints.
• Research Question:
o The research question and the associated objectives address the knowledge or information to
be gained from the study.
o Existing guidance on this aspect includes the EU Guidance on the format and content of the
protocol of non-interventional post-authorization safety studies, the ISPE GPP and the ENCePP
Checklist for Study Protocols.
o It should be clearly explained why the study is to be conducted (e.g. to answer an important
public health concern, to confirm or further characterize a risk identified in a Risk Management
Plan, to assess a new or emerging safety issue, to understand how a drug is used in the real-
world setting, to determine health outcomes or the benefit/risk profile or to evaluate the impact
of risk minimization measures).
o It also should be clear whether the results that will be reported represent pre-formed hypotheses
or research questions or are data driven
o If there is no pre-formed hypothesis, this should be clearly stated.
o A critical and thorough review of the literature usually forms the basis for the theoretical
framework of the research question and should be included in the background description of a
protocol when relevant.
o Such a review aims to evaluate information that is pertinent and to identify gaps in knowledge.
o The review should include findings of relevant animal studies, clinical trials and previous
epidemiological studies.
o The findings of similar studies should be mentioned and gaps in knowledge that a study is
intended to fill should be described.
• Approaches to data collection:

o There are two main approaches for data collection

o One is primary collection of data specifically for a study.
 o Another option is to use data already collected for another purpose, e.g. as part of administrative
records of patient health care (“secondary data collection”). Module VIII Post-authorisation
safety studies of the Good pharmacovigilance practice distinguishes between studies that
involve either approach.
o Increasingly often, a combination of approaches is used
o In addition, networking among centers active in pharmacoepidemiology and
pharmacovigilance is rapidly changing the landscape of drug safety research in Europe, both in
terms of data networks and networks of interested researchers who may have data sources that
they can contribute to a particular study.
• Study designs and methods:
o The choice of epidemiological methods to answer a research question is based on principles
rather than on rules.
o These principles may provide opportunities for creativeness and new innovative methods,
when appropriate and needed.
o However, there are certain ‘dos and don’ts’ and certain standards in order to assure validity
and robustness of the study results.
o General aspects of study designs, their relevance to types of research question and issues
relating to internal and external validity, including biases and confounding, are covered by
many textbooks on epidemiology and pharmacoepidemiology.
o The following list proposes a list of textbooks recommended for consultation.
o Researchers may find other textbooks more appropriate to their specific needs.

• Quality Management:
o Biomedical research is characterized by a tremendous expansion of knowledge in recent years
and it is in the focus of public interest and discussions since the quality in biomedical research
will result in quality of patient care.
o Quality is a measure of excellence or a state of being free from defects, deficiencies and
significant variations and the quality management includes all the activities that organizations
use to direct, control and coordinate quality (International Standards Organization, ISO 9000)
and that managers carry out in effort to implement their quality policy.
o The seven quality management principles (QMPs), i.e., customer focus, leadership,
engagement of people, process approach, improvement, evidence-based decision-making and
relationship management have been introduced in ISO Quality management principles on
which ISO 9000, ISO 9001 and related ISO quality management standards are based on.

Q:13 What information is provided in EU annual safety report.

➢ Introduction :
• Periodic safety update report (PSURs) are pharmacovigilance documents intended to provide an
evaluation of the risk benefit balance of a medicinal product for submission by marketing authorization
holders at a defined time points during the post authorization phase.
• PBRER (Periodic Benefit Risk Evaluation Report) are referred to as PSUR since implementation in
Europe via GVP module 7.

➢ Objective of PSUR:
• To present a comprehensive and critical analysis of new or emerging information on the risks and
where pertinent new evidence of benefit to enable an appraisal of overall benefit risk.
• To contain an evaluation of new relevant information that become available to the MAH during the
reporting interval, in the context of cumulative information:
o Examine whether new information is in accord with previous knowledge of the benefit risk profile.
o Summarizes relevant new safety information that may impact the benefit risk profile.
o Summarizes any important new efficacy and effectiveness information.
o Conduct an integrated benefit/risk evaluation.
➢ Periodicity:
• PSUR must be prepared at following intervals:
o Immediately upon request.
o Every 6 months from authorization.
o Every 6 months for the first two years on the market.
o Annually for next 2 years.
o Thereafter every 3 years.
➢ International birth date and data lock point:

• The date of the first marketing approval for the medicinal product in any country in the world is
the International birth date (IBD).
• Data lock point is the date designated as the cut off for data to be included based on IBD.
➢ EU Reference date list:

• The EU reference date list is a comprehensive list of active substance and combinations of
active substances for which PSURs shall be submitted:
o Legally binding
o Periodicity defined on a risk based approach
• The EU reference date list was put in place in order to facilitate the harmonization of data lock
points (DLPs) and frequency of submission of PSURs for medicinal products containing the
 same active substance or the same combination of active substance subject to different
marketing authorizations, authorized in more than 1 member state.
• EMA has published the list of union reference dates and frequency of submission information
which will be legally binding when module 7 becomes effective 2 July 2012.
• The EURD list is a living document which will be amended whenever considered necessary by
the PRAC, the CHMP or CMDh in response to the emergence of relevant new safety
information, newly authorized substances and requests received from MAHs.
• Substances can be added or removed as appropriate.
• The EURD list is updated on a monthly basis, MAHs should therefore maintain an awareness
of the current status of the list.
• PSURs shall also be submitted at any time immediately upon request by the regulatory
authorities.
➢ Exemption from submitting PSURS:
• Generics, well established, and traditional herbal medicinal products are exempted from submitting
PSURs except in the following circumstances:
o The marketing authorization provides for the submission of PSURS as a condition.
o PSURs are requested due to concerns relating to the PV data or due to lack of PSURs to an active
substance after the MA have been granted.
• For the products where PSURs are no longer required to be submitted routinely, it is expected that
marketing authorization holders will continue to:
o Evaluate the safety of their products on a regular basis and report any new safety information that
impacts on the benefit risk profile or the product information.
➢ EU single assessment of PSUR (PSUSA):
• PSUR is a PSUR single assessment of substances contained in centrally authorized product and
nationally authorized product.
• These assessment lead to legally binding outcomes: Maintenance, variation, suspension, revocation of
the marketing authorization.
• Objectives:
o Harmonize and strengthen the safety and benefit risk review of medicines across the EU.
o Increase the shared use of resources between competent authorities.
o Assessment by the PRAC with CHMP involvement or CMDh in case of regulatory action .
• The EMA publishes a list of outcomes for NAPs on their website while outcomes for CAPs are
published as a part of each medicines European public assessment report (EPAR).
• Any changes to the product information as a result of PSUR assessment are implemented without
subsequent variation for CAPs and through the appropriate variation at national level for NAPs.
Q:14 Discuss Bioavailabilty and Bioequivalance requirements according to
CFR 21 part 320.

• For IND/NDAs:
• To establish equivalence between:
o Early & late clinical trial formulations
o Formulations used in clinical trial & stability studies, if different
o Clinical trial formulations & to-be-marketed drug product
o Any other comparisons, if appropriate
• ANDA for a generic drug product
• Change in components, composition, &/or manufacturing process
• Change in dosage form (capsules to tablet)
• NDA VS. ANDA REVIEW PROCESS
• NDA Requirements :
1. Chemistry
2. Manufacturing
3. Controls
4. Labeling
5. Testing
6. Animal Studies
7. Clinical Studies
8. Bioequivalence
• ANDA Requirements:
1. Chemistry
2. Manufacturing
3. Controls
4. Labeling
5. Testing
6. Bioequivalence
• DESIGN AND CONDUCT OF STUDIES:
1. Pharmacokinetic Studies
2. Pharmacodynamics Studies
3. Comparative Clinical Studies
4. Comparative Clinical Studies
• PHARMACOKINETIC STUDY:
o Study design
o Study population
 o Selection criteria
o Statistical evaluation
• STUDY DESIGN:
o The basic design of an in-vivo bioavailability study is determined by the following:
o What is the scientific question(s) to be answered
o The nature of the reference material and the dosage form to be tested.
o The availability of analytical methods.
o Benefit-risk ratio considerations in regard to testing in humans.
• STUDY POPULATION:
o The number of subjects to be included in the study based on an appropriate Sample size which
is estimated by:
✓ Pilot experiment
✓ Previous studies
✓ Published data
o The number of subjects recruited should be sufficient to allow for possible withdrawals or
removals (dropouts) from the study.
o Significance level desired, usually 0.05
o Power of the study, normally 80% or more
o Minimum 12 subjects, unless ethical justification
o If the drug product is intended for use in both sexes, the sponsor attempt to include similar
proportions of males and females in the study.
• SELECTION OF SUBJECTS:
o Healthy adult volunteers
o Age: 18years or older
o Age/Sex representation corresponding to therapeutic & safety profile
o Non-smokers/without a history of alcohol or drug abuse Medical history/Clinical Lab test
values must be within normal ranges
o Weight within normal limits→ BMI (18.5-30 kg/m2)
o Women: Women should be required to give assurance that they are neither pregnant, nor likely
to become pregnant until after the study.
o Drug use intended in Elders, the sponsor attempt to include as many subjects of 60yrs of age
or older as possible.
o Teratogenic Drugs→ Male volunteers
o Highly toxic drugs: Patients with concerned disease (stable) eg. Cancer
• STUDY CONDITION:
o Selection of Blood Sampling Points/Schedules
o For at least three elimination half-lives (cover >80% of AUC)
• Absorption phase: 3-4 points
 • Around Tmax: 3-4 points
• During elimination: 4 points
o Intervals not longer than the half-life of the drug
o If urine tested, collect it for at least 5 half-lives
o The lot Numbers of both reference listed products and the expiration date for the reference
product would be stated.
o The drug content of the test product cannot differ from that of reference product by more than
± 5%.
o The sponsor can include a statement of the composition of the test product and if possible a
side-by-side comparison of the compositions of the test and reference product.
o Samples of the test and reference listed product must be retained for 5 years.
o Fasting or fed conditions
o Fasting state:
✓ A single dose study should be conducted after an overnight fast (at least 10 hours),
with subsequent fast of 4 hours following dosing.
✓ For multiple dose fasting state studies, when an evening dose must be given, two hours
of fasting before and after the dose is considered acceptable.
o Fed State:
Required when:
✓ Drug recommended with food
✓ Modified release product
✓ Assessment of Cmax and Tmax difficult with fasting state study
▪ Requires consumption of a high fat food, 30 minutes before dosing
▪ Provide 800-1000 kcals with about 50% of calories derived from fat.
▪ Fat- 500-600, Proteins - 150, Carbohydrate- 250 Kcal
▪ Ethnic & cultural variation considered
▪ Specified in protocol
o In general BE Study conducted under fasting condition.
1. Where the SmPC recommends intake of the reference medicinal product on an
empty stomach or irrespective of food intake, BE study conducted under fasting
condition.
2. Where SmPC recommends intake of RMP only in fed state, BE Study conducted
under fed state.
3. For specific formulation both study recommended, unless product taken only in
fasting or fed state.
o Where information is required in both Fasting and fed state, it is acceptable to conduct either;
a. Two separate two-way cross-over
OR,
 b. A four way cross-over study
• STEADY STATE/ MULTIPLE DOSE STUDIES :
o Long elimination half-life→ Accumulation in the body
o Toxic drugs requiring multiple dose therapy
o Some Modified-release drugs
o Combination products
o Drugs inducing own metabolism
o Drugs showing non-linear pharmacokinetics
o Disadvantages:
• Difficult to conduct • Costly • Longer monitoring • Longer exposure to drug

• CHARACTERISTICS TO BE MEASURED
o Evaluations of BA/BE will be based upon the measured concentrations of the active drug
substance(s) in the biological matrix.
o The measurements of an active or inactive metabolite may be necessary:
A.where the concentrations of the drug(s) may be too low to accurately measure in the
biological matrix,
B. Limitations of the analytical method,
C. unstable drug(s),
D. Drug(s) with a very short half-life or
E.in the case of prodrugs.
o Racemates should be measured using an achiral assay method.
o The plasma-time concentration curve is mostly used to assess the rate and extent of absorption
of the study drug. This include Cmax, Tmax, AUC0-t and AUC0-∞.
o Pharmacokinetic Parameters measured are:
✓ Plasma conc. and time points
✓ Subject, period, sequence, treatment
✓ Cmax, Tmax, AUC0-t ,AUC0-∞
✓ Partial AUC only for early exposure of drug content.
o For steady state studies:
• Swing
• Cav
• Cmin
• Degree of fluctuation
o Measurement of Individual enantiomers in BE Studies is recommended if
1. Exhibit different Pharmacodynamic characteristics
2. Exhibit different Pharmacokinetics characteristics
3. Primary efficacy and safety activity resides with minor enantiomers
 4. Nonlinear absorption is present
• STATISTICAL EVALUATION:
o Primary concern of bioequivalence is to limit Consumer’s & Manufacturer’s risk
• Cmax & AUC analysed using ANOVA
• Tmax analysed by non-parametric methods
o Use natural log transformation of Cmax and AUC
o Calculate 90% confidence interval for this GMR for Cmax
o Similarly calculate GMR for AUC
o Criteria for bioequivalence
✓ To establish Bioequivalence, the calculated 90% confidence interval for AUC and
Cmax should fall within the bioequivalence range, usually 80-125%.
✓ Tighter limits for permissible differences in bioavailability may be required for drugs
that have: I A narrow therapeutic index. II A serious, dose-related toxicity. III A steep
dose/effect curve, or IVA non-linear pharmacokinetics within the therapeutic dose
range.
1. Two-Period Crossover Design:
o 2 formulations, even number of subjects, randomly divided into 2
equal groups
o First period , each member of one group receive a single dose of the
test formulation; each member of the other group receive the standard
formulation .
2. Latin Square Design
o More than two formulations
o A group of volunteers will receive formulations in the sequence shown
3. Balance Incomplete Block Design (BIBD)
o More than 3 formulations, Latin square design will not be ethically advisable
o Because each volunteer may require drawing of too many blood samples
o If each volunteer expected to receive at least two formulation, then such a study can be carried
out using BIBD
4. Parallel-Group Design
o Even number of subjects in two groups
o Each receive a different formulation
o No washout necessary
o For drugs with long half life
5. Replicate Crossover-study design
o For highly variable drugs
o Allows comparisons of within-subject variances
o Reduce the number of subjects needed
 o Four-period, two-sequence, two-formulation design (recommended)
OR
o Three-sequence, three-period, single-dose, partially replicated
6. Pilot Study
o If the sponsor chooses, in a small number of subjects
o To assess variability, optimize sample collection time intervals & provide other information,
Validate analytical methodology.
o Example:
o Immediate-release products: careful timing of initial samples→ avoid a subsequent finding
that the first sample collection, occured after the plasma concentration peak
o Can be appropriate, provided its design & execution are suitable & sufficient number of
subjects have completed the study

Q:15 What are the regulatory requirements to market a pharmaceutical

product in European countries.

➢ NEW DRUG APPLICATION IN EUROPE:

• Currently different countries have to follow different regulatory requirements for approval of
new drugs

• EMA is the regulatory agency/ decentralized body which is responsible for safety regulation
of the food and drug products in Europe.

• For marketing authorization application (MAA) a single regulatory approach is applicable to

various countries is almost a difficult task.

• EU establishes 4 different drug approval processes: 1) Centralized Procedure 2) Decentralized

Procedure 3) National Procedure4) Mutual Recognition Procedure

• There are two regulatory steps to go through before a drug is approved to be marketed in the
European Union.

• These two steps are (1) Clinical trial application and (2) Marketing authorization application.

• There are 31 EEA countries (28 EU Member States plus Iceland, Liechtenstein and Norway);
Clinical Trial Applications are approved at the member state level, whereas marketing
authorization applications are approved at both the member state and centralized levels.

• All new drug products must be approved by the respective regulatory agency governing the
respective market before a particular product can be introduced into the market.
 • By law, all new drugs must first be shown to be safe and effective before they can be
approved by the respective regulatory agency for marketing .

Figure: New drug application

• Different Drug Approval Processes:
1. Different Drug Approval Processes
o The centralized procedure allows the marketing of a medicine on the basis of a single EU-
wide assessment and marketing authorization which is valid throughout the EU.

o The use of the centrally authorized procedure is compulsory for most innovative
medicines, including medicines for rare diseases.

o Pharmaceutical companies submit a single authorization application to EMA.

o The centralized procedure is compulsory for certain medication like:
a) Human medicine containing a new active substance.

b) Human medicine containing a new active substance.

c) Medicines derived from biotechnology processes, such as genetic engineering;

 d) Advanced-therapy medicines, such as gene-therapy, somatic cell- therapy or
tissue-engineered medicines;
e) Orphan medicines (medicines for rare diseases);

f) Veterinary medicines for use as growth or yield enhancers.

2. Decentralized procedure:
• The decentralized procedure where companies can apply for the simultaneous authorization of a
medicine in more than one EU Member State if it has not yet been authorized in any EU country
and does not fall within the scope of the centralized procedure.

3. Mutual-Recognition:
• The mutual-recognition procedure where companies that have a medicine authorized in one
EU Member States can apply for this authorization to be recognized in other EU countries

• This process allows Member States to rely on each other’s scientific assessments.
• Applicant submits identical dossier to all EU member states in which it wants authorization,
including required information.
• As soon as one Member State decides to evaluate the medicinal product (at which point it
becomes the "RMS"), it notifies this decision to other Member States (which then become the
"CMS"), to whom applications have also been submitted.
• RMS issues a report to other states on its own findings.
• Generic industry is the major user of this type of drug approval procedure. This process may
consume a time period of 390days.
3. National Procedure:
• The Nationalized procedure is one which allows applicants to obtain a marketing authorization
in one-member state only.
• In order to obtain a national marketing authorization, an application must be submitted to the
competent authority of the Member State.
• New active substances which are not mandatory under Centralized procedure can obtain
marketing authorization under this procedure.
• Timeline for this procedure is 210Days.