Investigational new drug application

Current Federal law requires that a drug be the subject of an approved marketing
application before it is transported or distributed across state lines. Because a sponsor
will probably want to ship the investigational drug to clinical investigators in many
states, it must seek an exemption from that legal requirement. The IND is the means
through which the sponsor technically obtains this exemption from the FDA.

During a new drug's early preclinical development, the sponsor's primary goal is to
determine if the product is reasonably safe for initial use in humans and if the
compound exhibits pharmacological activity that justifies commercial development.
When a product is identified as a viable candidate for further development, the sponsor
then focuses on collecting the data and information necessary to establish that the
product will not expose humans to unreasonable risks when used in limited, early-
stage clinical studies.

FDA's role in the development of a new drug begins when the drug's sponsor (usually
the manufacturer or potential marketer), having screened the new molecule for
pharmacological activity and acute toxicity potential in animals, wants to test its
diagnostic or therapeutic potential in humans. At that point, the molecule changes in
legal status under the Federal Food, Drug, and Cosmetic Act and becomes a new drug
subject to specific requirements of the drug regulatory system.

What is the new drug application?

The NDA application is the vehicle through which drug sponsors formally propose
that the FDA approve a new pharmaceutical for sale and marketing in the U.S. The
data gathered during the animal studies and human clinical trials of an Investigational
New Drug (IND) become part of the NDA.

The goals of the NDA are to provide enough information to permit FDA reviewer to
reach the following key decisions:

 Whether the drug is safe and effective in its proposed use(s), and whether the
benefits of the drug outweigh the risks.
 Whether the drug's proposed labelling (package insert) is appropriate, and
what it should contain.
 Whether the methods used in manufacturing the drug and the controls used to
maintain the drug's quality are adequate to preserve the drug's identity,
strength, quality, and purity.
The documentation required in an NDA is supposed to tell the drug's whole story,
including what happened during the clinical tests, what the ingredients of the drug are,
the results of the animal studies, how the drug behaves in the body, and how it is
manufactured, processed and packaged. The following resources provide summaries
on NDA content, format, and classification, plus the NDA review process:

Approval of new drug in India

When a company in India wants to manufacture/ import a new drug it has to apply to
seek permission from the licensing authority (DCGI) by filing in Form 44 also
submitting the data as given in Schedule Y of Drugs and Cosmetics Act 1940 and
Rules 1945. In order to prove its efficacy and safety in Indian population it has to
conduct clinical trials in accordance with the guidelines specified in Schedule Y and
submit the report of such clinical trials in specified format.

But a provision is there in Rule- 122A of Drugs and Cosmetics Act 1940 and Rules
1945 that the licensing authority may waive certain trails if he considers that in the
interest of public health he may grant permission for import of new drugs basing on
the data of the trials done in other countries. Similarly there is another provision in
Rule- 122A which says that the clinical trials may be waived in the case of new drugs
which are approved and being used for several years in other countries.

Section 2.4 (a) of Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945 says
for those drug substances which are discovered in India all phases of clinical trials are
required.

Section 2.4 (b) of Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945 says
that for those drug substances which are discovered in countries other than India; the
applicant should submit the data available from other countries and the licensing
authority may require him to repeat all the studies or permit him to proceed from
Phase III clinical trials.

Section 2.8 of Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945 says that
the licensing authority may require pharmacokinetic studies (Bioequivalence studies)
first to show that the data generated in Indian population is equal to data generated
abroad and then require him to proceed with Phase III trials.

In summary, the exact requirements of Clinical trials may change from case to case
and depend on the extent to which licensing authority is satisfied about its safety and
efficacy.
The process of approval of new drug in India is a very complicated process, which
should meet necessary requirements along with NDA to FDA. The need of the present
work is to study and document the requirements for the process of approval of new
drug in India with emphasis on clinical trials as per Drugs Control department,
Government of India.

New Drug Application

NDA is an application submitted to the FDA for permission to market a new drug. To
obtain this permission a sponsor submits preclinical and clinical test data to NDA for
analysing the drug information, description of manufacturing procedures.
After NDA received by the agency, it undergoes a technical screening. This evaluation
ensures that sufficient data and information have been submitted in each area to justify
“filing” the application that is FDA formal review. At the conclusion of FDA review
of an NDA, there are 3 possible actions that can send to sponsor: Not approvable- in
this letter list of deficiencies and explain the reason. Approvable - it means that the
drug can be approved but minor deficiencies that can be corrected like-labelling
changes and possible request commitment to do post-approval studies. Approval- it
state that the drug is approved.
If the action taken is either an approvable or a not approvable, then FDA provides
applicant with an opportunity to meet with agency and discuss the deficiencies.
Examples of products eligible for the 505(b)(2) approval process include but are not
limited to the following:

 Change in the route of administration

 Conversion to lower or higher strength

 Change in the route of administration of dosage form or dosage regimen

 Change in the formulation

 Substitution of an active pharmaceutical ingredient (API) in a combination

product

 New molecular entity (NME)

 Conversion from prescription drug (Rx) to over-the-counter (OTC) drug

 Drug with new ingredients from animal or botanical sources (naturally derived
or recombinant)

 A bioequivalent product

A generic drug is a medication that has exactly the same active ingredient as the
brand name drug and yields the same therapeutic effect. It is the same in dosing,
safety, strength, quality, the way it works, the way it is taken, and the way it
should be used. Generic drugs do not need to contain the same inactive ingredients
as the brand name product.

 However, a generic drug can only be marketed after the brand name drug's
patent has expired, which may take up to 20 years after the patent holder’s
drug is first filed with the U.S. Food and Drug Administration (FDA).
 Generic drugs are usually much less expensive than brand name drugs once
they reach the market.
 A drug company develops new drugs as brand name drugs under patent
protection. This protects their investment in drug research by giving the drug
 company the sole right to manufacture and sell the brand name drug while the
patent is in effect.
 When patents or other periods of exclusivity expire, other manufacturers can
submit an abbreviated new drug application (ANDA) to the FDA for approval
to market a generic version of the brand name drug.

Generic drugs are medicinal products that can be manufactured and marketed by
others than the innovator company after the original patents have
expired. Bioequivalence is the main regulatory principle for generic drug approval in
European Union and the United States. For two drugs to be bioequivalent they have to
contain identical amounts of the same active ingredient in the same strength and
dosage form and their bio availabilities have to be similar in such a degree that their
effects can be expected to be essentially the same. There are two main categories of
generic drug policies: supply-side and demand-side policies. Supply-side policies
comprise regulation of generic drug approval and market access, pricing,
reimbursement, and tendering. Generic prescribing, generic substitution, prescribing
budgets and indicators, targeted information, academic detailing, and public
information campaigns are examples of demand-side policies. The ultimate aim of
these policies is to increase the global access to and regulation of generic drugs, reduce
drug costs, and prevent drug shortages and supply disruption. Particularly, the
availability of low-priced generic drugs is important to increase the economical access
to drug treatment in low- and middle-income countries. Despite this, most of the
existing policies remain unimplemented in the less mature health care systems.

Abbreviated new drug application

An abbreviated new drug application (ANDA) contains data which is submitted to

FDA for the review and potential approval of a generic drug product. Once approved,
an applicant may manufacture and market the generic drug product to provide a safe,
effective, lower cost alternative to the brand-name drug it references.

A generic drug product is one that is comparable to an innovator drug product in

dosage form, strength, route of administration, quality, performance characteristics,
and intended use. All approved products, both innovator and generic, are listed in
FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange
Book).

Generic drug applications are termed "abbreviated" because they are generally not
required to include preclinical (animal) and clinical (human) data to establish safety
and effectiveness. Instead, generic applicants must scientifically demonstrate that their
product is performs in the same manner as the innovator drug. One way applicants
demonstrate that a generic product performs in the same way as the innovator drug is
to measure the time it takes the generic drug to reach the bloodstream in healthy
volunteers. This demonstration of “bioequivalence” gives the rate of absorption, or
bioavailability, of the generic drug, which can then be compared to that of the
innovator drug. To be approved by FDA, the generic version must deliver the same
amount of active ingredients into a patient's bloodstream in the same amount of time as
the innovator drug.

Patent certificate under hatch-Waxman act

Under the Drug Price Competition and Patent Term Restoration Act of 1984, also
known as the Hatch-Waxman Amendments, a company can seek FDA approval to
market a generic drug before the expiration of patents related to the brand-name drug
that the generic seeks to copy. To seek this approval, a generic applicant must provide
in its application a "certification" that a patent submitted to FDA by the brand-name
drug's sponsor and listed in FDA's Approved Drug Products with Therapeutic
Equivalence Evaluations (the Orange Book) is, in the generic applicant's opinion and
to the best of its knowledge, invalid, unenforceable, or will not be infringed by the
generic product. This certification is called a "paragraph IV certification." The first
company or companies to submit an application that (1) is determined by the agency to
be "substantially complete" upon submission and (2) contains a paragraph IV
certification to at least one of the patents listed in the Orange Book is generally
eligible for the exclusive right to market the generic drug for 180 days.

In order to challenge a patent in court, the generic applicant that submitted a paragraph
IV certification must notify the brand product sponsor and any patent holder of the
submission of the ANDA and patent challenge. If the brand product sponsor or patent
holder files an infringement suit against the generic applicant within 45 days of the
ANDA notification, FDA approval to market the generic drug is generally postponed
for 30 months unless the patent expires or is judged to be invalid or not infringed
before that time. This 30-month postponement, commonly referred to as the "30-
month stay," gives the brand product sponsor and patent holder a prescribed amount of
time to assert patent rights in court before a generic competitor is approved and can
market the drug.

DMFs and types of DMF

The detailed information, which is usually confidential, relating to the manufacturing,

processing and storing of human drugs is contained in the Drug Master File or DMF.
This report is to be submitted to the FDA; however, it is not a requirement by law. The
information about any drug used as a basis to review and approve an investigational
New Drug Application or an Abbreviated New Drug application.
  Type I Manufacturing Site, Facilities, Operating Procedures and Personnel

 Type II Drug Substance, Drug Substance Intermediate, and Material Used

in Their Preparation, or Drug Product
 Type III Packaging Material

 Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their

Preparation

 Type V FDA Accepted Reference Information

 Type I DMF: This contains information regarding the manufacturing site,
facilities, operating procedures and personnel not specific to any drug
substance. The Type I DMFs are no longer accepted by the FDA but the old
documents remain on file.
 Type II DMF: This contains information related to drug substances, substance
intermediates, and materials used in the preparation of a drug, or a drug
product. A Type II DMF is the most commonly submitted form among all and
can include dosage from drugs manufactured under contract for another
company which would file an ANDA.
 Type III DMF: This contains information pertaining to packaging materials,
right from bottles and caps to PVC resin used during the manufacture of any
given drug.
 Type III DMF can also be referred to this article’s introduction. In a
recent web update, FDA has announced and clarified when and how a Type III
DMF needs to be submitted. It is not mandatory that the packaging
information be submitted to FDA in the form of a DMF. The one who is
submitting the NDA, ANDA or BLA documents or is the sponsor of an IND is
responsible to also provide information related to the packaging materials of a
given drug. This information is to be provided to the applicant or sponsor by
the manufacturer of a packaging component or material of construction and
can be directly included in the application instead of a separately filed DMF.
However, if there is any information that a manufacturer does not wish to
share with the applicant or sponsor (due to proprietary issues), it can be
thereby placed in a Type III DMF and included in the application by a letter of
consent from the manufacturer to the applicant or sponsor authorizing
reference to the DMF.
 Type IV: This mainly consists of information regarding the excipient (binding
material such as starch or cellulose), colourant, flavour, essence or material
used in the preparation of a given drug.
 Type V: This contains all reference information pertaining to the drug not
included in the previous DMF types.
The Investigator’s Brochure (IB)

The Investigator’s Brochure (IB) is a comprehensive compilation of

clinical and nonclinical data on the investigational product (drug,
supplement, device or other product) maintained by a drug developer or
investigator that contains the body of information about the
investigational product obtained before and during a drug trial. The IB is
a document of critical importance throughout the drug development
process and is updated with new information as it becomes available.

The purpose of the IB is to compile data relevant to studies of the

investigational product in human subjects gathered during preclinical and
other clinical trials to provide the investigator with information necessary
for the management of study conduct and study subjects throughout a
clinical trial.

An IB facilitates understanding of the rationale for, and their compliance

with, many key features of the protocol, such as:

 Dose (of the study drug)

 Dose frequency and dosing interval

 Methods of administration

 Safety monitoring procedures

Information in the IB should be presented in a concise, simple, objective,

balanced, and non-promotional form that enables a clinician, or potential
investigator, to understand it and make his/her own unbiased risk-benefit
assessment of the appropriateness of the proposed trial. When the
investigational product is marketed and its pharmacology is widely
understood by medical practitioners, an extensive IB may not be
necessary. In these cases, a basic product information brochure, package
leaflet or an expanded background information section in the trial protocol
may be permitted by regulatory authorities as an alternative, provided that
it includes current, comprehensive, and detailed information on all aspects
of the investigational product that might be of importance to the
investigator. The IB should be reviewed at least annually and revised as
necessary in compliance with a sponsor’s written procedures. When new
information relevant to the clinical trial becomes available, it should be
communicated to the investigators, and possibly to the Institutional
Review Boards (IRBs) prior to a scheduled revision of the IB. Generally,
the sponsor is responsible for ensuring that an up-to-date IB is made
available to the investigator(s) and the investigators are responsible for
providing the up-to-date IB to the responsible IRBs/IECs.

An IB contains a “Summary of Data and Guidance for the Investigator”

section, of which the overall aim is to “provide the investigator with a
clear understanding of the possible risks and adverse reactions, and of the
specific tests, observations, and precautions that may be needed for a
clinical trial. This understanding should be based on the available
physical, chemical, pharmaceutical, pharmacological, toxicological, and
clinical information on the investigational product(s). Guidance should
also be provided to the clinical investigator on the recognition and
treatment of possible overdose and adverse drug reactions that is based on
previous human experience and on the pharmacology of the
investigational product”.
The sponsor is responsible for keeping the information in the IB up-to-
date. The IB should be reviewed annually and must be updated when any
new and important information becomes available, such as when a drug
has received marketing approval and can be prescribed for use
commercially.

Owing to the importance of the IB in maintaining the safety of human

subjects in clinical trials, and as part of their guidance on Good Clinical
Practice (GCP), the U.S. Food and Drug Administration (FDA) has written
regulatory codes and guidances for authoring the IB, and the International
Conference on Harmonisation (ICH) has prepared a detailed guidance for
the authoring of the IB in the European Union (EU), Japan, and the United
States (US).

what are the provision specified for reporting safety information on

adverse reactions during the study in japan

Reporting of adverse reactions occurring during clinical trials is covered in sections

80-2-6 and 66-7 of the Pharmaceutical Affairs Law. This portion of the law as written
describes reporting to the Minister of Health, Labour and Welfare. In practice, though,
reports are submitted to the Pharmaceuticals and Medical Devices Agency (PMDA).
Section 20-2 of the Japanese regulation on GCP requires sponsors to report
"immediately" to investigators and the heads of institutions involved in the clinical
trial. Guidance on reporting is issued in Notifications, which are frequently modified
and superseded by subsequent Notifications. The most recent Notifications relevant to
this discussion were issued on 30 March 2004.

explain priority review of drug submissions in canada

Priority Review is a fast-track status granted to eligible new drug submissions for
human use, following review and approval of a request submitted by the sponsor of the
drug. Priority Review submissions are introduced into Health Canada's drug review
queue in accordance with an accelerated review target of 180 day.

Priority Review status assigns eligible submissions a shortened review target of 180
days, in comparison to 300 days for nonpriority. Health Canada believes it is in the
best interests of Canadians to review potentially life-saving drugs as early as possible.

Priority Review status may be granted to drug submissions intended for the treatment,
prevention or diagnosis of serious, life-threatening or severely debilitating illnesses or
conditions where a) there is no existing drug on the Canadian market with the same
profile or b) where the new product represents a significant improvement in the
benefit/risk profile over existing products.

Marketing Authorisation Application (MAA)

Marketing Authorisation Application (MAA) is an application submitted by a drug

manufacturer seeking marketing authorisation, that is permission to bring a medicinal
product (for example, a new medicine or generic medicine) to the market.
MAA is part of the official procedure before the Medicines and Healthcare products
Regulatory Agency in the United Kingdom and the Committee for Medicinal Products
for Human Use of the European Medicines Agency, a specialised agency of
the European Commission. In the United States, the equivalent process is called New
Drug Application.
The regulatory journey of your product does not end with its placement on the market:
regular marketing authorisation renewals are also required for safety profile
monitoring to ensure health of product consumers.
A marketing authorisation (MA) is valid for five years. The MA may be renewed upon
application by the marketing authorisation holder (MAH) to the Agency for Medicinal
Products and Medical Devices of Croatia (HALMED) for each pharmaceutical form
and product strength at least nine months before its expiry.

What is clinical trial medical review?

Medical review is the core activity throughout the life cycle of the clinical study
that will ensure the safety of the patients and the integrity of the data. It mainly
comprises of periodic data review activities and ad hoc medical assessments.

As specified in the 2019-CTRules, and according to IND-31, IND-17, and IND-18,

upon receipt of a clinical trial application (see the 2019-CTRules for Form CT-04), the
DCGI has 90 calendar days to evaluate the application for drugs developed outside
India and 30 days for drugs discovered, researched, and manufactured in India. If the
DCGI does not respond within 30 days to applications for drugs developed in India,
the sponsor (applicant) may conclude that permission to conduct the trial has been
granted.
The 2019-CTRules and IND-31 further specify that once the sponsor (applicant)
obtains approval from the DCGI, he/she must still formally notify CDSCO via Form
CT-4A (see the 2019-CTRules) prior to initiating the clinical trial.. The DCGI will
then record the information provided on the form and it will become part of the official
record known as the automatic approval of the DCGI. The DCGI grants permission to
initiate a clinical trial via either Form CT-06 (see the 2019-CTRules) or as an
automatic approval via Form CT-4A (see the 2019-CTRules). The DCGI’s permission
must remain valid for two (2) years from the date of its issue, unless extended by the
DCGI as noted in the 2019-CTRules and IND-31.
As delineated in the Hdbk-ClinTrial, CDSCO coordinates the clinical trial application
process. Upon receipt of an application, a CDSCO official is responsible for
conducting the initial administrative review. If the application is deemed complete,
within four (4) weeks following receipt, the official forwards the application along
with a summary of his/her evaluation and a statement referring the proposal to a
Subject Expert Committee (SEC) for further technical review. If the proposal is not
accepted by the SEC, the sponsor (applicant) may request additional consideration of
the proposal by the Technical Committee. Otherwise, only the SEC’s
recommendations are required for the DCGI (CDSCO) to issue a final decision to the
Technical or Apex Committee.
Per the Hdbk-ClinTrial, SECs are usually comprised of six (6) experts representing
various therapeutic areas, including pharmacologists/clinical pharmacologists, and
medical specialists. However, Order13Jan20, issued in accordance with the 2019-
CTRules, indicates that SECs will be comprised of eight (8) medical experts,
specifically one (1) pharmacologist and seven (7) medical specialists. Per the Hdbk-
ClinTrial, SECs are responsible for advising CDSCO with in-depth evaluations of non-
clinical data (including pharmacological and toxicological data) and clinical trial data
(Phases I-IV) provided by the sponsors (applicants) for approval. The 2019-
CTRules further notes that the DCGI may, when required, constitute one (1) or more
of these expert committees or group of experts with specialization in relevant fields to
evaluate scientific and technical drug-related issues. The committee/group may submit
its recommendations within 60 days from the date of the request. Additionally,
per Order13Jan20, SECs will evaluate and advise DCGI on proposals in various
categories for the approval of new drug and clinical trial applications. These include
the following: new drug substances of chemical and biological origin including
vaccines and r-DNA derived products; subsequent approval of new drug and biological
products including vaccines and r-DNA derived products already approved in the
country; global clinical trials; fixed dose combinations of two (2) or more drugs to be
introduced for the first time in the country; causality analysis, drug safety, or any other
technical matter requiring expert advice in the opinion of the Ministry of Health and
Family Welfare (MOHFW) or the DCGI. See Order13Jan20 for the complete terms of
reference required to constitute SECs.
Once an SEC has completed its review, the Hdbk-ClinTrial indicates that the
committee sends its comments via email to CDSCO. CDSCO will then compile any
written SEC comments requiring sponsor (applicant) clarification or modification and
sends this feedback to the sponsor (applicant) within one (1) week of receipt. The
sponsor (applicant) must submit a written reply to CDSCO within four (4) weeks of
receiving the comments, and his/her comments will, in turn, be sent to the SEC for
review.
Once the sponsor (applicant)’s response is received, the DCGI (CDSCO) will issue a
final decision by official communication (permission, rejection, or resubmission) to
the Technical or Apex Committee within 15 days. In the case of a sponsor
(applicant)’s request for reconsideration, CDSCO will review the resubmitted
application and send it to the SEC again, or, to the Technical Committee per the
sponsor (applicant)’s request. Following the SEC’s review, the DCGI (CDSCO) will
send a final decision to the Technical or Apex Committee within 15 days. If CDSCO
rejects the reconsideration request, the agency will send a letter to the sponsor
(applicant) to communicate this decision.
In accordance with the 2019-CTRules and the Hdbk-ClinTrial, the Drugs Controller
General of India (DCGI), who heads the Central Drugs Standard Control Organization
(CDSCO), is responsible for reviewing and approving clinical trial applications for all
new drugs, investigational new drugs (INDs), and imported drugs to be registered in
India. Additionally, per the 2019-CTRules, the G-ICMR, and IND-31, the DCGI and a
DCGI-registered ethics committee (EC) must approve a clinical trial application prior
to the sponsor initiating the trial, except in the case of non-regulatory
academic/research clinical trials that only require EC approval.

The primary scope of information assessed by ethics committees (ECs) relates to

maintaining and protecting the rights, safety, and well-being of all research
participants, especially those in vulnerable populations, in accordance with the
requirements set forth in the 2019-CTRules, the G-ICMR, the G-Children, the
Declaration of Helsinki (IND-63), and the International Council for Harmonisation's
Guideline for Good Clinical Practice E6(R2) (IND-41). (See the Vulnerable
Populations; Children/Minors; Pregnant Women, Fetuses & Neonates;
and Mentally Impaired sections for additional information about these populations).
The 2019-CTRules and the G-ICMR also state that ECs must ensure an independent,
timely, and competent review of all ethical aspects of the research protocols. They
must act in the interests of the potential research participants and the communities
involved by evaluating the possible risks and expected benefits to participants, and
they must verify the adequacy of confidentiality and privacy safeguards. Per the G-
Children, ECs providing opinions on studies involving children should also include
members with pediatric expertise. The expert(s) may be permanent EC members or
invited as subject experts to provide advice and be consulted on an ad hoc basis.
As delineated in the 2019-CTRules, ECs also have a continuing responsibility to
monitor approved clinical trials and biomedical and health research studies to ensure
ethical compliance throughout the study duration.
For all studies, the G-ICMR indicates that ECs must review and approve any protocol
amendments, major deviations, or violations at regular intervals.
There is no stated expiration date for an EC approval in the 2019-CTRules or the G-
ICMR. However, per the 2019-CTRules, in the event that an EC revokes its approval
of a clinical protocol, it must record its reasons for doing so and immediately
communicate this decision to the investigator as well as to the Drugs Controller
General of India (DCGI). For detailed EC review procedures and information on other
administrative processes, see the 2019-CTRules, the G-ICMR, IND-5, and IND-27.
See also IND-36 for the EC clinical trial application form and IND-52 for other
commonly used EC review forms.

Phase III or confirmatory trials

Purpose is to obtain sufficient evidence about the efficacy and safety of the drug in a
larger number of patients, generally in comparison with a standard drug and/or a
placebo as appropriate. In this phase, the group is between 1000-3000 subjects. If the
results are favorable, the data is presented to the licensing authorities for a commercial
license to market the drug for use by the patient population for the specified and
approved indication.

This phase allow experimental clinical study with detail assessment of the treatment
protocol by comparing data of new treatment with standard treatment. This is the most
well-known scientific investigation of the newer drug treatment. This phase is also
known as pre- marketing phase. This phase consumes time and it is very expensive
trial.
Human subject- 1000- 3000
This phase includes randomized controlled trials, uncontrolled trial, historical control,
and no randomized concurrent trial etc. This trial is classified into two steps, one is
trial after efficacy study but before the NDA submission, second one is carried out
after the NDA submission but before the approval. In the year 1980 the FDA has given
the guidance document which states that efficacy must be showed to prolongation of
life and enhances the health related quality of patient’s life.
NOC/c

NOC/c is authorization to market a drug (i.e. a Notice of Compliance (NOC)), with the
condition that the sponsor undertake additional studies to verify the clinical benefit.
The NOC, qualifying under the NOC/c policy, is issued under section C.08.004 of the
Food and Drug Regulations.

On June 13, 2015, the Regulations Amending the Food and Drug Regulations
(Labelling, Packaging and Brand Names of Drugs for Human Use), commonly known
as the Plain Language Labelling amendments, come in to force for prescription
products and products administered or obtained through a health professional
for human use. As a result, the current guidance no longer provides the most up to
date information for these products.

Guidance documents are meant to provide assistance to industry and health care
professionals on how to comply with the policies and governing statutes and
regulations. They also serve to provide review and compliance guidance to staff,
thereby ensuring that mandates are implemented in a fair, consistent and effective
manner.
Guidance documents are administrative instruments not having force of law and, as
such, allow for flexibility in approach. Alternate approaches to the principles and
practices described in this document may be acceptable provided they are supported by
adequate scientific justification. Alternate approaches should be discussed in advance
with the relevant program area to avoid the possible finding that applicable statutory or
regulatory requirements have not been met.
As a corollary to the above, it is equally important to note that Health Canada reserves
the right to request information or material, or define conditions not specifically
described in this guidance document, in order to allow the Department to adequately
assess the safety, efficacy or quality of a therapeutic product. Health Canada is
committed to ensuring that such requests are justifiable and that decisions are clearly
documented.
What Are the Four Stages of the Drug Discovery Process?

The Drug Discovery Process involves many different stages and series of actions.
Typically, it can be divided into four main stages: Early Drug Discovery, Pre-
Clinical Phase, Clinical Phases, and Regulatory Approval. Let’s explore the major
steps that are taken in each of these stages to develop a new drug.

1. Early Drug Discovery

The Early Drug Discovery Process involves many different actions and testing.
Researchers collaborate to identify and optimize potential leads to a specific target.
Essentially, the leads must elicit a desirable effect on a specific biological target
implicated in a disease, in the hopes of treating it. Research at this point is performed
in the laboratory using in silico platforms, biochemical assays, cell cultures, and
various animal models. This stage flows through these sub-processes: Target
Identification and Validation, High Throughput Screening or High Content
Screening, Hit Identification, Assay Development and Screening, Hit-To-Lead
(H2L), Lead Generation and Optimization, and In vivo and In vitro Assays. Keep
reading on to learn more about each of these different steps within the Early Drug
Discovery process.

2. Pre-Clinical Phase

In keeping with the four major phases of the Drug Discovery process, the second stage
is the Pre-Clinical Phase. In the Pre-Clinical Phase, the substances identified during
Early Drug Discovery are refined, optimized, and extensively tested in a
laboratory and in animal or alternative models. The aim is to provide sufficient
evidence of safety and efficacy before Clinical Trials in humans can begin, and once
this point is assured, it is also useful to calculate the appropriate doses to test in
humans. Before the Clinical Trials start it must be ensured that the new substance is
available in sufficient quantities during the clinical studies. Since only small quantities
were previously required, production now has to be adapted to the significantly higher
demand in the Clinical Phase.

Regulatory authorities require preclinical studies before submitting any investigational

new drug application to progress to Clinical Phases.

3. Clinical Phases

Clinical Trials are composed of four phases: Phase I, II, III, and IV. We will discuss
each of these phases in greater detail further on. Nevertheless, in the first stage, the
tolerance and safety of the drug candidate will be tested in a very small group of
healthy subjects, usually 20 to 80. Phase I aims to answer the following questions:

For these studies, the active ingredient must first be manufactured under GMP
conditions. That means strictly controlled according to the guidelines of "Good
Manufacturing Practice."

After tolerance and effectiveness have been tested in a small group, phases IIa and
IIb are started to examine the effectiveness, tolerability and dosage in a larger
group. For this, the dosage form is first developed.

In phase IIa studies, the therapy concept is primarily checked (proof of concept); in
phase IIb studies, the aim is to find the right dose. Phase II studies usually include
100 to 500 adult patients in the study.

In the last phase before a possible approval as a drug, doctors test the drug on
thousands of patients to see whether the effectiveness and safety can be confirmed
in many different patients. Interactions with other drugs are also tested. Phase II and
phase III studies are typically so-called controlled studies: some of the patients receive
the new drug, another group the previous standard drug.

4. Regulatory Approval
When an active substance completes the Clinical Trials, the data is then collected and
analyzed. Then, it can be submitted to the appropriate authorities for review. Before a
drug or vaccine can be sold, approval from a national regulatory authority or
centralized process is required. Ultimately, only one of a large number of
compounds tested makes it through the process of clinical study phases and regulatory
tests. Therefore, only one compound is approved as a drug or vaccine.

Post-Market Monitoring

Phase IV studies (also known as Post-Marketing Surveillance Trials) take place after
receiving marketing authorization from the authorities. More comprehensive data can
be gathered regarding the effectiveness and safety of the new drug. A larger number of
patients taking the drug provides much data as well as compares against treatments
that are already available. These studies are designed to assess the long-term effects of
a drug. In this way, adverse events can be recorded and avoided.

What Is a Regulatory Strategy?

A regulatory strategy is a business's game plan for managing the entire regulatory
process so business actors can proactively communicate with regulatory bodies,
complete requirements as efficiently as possible, and integrate the steps of the
regulatory approval process into the product design. Regulatory frameworks often
have an impact on product design, testing rigor and procedures, product labelling, and
even marketing. A regulatory strategy organizes all of these steps so they complement
— rather than obstruct — business processes. The components of a regulatory strategy
include:

 A plan document that includes the regulatory requirements for a specific

product
 The strategic plan for communicating with regulatory bodies
 Identification of specific Intended Use(s) for the product
 Marketing claims needed to achieved business objectives after
product approval
 An outline of the process, anticipated timelines
 Lists of risks or costs that can jeopardize the regulatory process
 Considerations that jeopardize the profitability or timely release of a product

A regulatory strategy is more than choosing the right pathway; in fact, that's only one
step in the six-step process of successfully developing a strategy. Read this overview
of each step to better understand how a regulatory strategy comes together:
 1. Choose the Target Market

Before you can determine the path to your market, you need to choose the right market
for your product. Identify your target market based on their market size, the
profitability of the market (which can be impacted by pricing requirements and
medical practices), and more. Different geographic markets also have different
regulatory agencies, so you should know which ones will need to approve your
product.

2. List the Product Attributes

Thoroughly defined your product based on its form, its intended purpose, and its
classification type. Not only will these details play an important part in securing
funding or customers, but the attributes can actually impact which regulatory standards
you must meet. Even during early development, create a list of known or proposed
features, potential regulatory issues or questions, and the intended use and benefits for
the users.

3. Conduct Regulatory Intelligence

The more you know about the legal and industry requirements that make up your
product's environment, the better you can plan for them. In your regulatory strategy,
research these three key areas of intelligence:

1. Competitor Information: You should know what competing products are

already on the market or are in the process of developing. This can help you
determine if a product needs a new focus or if you need to streamline
development to beat a competitor to market.

2. Regulatory Environment: By researching the development of competitor or

similar products, you can analyze their route to approval. Seeing how a
comparable product navigated the FDA's premarket requirements, for
example, can let you either leverage the process and/or find areas for
improvement.

3. Legal Requirements: Regulatory strategies often require legal components

such as filing an Investigational Device Exception (IDE) and other patent
documents. Knowing these requirements ahead of time can allow legal
representatives to file the documents properly to protect your new product.

4. Determine Device Classification

Different device or product classifications have different verification scopes, timelines
for approval, and estimated costs for bringing the product to market. Determining your
device classification early in the process can help you manage risks and create the
right controls as the product continues to develop.

5. Identify Available Regulatory Pathways

Every regulatory agency has its own set of possible pathways, so the earlier
determination of your target market is now crucial. The FDA, for example, has a
diverse array of pathways, including:

 Biologics License Application (BLA)

 De Novo Classification Request

 Humanitarian Use Exemption (HDE)
 Premarket Approval (PMA)
 Premarket Notification (510(k))
 Product Development Protocol (PDP)

Researching each of the relevant options for your chosen area and field can help you
choose the best fit.

6. Compare Pathways

This next step is when you or your regulatory strategies finalize which route to
approval is the best fit based on your product's particulars and your research. Compare
the duration of each process, any potentially costly requirements, and the robustness of
the end approval. By the end of this step, you'll determine which pathway is right for
your product and timeline.

7. Create a Living Document

As your regulatory strategy comes together, nothing will be concrete. FDA

requirements (or the requirements of other regulatory agencies) may change to include
new regulations or modify old processes. While your regulatory strategy is still in
play, your team should be alert for new developments, restrictions, and requirements
so you can adjust your total strategy.

What are the Procedures for authorizing medicines in Europe?

A sponsor has several options to seek market approval for a new drug in Europe:
a National Authorization Procedure, a Decentralized Procedure, a Mutual
Recognition Procedure, and a Centralized Procedure.
Based on the drug category, number of countries planning to market the drug, timeline
of approval and the budget sponsor can go this one of the pathways described below

National authorization procedure

This procedure is for the sponsor who is planning to market the drug in one of the
European countries

 Within Europe, each country has its own procedures for authorizing market
approval for a new drug.
 The National procedure is specific to each country within the EU has its own
systems for authorizing a marketing application for a new drug. The sponsor
can visit the regulatory agency website for each country in which he is
interested to obtain market approval.
 To obtain marketing authorization in a country, the application must be
submitted to the Competent Authority of that Member State in its own
language.
 The timeline for this procedure is 210 Days. (without any stop clock queries)

Advantages of this procedure

 The fees are affordable even for small firms

 It saves on translation cost to English or Regional languages
 It provides a base for Mutual recognition Procedure, where if sponsor plans to
extend to other countries for marketing

Medicines that cannot follow this procedure

Some of the medicines don’t fall under this category and is regulated by EMA and the
following categories are

 Orphans Medicinal Product

 All Biotechnology Based Product
 Specified Aids and Cancer Medicines
 Specified Antiviral Medicines
 Specified Medicines for Neurodegenerative Disorder including diabetes and
Specified Medicines for Autoimmune Disorders
Centralized procedure

A single marketing authorization allows the sponsor to market the medicine and
make it available to patients and healthcare professionals throughout Europe in
the “Centralized procedure” and is granted by the European Commission following
the scientific assessment of the application by the European Medicines Agency.

 The centralized process is controlled through the EMA and issues a single
license valid in all EU member states.
 An identical application for marketing authorization is simultaneously
submitted to the competent authorities of the Reference Member State –
RMS and of the Concerned Member States – CMS.
 One Member State is assigned Rapporteur (reviewer) for an application and
takes the lead in the evaluation process of the Committee for Medicinal
Products for Human Use – CHMP
 At the end of the process, the draft assessment report, Supplementary
Protection Certificate – SPC, labeling and package leaflet, as proposed by
the Reference Member State, are approved.
 Under the centralized procedure, a company may only obtain one marketing
authorization per medicinal product. However, in specific cases, a company
may apply for duplicate marketing authorization.

Products that are eligible for review under the centralized procedure must meet the
following criteria:

 Biologic drugs developed by recombinant technology, controlled expression of

genes coding for biologically active proteins in prokaryotes and eukaryotes
including transformed mammalian cells, and hybridoma and monoclonal
antibody methods
 Orphan medicinal products or drugs for rare diseases
 Medicinal products that contain new active substances for indications like
AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune disorders.

The centralized procedure was mandatory only for biotechnology medicines initially,
but later on, the mandatory scope of the centralized procedure has been gradually
extended and included orphan drugs or medicines for rare diseases, human medicines
that contain a new active substance, advanced therapy medicines and medicines that
are intended for the treatment of AIDS, cancer, neurodegenerative disorders, diabetes,
auto-immune and other immune dysfunctions, and viral diseases.
Procedure

Pre-submission

 A sponsor must notify the EMA of their intention to submit a market

authorization application and the month of submission at least seven months
prior to submitting the application.
 This includes
o A document outlining the reasons the sponsor believes the application
should fall under the centralized procedure.
 The EMA will consider the presubmission and notify the sponsor of its
decision regarding acceptance of the MAA.

Submission

 Companies wishing to market a medicinal product submit their application

directly to the European Medicines Agency (EMA)
 The EMA‘s Committee for Medicinal Products for Human
Use (CHMP) conducts a scientific assessment of the application and gives a
recommendation on whether the medicine should be authorized or not.
 The scientific review process consists of periods of evaluation and periods
during which the clock is stopped in order to give the applicant time to resolve
any issues identified during the evaluation.
 A positive opinion is accompanied along with a draft summary of the
product’s characteristics, the package leaflet, and the proposed text for the
packaging.
 The time limit for the evaluation procedure is 210 days, subject to extensions
if additional questions need to be addressed.
 Within 15 days of the adoption, the EMA will forward its opinion to the
European Commission to start the decision-making phase and within 15 days a
draft implementing decision is sent by the Commission to the Standing
Committee on Medicinal Products for Human [Link] allows for its
scrutiny by EU countries.
 The Commission’s Secretariat-General then notifies the decision to the
sponsor or marketing authorization holder and the decision is published in the
Union Register.
Post authorization

 Before a medicine is marketed, it will be subject to pricing negotiations and a

review of its cost-effectiveness. This is carried out at the national level by the
Member States to determine reimbursement criteria.
Product name

 The name for the drug product shall be the same in all countries within
Europe, besides where it violates trademark rules.
 The sponsor shall submit the proposed name in advance, usually 4 to 6
months, and not more than 12 months of the marketing authorization
application.
Pricing and reimbursement
After granting marketing authorization, decisions about price and reimbursement take
place at the level of each Member State considering the potential role and use of the
medicine in the context of the national health system of that country.
Validity

 A National Marketing Authorisations are valid for five years.

 Applications for renewal must be made to the EMA at least six months before
this five-year period expires and this review takes into consideration of any
learning obtained about the product from the experience gained by its use
since it was first authorized,
Advantage of the centralized procedure

 The main advantage of this procedure is, It requires a single market approval
procedure and if authorized, results in the authorization valid in all EU
countries and the same product information available in all EU languages.
Decentralized Procedure

Sponsors can apply for market approval in more than one EU state for products
simultaneously, that have not yet been authorized in any EU state and do not fall under
the mandatory centralized process.

 The applicant chooses one country as the Reference Member State –

(RMS) when making its application for marketing authorization. Chosen
reference Member State then prepares a draft assessment report that is
submitted to the other Member States where approval is sought for their
simultaneous consideration and approval.
 The RMS forwards a preliminary Assessment Report on the dossier to
the Concerned Member States – CMS(s) and the applicant within 70 days
 Allowing the other Member States access to this assessment at an early stage,
any issues and concerns can be dealt with quickly without any delay
 The CMS(s) are asked to give their comments on the proposed national
prescription status and to inform the RMS.
 The RMS will forward all comments to the applicant and stops the clock if
necessary until the applicant prepares a response document.
 The RMS prepares a Draft Assessment Report on day 120 and may close the
procedure if a consensus has been reached between the CMS(s) and the RMS.
 Or, the CMS(s) has 90 more days to approve the Draft Assessment Report and
other documents.
 The competent authorities of the RMS and the CMS(s) adopt a decision within
30 days after acknowledgment of their agreement to the Assessment Report
and other documents.
  Finally, at the end of the Decentralized Procedure with a positive agreement, a
national marketing authorization will be issued in the RMS and each of the
CMS(s).

Advantages of this procedure

 The sponsor or manufacturer receives identical marketing authorization for its

medicinal product in all chosen member states at the same time.
 It is possible to launch a product on the market in several different EU
countries simultaneously, thus reducing the associated launch costs and
potentially creating a strong brand and presence for the product in the EU from
day one.
 The sponsor who seeks generic medicines prefers this decentralized procedure
often

Mutual Recognition Procedure

In this procedure, the medicinal products, approved in one European country and seek
further marketing authorizations from other EU countries, who, rather than conducting
their own review, agree to recognize the decision of the first country.

 The sponsor is required to make an application only once for initial

registration. The same application with some regional changes is accepted by
another member country.
 The first Member State that reviews the application is called the Reference
Member State – RMS and notifies other states, called ‘Concerned Member
States – CMS.
  The concerned Member States may suspend their own evaluations to await
assessment by the Reference Member State.
 The decision of the Reference Member State is forwarded to the Concerned
Member States and If the Concerned Member States reject mutual recognition,
the matter is referred to as the CHMP of the EMA for arbitration.
 The EMA forwards its opinion to the European Commission, which makes the
final decision. Altogether, the decision process may take up to 300 days if
there is no objection and 600 days when objections are raised.
 This process may consume a time period of 390 days.

Clinical trials in India refers to clinical research in India in which researchers test
drugs and other treatments on research participants. NDCTR 2019 and section 3.7.1 to
3.7.3 of ICMR guidelines[1] requires that all researchers conducting a clinical trial must
publicly document it in the Clinical Trials Registry - India.[2]
In the years around 2010 there were various scandals in media and popular discussion
in which companies conducted clinical trials in unethical ways. There were many
discussions raising many complaints, including that researchers were not
getting informed consent from research participants, and that the medical research was
dismissing high rates of injury and death among research participants. Following the
2013 case Swasthya Adhikar Manch v. Union of India in the Supreme Court of India,
various government agencies reformed their regulations to make clinical trials more
ethical.[5] There have been many changes with various responses. Among the
responses, some say that the clinical trials are safer for participants, and others say that
the new rules favor large domestic and international companies over other
stakeholders.
Health Canada is the federal body that regulates the drug approval process under the
Food and Drugs Act (FDA) and its regulations (FDR), its related policies and
guidance. Before a drug can be distributed and sold in Canada, its manufacturer must
receive a Notice of Compliance (NOC) from Health Canada, and the drug must be
assigned a Drug Identification Number (DIN), uniquely identifying all drug products
sold in a dosage form in Canada. New drugs must also go through extensive testing
before being granted an NOC.

It can take anywhere from 6 months to 2 years for Health Canada to review drug safety
and efficacy information before providing a decision on whether an NOC is to be
granted. Once granted, it represents that the drug meets the required standards under
the Food and Drugs Act and its regulations, for use in humans.

1. When a sponsor decides that it would like to market a drug in Canada, it files a
"New Drug Submission" with HPFB. This contains information and data about
the drug's safety, effectiveness and quality. It includes the results of the
preclinical and clinical studies, whether done in Canada or elsewhere, details
regarding the production of the drug, packaging and labelling details, and
information regarding therapeutic claims and side effects.
2. HPFB performs a thorough review of the submitted information, sometimes
using external consultants and advisory committees.
3. HPFB evaluates the safety, efficacy and quality data to assess the potential
benefits and risks of the drug.
4. HPFB reviews the information that the sponsor proposes to provide to health
care practitioners and consumers about the drug (e.g. the label, product
brochure).
5. If, at the completion of the review, the conclusion is that the benefits outweigh
the risks and that the risks can be mitigated, the drug is issued a Notice of
Compliance (NOC), as well as a Drug Identification Number (DIN) which
permits the sponsor to market the drug in Canada and indicates the drug's
official approval in Canada.
6. In addition, Health Canada laboratories may test certain biological products
before and after authorization to sell in Canada has been issued. This is done
through its Lot Release Process, in order to monitor safety, efficacy and
quality.
7. A monograph is a scientific standard. It contains information about an
ingredient, product or class of products: its properties; acceptable use or
purpose; dosage; duration of use; risk information; etc. The monograph
represents Health Canada's knowledge and experience about what is necessary
for the safe and effective use of the ingredient, product, or class of products.
8. Monographs have been developed for many natural health products and some
non-prescription and disinfectant drugs. If an applicant wants to market a
product that follows a monograph exactly, the process to obtain approval will
be faster because Health Canada has already pre-cleared the information.
9. The Natural and Non-prescription Health Products Directorate's (NNHPD)
product licensing system allows applicants to reference monographs for
certain non-prescription drugs to support the safety and efficacy of these
products, allowing for an expedited review of the Licence/DIN application.
Module 4&5
Explain the ethical Principles for WMA Declaration of Helsinki as per 2013 revision.
64th WMA General Assembly, Fortaleza, Brazil, October 2013
PREAMBLE

1. The World Medical Association (WMA) has developed the Declaration of

Helsinki as a statement of ethical principles for medical research involving human
subjects, including research on identifiable human material and data.

The Declaration is intended to be read as a whole and each of its constituent

paragraphs should be applied with consideration of all other relevant paragraphs.

2. Consistent with the mandate of the WMA, the Declaration is addressed

primarily to physicians. The WMA encourages others who are involved in medical
research involving human subjects to adopt these principles.

GENERAL PRINCIPLES

3. The Declaration of Geneva of the WMA binds the physician with the words,
“The health of my patient will be my first consideration,” and the International Code
of Medical Ethics declares that, “A physician shall act in the patient’s best interest
when providing medical care.”

4. It is the duty of the physician to promote and safeguard the health, well-being
and rights of patients, including those who are involved in medical research. The
physician’s knowledge and conscience are dedicated to the fulfilment of this duty.

5. Medical progress is based on research that ultimately must include studies

involving human subjects.

6. The primary purpose of medical research involving human subjects is to

understand the causes, development and effects of diseases and improve preventive,
diagnostic and therapeutic interventions (methods, procedures and treatments). Even
the best proven interventions must be evaluated continually through research for their
safety, effectiveness, efficiency, accessibility and quality.

7. Medical research is subject to ethical standards that promote and ensure respect
for all human subjects and protect their health and rights.
8. While the primary purpose of medical research is to generate new knowledge,
this goal can never take precedence over the rights and interests of individual research
subjects.

9. It is the duty of physicians who are involved in medical research to protect the
life, health, dignity, integrity, right to self-determination, privacy, and confidentiality
of personal information of research subjects. The responsibility for the protection of
research subjects must always rest with the physician or other health care professionals
and never with the research subjects, even though they have given consent.

10. Physicians must consider the ethical, legal and regulatory norms and standards
for research involving human subjects in their own countries as well as applicable
international norms and standards. No national or international ethical, legal or
regulatory requirement should reduce or eliminate any of the protections for research
subjects set forth in this Declaration.

11. Medical research should be conducted in a manner that minimises possible

harm to the environment.

12. Medical research involving human subjects must be conducted only by

individuals with the appropriate ethics and scientific education, training and
qualifications. Research on patients or healthy volunteers requires the supervision of a
competent and appropriately qualified physician or other health care professional.

13. Groups that are underrepresented in medical research should be provided

appropriate access to participation in research.

14. Physicians who combine medical research with medical care should involve
their patients in research only to the extent that this is justified by its potential
preventive, diagnostic or therapeutic value and if the physician has good reason to
believe that participation in the research study will not adversely affect the health of
the patients who serve as research subjects.

15. Appropriate compensation and treatment for subjects who are harmed as a
result of participating in research must be ensured.

Risks, Burdens and Benefits

16. In medical practice and in medical research, most interventions involve risks
and burdens.
Medical research involving human subjects may only be conducted if the importance
of the objective outweighs the risks and burdens to the research subjects.

17. All medical research involving human subjects must be preceded by careful
assessment of predictable risks and burdens to the individuals and groups involved in
the research in comparison with foreseeable benefits to them and to other individuals
or groups affected by the condition under investigation.

Measures to minimise the risks must be implemented. The risks must be continuously
monitored, assessed and documented by the researcher.

18. Physicians may not be involved in a research study involving human subjects
unless they are confident that the risks have been adequately assessed and can be
satisfactorily managed.

When the risks are found to outweigh the potential benefits or when there is conclusive
proof of definitive outcomes, physicians must assess whether to continue, modify or
immediately stop the study.

Vulnerable Groups and Individuals

19. Some groups and individuals are particularly vulnerable and may have an
increased likelihood of being wronged or of incurring additional harm.

All vulnerable groups and individuals should receive specifically considered

protection.

20. Medical research with a vulnerable group is only justified if the research is
responsive to the health needs or priorities of this group and the research cannot be
carried out in a non-vulnerable group. In addition, this group should stand to benefit
from the knowledge, practices or interventions that result from the research.

Scientific Requirements and Research Protocols

21. Medical research involving human subjects must conform to generally

accepted scientific principles, be based on a thorough knowledge of the scientific
literature, other relevant sources of information, and adequate laboratory and, as
appropriate, animal experimentation. The welfare of animals used for research must be
respected.
22. The design and performance of each research study involving human subjects
must be clearly described and justified in a research protocol.

The protocol should contain a statement of the ethical considerations involved and
should indicate how the principles in this Declaration have been addressed. The
protocol should include information regarding funding, sponsors, institutional
affiliations, potential conflicts of interest, incentives for subjects and information
regarding provisions for treating and/or compensating subjects who are harmed as a
consequence of participation in the research study.

In clinical trials, the protocol must also describe appropriate arrangements for post-
trial provisions.

Research Ethics Committees

23. The research protocol must be submitted for consideration, comment, guidance
and approval to the concerned research ethics committee before the study begins. This
committee must be transparent in its functioning, must be independent of the
researcher, the sponsor and any other undue influence and must be duly qualified. It
must take into consideration the laws and regulations of the country or countries in
which the research is to be performed as well as applicable international norms and
standards but these must not be allowed to reduce or eliminate any of the protections
for research subjects set forth in this Declaration.

The committee must have the right to monitor ongoing studies. The researcher must
provide monitoring information to the committee, especially information about any
serious adverse events. No amendment to the protocol may be made without
consideration and approval by the committee. After the end of the study, the
researchers must submit a final report to the committee containing a summary of the
study’s findings and conclusions.

Privacy and Confidentiality

24. Every precaution must be taken to protect the privacy of research subjects and
the confidentiality of their personal information.

Informed Consent

25. Participation by individuals capable of giving informed consent as subjects in

medical research must be voluntary. Although it may be appropriate to consult family
members or community leaders, no individual capable of giving informed consent may
be enrolled in a research study unless he or she freely agrees.

26. In medical research involving human subjects capable of giving informed

consent, each potential subject must be adequately informed of the aims, methods,
sources of funding, any possible conflicts of interest, institutional affiliations of the
researcher, the anticipated benefits and potential risks of the study and the discomfort
it may entail, post-study provisions and any other relevant aspects of the study. The
potential subject must be informed of the right to refuse to participate in the study or to
withdraw consent to participate at any time without reprisal. Special attention should
be given to the specific information needs of individual potential subjects as well as to
the methods used to deliver the information.

After ensuring that the potential subject has understood the information, the physician
or another appropriately qualified individual must then seek the potential subject’s
freely-given informed consent, preferably in writing. If the consent cannot be
expressed in writing, the non-written consent must be formally documented and
witnessed.

All medical research subjects should be given the option of being informed about the
general outcome and results of the study.

27. When seeking informed consent for participation in a research study the
physician must be particularly cautious if the potential subject is in a dependent
relationship with the physician or may consent under duress. In such situations the
informed consent must be sought by an appropriately qualified individual who is
completely independent of this relationship.

28. For a potential research subject who is incapable of giving informed consent,
the physician must seek informed consent from the legally authorised representative.
These individuals must not be included in a research study that has no likelihood of
benefit for them unless it is intended to promote the health of the group represented by
the potential subject, the research cannot instead be performed with persons capable of
providing informed consent, and the research entails only minimal risk and minimal
burden.

29. When a potential research subject who is deemed incapable of giving informed
consent is able to give assent to decisions about participation in research, the physician
must seek that assent in addition to the consent of the legally authorised representative.
The potential subject’s dissent should be respected.
30. Research involving subjects who are physically or mentally incapable of giving
consent, for example, unconscious patients, may be done only if the physical or mental
condition that prevents giving informed consent is a necessary characteristic of the
research group. In such circumstances the physician must seek informed consent from
the legally authorised representative. If no such representative is available and if the
research cannot be delayed, the study may proceed without informed consent provided
that the specific reasons for involving subjects with a condition that renders them
unable to give informed consent have been stated in the research protocol and the
study has been approved by a research ethics committee. Consent to remain in the
research must be obtained as soon as possible from the subject or a legally authorised
representative.

31. The physician must fully inform the patient which aspects of their care are
related to the research. The refusal of a patient to participate in a study or the patient’s
decision to withdraw from the study must never adversely affect the patient-physician
relationship.

32. For medical research using identifiable human material or data, such as
research on material or data contained in biobanks or similar repositories, physicians
must seek informed consent for its collection, storage and/or reuse. There may be
exceptional situations where consent would be impossible or impracticable to obtain
for such research. In such situations the research may be done only after consideration
and approval of a research ethics committee.

Use of Placebo

33. The benefits, risks, burdens and effectiveness of a new intervention must be
tested against those of the best proven intervention(s), except in the following
circumstances:

Where no proven intervention exists, the use of placebo, or no intervention, is

acceptable; or

Where for compelling and scientifically sound methodological reasons the use of any
intervention less effective than the best proven one, the use of placebo, or no
intervention is necessary to determine the efficacy or safety of an intervention

and the patients who receive any intervention less effective than the best proven one,
placebo, or no intervention will not be subject to additional risks of serious or
irreversible harm as a result of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.

Post-Trial Provisions

34. In advance of a clinical trial, sponsors, researchers and host country

governments should make provisions for post-trial access for all participants who still
need an intervention identified as beneficial in the trial. This information must also be
disclosed to participants during the informed consent process.

Research Registration and Publication and Dissemination of Results

35. Every research study involving human subjects must be registered in a publicly
accessible database before recruitment of the first subject.

36. Researchers, authors, sponsors, editors and publishers all have ethical
obligations with regard to the publication and dissemination of the results of research.
Researchers have a duty to make publicly available the results of their research on
human subjects and are accountable for the completeness and accuracy of their reports.
All parties should adhere to accepted guidelines for ethical reporting. Negative and
inconclusive as well as positive results must be published or otherwise made publicly
available. Sources of funding, institutional affiliations and conflicts of interest must be
declared in the publication. Reports of research not in accordance with the principles
of this Declaration should not be accepted for publication.

Unproven Interventions in Clinical Practice

37. In the treatment of an individual patient, where proven interventions do not

exist or other known interventions have been ineffective, the physician, after seeking
expert advice, with informed consent from the patient or a legally authorised
representative, may use an unproven intervention if in the physician’s judgement it
offers hope of saving life, re-establishing health or alleviating suffering. This
intervention should subsequently be made the object of research, designed to evaluate
its safety and efficacy. In all cases, new information must be recorded and, where
appropriate, made publicly available.

What do you mean by the term “Nuremberg Code”?

An international code of research ethics developed during the trials of Nazi war crimin
als after World War II and widely adopted as a standard during the 1950s and 1960s fo
r protecting human subjects involved in clinical trials and research or
A set of principles established after World War II to protect the rights of research parti
cipants (subjects).
The Nuremberg Code aimed to protect human subjects from enduring the kind of
cruelty and exploitation the prisoners endured at concentration camps. The 10
elements of the code are:

1. Voluntary consent is essential

2. The results of any experiment must be for the greater good of society
3. Human experiments should be based on previous animal experimentation
4. Experiments should be conducted by avoiding physical/mental suffering and
injury
5. No experiments should be conducted if it is believed to cause death/disability
6. The risks should never exceed the benefits
7. Adequate facilities should be used to protect subjects
8. Experiments should be conducted only by qualified scientists
9. Subjects should be able to end their participation at any time
10. The scientist in charge must be prepared to terminate the experiment when
injury, disability, or death is likely to occur.

The Belmont Report is a report created by the National Commission for the Protection
of Human Subjects of Biomedical and Behavioral Research.

The 3 Basic Ethical Principles and Their Applicability to Clinical Trials

Respect for Persons

The first ethical principle in the Belmont Report, respect for persons, is made up of 2
important but distinct requirements. The first is the recognition that people are
autonomous and entitled to their own opinions and choices, unless detrimental to
others. The second is the recognition that due to various reasons, not all people are
capable of self-determination and instead require protection. The amount of protection
provided to an individual should depend on the risk of harm and the likelihood of
benefit offered by the research. The Report promotes the idea that in most cases,
respect for persons demands that people enter into research voluntarily and with
adequate information.

Beneficence

The Report’s second ethical principle, beneficence, is the recognition that people are
treated in an ethical manner not only by respecting their decisions and protecting them
from harm, but also by making efforts — or, more specifically, making it an obligation
to secure their well-being. The Belmont Report identifies 2 general and
complementary rules regarding beneficence:

1. Do not harm
2. Maximize possible benefits and minimize possible harms

While the obligation to “do no harm” is often the focus of discussions, the obligation
to maximize possible benefits, while minimizing possible harms, is an obligation that
warrants equal consideration.

Justice

The last of the Belmont Report’s 3 basic ethical principles, justice, raises questions
about who ought to receive the benefits of research and who ought to bear its burdens.
Following a provocative discussion of equality and differential treatment, the Belmont
Report considers the need to scrutinize whether some classes of people —
economically disadvantaged, racial and ethnic minorities, or persons confined to
institutions — are systematically selected as research subjects due to their position or
vulnerability rather than their connection to the problem being researched.

Today, the principle of justice may demand scrutiny of whether classes of people
considered compromised or vulnerable are excluded from participation in clinical trials
due to financial and other barriers even though they have a connection to the problem
being considered. The Report states that justice demands therapeutic devices and
procedures developed from public funds must not provide advantages only to those
who can afford them.

Explain the essential documents required before the Clinical Phase of the Trial
Commences.

Title of Document Purpose

1 INVESTIGATOR’S BROCHURE To document that relevant
and current scientific
information about the
investigational product has
been provided to the
investigator
2 SIGNED PROTOCOL AND To document investigator
AMENDMENTS, IF ANY, AND and sponsor agreement to the
SAMPLE CASE REPORT FORM protocol/amendment(s) and
 (CRF) CRF
3 INFORMATION GIVEN TO To document the informed
TRIAL SUBJECT-INFORMED consent
CONSENT FORM
- ANY OTHER WRITTEN To document that subjects
INFORMATION will be given appropriate
written information (content
and wording) to support their
ability to give fully informed
consent
ADVERTISEMENT FOR To document that
SUBJECT RECRUITMENT (if recruitment measures are
used) appropriate and not coercive
4 FINANCIAL ASPECTS OF THE To document the financial
TRIAL agreement between the
investigator/institution and
the sponsor for the trial
5 INSURANCE STATEMENT To document that
(where required) compensation to subject(s)
for trial-related injury will be
available
6 SIGNED AGREEMENT
BETWEEN INVOLVED PARTIES, To document agreements
e.g.:
- investigator/institution and sponsor
-investigator/institution and CRO
-sponsor and CRO
-investigator/institution and
authority(ies) (where required)
7 DATED,DOCUMENTED To document that the trial
APPROVAL/FAVOURABLE has been subject to IRB/IEC
OPINION OF INSTITUTIONAL review and given
REVIEW BOARD (IRB) approval/favourable opinion.
/INDEPENDENT ETHICS To identify the version
COMMITTEE (IEC) OF THE number and date of the
FOLLOWING: document(s)
-protocol and any amendments
-CRF(ifapplicable)
-informed consent form(s)
- any other written information to be
provided to the subject(s)
- advertisement for subject recruitment
 (if used)
- subject compensation (if any)
- any other documents given approval/
favourable opinion
8 INSTITUTIONAL REVIEW To document that the
BOARD / INDEPENDENT ETHICS IRB/IEC is constituted in
COMMITTEE COMPOSITION agreement with GCP
9 REGULATORY To document appropriate
AUTHORITY(IES) authorisation / approval /
AUTHORISATION / APPROVAL / notification by the regulatory
NOTIFICATION OF PROTOCOL authority(ies) has been
(where required) obtained prior to initiation of
the trial in compliance with
the applicable regulatory
requirement(s)
10 CURRICULUM VITAE AND/OR To document qualifications
OTHER RELEVANT and eligibility to conduct trial
DOCUMENTS EVIDENCING and/or provide medical
QUALIFICATIONS OF supervision of subjects
INVESTIGATOR(S) AND SUB-
INVESTIGATOR(S)
11 NORMAL VALUE(S)/RANGE(S) To document normal values
FOR MEDICAL / LABORATORY / and/or ranges of the tests
TECHNICAL PROCEDURE(S)
AND/OR TEST(S) INCLUDED IN
THE PROTOCOL
12 EDICAL/LABORATORY/ To document competence of
TECHNICAL PROCEDURES / facility to perform required
TESTS test(s) , and support
- certification or reliability of results
- accreditation or
- established quality control and/or
external quality assessment or
- other validation (where required)

13 SAMPLE OF LABEL(S) To document compliance

ATTACHED TO with applicable labelling
INVESTIGATIONAL PRODUCT regulations and
CONTAINER(S) appropriateness of
instructions provided to the
subjects
14 INSTRUCTIONS FOR HANDLING To document instructions
 OF INVESTIGATIONAL needed to ensure proper
PRODUCT(S) AND TRIAL- storage, packaging,
RELATED MATERIALS dispensing and disposition of
(if not included in protocol or investigational products and
Investigator’s Brochure) trial-related materials
15 SHIPPING RECORDS FOR To document shipment dates,
INVESTIGATIONAL batch numbers and method of
PRODUCT(S) AND TRIAL- shipment of investigational
RELATED MATERIALS product(s) and trial-related
materials. Allows tracking of
product batch, review of
shipping conditions, and
accountability
16 CERTIFICATE(S) OF ANALYSIS To document identity, purity,
OF INVESTIGATIONAL and strength of
PRODUCT(S) SHIPPED investigational product(s) to
be used in the trial
17 DECODING PROCEDURES FOR To document how, in case of
BLINDED TRIALS an emergency, identity of
blinded investigational
product can be revealed
without breaking the blind
for the remaining subjects'
treatment
18 MASTER RANDOMISATION To document method for
LIST randomisation of trial
population
19 PRE-TRIAL MONITORING To document that the site is
REPORT suitable for the trial
20 TRIAL INITIATION To document that trial
MONITORING REPORT procedures were reviewed
with the investigator and the
investigator’s trial staff

What are the specific considerations for vulnerable populations as per EU Regulations
for Clinical Trial?

i. Children : Before undertaking research/trial in children the investigator must ensure

that –
a. Children will not be involved in research that could be carried out equally well with
adults;

b. The purpose of the research is to obtain knowledge relevant to health needs of

children. For clinical evaluation of a new drug the study in children should always be
carried out after the phase III clinical trials in adults. It can be studied earlier only if
the drug has a therapeutic value in a primary disease of the children;

c. A parent or legal guardian of each child has given consent;

e. Research should be conducted in settings in which the child and parent can obtain
adequate Medical and psychological support;

The child’s refusal to participate in research must always be respected unless there is no
medically acceptable alternative to the therapy provided/ tested, provided the consent
has been obtained from parents / guardian;

ii. Pregnant or nursing women: Pregnant or nursing women should in no circumstances

be the participant of any research unless the research carries no more than minimal risk
to the foetus or nursing infant and the object of the research is to obtain new
knowledge about the foetus, pregnancy and lactation.

c. Rights and welfare of mentally challenged and mentally differently able persons who
are incapable of giving informed consent or those with behavioural disorders must be
protected. Appropriate proxy consent from the legal guardian should be taken after the
person is well informed about the study, need for participation, risks and benefits
involved and the privacy and confidentiality procedures. The entire consent process
should be properly documented;

e. Persons who are terminally ill, have incurable disease and mental illness and
cognitively impaired and physically disabled.

h. Tribal and marginalized communities

i. Refugee, migrants, homeless, persons or populations in conflict zones, riots areas or

disaster situations;

j. Suffering from stigmatizing or rare diseases etc.

What are the specific considerations for minors as per EU regulation for Clinical Trial?
Article 2(2.20) of the Clinical Trials Regulation and these recommendations define a
legally designated representative as:

“a natural or legal person, authority or body which, according to the law of the Member
State concerned, is empowered to give informed consent on behalf of a subject who is
an incapacitated subject or a minor.”

For most minors, the legally designated representative will be one or both parents,
depending on national law. Independent of applicable legal requirements, both parents
should be encouraged to participate in the informed consent process. Orphans, or
children whose parents no longer have parental authority, should not be excluded from
clinical trials; informed consent will be requested from the legally designated
representative. Parents/legally designated representative have the duty to protect their
child, and consider the child’s point of view, based on their knowledge of the child and
the child's life.

Minor Article 2(2.18) of the Clinical Trials Regulation and these recommendations
define minor as:

“a subject who is, according to the law of the Member State concerned, under the age of
legal competence to give informed consent.”

The age of legal competence differs across national laws, for example adolescents from
16 years of age may not be regarded as minors in some Member States. This may have
consequences for multinational trials, as the additional conditions applicable to clinical
trials with minors will not be relevant for the clinical trials in the Member states where
the children are not considered to be minors.

How is electronic database important for safety reporting in the clinical trial?

The objective of collecting safety data from clinical trials is early detection of important
safety signals, protecting patients from unnecessary risks, and developing the safety
profile of the drug contributing to its benefit-risk assessment.

In a nutshell, electronic data capture (EDC) is a system of capturing and managing

clinical trial data on a digital platform to replace traditional paper-based data capture.
Using such a system not only lets you capture data securely but also expedites the
research process and ensures data reusability. Most EDC systems nowadays are cloud-
based, ensuring secure access from anywhere.
 When researchers conduct a clinical study, they collect information about their patients
using Case Report Forms (CRFs). For example, a diabetes study with a demographics
form and a lab result form.

CRFs are traditionally paper-based, and when the study is completed, the CRF
documents are gathered and sent to the sponsor, who then transfers the data to a
statistical analysis tool. Not only is this a lot of manual work, but also a LOT of paper,
and in some cases this paper must be stored for 15 years!

However, by using an electronic data capture system, these Case Report Forms are
filled out on a web-based platform, and the data is stored directly in a central database.
This saves the hassle and risks of storing potentially sensitive data on paper, Excel,
and other less secure and non-reusable methods. An electronic data capture system
helps ensure compliance with medical data privacy, security, and Good Clinical
Practice regulations. Furthermore, most professional EDC systems today provide
automatic identification of data errors. This helps the Monitors to ensure the highest
data quality. This process significantly improves the quality of the data and decreases
the time needed for data review and corrections.

Features should you look for in an EDC

1. A user-friendly interface, designed to meet the specific needs of medical

researchers
2. A user-access controlled platform that facilitates collaboration among multiple
sites and researchers around the world
3. The ability to set data limits for all captured data to reduce human error
4. Assured compliance with privacy and data protection policies, ensuring that
mandatory regulations are met and that research data is collected and
maintained
5. Seamless integration with existing tools, wearables, legacy systems, and other
technology
6. The ability to reuse research data for the initial research team, the statistical
analysis team, and any future users of the data
7. Access to proactive support and technical advisors to help set up your clinical
trials

What are the labeling requirements of an investigational medicinal product which is

used in the clinical trial?

In clinical studies, pharmaceutical companies use labels to

provide important information to stakeholders. These labels must
include instructions for use, mode and route of drug administration,
product strength, storage requirements and expiry dates, amongst other
information.
Each label is unique to the individual patient and must also be
specific to the trial and country in question. If a patient experiences a
severe reaction, the study sponsor needs to be able to trace what was
given to that patient. For blind studies, labels for placebos must appear
identical to the labelling of the active product, while still being
identifiable to the trial sponsor. This traceability is achieved via a
unique identifier that is contained in the label.

Explain the following as per ethical guidelines for Biomedical Research on Human
Participants by Indian Council of Medical Research (ICMR), India: Principles of
Essentiality, Principles of privacy and confidentiality and principles of totality of
responsibilities.

Principle of essentiality:
The research being carried out should be essential for the advancement of
knowledge that benefits patients, doctors and all others in aspects of health care
and also for the ecological and environmental well being of the planet.

Principle of privacy and confidentiality:

All the data acquired for research purpose should be kept confidential to prevent
disclosure of identity of the involved participant and should not be disclosed
without valid legal and/or scientific reasons.

Principle of totality of responsibility:

All those directly or indirectly connected with the research should take the
professional and moral responsibility, for the due observance of all the principles,
guidelines or prescriptions laid down in respect of the research.

What is the composition of IEC as per ethical guidelines for Biomedical Research on
Human Participants by Indian Council of Medical Research (ICMR), India?

BASIC RESPONSIBILITIES OF IEC

1. To protect the dignity, rights and` well-being of potential research participants.
2. To ensure that universal ethical values and International Scientific Standards are
expressed in terms of local community values and customs.
3. To assist in the development and the education of a research community responsive
to local health care requirements.

TERMS OF REFERENCE AND REVIEW PROCEDURES

1. The IEC should be aware of their role and responsibilities as Committee Members.
2. Each Committee should have its own operating procedures available with each
member
3. Any change in the regulatory requirement should be brought to the notice of
members, keeping in view the National and International developments.
4. The terms of references should include a statement on terms of appointment with
reference to
a. the duration of the term of membership
b. the policy for removal / replacement
c. the resignation procedure etc.
5. The ethical review should be done through formal meetings and discussion should
not be taken through circulation of proposals.
6. Every research proposal on human subjects should be reviewed scientifically,
evaluated in terms of risks and benefits with proper justification
7. Scientific evaluation should be done completely prior to ethical review
8. The Committee should evaluate for the adequacy of documentation to ensure
privacy confidentiality and legal aspects.
9. All proposals on biomedical researches involving human subjects should be cleared
by an appropriately constituted Institutional Ethics Committee (IEC), to safeguard the
welfare of the rights of the subject involved.
10. The sponsor and / or investigator should seek the opinion of Institutional Ethics
Committee regarding suitability of the protocol, methods and documents to be used in
recruitment of subjects and obtaining their informed consent including adequacy of the
information being provided to the subjects. The Ethics Committees are entrusted not
only with the initial view of the proposed research protocols prior to the initiation of
the projects but also have a continuing responsibility of regular monitoring for the
compliance of the ethics of the approved programme till the same are completed. Such
an ongoing review is in accordance with the ‘Declaration of Helsinki’.
11. Interim review : can be resorted to instead of waiting for the scheduled time of the
meeting and decisions can be taken urgently and should be brought to the notice of the
main committee for the following reasons :
a. Re-examinations of a proposal already examined by the IEC
b. Research study of a minor nature such as examination of case records etc.
c. An urgent proposal of national interest.
What do you understand by Waiver of consent?
This form should be used when requesting a full Waiver of Informed Consent (no
consent) or when requesting an Alteration of Informed Consent (some elements are
missing, full information is not disclosed to participants, or deception is used).

The IRB may approve a consent procedure which does not include some or all of
the required elements of informed consent provided all of the following are true:

 The research involves no more than minimal risk

 The waiver of informed consent will not adversely affect the rights and welfare
of the subjects
 It is not practicable to conduct the research without the waiver or alteration

Explain how the trial on vaccine can be conducted?

The general stages of the development cycle of a vaccine are:

 Exploratory stage
 Pre-clinical stage
 Clinical development
 Regulatory review and approval
 Manufacturing
 Quality control
Clinical development is a three-phase process. During Phase I, small groups of people
receive the trial vaccine. In Phase II, the clinical study is expanded and vaccine is
given to people who have characteristics (such as age and physical health) similar to
those for whom the new vaccine is intended. In Phase III, the vaccine is given to
thousands of people and tested for efficacy and safety.

Many vaccines undergo Phase IV formal, ongoing studies after the vaccine is approved
and licensed.

After approving a vaccine, FDA continues to oversee its production to ensure

continuing safety. Monitoring of the vaccine and of production activities, including
periodic facility inspections, must continue as long as the manufacturer holds a license
for the vaccine product.

FDA can require a manufacturer submit the results of their own tests for potency,
safety, and purity for each vaccine lot. FDA can require each manufacturer submit
samples of each vaccine lot for testing.
The Vaccine Adverse Event Reporting System (VAERS) is a national vaccine safety
surveillance program co-sponsored by the Food and Drug Administration (FDA) and
the CDC.

VAERS collects and analyzes information from reports of adverse events (side effects)
that occur after the administration of US licensed vaccines. Reports are welcome from
all concerned individuals: patients, parents, healthcare providers, pharmacists, and
vaccine manufacturers.

What do you understand by ‘Pedigree Studies’?

A pedigree shows relationships between family members and indicates which

individuals have certain genetic pathogenic variants, traits, and diseases within a
family as well as vital status. A pedigree can be used to determine disease inheritance
patterns within a family. Enlarge. Standard pedigree nomenclature.

Pedigree analysis was developed to understand the inheritance of genes from

parents to offspring. It was developed as a chart that can represent a family tree along
with the family members and their genetic traits, respectively.
Explain the term Liability and Indemnity. What are the types of clinical trials
insurance provided by commercial insurers?
Liability and indemnity both are very critical elements of clinical research process and
often misunderstood. A clear understanding of liability and indemnity are very
important in order to have proper risk management measures in place for clinical trials.

Liabilities- Clinical Trial Liability Insurance (CTLI) basically covers legal liability
arising out of lack of care, negligence resulting in injury or death of the subject. The
sponsor of a clinical trial has the overall responsibility for the conduct of the trial and
usually initiates, organizes and supports the clinical trial. Sponsor-related liabilities
means claims made by or on behalf of clinical trial participants for personal injury that
occurs as a result of their participation in the clinical trial. These injuries may be due
to:
a) negligence in the design of the trial protocol, which may give rise to professional
liability; or
b) the unintended, harmful effect of a product under investigation, which may give rise
to products liability.

Indemnity means a legally binding promise by which one party undertakes to accept
the risk of loss or damage of another party that may suffer from the loss or damage. In
simpler terms, Indemnity is a contractual arrangement whereby parties agree to
provide compensation for any losses suffered by another party. Indemnity specifies
that the insured should not collect more than the actual cash value of a loss but should
be restored to approximately the same financial position as existed before the loss.
Indemnity is one of the risk management measures for clinical trials. The purpose of
an indemnity arrangement is to provide legal protection for the participants in the
event of an unforeseen adverse circumstance arising during the course of a clinical
trial. Protocol violation, malpractice and negligence by investigators and study site
personnel are not covered under indemnity for sponsored clinical trials. There are 3
major indemnity elements:
a) Triggering events-In what circumstances will an indemnity become effective
b) Excluded events-In what circumstances will an indemnity will not be effective
c) Liabilities covered-What kinds of liabilities will be covered

This insurance policy should be one of the first things a research institute should look
for. The policy comes with the following coverage:

 Personal damage: All forms of compensatory, monetary and statutory

compensation caused due to physical injury or illness of the participants.
These physical issues should be a cause of the medical tests
 Material damage: This refers to the damage caused to equipment during the
clinical trial
 Data breach: This refers to the expenses associated with the data breach. The
data loss must be related to the clinical trial
 Extended period offering: This refers to the time period after the policy
period has expired. It might happen that the insured receives a claim after the
policy has expired for a trial which took place within the policy period. The
insurance companies pay for such claims
 Cross liability: This refers to coverage of more than one insured candidate;
the total liability amount remains the same.

Explain the concept of Indemnity Insurance in India.

 Indemnity insurance is a type of insurance policy where the insurance

company guarantees compensation for losses or damages sustained by a
policyholder.
 Indemnity insurance is designed to protect professionals and business owners
when found to be at fault for a specific event such as misjudgment.
 Certain professionals must carry indemnity insurance including those
involved in financial and legal services, such as financial advisors, insurance
agents, accountants, mortgage brokers, and attorneys.
 Medical malpractice and errors and omissions insurance are examples of
indemnity insurance.
 Section C

Answer the following questions in detail (800 words)

1) Explain in brief the ICH GCP Guidelines: E6 for Good Clinical Practice.

2.1 Clinical trials should be conducted in accordance with the ethical principles that
have their origin in the Declaration of Helsinki, and that are consistent with GCP and
the applicable regulatory requirement(s).
2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed
against the anticipated benefit for the individual trial subject and society. A trial should
be initiated and continued only if the anticipated benefits justify the risks.
2.3 The rights, safety, and well-being of the trial subjects are the most important
considerations and should prevail over interests of science and society.
2.4 The available nonclinical and clinical information on an investigational product
should be adequate to support the proposed clinical trial.
2.5 Clinical trials should be scientifically sound, and described in a clear, detailed
protocol.
2.6 A trial should be conducted in compliance with the protocol that has received prior
institutional review board (IRB)/independent ethics committee (IEC)
approval/favourable opinion.
2.7 The medical care given to, and medical decisions made on behalf of, subjects
should always be the responsibility of a qualified physician or, when appropriate, of a
qualified dentist.
2.8 Each individual involved in conducting a trial should be qualified by education,
training, and experience to perform his or her respective task(s).
2.9 Freely given informed consent should be obtained from every subject prior to
clinical trial participation.
2.10 All clinical trial information should be recorded, handled, and stored in a way that
allows its accurate reporting, interpretation and verification.
ADDENDUM
This principle applies to all records referenced in this guideline, irrespective of the
type of media used.
2.11 The confidentiality of records that could identify subjects should be protected,
respecting the privacy and confidentiality rules in accordance with the applicable
regulatory requirement(s).
2.12 Investigational products should be manufactured, handled, and stored in
accordance with applicable good manufacturing practice (GMP). They should be used
in accordance with the approved protocol.
2.13 Systems with procedures that assure the quality of every aspect of the trial should
be implemented.
Explain the informed consent process in detail.

The researcher must obtain voluntary written informed consent from the prospective
participant for any biomedical and health research involving human participants. This
requirement is based on the principle that competent individuals are entitled to choose
freely whether or not to participate or continue to participate in the research. Informed
consent is a continuous process involving three main components – providing relevant
information to potential participants, ensuring competence of the individual, ensuring
the information is easily comprehended by the participants and assuring voluntariness
of participation. Informed voluntary consent protects the individual’s freedom of
choice and respects the individual’s autonomy.
5.1 Requisites
5.1.1 The participant must have the capacity to understand the proposed research, be
able to make an informed decision on whether or not to be enrolled and convey her/his
decision to the researcher in order to give consent.
5.1.2 The consent should be given voluntarily and not be obtained under duress or
coercion of any sort or by offering any undue inducements.
5.1.3 In the case of an individual who is not capable of giving voluntary informed
consent, the consent of LAR must be obtained. See section 6 for further details.
5.1.4 It is mandatory for a researcher to administer consent before initiating any study
related procedures involving the participant.
5.1.5 It is necessary to maintain privacy and confidentiality of participants at all
stages.
5.2 Essential information for prospective research participants
5.2.1 Before requesting an individual’s consent to participate in research, the
researcher must provide the individual with detailed information and discuss her/his
queries about the research in the language she/he is able to understand. The language
should not only be scientifically accurate and simple, but should also be sensitive to
the social and cultural context of the participant.
5.2.2 The ICD has two parts – patient/participant information sheet (PIS) and the
informed consent form (ICF). Information on known facts about the research, which
has relevance to participation, is included in the PIS. This is followed by the ICF in
which the participant acknowledges that she/he has understood the information given
in the PIS and is volunteering to be included in that research.
5.2.3 Adequate time should be given to the participant to read the consent form, if
necessary discuss it with family and friends, and seek clarification of her/his doubts
from the researchers/research team before deciding to enroll in the research.
5.2.4 Essential elements of an informed consent document are given in Box 5.1.
5.3 Responsibility of researchers
5.3.1 The researcher should only use the EC approved version of the consent form,
including its local translations.
5.3.2 Adequate information necessary for informed consent should be communicated
in a language and manner easily understood by prospective participants.
5.3.3 In case of differently abled participants, such as individuals with physical,
neurological or mental disabilities, appropriate methods should be used to enhance the
participants’ understanding, for example, braille for the visually impaired.
5.3.4 There should be no restriction on the participant’s right to ask questions related
to the study or to discuss with family and friends or take time before coming to a
decision.
5.3.5 The researcher should not give any unjustifiable assurances or influence or
intimidate a prospective participant to enroll in the study.
5.3.6 The researcher must ensure that the participant is competent and has understood
all aspects of the study and that the consent is given voluntarily. Where the participant
and/or the LAR are illiterate, an impartial literate person, not connected to the
research, should be present throughout the consent process as witness.
5.3.7 The researcher should administer a test of understanding whenever possible for
sensitive studies. If need be, the test may be repeated until the participant has really
understood the contents.
5.3.8 When a participant is willing to participate but not willing to sign or give a
thumb impression or cannot do so, then verbal/oral consent may be taken on approval
by the EC, in the presence of an impartial witness who should sign and date the
consent document. This process can be documented through audio or video recording
of the participant, the PI and the impartial witness, all of whom should be seen in the
frame. However, verbal/oral consent should only be taken in exceptional
circumstances and for specific, justifiable reasons with the approval of the EC. It
should not to be practiced routinely.
5.3.9 Reconsent or fresh informed consent of each participant must be taken under
circumstances described in section 5.8.
5.3.10 The researcher must assure prospective participants that their decision whether
or not to participate in the research will not affect their rights, the patient–clinician
relationship or any other benefits to which they are entitled.
5.3.11 Reimbursement may be given for travel and incidental expenses/participation in
research after approval by the EC.
5.3.12 The researcher should ensure free treatment for research related injury
(disability, chronic life-threatening disease and congenital anomaly or birth defect) and
if required, payment of compensation over and above medical management by the
investigator and/institution and sponsor(s), as the case may be.
5.3.13 The researcher should ensure that the participant can continue to access routine
care even in the event of withdrawal of the participant.
5.4 Documentation of informed consent process
Documentation of the informed consent process is an essential part of this exercise.
5.4.1 Each prospective participant should sign the informed consent form after going
through the informed consent process of receiving information, understanding it and
voluntarily agreeing to participate in the research.
5.4.2 In case the participant is incompetent (medically or legally) to give consent, the
LAR’s consent must be documented.
5.4.3 The process of consent for an illiterate participant/LAR should be witnessed by
an impartial literate witness who is not a relative of the participant and is in no way
connected to the conduct of research, such as other patients in the ward who are not in
the study, staff from the social service department and counsellors. The witness should
be a literate person who can read the participant information sheet and consent form
and understand the language of the participant.
5.4.4 If the participant cannot sign then a thumb impression must be obtained.
5.4.5 The researcher who administers the consent must also sign and date the consent
form.
5.4.6 In the case of institutionalized individuals, in addition to individual/LAR
consent, permission for conducting the research should be obtained from the head of
that institution.
5.4.7 In some types of research, the partner/spouse may be required to give additional
consent.
5.4.8 In genetic research, other member of a family may become involved as
secondary.
5.9 Procedures after the consent process
5.9.1 After consent is obtained, the participant should be given a copy of the PIS and
signed ICF unless the participant is unwilling to take these documents. Such reluctance
should be recorded.
5.9.2 The researcher has an obligation to convey details of how confidentiality will be
maintained to the participant.
5.9.3 The original PIS and ICF should be archived as per the requirements given in the
guidelines and regulations.

What do you mean by the following: Principles of voluntariness, informed consent and
community agreement and Principles of non-exploitation?

Principle of voluntariness whereby respect for the right of the participant to agree or
not to agree to participate in research, or to withdraw from research at any time, is
paramount. The informed consent process ensures that participants’ rights are
safeguarded.
Principle of non-exploitation whereby research participants are equitably selected so
that the benefits and burdens of the research are distributed fairly and without
arbitrariness or discrimination. Sufficient safeguards to protect vulnerable groups
should be ensured.

Informed consent is a process of communication between you and your health care
provider that often leads to agreement or permission for care, treatment, or
services. Every patient has the right to get information and ask questions before
procedures and treatments. If adult patients are mentally able to make their own
decisions, medical care cannot begin unless they give informed consent.
The informed consent process makes sure that your health care provider has given you
information about your condition along with testing and treatment options before you
decide what to do.
This information can include:

 The name of your condition

 The name of the procedure or treatment that the health care provider
recommends

 Risks and benefits of the treatment or procedure

 Risks and benefits of other options, including not getting the treatment or
procedure

A clinical trial agreement (“CTA”) is the legally binding agreement between a

sponsor, usually a medical device or pharmaceutical company which provides the
study device or drug and financial support, and the clinical institution, which provides
the patients and the clinical data.

Other parties may also be involved in the execution of the clinical investigations, such
as a contract research organization (CRO), clinicians, manufacturers, suppliers, and, of
course, patient volunteers. Each party’s roles and responsibilities, and perhaps most
importantly, liabilities, must be clearly defined before any investigation or trial is
undertaken. Here we provide an overview of some of the critical issues that must be
addressed in any CTA.

Elements of a CTA include:

 The terms of the collaboration.

 The responsibilities of each party.
 Payment and reimbursement procedures and requirements.
 Intellectual property and publication terms.
 Insurance and indemnification.
 Coverage for subject injury.
 Dispute resolution guidelines.
 The procedure for amending contract terms.
 The guidelines to terminate the contract.

Explain the ICH E 7 Guidelines in detail.

Explain the concept of Fraud and Misconduct in clinical trial in detail.

Fraud and misconduct are the two terminologies often used
interchangeably. However, there is a gross distinction between
Fraud and misconduct are the two terminologies often used interchangeably. However,
there is a gross distinction between the two. Scientific misconduct/fraud is a violation
of the standard codes of scholarly conduct and ethical behavior in scientific research.
Definition of fraud as defined in court is “the knowing breach of the standard of good
faith and fair dealing as understood in the community, involving deception or breach
of trust, for money.”[1] Fraud is an intentional deception made for personal gain or to
damage another individual, for instance, intentionally falsifying and/or fabricating
research data, and misleading reporting of the results. Misconduct may not be an
intentional action, rather an act of poor management. It also includes failure to follow
established protocols if this failure results in unreasonable risk or harm to humans.[3]
Fraud should have an element of deliberate action, which is not the case with
misconduct.

The Medical Research Council (MRC) definition of misconduct and fraud (or a
variation of the MRC code) is widely used. This code states the following definition:
The fabrication, falsification, plagiarism or deception in proposing, carrying out or
reporting results of research or deliberate, dangerous or negligent deviations from
accepted practices in carrying out research. It includes failure to follow established
protocols if this failure results in unreasonable risk or harm to humans, other
vertebrates or the environment and facilitating of misconduct in research by collusion
in, or concealment of, such actions by others. It also includes intentional, unauthorised
use, disclosure or removal of, or damage to, research-related property of another,
including apparatus, materials, writings or devices used in or produced by the conduct
of research. It does not include honest error or honest differences in the design,
execution, interpretation or judgement in evaluating research methods or results or
misconduct unrelated to the research process. Similarly it does not include poor
research unless this encompasses the “intention to deceive” (MRC, 1997).

Fraud can be fabrication, falsification, and plagiarism of data or even deception in

conduct. Fabricating data involves creating a new record of data or results. Most
commonly fabricated documents are Informed consent Forms and Patient diaries.
Falsifying data means altering the existing records. It is the deliberate distortion or
omission of undesired data or results. Plagiarism on the other hand is an
unacknowledged presentation or exploitation of work and ideas of others’ as one's
own. Deception in clinical research is the deliberate concealment of a conflict of
interest or inclusion of deliberately misleading statements in research proposals or
other documents.

The most common types of misconduct in clinical research are: Failure to follow an
investigational plan; inadequate and inaccurate records; inadequate drug
accountability; inadequate completion of informed consent forms; failure to report
adverse drug reactions; failure to obtain and/or document subject consent; failure to
notify an Institutional Review Board (IRB)/Ethics Committee (EC) of
changes/progress reports; failure to obtain or document IRB approval.

The impact on affected individuals and the research community can be profound. Such
incidents result in huge cost to the sponsor in terms of additional resource for
investigating fraud and cost of possibly repeating those aspects of research, which
were fraudulent. It can also leads to disciplinary action for researchers. Such a
researcher may not be allowed to be a part of any advisory committee or peer review
board. Any article published by such a researcher might be re-reviewed and retracted if
required. Fraudulent clinical research also affects the validity of data and impacts the
core of good clinical practice adversely, i.e., rights, safety and well-being of research
participants. On a broader scale of impact on health-care, it can lead to wrong or
ineffective or harmful molecules being brought in the market.
Role of IRBs/ECs should be strengthened in safeguarding interest of research
participants. They should have internal control and review mechanisms for monitoring
the ethical and quality aspects of ongoing studies. Existing regulations if any must be
simplified and made more effective. Should there be no existing regulations, they must
be put in place to manage fraudulent issues. All organizations who are involved in
clinical research should have clear operational policies and procedures for approach to
research misconduct and fraud. Whistle blowers should be cultivated and there should
be guidelines agreed upon internationally to safeguard them.

Module 6

What is CRO?

Contract research organization (CRO) is a company that provides

support to the pharmaceutical, biotechnology, and medical
device industries in the form of research services outsourced on a contract
basis. A CRO may provide such services as biopharmaceutical
development, biological assay development, commercialization, clinical
development, clinical trials management, pharmacovigilance, outcomes
research, and Real world evidence.

CROs are designed to reduce costs for companies developing new

medicines and drugs in niche markets. They aim to simplify entry into drug
markets, and simplify development, as the need for large pharmaceutical
companies to do everything ‘in house’ is now redundant. CROs also support
foundations, research institutions, and universities, in addition to
governmental organizations (such as the NIH, EMA, etc.).
Many CROs specifically provide clinical-study and clinical-trial support for
drugs and/or medical devices. However, the sponsor of the trial retains
responsibility for the quality of the CRO's work. CROs range from large,
international full-service organizations to small, niche specialty groups.
CROs that specialize in clinical-trials services can offer their clients the
expertise of moving a new drug or device from its conception
to FDA/EMA marketing approval, without the drug sponsor having to
maintain a staff for these services.
Organizations who have had success in working with a particular CRO in a
particular context (e.g. therapeutic area) might be tempted or encouraged
to expand their engagement with that CRO into other, unrelated areas;
however, caution is required as CROs are always seeking to expand their
experience and success in one area cannot reliably predict success in
unrelated areas that might be new to the organization.
 What do you mean by Outsourcing process in the clinical trial?

Outsourcing models in clinical research have evolved to accommodate the

industry’s changing needs. Biotech companies are increasingly looking to
outsource key capabilities to gain new functionality and expertise, while
being able to spend more time in-house on core competencies. This
translates to operational efficiencies and growth for biotech ventures, while
bending the cost and time curve of drug development.

Contract research organizations (CROs) work in various outsourcing models

that are customized to meet customers’ unique needs. These models range
from contracting specific functional services to providing full-service
outsourcing capabilities.

For example, some of the outsourcing models offered by the PPD clinical
research business of Thermo Fisher Scientific include:

 Functional service provider (FSP): With FSPs, clients outsource all or

some portion of one or multiple functions, such as data management or
monitoring. FSP models provide resource flexibility and access to specific
expertise not readily available in-house.
 Full-service outsourcing (FSOs): FSOs are the complete outsourcing of
most — if not all — tasks for a clinical development project on a trial-by-trial
basis. Because this model reduces the client’s management burden, the
FSO approach is useful for sponsors who do not have any study-related task
expertise or the resources or expertise to execute and manage the entire
project.
 Hybrid studies: With hybrid studies, elements of FSP and FSO models are
incorporated in a bespoke manner. This can drive flexibility and access to
complementary expertise, as needed, for each client.

In recent years, PPD’s experts are seeing clients lean more toward
functional service provider and hybrid models, as clients contend with
increasingly competitive talent markets for most roles, including senior
positions.

Functional service provider and hybrid models enable drug developers to

outsource individual functional services to gain flexibility and efficiency.
Sponsors are freed to spend their time developing core competencies in-
house and can turn to their partner CRO for specialized scientific and
technical services.

Examples of in-demand outsourced capabilities include clinical monitoring,

data management and pharmacovigilance, as well as specific therapeutic
expertise in oncology and rare diseases.
What are the need, benefit, and purpose of outsourcing process in clinical
trial?
Outsourcing reaps numerous benefits. Poole says, “Outsourcing is efficient and
budget driven, and it can be beneficial to embed safety into outsourcing
arrangements from the beginning. Knowledge is key, and access to relevant
safety expertise supports clinical trial efficiency, without which can lead to
unexpected increases in a sponsor’s clinical safety budget. Outsourcing is also
more cost-effective when maintaining a global safety database. The ultimate aim
of clinical development is to get new drugs to market, and partnering with a
pharmacovigilance provider who offers both clinical safety and post-authorisation
services can make this transition much smoother.”

There are also advantages to clinical trial outsourcing which extend beyond just
cost effectiveness and flexibility. It provides the ability to rapidly scale up and
down, because it makes resources easier to maintain. Managing resources in
house can come with all sorts of difficulties, including internal legislation and
labour laws, among others.

The benefits of outsourcing are also determined by qualitative factors, such as

feedback from working partners on how the relationship is progressing.
Outsourcing relationships have evolved over the last 10 years, and digital
innovation has made communication more plain sailing. There has also been a
change in the style of outsourcing relationships – Colin Mackay, founder and CEO
of Symbiosis, says: “There has been significant consolidation in the contract
manufacturing sector, meaning that the industry is less fragmented with fewer
service providers. This reduces the choices available to drug developers when
selecting partners to work with to develop their promising molecules. As a result
relationships seem to be a lot more about strategic partnerships and less about
straightforward, operational outsourcing.”

For outsourcing to work effectively, CROs need to operate according to the quality
systems of the sponsor organisations that hired them8. In the US, this is a
necessity for compliance with FDA regulations. This quality system should also
include an agreement between sponsor and CRO, underlining the responsibilities
of both parties to ensure effective communication, and successful collaboration.
Lines of communication should also be as clear as possible, and information
overload should be avoided.

Effective communication is also mandatory, and this means ensuring fast

response times, and leaving no room for assumption. CROs and customers
should also work together as a single team as much as possible to develop a
shared understanding of the end goals of their partnership. The more effectively
sponsors and partners can communicate, the more they will get out of their
strategic collaboration. A strong working relationship is crucial, and by following
clear guidelines, both parties can make the most out of the outsourcing
partnership.

What is segmentation?

Segmentation divides a patient population into distinct groups—each with

specific needs, characteristics, or behaviors—to allow care delivery and
policies to be tailored for these groups.

The idea of segmenting patients for integrated care is not new. In 1970
Sidney R. Garfield, Kaiser Permanente’s cofounder, described how Kaiser
Permanente’s integrated care model distinguished between sick, well,
worried well, and early sick patients to tailor medical and preventive
services for the different groups. However, the exponential growth in
health care big data together with the developments in data-mining
tools, provides new opportunities to use data for segmentation analysis.

Data from administrative systems or electronic health records (EHRs) can

be used to allocate patients to segments—based, for example, on their
long-term conditions—and analyze costs and outcomes per segment. There
are also a range of off-the-shelf tools for patient segmentation data
analysis, which vary in type and sophistication (for more details, see online
Appendix 1). The Johns Hopkins Adjusted Clinical Groups System uses a
granular system of diagnosis code mapping as the basis for different
groupings. The Community Assessment Risk Screen provides a simple
method for allocating patients to one of ten risk levels. And the 3M Clinical
Risk Groups system distributes patients among 272 groups for a more
detailed risk analysis.

Based on the case studies, we discuss why and how policy makers should
encourage the use of data for segmentation in practice.

A Framework For Patient Segmentation In Integrated Care

Levels Of Integration

Integrated care can be organized in a variety of ways. The following three

levels of integration have been described in the literature: macro-, meso-,
and micro-level integration. For each level, a corresponding population
strategy can be identified.

Whole Population:
Macro-level integration applies to the whole population. Although the types
of providers included in a macro-level program may vary, these programs
aim to integrate care for all patients. Examples are integrated care
organizations such as Kaiser Permanente in the United States, which
provide integrated services for their entire covered population.
Subpopulation:
Meso-level integration provides integrated care services to a specific
subpopulation. Often this subpopulation is based on a long-term condition
(for example, diabetes or dementia) or age (such as patients older than
seventy-five), which allows specialist services to be included in the
integrated care package. An example is bundled payments in the
Netherlands, where care providers receive an annual payment to manage
and deliver care for a group of patients with a specific condition.
High-Risk Population:

Micro-level integration focuses on selected individuals deemed to be at high

risk of certain outcomes, such as an unplanned hospitalization. Instead of
integrating care across the entire delivery system, this type of integrated
care relies on teams or individuals who coordinate services and provide
case management. In the English National Health Service, primary care
providers are encouraged to identify patients through risk stratification and
proactively manage their conditions and coordinate their care with other
providers.

Identifying And Understanding The Target Population

Patient segmentation can support these three population strategies in the

following two ways: it can help identify a target population, and it can
provide detailed insights into the target population (for an overview of the
framework, see Appendix 2).

Understanding the population is particularly important for macro-level

integration, where an entire population is included, since care needs will
vary significantly across the members of the population. Through patient
segmentation, different needs can be identified, and tailored policies and
budgets can be set for homogeneous patient groups. The “Better Health for
London” report, developed by the London Health Commission, segments
the entire population of London into fifteen groups, around which
multistakeholder population health initiatives are organized (for more
details, see Appendix 1).
Meso-level integrated care models, which focus on specific subpopulations,
can use segmentation to choose the subpopulation. Delaware’s State
Health Care Innovation Plan segments the state’s population and uses this
information to select priority subgroups for two focused interventions:
improved care coordination for patients with multiple long-term conditions
or mental health needs, and overall effective diagnosis and treatment for
people with no long-term care needs.

For meso-level integrated care, segmentation can also help health

professionals better understand the targeted subpopulation. While the care
needs of a defined subgroup will not be as diverse as those of an entire
population, there will still be significant variation across members of the
subgroup. Kaiser Permanente’s Senior Segmentation Algorithm segments
the population over age sixty-five into four groups, and care priorities are
set for each segment. The segment assignment is included in the patient’s
EHR, and it prompts medical specialists to take certain actions that are
tailored to the segment’s specific needs. The ValCrònic pilot program in
Spain focuses on the subpopulation with long-term conditions, which is
segmented by risk level to adjust the intensity of telemonitoring
interventions.

Micro-level integration requires high-risk patients to be identified. The

Counties Manukau district health board in New Zealand is including an
automated risk score in its e-summary health record, which is available to
all system providers across care settings. Based on patients’ risk strata,
different care management interventions are offered to improve outcomes
and reduce unplanned hospitalizations.

How can a sponsor make a good contract with CRO?

Many factors impact the relationship between a contract research

organization and its sponsors. First and foremost, both entities must add
value to the program. They should each contribute certain expertise,
knowledge, and resources to the mix in order to supplement each
others’ capabilities.