ASSIGNMENT

ON

CRITICAL ANALYSIS OF NEW

GUIDELINES FOR CLINICAL
RESEARCH ORGANIZATIONS

SUBMITTED BY
Ankita Ahuja
K. S
Jisha
Jeena Mary
Manisha Mittal
Sameera Singh
OUTSOURCING IN CLINICAL RESEARCH
The CRO industry emerged mostly in the late 1990s when pharmaceutical R&D efforts
became more complex and competition in rapidly-growing therapeutic areas increased. In order
to realize profit margins and be competitive, Pharmaceutical companies began outsourcing
activities to other organizations (CROs).

A Contract Research Organization, also called a Clinical Research Organization

(CRO) is a service organization that provides support to the pharmaceutical and biotechnology
industries. CROs offer clients a wide range of "outsourced" pharmaceutical research services to
aid in the drug and medical device research and development process.

In the Code of Federal Regulations (CFR), the U.S. Food and Drug Administration
regulations state that a CRO is "a person [i.e., a legal person, which may be a corporation]
that assumes, as an independent contractor with the sponsor, one or more of the obligations
of a sponsor, e.g., design of a protocol, selection or monitoring of investigations, evaluation of
reports, and preparation of materials to be submitted to the Food and Drug Administration."
[21 CFR 312.3(b)]

Services offered by CROs include:-

 Product development.
 Formulation and manufacturing;
 Clinical trial management (preclinical through phase IV);
 Clinical, medical and safety monitoring;
 Preclinical, toxicology, and clinical laboratory services for processing trial
samples;
 Data management,
 Biostatistics and medical writing services for preparation of an FDA New Drug
Application (NDA),
 Abbreviated New Drug Application (ANDA), or
 Biologics License Application (BLA);
 Regulatory affairs support; and many other complementary services.

CRO Market Size and Growth

Industry analyzers IMS Health and BCC Research estimated that the global
pharmaceutical market will grow at about a 5% rate in 2011 to over $820 billion and be worth
over $1 trillion by 2013. Pharmaceutical and biotechnology companies in the US spent
approximately $59 billion on R&D in 2009, which equates to roughly 18% of their sales and is a
5% increase from the previous year.

A significant portion of R&D budgets are used for the outsourcing services offered by
the CRO industry, approximately $15 billion in 2009. This figure is expected to grow at 15%
over the next seven years and should increase further with the broadening of the spectrum of
services outsourced to cover the entire value chain.

As outsourced services in developing countries such as China and India move up the
value chain to cover phase 1/2 trials, the total contracts value may go up to $20 billion by 2011.
Further, certain therapeutic areas within pharmaceutical development are slated for an even
greater growth curve, namely the oncology class, expected to see continued growth of upwards
of 21% over the next few years due to the large target market, strong unmet medical need, and
overwhelming number of drugs currently in development.

There are over 1,100 companies in the world. It is a very fragmented industry with the top 10
controlling 56.1% of the market in 2009.

At present, there are 40-50 CROs in the country, a number that is increasing steadily.

Reasons for Outsourcing to CROs

 Outsourcing offers a number of advantages to drug companies. These include:-

 Sponsor can convert the fixed costs of maintaining the personnel, expertise and
facilities like data management necessary for clinical trial management into
variable costs
 Non-availability of services in-house
 Knowledge of regulatory affairs in a particular country of interest
 Increased complexity of clinical trials
 Necessity for medical and clinical knowledge in specific therapeutic areas or indications
 Increased amount of data required from clinical trials
 Multinational and multi-center nature of current clinical trials
 Large requirement of patient populations
 Regionalized diseases

CROs range from large, international full service organizations to small, niche specialty
groups and can offer their clients the experience of moving a new drug or device from its
conception to FDA marketing approval without the drug sponsor having to maintain a staff for
these services.
 REGULATORY AFFAIRS IN CLINICAL TRIALS

ROLE OF RRRRRRRR
Regulatory affairs play a crucial role in the clinical trials.

The regulatory body governing the regulatory aspects of the clinical trials in India is The
Central Drugs Standard Control Organization (CDSCO).

Some of the regulatory authorities of different countries are:-

(1) Medicines and Healthcare products Regulatory Agency (MHRA) –U.K.

(2) European Medicines Agency (EMEA) – European Union.
(3) Food and Drug Administration (FDA) - United States.
(4) Danish Medicines Agency – Denmark.

THE CENTRAL DRUGS STANDARD CONTROL ORGANIZATION

(CDSCO)

The CDSCO headed by the Drugs Controller General (India) [DCG (I)], discharges
the functions allocated to the Central Government (similar to the US Federal Government) under
the Drugs & Cosmetic Act.

CDSCO is attached to the office of the Director General of Health Services in the Federal
Ministry of Health and Family Welfare. The DCG (I) has statutory authority under the Act with
port offices, zonal offices and drug testing laboratories. The Drugs Controller General of India
(DCGI) is responsible for regulatory approvals of clinical trials in India.
 DIFFERENCE BETWEEN USFDA & DCGI

USFDA DCGI
a. The work is more systematic, swift a. Till date DCGI’s work is not as
& stringent systematic, swift & stringent as required
b. The USFDA makes it mandatory
to arrange the documents in the b. There is no such hard & fast rule in
clinical trial application file in the DCGI
same order as given. If not so the
entire application is rejected
c. If there is no response from c. Even though the timeline given for fist
USFDA within 30 days of applying, response is 45 working days’ the 1st
then it is assumed that the response is received after 10 – 12
application is approved. weeks, which may be an approval or
query
d. Separate departments are there to d. Here a single person reviews the entire
review different parts of a single dossier. Therefore there is less expert
dossier/file. For e.g. toxicology scrutiny
deptt. reviews the toxicology data.
This leads to expert scrutiny
e. The sponsor/CRO can follow up e. The CRO can follow up with the ADC
with the ADC through phone & e only by meeting him personally. Thus a
mail. Thus saving the time and lot of time is wasted in travelling. At the
avoiding any unnecessary delay in same time ADC is available only on a
the process single day of week. Incase he is not
available; there will be a delay in the
process by a Min. of 1 week.
f. Proper guidelines for medical f. Proper guidelines for medical devices
devices has been formulated have not been issued
 FUTURE ADVANCEMENTS IN INDIAN REGULATORY
SYSTEM

Dr. Surinder Singh has made several important decisions for the future like:

A. Registration of CROs - Clinical trial industry is by and large an unregulated sector. Once the
law is implemented, the names of all the approved clinical research organizations (CROs) in the
country will be uploaded on the website of Drug Controller General of India (DCGI). A
violation of the norms could lead to the firm being barred from conducting clinical studies in
India. This will regulate the entire clinical protocols, ethical norms and other practices and thus
prevent Indian patients from being used as cheap targets.

B. e-governance system - The DCGI is planning to introduce e-governance for clinical trials.

The move will enable drug companies that that want to carry out
clinical trials in India to register online from any part of the world. The idea is to fast-track the
process of clinical trial approvals in the country. The drug regulator would deliver online
approvals to companies after validating all the information submitted by companies. Once the
required approval for conducting trials is obtained, the companies can also submit research data
online to the country’s drug regulator Drug Controller General of India (DCGI), seeking
marketing approval for their drug.
DCGI is planning to implement it by 2013.
However this decision has faced a lot of resistance from the CRO’s. Since in such a case the
regulatory department of the CRO’s will lose their business as the role played by them will now
be carried out by the sponsor themselves.

C. Fingerprinting of trial participants - The DCGI is also planning to start a system of

fingerprinting of trial participants to prevent them from participating in more than one trial.

D. Pharmacovigilance program at a national level – the DCGI plans to launch a

Pharmacovigilance program at a national level. The basic purpose of this program is to collate,
analyze and archive adverse drug reaction data for making regulatory decisions regarding drugs
marketed in India.
 NEW GUIDELINES TO MEET GLOBAL CLINICAL NORMS
• In views of mounting concerns over the way the Rs 1,500 crore Clinical Research
Organization (CRO) industries operated in India, the central drug regulator has announced
regulatory framework to ensure adherence to globally accepted Good Clinical Practice (GCP)
norms. The CRO industry is estimated to reach about $1 billion in 2012 given India’s
emergence as a preferred destination for clinical trials.

• The central drug regulator or the Drug Controller General of India (DCGI) has been
under pressure to establish and enforce standards in view of more and more clinical trial work
shifting to India given its cost advantage.

• The CRO industry body, Association of Indian Clinical Research Organization (ACRO),
president and chairman of Veeda Clinical Research, Apurva Shah said, “Regulation is welcome
since it would help scale up India’s potential as a CRO destination. The inspection
infrastructure, however, needs to be educated to be able to enforce standards.”

• “Already the CROs have internal audits or engage a third party to conduct audits of the
trials they conduct,” or “Sometimes the trial sponsor gets its own auditor to also check the
CRO”. A senior health ministry official said the DCGI has taken the first big step by
announcing guidelines for drug inspectors to conduct inspection of clinical trial sites, audit
CRO facilities involved in clinical trial and information to investigators, as also establish a
communication set up for clinical research firms about procedures for inspection and follow-up
of action.

• “The guidelines cover entire gamut of issues involved in the clinical trial inspection. It
aims to verify GCP compliance to protect rights, safety and well being of the subjects involved
in clinical trial; to verify the credibility and integrity of clinical trial data generated; and to
verify the compliance with various regulatory provisions as per Drugs & Cosmetics Rules,” he
added.

• Shah at ACRO, the CRO industry body said, “For long there has been a demand for
bringing in guidelines to govern the industry. Global pharma majors see a lot of merit in India
but with guidelines initiated they would have greater faith and confidence in the system. I am
confident the guidelines would help only increase the CRO business inflow into India.”

• He, however, asserted that the only concern was the need to ensure that drug inspectors
entrusted with the task of enforcement of these guidelines were trained enough to track defaults.

• Jubilant Life Sciences, a leading player in the CRO segment declined to comment on the
issue.
• As regards the timing of the inspection, guidelines prescribed that it can be carried in
normal circumstances before, during or after a clinical trial is completed.

• However, as per the requirement but under specific circumstances unannounced

inspection too might be conducted. It can either be routine or on a specific information or
complaint basis thus offering lot of discretionary powers to inspectors.

• The broad set of questions under the ambit of inspectors would range from asking
question on the nature of study, data irregularities, complaints, and vulnerability of subjects.

• According to a recent Thomson Reuters study the global figures for clinical trial
recruitment highlight a dramatic shift away from the US and toward Asia Pacific. The report
said, “In 2002, 53 per cent of patients recruited globally were in North America; in 2008 that
figure was down to 32 per cent. Asia Pacific saw an increase from 6 per cent to 11 per cent over
the same period, while Europe showed marginal growth from 14 per cent to 17 per cent.
Meanwhile, the number of new molecules in development by generic companies, particularly in
India, reflects a strong inclination to invest in R&D.”

INDIA TIGHTENS CLINICAL TRIAL GUIDELINES

• A parliamentary committee of the ministry of health has asked why CROs have been
permitted to conduct trials when they have no legal status in India. They are not mentioned
anywhere in the Drugs and Cosmetics Act and there has been no notification to clarify their status
either. “This is the bigger question because nearly 90% of the trials are being conducted by so-
called CROs.”

• India’s Central Drugs Standard Control Organization (CDSCO) has drawn up guidelines
for regulators and sponsors to help tighten up clinical trial inspection procedures.

• A branch of India’s Ministry of Health and Family Welfare, the CDSCO’s new guidelines
constitute part of wider government efforts to shore up the regulatory framework for clinical
research in India.

• The document outlines plans to protect the rights, safety and well-being of clinical trial
volunteers, as well as ensuring better GCP compliance during clinical trial inspections.
• The stricter guidelines also aim to increase the credibility and integrity of clinical trial data,
helping increase compliance with drugs and cosmetics regulations.

• The CDSCO claims a tighter framework will provide direction for inspectors and CDSCO
officers when conducting inspections of sponsors, CROs (contract research organisations) and
clinical trial sites.

• Conversely, CROs will be provided with information concerning inspection procedures

and any follow-up actions.
 • CDSCO headquarters say “inspection of clinical trial sites would generally be pre-
announced,” but insist that spot-checks may occur “under some specific circumstances”.
Inspection of the CRO or trial sponsor can still be conducted without prior notice.

SUGGESTIONS & RECOMMENDATIONS

1) The Indian regulatory system needs to be polished.

2) The Regulatory authority should work closely with t international bodies to

update the processes to harmonize with US and international standards and
smooth out kinks in the system.

3) Initiative should be taken to create a regulatory body in line with FDA, a

central authority governing all drug development-related activities.
.

4) The Regulatory Authority should stick to the set timeframe for approval of
clinical trials, issue of test license etc by streamlining of the internal
processing channel, proper man-management and increase in the
manpower since DGCI is highly understaffed.

5) Acute shortage of competent staff in the Clinical Trials Organisations in

India should be addressed by increasing the number of training institutes in
this field to equip them with proper infrastructure to carry out inspection of
clinical trial sites and facilities.

6) Well versed manpower in the Regulatory Affairs Department in a company

should be provisioned since other branches of a Pharmaceutical Company
such as Production, Marketing, Accounting etc may become superfluous
and unproductive if the company find it difficult to clear the initial stage of
getting license to conduct clinical trial of the drug, since a drug can be
marketed only after that.

7) Strong centralized regulatory regime which can give high quality

development of ethical capacity, with extra vigilance but with an informed
understanding of acceptable risk.

8) Establishing appropriate communication framework for clinical research

firms about procedures for inspection and follow-up of action.