Introduction to Clinical Trials of New Drugs:

As specified in the FDA's 1977 General Considerations for the Clinical Evaluation of Drugs,
drugs are tested in three phases before a sponsor submits the new drug application required for
marketing approval.
Phase 1 studies are the initial studies in humans and generally involve small numbers of healthy
volunteers or patients treated over a short period of time. These studies assess individual
tolerance of the drug and examine its metabolism and short-term pharmacokinetics. They may
also provide preliminary pharmacologic information related to clinical effectiveness.
Phase 2 studies, which normally involve a few hundred patients, are the earliest controlled trials
designed to demonstrate effectiveness and relative safety.
Phase 3 studies, the final testing phase before a marketing application is submitted to the FDA
for review, as many as several thousand patients are studied. These studies provide additional
evidence regarding safety and effectiveness, including data on long-term exposure; refine
information on dose-response and concentration-response relations; and identify relatively rare
adverse effects.
The inclusion of a broad sample of the population in phase 3 trials and the examination of the
data for differences in response make it possible to identify demographic, patho-physiologic, and
other characteristics that affect patients' responses to the drug.
CROs: Contract Research Organisations (CROs) provide independent product development
services primarily for the pharmaceutical, biotechnology and medical device industries.
Companies in these industries (Sponsors) outsource product development services to CROs in
order to manage the product development process more efficiently and cost-effectively, and to
maximise the benefits in time and profit of patient-protected products. CROs contribute to a
large percentage of all products developed worldwide.

Their continued success is reliant on high ethical and professional standards, and compliance
with Good Clinical Practice (GCP) and Good Laboratory Practice (GLP) guidelines as
prescribed by the regulatory authorities.

Legal Status of CROs in India:

In India, a CRO (contract clinical research organization) have no legal status. They are not
mentioned anywhere in the Drugs and Cosmetics Act and there has been no notification to clarify
their status. This is the bigger question because nearly 90% of the trials are being conducted by
so-called CROs.
Most Indian registration trials are of low cost and non-GCP quality. Companies developing a
new chemical entity (NCE), conduct low cost non-GCP or paper GCP clinical trials to obtain
data used for licensing their NCE. Costs of a GCP trial are invariably several times higher than
for a non-GCP study. Although Qunitiles ventured into India, other major CRO like PPD, MDS
Pharma, Ingenix, Parexel, ClinTrials and Kendle have stayed away.
SRL (Ranbaxy) and DRL are the only central laboratories functioning in India and has filled a
major need for GCP clinical study. For many GCP studies, central laboratories in Europe and
USA are used.

Compliance for Foreign CROs in India:

According to a statement from schedule Y (Ministry of Health and Family Welfare, Government
of India), it is mentioned under 3.1.17. Role of Foreign Sponsor that...
If the sponsor is a foreign company, organization or person(s) it shall appoint a local
representative or CRO to fulfill the appropriate local responsibilities as governed by the national
regulations. ...."

Recent Issues in Guidelines of Clinical Trials on Humans

Recently in the same Month, the drugs regulator has issued guidelines for inspecting human
clinical trials for drugs that are being increasingly outsourced to India in an effort to ensure the
safety of people who participate in such trials.

The inspection program will verify if clinical trial investigators and sponsors are complying with
the safety guidelines listed in the Drugs and Cosmetics Act, and also sign off on the authenticity
of data generated by the trial, said the website of the Central Drugs Standard Control
Organization, or CDSCO. All trials of drugs, biologic drugs and medical devices will be
inspected.

A study by research firm RNCOS Industry Solutions estimates that the clinical trial outsourced
market in India will grow at a compound annual growth rate of at least 30% between 2010 and
2012 to around $600 million (2,664 crore). This rapid growth is set to make India one of the
preferred destinations for clinical trialsat least in terms of growth.

The new guidelineswhich specify who will conduct the inspection, how will it be conducted
and the documents required from trial sponsors and investigatorsare expected to make such
inspections the norm rather than the exceptions they currently are.

The CROs, already have internal audits or engage a third party to conduct audits of the trials they
conduct but sometimes the trial sponsor gets its own auditor to also check the CRO. All this is
already a standard operating procedure for big companies. Many companies take corrective
measures based on such internal audits of trials as they dont want their image to be tarnished.
Still, the regulator wants to do an audit by trained people, who know what to look for. CDSCOs
drug inspectors have been trained by the US Food and Drug Administration. Thus, it is another
important compliance for CROs.

Introduction to GCP Guidelines

Good Clinical Practice (GCP) is a set of guidelines agreed at International Conference on
Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human
Use. The definition of ICH-GCP is A standard for the design, conduct, performance,
monitoring, auditing, recording, analyses, and reporting of clinical trials that provides
assurance that the data and reported results are credible and accurate, and that the rights,
integrity, and confidentiality of trial subjects are protected. Although developed for clinical
trials of pharmaceuticals, the principles of ICH-GCP are relevant to most clinical research.
Clinicians, involved in research and clinical trials, are therefore expected to know and
understand ICH-GCP.
There are no differences in the spirit of Indian GCP and ICH-GCP. However, some sections - e.g.
ethics are quite different. Schedule Y recommends that the sponsor should follow GCP
guidelines issued by CDSCO. However, if a sponsor is conducting an international trial in India,
it needs to follow both ICH-GCP and Indian GCP.
Good Clinical Practice (GCP) guidelines for biomedical studies in India were developed for
specific guidelines to encompass the design, conduct, termination, audit, analysis, reporting and
documentation of the studies involving human subjects in India to ensure uniform quality of
clinical research throughout the country and to generate data for registration for new drugs
before use in the Indian population. The Indian adaptation of GCP also aims to ensure that the
studies are scientifically authentic and that the clinical properties of the investigational product
are properly documented. It incorporates essential elements of Schedule Y as well as the ethical
principles.

The Indian Good Clinical Practices (GCP) guidelines which were released in December 2001 led
to a lot of discussion but little implementation. Being guidelines, most companies ignored them.
The international pharmaceutical companies in India, which were conducting clinical trials in
compliance with International Conference on Harmonisation - Good Clinical Practices (ICH-
GCP), continued to follow the same. Similar was the attitude of big Indian pharma companies
competing globally.
The new revised schedule Y, likely to come into effect in near future, links most provisions to the
Indian GCP. This means that Indian GCP guidelines will become law and have to be followed for
clinical trials in India.
In general, Indian GCP guidelines are in line with ICH-GCP. However, there are significant
differences in some of the areas, which will make the task of compliance difficult for the
sponsors, investigators and ethics committees.

An Evaluation of Indian GCP Guidelines

Since, Good Clinical Practice (GCP) is the international ethical and scientific quality standard
for designing, conducting and recording trials that involve the participation of human subjects.
Several international clinical trials have been conducted in India following ICH-GCP guidelines.
However, there were no Indian GCP guidelines for local clinical trials.
In 2001, a committee set up by Central Drugs Standard Control Organisation in consultation with
clinical experts has formulated the Indian GCP (ICGP) guidelines. Besides GCP, the document
also covers special concerns about clinical trials of vaccines, contraceptives, surgical/medical
devices, diagnostic agents and herbal remedies. This could imply that all these trials also should
comply with ICGP guidelines.

ICGP lists several activities - ethics, monitoring, audit, adverse event reporting, drug supply
management, documentation, record keeping etc which are currently not carried out or are
done to a limited extent. A company, which wants to comply with ICGP, will need to invest in
personnel and infrastructure. This will increase the financial cost of the trial and probably delay
the conduct and execution of trial.

According to ICGP guidelines, the company will have to invest in hiring and training medical
advisers, monitors, QA manager, project manager. The monitor will have to travel to each centre
regularly every 4-6 weeks for initiation, monitoring and trial closeout visits. For a trial
lasting 12 months in five centres, this could mean 40-48 visits! Besides, there will be new
expenses for documentation, investigational site, drug supply and other costs.

If the company does not wish to invest in personnel, the trial will have to be done through a
CRO. Even if a CRO is involved, the sponsor still needs to employ qualified personnel to fulfil
GCP responsibilities and to co-ordinate and monitor CRO activities. From a long-term
viewpoint, it would be prudent for a company to strengthen and expand medical department.

As per ICGP, guidelines, involvement of an appropriately qualified and experienced statistician

is necessary in the planning stage as well as throughout the study. Besides, all data entry and
management has to conform to GCP guidelines.

Assessment and reporting of serious adverse events (SAE) to regulatory authorities and ethics
committee requires understanding of the causality and severity. In addition, the reporting of
SAEs has to be expedited, usually within 24 hours. At present, this activity is given low priority.
Both medical advisers and monitors have to be trained to comply with this requirement.

There are several other important points that can be evaluated for Indias GCP guidelines. These
are discussed below:

1. Investigator qualifications

The Indian GCP insists that the investigator should be qualified as per the requirement of the
Medical Council of India (MCI). This means that non-medical scientists e.g. pharmacists who
organise the bio-equivalence studies, cannot become investigators. Even in the medical field,
several eminent investigators have medical degrees from UK or US, which are not prescribed by
MCI.

The qualifications of some of the senior investigators were not recognised as the medical
institutions from where these investigators studied were not approved by MCI at that time.
Implementation of this provision will require the monitors and auditors to ask the investigators
for proof that their qualifications are in line with MCI. This provision can become a major hurdle
for sponsors in selecting investigators and needs to be modified in line with ICH-GCP.

2. Investigator and sponsors SOPs

The Indian guideline mandates that the sponsor and the investigator should sign a copy of the
Standard Operating Procedures (SOPs). Besides, the investigator and his staff have to be aware
and comply with SOPs. This provision is practically impossible, as the sponsor will have to
obtain signatures of all investigators in a trial on its large number of SOPs. Imagine the task of
making multiple copies of hundreds of SOPs, delivering them to investigators, and obtaining
their signatures! Besides, SOPs also get revised periodically and the whole cycle has to be
repeated.

ICH-GCP expects the investigator to comply with the protocol and leaves the task of monitoring
compliance to SOPs to the monitors and auditors.

3. Investigators responsibility for data analysis

Indian GCP demands that the investigator should sign and forward the data like Case Report
Forms (CRF), results and interpretations, analyses and reports of the study from his/her centre to
the sponsor and the ethics committee.

Usually data analysis is the function of the sponsor. However, this provision makes it a
responsibility of the investigator, increasing his burden. The CRFs are never sent to Independant
Ethics Committee (IEC) unless the IEC asks for them for some specific purpose e.g. suspected
fraud. The IECs of major institutes, which are involved in several international trials, are already
struggling to cope with large number of bulky documents submitted for their approval. This
provision will increase IECs troubles, as they will have to create space for bulky CRFs and the
clinical trial reports.

As per ICH-GCP, when the trial is completed, the investigator has to provide the Independent
Ethics Committee (IEC) with a summary of the outcome of trial.

4. Powers of IEC and IDMC

According to Indian GCP, the IEC has power to order discontinuation of a trial if the IEC finds
that the goals of the trial have already been achieved mid-way or unequivocal results obtained.

As per ICH-GCP, this is the responsibility of independent data-monitoring committee (IDMC).

The sponsor may consider establishing an IDMC to assess the progress of a clinical trial,
including the safety data and the critical efficacy endpoints at intervals, and to recommend the
sponsor whether to continue, modify, or stop a trial.

This is possible, as the sponsor has to provide regular feedback and interim analysis of trial data
on efficacy and safety to IDMC. For most global trials, the sponsor establishes an IDMC in a
western country.

As Indian centres are part of global trials, they are reviewed by IDMC. This means that Indian
IECs at different sites will not be involved in this process and cannot fulfil this requirement of
Indian GCP. IDMC is also recommended in Indian GCP. Hence, these two provisions are likely
to create a conflict of responsibilities between IEC and IDMC!

This provision also could become a nightmare for regulatory authorities, as there is scope for
misuse of this provision by sponsors of local Schedule Y open registration trial. The goal of these
local trials is to confirm whether the Indian safety and efficacy results are in line with the
international clinical trial data. If a sponsor finds that the results are comparable to international
data in initial 25-30 patients, he can submit this data to IEC to request them to stop the trial and
later present the IEC recommendation to the regulatory authorities for obtaining registration.

5. Essential documents for IEC

Indian GCP mandates that the sponsor and the investigator have to provide additional copies of
most documents to IEC and also ensure that they are filed.

It will be difficult for the monitor and the auditor to check compliance to this provision, as the
sponsor does not have direct access to IEC documents.

6. Essential items for informed consent

Besides the essential items for informed consent listed in ICH-GCP, Indian guidelines also cover
issues of biological samples.

The consent has to include:

Right to prevent use of his/her biological sample (DNA, cell-line, etc) at any time during
the conduct of the research
Foreseeable extent of information on possible current and future uses of the biological
material and of the data to be generated from the research and if the material is likely to
be used for secondary purposes or would be shared with others, clear mention of the
same
Risk of discovery of biologically sensitive information

These items will make the consent form more complex to explain to the subject and may
discourage him from participating in the research.

7. Compensation

Indian GCP mandates that when a subject is withdrawn from research for medical reasons related
to the study, the subject should get the benefit for full participation.

While this provision seems appropriate for studies in healthy volunteers e.g. bio-equivalence
study, it could lead to issues in a clinical trial of a chronic disease in patients. A cancer patient
taking part in a long trial of a new product is assured of regular follow up and costly
investigations. If he is withdrawn because of a medical reason e.g. adverse event, he receives
free medical treatment for the event but does not receive any other benefit.

However, such a patient can cite this provision and insist on regular follow up and free
investigations assured for the trial for the whole duration of trial!

The other provisions for compensation are prescriptive:

The sponsor (company, government, institution) should agree to provide compensation

for any serious physical or mental injury or to provide insurance coverage
 Research subjects who suffer physical injury in a trial are entitled to financial/other
assistance to compensate them equitably for any temporary or permanent impairment or
disability subject to confirmation from IEC.

In cases of death, their dependents are entitled to material compensation. These

provisions, probably, are an attempt to protect Indian patients, who are often illiterate and
from lower socio economic class.

8. Monitors Qualifications

Indian GCP guidelines suggest that the monitor should have adequate medical, pharmaceutical
and/or scientific experience. As most monitors are pharmacists or science graduates, they would
not have adequate medical experience and hence will not qualify as monitors!

9. Monitors responsibilities

Monitor is supposed to inform the sponsor and IEC in case any unwarranted deviation from
protocol or any transgression from principles of GCP. The monitor is not in contact with IEC and
hence this requirement cannot be fulfilled. Monitor is also responsible for ensuring that CRFs are
legible. As per ICH-GCP monitor has to verify that the documents provided by the investigator
are legible.

There is a glaring omission in the functions of the monitor. It does not include verification of
informed consent.

10. Drug label

In the section on protocol, it is mentioned that drug label should include name and contact
numbers of investigator and name of institution. This is good practice but it can lead to practical
difficulties in global trials where the labels are uniform with minor changes made if required by
local laws and practice.

11. Document retention

Indian GCP mandates that the sponsor should make arrangements for safe and secure custody of
all study related documents and material for a period of three years after the completion of the
study or submission of the data to the regulatory authority/ies whichever is later. If the company
does not get marketing approval within 3 years of completion of trial and if there is a need for
regulator inspection after marketing approval, the records will not be available.

Conclusion
Time has to come to review some of the provisions of Indian GCP guidelines, as they are soon to
become a law. Some of the sections related to the investigator, IEC, monitor, drug label and
documentation have to be viewed pragmatically from compliance and practical considerations.

The sections related to informed consent and compensation, need discussion on global practices
vis-a-vis the Indian socioeconomic realities.

Indian pharmaceutical companies, till now, have done fast and cheap trials. Currently, the
companies expect medical departments to focus on marketing support function and give low
priority to clinical trials. The clinical trials done are rapidly without adherence to GCP
guidelines. There is an urgent need for a paradigm shift from such poor quality research to GCP
compliant clinical trials. Implementation of IGCP guidelines will compel them for a paradigm
shift.

The main principle at the heart of GCP is What is not documented is not done! The advice to
all the personnel is Do what you write. Write what you do. The assessment of quality in GCP
trials rests on adequate documentation. The ICGP guideline lists over 50 documents, which are
to be kept in relevant files with sponsor, investigator, EC and contract research organisation
(CRO). Thus, CROs need to comply with these documentation standards in order to prove their
quality.

At present, the budget for a clinical trial in 100 patients, depending on the quality and
complexity, ranges between Rs 3-5 lakhs. It is difficult to estimate financial cost of ICGP
compliant trial. But it will be several folds higher than the cost of so-called non-GCP low cost
trials.