Global Clinical Trials and Need for More Institutional Review Boards in India

Ms. Lisa Castro

Pfizer, the world’s largest drug
maker, announced on Monday, December 5
^th,
that they were pulling the
plug on their experimental drug, Torcetrapib. 

Pfizer made an investment of nearly
USD $1 billion on the development of Torcetrapib since its discovery in the
early 1990s.   This drug was expected to be a drug for patients that suffer
from heart disease.

The experimental drug was three years into late-phase
clinical trials (phase 3) and had enrolled 15,000 patients. Although
Torcetrapib was close to receiving U.S. Food and Drug Administration (FDA) approval, this experimental agent that raises good cholesterol and reduces the
buildup of plaques in blood vessels that can cause heart attacks, resulted in
more study-drug related deaths.

The torcetrapib-related deaths
were identified by independent researchers monitoring the trial, called a Data
Safety Monitoring Board (DSMB), who reviewed the results and provided a monthly
progress report. But this month the progress report indicated that there were
31 more deaths and concerns of patients suffering from heart failure, among the
people receiving torcetrapid and the study was stopped. The 100 hospitals and medical
clinics in three continents that were clinical trial sites were notified to
halt the study.

Clinical trials

Clinical trials, “research
conducted with human subjects in which an investigator (usually a physician,
contracted by a pharmaceutical or biotechnology company or contract research
organization (CRO)) directly interacts with patients to test an experimental
product (example, drug)”.  Clinical trials are essential to the discovery of
new drugs, medical devices, and vaccines. The primary three phases of clinical
trials are:

·  Phase I


(safety trials/

human clinical pharmacology trials

)
-

Experimental therapy is tested
for the first time in humans or for a new indication after approval. Often
given to a small population of healthy volunteers. Primary goal is to
determine safe dosage range for humans which include - SAD studies with the MTD
and, MAD studies. Single Ascending Dose (SAD) studies include groups of three
or six patients that are given a small dose of the drug and observed for a
specific period of time. If there are no adverse side effects another new group
is given a higher dose and this process is continued until intolerable side
effects begin to appear. This dose is called the Maximum tolerated dose (MTD). Multiple
Ascending Dose (MAD) studies are Phase I studies that are conducted to develop a
greater understanding of pharmacokinetics
¹
/pharmacodynamics
²
of the drug. In these studies, patient groups receive a low dose of the drug
and the dose is subsequently escalated up to a predetermined level (below the MTD)
and samples (blood and other bodily fluids) are collected at various time
points and analyzed to determine how the drug is processed within the body. Total
number of research participants =
20- 80. Duration = 3-6
months

·  Phase II (exploratory trials)
- 

Phase II study participants have the targeted
condition and no concurrent illnesses. Main objective is to determine
minimum dose of the trial medication that is maximally effective (or
sufficiently effective) without undue toxicity. Phase II is divided in Phase A
to assess dosing requirements and Phase II B to assess study efficacy. Total
number of subjects ranges=

up to 300.  Duration = 1-3 years

·  Phase III
(confirmatory trials) -

 Phase III studies include
a large number of study participants. Study participants that are more
representative of the population as a whole. Generally, compares the experimental
agent (s) with approved medications. Phase III is divided into Phases III A and
Phase III B, final stage before submission to regulatory authorities. Total
number of subjects ranges=

up to 3000. Duration = 3-5 years

The pharmaceutical industry is
growing as result of greater needs for more drugs, vaccines and medical
devices. In fact it is reported that there were 4,194 drugs in development in
1997 and today there are over 8,000 new drugs in development. Therefore in less
than 10 years the number of potential new drugs has more than doubled and some
estimates indicate tripled in 2006. As a result there is a greater need for
more clinical trials as we become a more global economy.

The international pharmaceutical
market will undergo major changes as a result of the loss of blockbuster drugs,
going off patent protection (in the United States) and the need for newer drugs
due to the prevalence of more diseases or conditions. The conduct of efficient
clinical trials is going to be essential for success in order for
pharmaceutical and biotech companies to remain responsive and capable of
meeting the healthcare needs of a world population that has greater access to
medicines and therapeutics.

{mospagebreak title=India : Emerging as New Global Clinical Trials Outsourcing Leader}

India
: Emerging as New
Global Clinical Trials Outsourcing Leader

India has been identified as the
preferred clinical trials outsourcing destination for both global
pharmaceutical and biotechnology companies. It is projected that “US- based companies clinical trials projects are growing at 12% and should generate $26.5
billion dollars by 2007” (Business Communications Corporation, BCC). Therefore,
the advantages to conducting clinical trials in India are:

·  Large, multiethnic,  and
multiracial patient population patients (over 1 billion people)

·  Rapid patient recruitment
(significant reduction in  the clinical development process)

·  Spectrum of diseases are similar
to or exceed rates seen in the  West

·  Drug companies can save up to 60%
by conducting trials in India as compared to the West

·  Physician investigators speak
English

·  Most hospitals and private nursing
homes have medical records in English

·  Faster subject recruitment
(reducing study timelines without diminishing quality or increasing costs)

Global clinical trials require
the successful completion of three phases (phase I, II, and III) conducted in
multiple countries in order to determine the effectiveness of the drug in
different populations and ethnic groups that may be prescribed the medication,
vaccine or medical device, if approved by the regulatory authorities. These
studies are referred to as “global clinical trials”. In India, phases II, III, and IV are similar to other countries participating in multinational
clinical trials. Phase II, referred to as exploratory trials, focus on a
limited number of study participants (approximately 100 – 300 patients) with a
disease or condition that the drug is designed to treat to determine if the
treatment is effective. Phase III trials (confirmatory trials) are studies in
which the experimental drug is compared to the currently available drug or
therapy, if possible, or a placebo (drug without therapeutic value). Typically,
these studies are designed to be randomized, double-blind
(neither the participant nor the investigator know if the participant is
receiving the experimental drug or the currently approved drug), and placebo-controlled
(experimental drug compared to a placebo). Phase III trials confirm the
efficacy, safety and the therapeutic benefits of the experimental drug compared
to what is currently available.  Phase IV research is conducted after the drug has
been approved for sale, called post-marketing research, and may enroll 10,000’s
of patients which provides surveillance designed to detect any rare or
long-term adverse effects over a much larger patient population and time period
than possible during the initial (phase I – III) clinical trials.

Unlike other
countries, India historically has not allowed Phase I trials to be initiated
for new drugs, Phase I data must be available from other countries to initiate
a Phase II or III studies. If the experimental drug is discovered in India, then clinical trials may be conducted on as human/clinical pharmacology
trials with healthy human volunteers to determine maximum tolerated dosage in
humans and adverse effects. However, more Phase I studies have been initiated
in India in the past 5 years by global pharmaceutical and biotech companies and
CROs.

Some of the reasons for this
difference in India, compared to other parts of the world, are due to fears
that Indian patients may be treated like “guinea pigs” because of the need for
regulatory policing that ensures protection of human subjects on clinical
trials. The low literacy levels of many poor patients, potential volunteers, raises
concerns of adequate informed consent about the clinical trials risks. As India becomes increasingly preferred as a destination for the outsourcing of clinical
trials, issues of informed consent and safety will become more significant. It
is estimated that there are over 80 hospitals (government and privately owned)
actively engaged in global and local clinical trials. Those numbers are
expected to double or even triple each year by 2010, with 14,000 hospitals in
the country.

{mospagebreak title=Need for More IRBs in India}

Need for More IRBs in India

Since clinical research is vital
to the development of new drugs and therapeutics, the international community
created, Good Clinical Practice (GCP) to provide guidelines for clinical
research and ethics that participating nations and investigators are expected
to comply with. The European Union (EU) Directive 2001/20/EC definition of GCP
is:

 “Good clinical practice is a set of internationally
recognised ethical and scientific quality requirements which must be observed
for designing, conducting, recording and reporting clinical trials that involve
the participation of human subjects.”

GCP Compliance provides assurance
that the rights, safety and well-being of trial subjects are protected, and
that the results of the clinical trials are credible and accurate.

Institutional review boards (IRB)
(independent ethics committees (IEC), or ethics review boards (ERB)) are formal
groups of professionals designated to review and monitor research involving
human subjects.  The IRB provides critical review and oversight for research
and has the authority to approve, require modifications or disapprove research.
The main function of the IRB is to assess the scientific, ethical, and
regulatory aspects of a trial, in order to protect the rights and safety of
study participants.

Worldwide IRBs were developed as
a result of research abuses demonstrated in the notorious experiments of Nazi
physicians in World War II, referred to as the Nuremberg Trials, and several
other international cases of research misconduct. The result was the
development of ethical principles under the oversight of the World Medical
Association (such as, Nuremberg Code and the Declaration of Helsinki: “Ethical Principles
for Medical Research Involving Human Subjects”) or national ethical guidance
from specific nations that must be followed if conducting research in
association with that country for example, The Belmont Report in the United
States. These ethical principles guide IRBs on principles such as, beneficence,
respect for persons, and justice.

Table 1.0 Basic Ethical
Principles and Application of Ethical Principles

 Source:
www.hku.hk(University of Hong Kong) – The Belmont Report

IRBs only approve research in which
the risks to subjects are balanced by potential benefits to society, where the
subjects have an informed consent process that allows eligible patients the
opportunity to agree to participate or refrain from participating without fear
of loss of medical care.

The IRB/IEC/ERB purpose is to safeguard
the rights, safety, and well-being of all trial subjects with special attention
provided to vulnerable subjects, such as pregnant women, children, prisoners,
the elderly, or persons with diminished comprehension. General responsibilities
of the IRB include:

(a) Members should be from
various and diverse backgrounds that are able to adequately review the
scientific and non-scientific aspects of the clinical trial.

(b)
In addition to
professional competition (medicine, science, etc.), the IRB should also know
international and national (Indian) regulations, applicable law, and standards
of professional conduct and practice.

(c)
The IRB should include
persons knowledgeable in these areas and should meet regularly.

(d)
IRB should be composed of
both men and women and should not consist entirely of members from one
profession (such as medicine).

(e)
No IRB should have the
researcher involved in the study review and approval of the ethical merits of
the clinical trial because of conflicting interests.

The IRB determines the nature and
merit of the study by reviewing the research protocol, written informed
consent, and other documents. As a result, the IRB has the authority to provide
an opinion about the research study:

·  approval/favourable opinion;

·  modifications required prior to
its approval/favourable opinion;

·  disapproval/negative opinion; and

·  termination/suspension of any
prior approval/favourable opinion.

The opinion (or
decision) of the IRB should be unbiased and have sensitivity for concerns of
the targeted subjects to be included in the study.

India is positioned to become the
next major location for clinical trials but as a nation it must be able to
respond to the clinical trials infrastructure requirements which includes
incorporating international ethical principles and human subject protection
issues, incorporating the role of the Institutional Review Boards (IRBs) that
comply with the international community. 

The United States has mandated
that all clinical trials be reviewed and approved by an IRB, before the research
study begins, since 1974 (Research Act of 1974) for all human research, which
means that any clinical trial that is reviewed and approved by the Food and
Drug Administration (FDA) must be reviewed and approved by an IRB. India’s emergence as the next clinical trials hub, as a result of an increase in clinical
study outsourcing, must deal with these issues to be a viable location for
global clinical trials. Some of the concerns will include the quality and
nature of the IRBs that review clinical research protocols, ethical informed
consent process/subject recruitment and availability of GCP trained
investigators and research teams. A large patient pool with diseases and
conditions found in the West and highly qualified physicians are essential but India must overcome these barriers in order to fully capitalize on the emerging
opportunities of clinical research because of the large financial investment by
pharmaceutical companies.   

Clinical Research is Changing

Pharmabiz.com
estimates that global pharmaceutical companies have invested Rs 3.5 billion
(about US $ 75 million) in India through clinical trials outsourcing and this
investment is expected to increase to Rs13.2 billion (approximately US $ 281
million) or even as high as Rs 44 billion (approximately US $ 950 million) by
2010. But major clinical trials cases such as the, torcetrapid-related deaths
from Pfizer or Merck’s painkiller and arthritis drug, Vioxx, which was
withdrawn because of emerging evidence that the drug caused heart attacks and
stroke, are changing clinical research expectations each day.

In the
Pfizer experimental drug (torcetrapid) issue, the pharmaceutical company will
not face the product liability lawsuits of Merck because patients in clinical
trials must sign  a waiver or informed consent form that indicates they
understand the risks they face and accept that this is an unapproved
experimental medicine evaluated through clinical research. Therefore, the informed
consent process is important and must be a process of information and not just
a form that is signed once before the study begins.

Trial
Participant Benefits & Responsibility of the International Community

Clearly,
there are risks but there are also tremendous benefits for study participants
in clinical trials that include access to the newest medicines and best
technology but, the responsibility of the IRB and investigator is to evaluate
the safety and risks and inform patients. Many pharmaceutical companies are
doing their part to ensure the protection and safety of study participants
however the international community and regulatory bodies are expecting that
IRBs and Investigators take their responsibility to protect the participants
under their care.

The FDA has certain restrictions regarding the
number of patients that can be recruited for clinical studies outside the US and Western Europe and only allows 25%–30% of subjects from rest of world, ROW (countries outside
of US and Western Europe) to participate. Part of this issue is due to the
acceptance and incorporation of international standards, such as ICH GCP, into the
regulatory requirements of the country. In the US and Western Europe most
clinical trials are conducted based upon the requirements of ICH GCP and
compliance with the international ethical principles. There are continuing
concerns about India’s informed consent process, Institutional Review Board
compliance and oversight, subject recruitment practices, patient safety
standards, adverse event reporting procedures, as well as regulatory issues.
These issues are more than simple logistical barriers but more complex issues
that must be addressed. Large global pharmaceutical companies have begun to
develop facilities in India but small – and mid-sized pharmaceutical and
biotechnology companies are not transitioning to India as quickly.

In general, major pharmaceutical company investors
have become accustomed to double-digit growth performance, thus a constant need
to reduce cost and speed clinical trials. And there are an ever greater needs
for more new products (drugs, vaccines, and medical devices) with higher sales
potential and increasing competition therefore, India will still be a well
sought out location. However, India must consider that clinical trials are very
costly and time consuming component of the research and development (R&D)
process with more than 60% of the total R& D budget for most companies going
to clinical trials the cost to develop one new drug in the US market ranges
from $800 million to $1.1 billion over 10–15 years. This
is a significant investment when you consider that only 2% of all new drug
development programs ever go into clinical trials (phases II – III) and only
about 20% of the compounds discovered in the lab enter phase I clinical trials.

India offers a great location for the development
of a robust clinical trials outsourcing market with faster study completion
which translates into opportunities for more new drugs to treat major diseases
and conditions (particularly in, cancer, diabetes, cardiovascular disease,
inflammatory disease). In addition, recruitment costs in India are much lower, allowing pharmaceutical companies to meet financial and time demands
of the research program. Industry officials anticipate that the number of drugs
will increase significantly in the next 5-10 years and India is expected to benefit from that development. Even though clinical trials outsourcing
to India relies heavily upon the cost-savings, quantity of physicians,
available patients and IT strengths (important in data management), there is
also increased awareness and requirements from the international community with
greater focus on clinical trials quality, international GCP, ethical
compliance, drug safety, risk management, and government enforcement of
clinical trials standards and these challenges need to be addressed in order to
meet global standards. Research indicates that by the end of 2006, the top ten
major pharmaceutical companies will be investing $54 billion with 60% of those
dollars to R&D and this investment is expected to increase to $65 billion
dollars by 2008 and India could benefit from their investment.

One of the immediate changes that India can make is developing more IRBs that meet international standards and ensuring
patient safety. Additionally, important are the training of more GCP-trained
investigators, improving the informed consent process, and ensuring quality
data at the investigator site level. The other changes may have to occur over
time and with the involvement of the government but, there are many things that
can be done at the local, physician, and hospital level.

http://www.nytimes.com/2006/12/04/health/04pfizer.html?bl&ex=1165554000&en=b622d9e53553e1ea&ei=5087%0A

¹

Pharmacokinetics is a branch of pharmacology
dedicated to the study of the time course of substances and their
relationship with an organism or system. In practice, this discipline is
applied mainly to drug substances, though in principle it concerns itself
with all manner of compounds residing within an organism or system, such as
nutrients, metabolites, endogenous hormones, toxins, etc.

²

Pharmacodynamics explores what a drug does to the
body, pharmacokinetics explores what the body does to the drug.
Pharmacodynamics is the study of the biochemical and physiological effects
of drugs and the mechanisms of drug action and the relationship between
drug concentration and effect. It is often summarily stated that
pharmacodynamics is the study of what a drug does to the body, whereas
pharmacokinetics is the study of what the body does to a drug.

{mospagebreak title=About Lisa Castro}

About Lisa Castro

LISA CASTRO, BSc, MHS, DMH (C)

President, Sephmer Sciences Incorporated

E-mail: lisa.castro@sephmersciencesitgo.com

Ms. Lisa Castro, is the founder and President of Sephmer Sciences, Incorporated. She is a trained scientist from Johns Hopkins University who has over a decade of experience in clinical research. Ms. Castro has worked with and consulted for notable organizations such as Aventis Pharmaceuticals, Schering Plough Pharmaceuticals, Bristol Myers Squibb Pharmaceuticals, Novartis Pharmaceuticals, and the Johns Hopkins Center for Immunization Research, United States National Institutes of Health, National Cancer Institute, and Bethesda Naval Medical Center. She has worked on national and international medical projects dealing with HIV/AIDS, reproductive medicine, oncology, endocrinology, internal medicine, and gastroenterology and training physicians for clinical research. In addition, she has been responsible for clinical research training of physicians, scientists and healthcare professionals in India and the USA.