Pfizer, the world's largest drug maker, announced on December 5, 2006 that they were pulling the plug on their experimental drug, Torcetrapib. Pfizer made an investment of nearly US$ 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 III) and had enrolled 15,000 patients. Although Torcetrapib was close to receiving US FDA approval, this experimental agent that raises good cholesterol and reduce 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 biotech company or CRO) directly interacts with patient 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/pharmacodynamics 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 phase IIIA and phase IIIB, final stage before submission to regulatory authorities. Total number of subjects ranges = up to 3000. Duration = 3-5 years.


The pharma industry is growing as result of greater needs for more drugs, vaccines and medical devices. 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-year 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 pharma market will undergo major changes as a result of the loss of blockbuster drugs, going off patent protection (in US) and the need for newer drugs due to the prevalence more diseases. The conduct of efficient clinical trials is going to be essential for success in order for pharma 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.

India emerging as new global clinical trials outsourcing leader
India has been identified as the preferred clinical trials outsourcing destination for both global pharma and biotech companies. It is projected that "US-based companies clinical trials projects are growing at 12% and should generate $26.5 billion 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 (approx 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 in 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-year by global pharma 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.


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 EU Directive 2001/20/EC definition of GCP is:

"GCP 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 (IRBs) (independent ethics committee (IEC), or ethics review board (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 in association with 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 US. These ethical principles guide IRBs on principles such as, beneficence, respect for persons, and justice.

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 and have members knowledgeable in these areas.
(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 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 the international ethical principles and human subject protection issues, incorporating the role of the IRBs that comply with the international community.

The US 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 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 the India must overcome these barriers in order to fully capitalize on the emerging opportunities of clinical research because of the large financial investment by pharma companies.


Clinical research is changing
Pharmabiz.com estimates that global pharma companies have invested Rs 3.5 billion (about US$ 75 mn) in India through clinical trials outsourcing and this investment is expected to increase to Rs 13.2 billion (approx US$ 281 mn) or even as high as Rs 44 billion (approx US$ 950 mn) by 2010. But major clinical trial 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 pharma 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 pharma 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, IRB 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 pharma companies have begun to develop facilities in India but small- and mid-sized pharma and biotech companies are not transitioning to India as quickly.

In general, major pharma 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 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 programmes ever go into clinical trials (phases II-III) and only about 20% of the compounds discovered in the lab that 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 pharma companies to meet financial and time demands of the research programme. 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 pharma companies will be investing $54 billion with 60% of those dollars to R&D and this investment is expected to increase to $65 billion 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.

The author is President/CEO of
Sephmer Sciences, Incorporated 331 Newman Springs Road Building 1, Suite 143
E-mail:lisa.castro@sephmersciencesitgo.com