Clinical Trials : Present and future in India

The huge and skilled manpower available in India could revolution the clinical trial field. The implementation of the GATT has opened a new opportunities for India to concentrate on the clinical trial market. In India the infrastructure is available for the smooth conduct of clinical trials. The Indian Pharmaceutical Companies with the available resources can successfully accept the challenge of globalization and can play a major role in the clinical trials.

Introduction :

Clinical trials are designed to help us find out how to give a new treatment safely and effectively to people. All patient who participate in a clinical trial provide information on the effectiveness and risks of the new treatment. Advances in medicine and science are the result of new ideas and approaches developed through research. New treatments must prove to be safe and effective in scientific studies with a certain number of patients before they can be made available to all patients. Clinical trials shows that which therapies are more effective than others. This is the best way to identify an effective new treatment. New therapies are designed to take advantage of what has worked in the past and to improve on this base. There are certain steps and protocols which needed to be followed while carrying out the actual clinical trials.Pre-clinical Testing

The sponsor of the clinical trial needs to gather data regarding safety of a new drug in small-scale clinical studies before it is studied in humans. Animal studies provide data regarding the absorption, distribution, metabolism and excretion of a new drug. Data regarding the short-term toxicity of the drug in animals is also obtained. Short-term studies in animals can range from 2 weeks to 3 months depending on the proposed action of the new drug.

The sponsor then files the IND (Investigational New Drug) application. The main purpose of the IND application is to provide documentation that it is indeed reasonable to conduct human trials with the drug.



The different steps involved in the clinical trials are as follows.

Phase-I

These studies are designed to determine the metabolic and pharmacological actions of the drug in humans, the safety of the drug associated with increasing doses, and, some evidence on efficacy. The total number of subjects included in Phase 1 studies is in the range of 50-100.

Phase-II

These studies are carried out to evaluate efficacy and short-term safety of the drug in selected populations. A dose range for the drug is established. Optimal dose of the drug is also established. Phase 2 studies involve several hundred people.

Phase-III

These trials are conducted in several hundred to several thousand people. The objective of these trials is to confirm efficacy of the study drug and to establish its safety profile.

Regulatory review

The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) become part of the NDA (New Drug Application). The FDA (Food and Drug Administration) sends an action letter that provides an approval, approvable or non-approvable decision and a justification for that recommendation.

Phase-IV Once the drug is marketed, a large number of subjects are exposed to it. Therefore, new adverse events may be found. Post-marketing surveillance studies are carried out in order to detect previously unknown adverse events and risk factors.

Phase 4 studies are additional safety and efficacy analyses focusing on formulations, dosages, durations, drug interactions and/or new patient groups.

Prior to conducting a clinical trial the following parameters are needed :

• Protocol

• CRF (Case Report Form)

• Informed consent form

• Investigator’s brochure

• Regulatory approvals (Phase I, II, III)

• Ethics Committee approvals

• Documentation formats for monitoring

The actual clinical trial involves the following personnel

Investigator/s (at the site where subjects are actually given the study drug)

• Site coordinator

• Clinician (responsible for the trial from the sponsor’s end)

• Project manager

• Clinical Research associate

• Data Manager

• Programmer

• Statistician

• Medical writer

The data passes through the following steps before it is compiled in the form of a clinical study report.

• Data transcribed onto paper case report forms/ electronic data capture systems at the site.

• Scanning/Indexing into imaging system (for paper CRF’s)

• Data entered in the databases

• Electronic checks run for data errors

• Clarification of errors through Data Clarification forms sent to the site.

• Resolution of Data clarification forms and database updated

• The “clean” data is then forwarded to the programmer and statistician

• Data is analyzed and represented in formats as per FDA requirements

• The clinical study report is written

• Data for the clinical trial is submitted to the FDA or relevant regulatory authorities

Based on the clinical study report drugs can be introduced in the market.

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Scope and Future:

Worldwide, the average cost of developing one molecule costs about $282 million and takes about seven years to complete. According to industry estimates, the cost of phase I trial is 50% cheaper in India and for phase II it is 60% less.

India has implemented product patents since 2005, which will lead to widening of the market for indigenous (say, Ayurvedic products) as they will have the authenticity of internationally recognised product patents. Product patent protection will encourage multinational companies to import technology into India to develop new products. These developments will open up increased opportunities for the clinical trials of bio-tech and medicinal products.

Clinical research is losing its attractiveness in the US due to the shortage of investigators. By 2005, there will not be enough clinical investigators to handle the number of drugs in clinical development. Center Watch estimates that against a 2005 demand for 56,000 investigators, only 48,000 will be available, a shortfall of 15 percent.

According to industry sources, India has about 500 investigators. India has over 572,000 doctors, 43,322 hospitals and dispensaries and about 8.7 lakh beds including both private and public. Majority of the doctors are graduates with little or no knowledge about clinical trials and hence would not qualify as investigators for complex international clinical trials. The situation requires tremendous efforts to attract the medical professionals/specialists to clinical research. Identifying and attracting potential investigators is the biggest challenge, requiring innovative approaches. The current efforts at training are fragmented. The training focus of sponsors and CROs is on the investigators involved in their trials and their own monitors and other professionals. The enormous challenge of large number of quality professionals in medical and clinical research can only be met by cooperative and collaborative efforts between industry, academia and government. Besides the manpower efforts, the training activity will need financial support. In the US, the industry spends over $300 million on training. The funding has to come from all stakeholders, with majority share coming from the major beneficiary, the pharma industry.

Around 25 contract research organisations (CROs) and almost all multinational pharmaceuticals companies have started full-fledged clinical trials in India since last three years. Further, the amendment to Schedule Y of the Drugs and Cosmetics Act in February, now allows MNC s to conduct simultaneous trails in India and abroad

MNCs like Pfizer, Eli Lilly, GlaxoSmithKline, Sanofi-Aventis and Roche have already started phase-I and II trails in India. There are many independent CROs in the fray too, which are consolidating their base and expanding operations.

Mumbai-based CRO, Metropolis Health Services which conducts clinical trials in various therapeutic segments and offers a spectrum of clinical development services, is in the process of offering site management services to various pharma firms and other CROs. It offers trials in 16 therapeutic segments like anti-inflammatory, allergic disorders, cardiovascular, central nervous system and oncology.

Ahmedabad-based CRO, Synchron Research offers services like rapid pharmacokinetic (PK) analysis, qualitative and quantitative medical imaging and silico drug metabolism studies. It has conducted over 200 bio-availability studies. Bangalore-based Lotus Labs has also completed more than 450 bio-studies and is conducting several phase III trials. It has set up research facilities in Bangalore and Chennai and has recently tied up with St John’s National Academy of Health Sciences, Bangalore, for conducting phase I trials.

Mumbai-based ClinInvest Research focuses on all phases of clinical trials mainly in the areas of oncology, neuro-psychiatry, cardiology and diabetes drugs. Clingene International, a Biocon subsidiary, concentrates on bio-analytical, bio-statistical and data management services to its clients

Quintiles Spectral (India), a subsidiary of Quintiles Transnational, the clinical services segment, conducts studies in oncology, psychiatry, neurology and anti-infectives. The company has conducted over 90 clinical studies on 13,000 patients.

In fact, many new CROs have outlined plans to tap India’s large pool of patients suffering from cancer, diabetes and other diseases for various drug developments. Belgium-based CRO Trainor and Partners (T&P) has decided to launch its Indian operations soon. Pharma giant Pfizer has already chosen a city in one of the northeast part of India to conduct clinical trials on 300 patients for a new malaria drug that combines chloroquine (to which several Indian malarial strains have developed resistance) and azithromycin, an antibiotic. It is also carrying out clinical trials for drugs to treat osteoporosis, breast cancer and schizophrenia. According to industry sources, Pfizer’s cumulative investment on clinical research in India is believed to be $13 million.

At present, Pfizer is conducting around 20 clinical trials. It has independently conducted more than 40 good clinical practices (GCP) workshops and has trained more than 2,000 investigators.

The company has also contributed to research infrastructure development at various institutes through clinical trials that have already been conducted. For instance, it has contributed dual energy X-ray absorptiometry (DeXA) machines, costing over $600,000, to develop osteoporosis centres at leading hospitals in the India.

According to industry sources, the pace at which drug trials are being instituted in the country is so fast that the Clinical Data Interchange Standards Consortium (CDISC), USA, a non-profit organisation committed to the development of clinical research organisations’ standards the world over, is looking at setting up a chapter in India.

Eli Lilly has over 17 large and small clinical research projects running in 40 hospitals across India. The company has already held clinical trials involving more than 600 patients for human insulin and insulin lispro. It is also conducting trials on oncology besides developing a new molecule for lung cancer.

GlaxoSmithKline (GSK) Plc has started seven simultaneous clinical trials of its vaccine and pharma molecules. The company has tied up with a series of hospitals in India to do the trials.

Aventis Company sources say it will conduct clinical trials in the cardiovascular, diabetes and oncology segments and is presently setting up trial infrastructure in India.

Roche, the Swiss pharma major, has set up clinical trial sites in India as part of its global trials of a new drug for a particular variant of lung cancer. India, also, has a vast patient population afflicted by this type of lung cancer, primarily triggered by the sustained use of tobacco products. The company is also considering India as a prospective site for its future clinical trials involving new drugs and therapies for variants of blood cancer.

Gujarat, a prime exporter of pharmaceuticals drugs and formulations, has taken several steps to increase clinical trials in the state. The state pharma industry offers expertise in conducting phase I to phase IV trials in bio-equivalence and bio-availability studies and data management for almost all therapeutic drugs. Many Gujarat-based CROs have tied-up with leading research institutes across the country to develop new methodologies in clinical trials.

Pharma experts feel that Gujarat can be the prime location for conducting clinical trials in the country because of multispeciality hospitals, availability of subjects and high literacy rate.

In fact, the presence of many pharma MNCs in the state gives it an extra edge in R&D. Companies like Zydus Cadila and Torrent offer exciting prospects in this field. The facility of Zydus Research Center has been approved by ANVISA, a Brazilian regulatory agency, and complies to international standards and practices in the field of pharma research. Much of the research is directed towards development of new molecular entities.

Similarly, Torrent Pharmaceutical Ltd has six projects in the pipeline. One of them, the New Safer Anti-Arrhythmic Agents, is ready for phase II clinical trials. Till date, the company has filed 120 patents worldwide and the US and Indian patent offices have granted patents to four New Chemical Entities (NCEs).

The Gujarat government is also taking steps to promote clinical trials in the state. At the Vibrant Gujarat Investor’s meet last December, it proposed to invest Rs 30 crore in setting up an animal testing lab for toxicology. This involves creating an environment-controlled animal house under strict quality-control. The facility will be used for phase I clinical trials that will facilitate bio-medical research activity. The state has also proposed to set up a USFDA approved kilo quantity manufacturing plant at an investment of Rs 20 crore for manufacturing chemical solutions for clinical trials.

IT city Bangalore, known for its biotech ventures, is home for many clinical research organisations (CROs). Many big hospitals are also contributing plenty of patients to the clinical trials done by these companies. While Sagar Apollo hospital has a tie-up with Clinigene, Lotus Labs has signed an MoU with St John’s Medical College for multiple phase clinical studies and has also set up a clinical research facility in the medical college campus. Lotus Labs has an association with around 20 hospitals in the country for these studies and so do other CROs.

At the human ethic end, the CROs claim to strictly monitor the volunteers, that trials are done only after obtaining written consent. Volunteering, especially for phase I trials and bio equivalence studies which require healthy volunteers, is seen as a lucrative assignment by many unemployed youth according to industry sources.

According to USFDA and ICH guidelines , no volunteers can participate in more than one study per quarter. However, there are instances when people tried to violate this with forged documents, forcing many of the CROs to develop a barcoding system which would identify the finger print of the volunteer. Despite the regulatory hassles, foreign firms are interested in conducting clinical trials in India due to the availability of patients, volunteers and cost-effectiveness. A volunteer earns anything between Rs 3,000 and Rs 15,000 based on the requirement of the study and could take part in three studies in a year.

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Training Programmes in Clinical Trials:

At present there are two institutes offering courses related to clinical research and data management. One is the Academia of Clinical Excellence (ACE) and the other one is the Institute of Clinical Research India (ICRI). ACE was set up in October 2002 at the Bombay College of Pharmacy through the initiative and financial contribution of Pfizer India Ltd. It is expected that Pfizer will be contributing to the tune of $100,000 for a period of five years for the development of the academy. Subsequently, the academy was opened up for industry collaboration and Suven Life Sciences Ltd of Hyderabad has become a partner of ACE by making a financial contribution. The academy is conceived, as a one-stop-shop for all training needs of all clinical research professionals in the country. The ICRI commenced its operation in 2004 with its campuses located at Dehradun in Uttaranchal and in Mumbai.

There is a huge potential for the development of new institutes which can offer courses for carrying out clinical trials as per the regulations of FDA.

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Conclusion :

India has the largest pool of patients in many diseases, including cancer and diabetes. The study also points out that India’s biggest advantage is its low cost. For instance, trials for a standard drug in the US can cost up to $150 million. A similar drug could be tested in India for less than half that amount. CenterWatch has predicted that by 2010, the industry will spend around $250-300 million on clinical trials in India. Mc Kinsey estimates a much higher figure of $1-1.5 billion.The implementation of GATT has made it compulsory for all the companies to rely on research and development activities to survive in future. This will lead to a development of many new drug molecules which will require clinical trial studies .In conclusion we can say that Post 2005 GATT period will open a new opportunities for pharmaceutical companies in India in terms of clinical trials.

Refrences:

1)http://www.fda.gov/cder/about/default.htm

2)Clinical Pharmacology. D.R.Laurence, P.N.Bennett 8th edition, 1997

3) http://iis1.india.pfizer.com/Functional_Areas/ Medical_Research/clinical_trial/mrd_clinical_trials.asp

4) http://www.biospectrumindia.com

{mospagebreak title=About authors}

* Corresponding Author A.R.Chabukswar is working as Assistant Professor in Pharmaceutical Chemistry at MAEER’S Maharashtra Institute of Pharmacy, Pune-411038.

• Dr. Parakh S.R. is Principal and Prof. In Pharmaceutics at MAEER’S Maharashtra Institute of Pharmacy, Pune-411038

• Jagdale Swati C. is working as Assistant Professor in Pharmaceutics at

MAEER’S Maharashtra Institute of Pharmacy, Pune-411038