New Era of R&D Laws in India

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India has what pharmaceutical and biotech developers need: over 1 billion people, 14,000 hospitals, 700,000 beds, and half a million doctors. India's heterogeneous population includes a diverse ethnic mix of people who suffer from a high incidence of lifestyle diseases that are common in the West.

In considering India as a location for clinical trials, pharmaceutical companies often assess three primary factors. The first is patient enrollment opportunities that lead to quicker completion of clinical trials, the second is cost savings, and the third is an understanding of the Indian regulatory environment and quality issues to ensure that data can be used for U.S. and European regulatory approvals.

The first wave of outsourcing to India was based on economics. By moving tasks such as clinical data management to companies in India, pharmaceutical companies reduced the cost of entering and cleaning clinical trial data. This first step was followed rapidly by tasks associated with database set up (i.e., building screens and programming logic checks in systems such as Oracle Clinical) and analysis (using systems such as SAS to generate tables, listings, and figures) required as part of the final reporting in a clinical study report. This outsourcing of data entry, cleaning, and analysis to offshore companies included working with global or local companies with IT and process improvement expertise.

Today, outsourcing to India is far more strategic and broader in nature and focuses on accelerating drug development by discovering viable new drugs and biologics sooner to enrolling trials more rapidly.

Brief regulatory history

Under British rule, clinical research in India was governed by the Drug and Cosmetics Act, 1940. Following independence from Britain in 1947, an array of structural factors including weak patent laws, a protectionist economy, and a fear of Indians being used as guinea pigs by Western companies created challenges for the industry—until recently.

One of the recent changes is with The Indian Patents Act of 1970. The law originally recognized only process patents and not product patents. This meant Indian companies were able to copy Western drugs by slightly altering a production process. In 1995, as it ascended into the global economy under World Trade Organization (WTO) guidelines, India signed the Trade Related Aspects of Intellectual Property Rights (TRIPS) agreement. TRIPS became effective in India in January 2005. This new agreement changed India's patent laws to recognize 20 year product patents, and by 2005 Indian companies began to respect intellectual property (IP) rights, consistent with international standards.

In 2000, the Indian Council of Medical Research¹ issued the Ethical Guidelines for Biomedical Research on Human Subjects followed by 2002's Good Clinical Practices for Clinical Research in India. Also in 2002, the government allowed for 100% direct foreign ownership of pharma companies.

The year 2005 was a watershed year. The Indian government eliminated import duties for investigational drugs to be used in clinical trials. In addition, in 2007 the Indian Government gave a further boost to the industry by eliminating the 12% service tax on the conduct of clinical research.

Furthermore, in 2005 several key reforms were introduced to make India an attractive destination for drug development and in particular for conducting clinical trials. The number of drugs under price control was significantly reduced, the aforementioned new patent law became effective, and updated Schedule Y regulations (which detail requirements for the conduct of clinical trials) were issued.^2,3

Prior to 2005, a major stumbling block for conducting clinical trials in India was the requirement of a "phase lag." This meant that a Phase II study could only be performed so long as a Phase III study was ongoing in another country. The updated Schedule Y regulation has done away with phase lag. Updated Schedule Y also stipulates details of the data and documentation required to initiate clinical trials and provides several templates, including one for an informed consent document.

The only primary constraint still is the inability to perform first-in-man studies for drugs discovered outside India. Many do not see this as a real concern, as first-in-man studies can be done rapidly at a reasonable cost in Western countries. More recently, there have been discussions in the Indian Government to even remove this burden and update schedule Y to be more consistent with U.S. and ICH guidelines.

In July 2007, India joined the United States, UK, Australia, and New Zealand to create an online registry similar to the FDA's clinicaltrials.gov to allow for registration of trials being conducted in India (http://www.who.int/ictrip/en/). This registry allows data to be integrated with the World Health Organization's online database of clinical trials to ensure research meets global standards. This increased transparency is expected to ensure the ethical conduct of and public trust in clinical trials.

Today, the Drugs Controller General of India (DCGI), the regulatory body that oversees trials, is developing a structure of self regulation combined with government oversight similar to the FDA. In March 2008, Dr. Surinder Singh was selected as the new Drug Controller General to lead the Indian Regulatory Agency. In a series of meetings the author had with Dr. Singh, he indicated his vision to transform his office into a world-class regulatory body based on science and objectivity.

Recent changes at DCGI allow for expedited regulatory approval for multicenter and multicountry trials, so long as the trial is also being conducted in one or more of the following countries: the United States, UK, Switzerland, Australia, Canada, Germany, South Africa, and Japan. These are referred to as Category A trial applications. Current metrics for Category A trials are a response in two to four weeks and for Category B trials in eight to 12 weeks.

Many large multinational companies including Pfizer, Novartis, Eli Lilly, AstraZeneca, Wyeth, and Merck have been in India for several years. More recently, others including Bristol Myers Squibb, Boehringer Ingelheim, and Eisai have established clinical research capabilities in India. And this past June, Japan's Daiichi Sankyo announced it is acquiring Ranbaxy Laboratories, India's largest pharmaceutical company.

Patient safety, GCP, and quality

With the growing number of clinical trials being conducted in India, there is increased emphasis on patient safety, adherence to Good Clinical Practice (GCP), and quality issues. Several training institutions have been set up to supplement the extensive training programs within pharmaceutical companies and contract research organizations (CROs).

In his presentation at the 2008 DIA Annual Meeting, FDA's David Lepay, MD, PhD, senior advisor for Clinical Science, Science and Health Coordination and International Programs, Office of the Commissioner, indicated that the FDA has completed a small number of GCP inspections in India and that to date none have resulted in citation for a major violation requiring official FDA action.

Informed consent violations in India are similar to those in other emerging markets and are often a derivative of cultural and social dynamics that exist between the doctor and the patient. Anywhere in the world, whenever a patient visits a doctor, the doctor tends to be in a position of authority. At the risk of speaking in broad stereotypes and taking the United States as an example, American patients tend to be more individualistic and can be more doubting of a doctor's counsel than patients in many other parts of the world. In India and other Asian countries, patients hold their doctors in high esteem and tend to be more compliant with their suggestions. The cultural difference amplifies the importance of training investigators to ensure they learn and implement GCP.

There have been a few reports of GCP violations, including inappropriate administration of informed consent because trial participants were not fully aware of the investigation in which they were taking part. In April 2006, the BBC highlighted these problems in the documentary Drug Trials—The Dark Side.⁴

Several small and medium pharmaceutical companies have experienced recent successes in their clinical trials in India. Arthur Brown, MD, PhD, CEO of Chantest (Cleveland, OH), a provider of specialized laboratory testing services for drug discovery and development, recently completed a Phase II proof of concept study in India. He indicated that "the quality of investigators is at par with top investigators I have seen in the United States, and I was pleased that the IRBs scrutinized our protocol as thoroughly as U.S. IRBs in order to ensure patient safety." This optimism coupled with a strong desire of the investigators and other researchers to do things right is helping to ensure that quality is maintained.

Guy Boccia from La Jolla Pharmaceuticals (San Diego, CA), a specialty pharmaceutical company conducting a trial in India observed, "In general, investigators in India are extremely qualified to conduct clinical trials. These investigators have been educated and trained on par with global standards...Indian people are eager to do well and are determined and dedicated for excellence."

Regular conferences are now held in India with global development and regulatory experts presenting. The DIA, a leading U.S. organization for those involved in the discovery, development, regulation, surveillance, and marketing of pharmaceuticals, held its second annual DIA India meeting along with the Institute of Clinical Research and Biomedical Consulting Group in November 2007 and its first Indian Annual Regulatory Conference this past April in Mumbai. DIA also opened an office there the same month, appointing a Chair for the Regional Advisory Council of India led by Nandkumar Chondankar, PhD.

Cost savings

As noted, cost pressures in the pharmaceutical industry are a major reason why many companies are outsourcing to India. Several pharmaceutical companies and CROs set up operations to perform everything from clinical data management and statistical programming to medical writing. These tasks, which were typically done internally or at CROs, can be done accurately and cost effectively in India.

At a September 2006 DIA Conference in Princeton, NJ, "Clinical Research and Drug Registration in China and India," Vip Mody, MD, FACP, clinical research director of Sanofi Aventis, stated that in a recent trial they undertook, they had seen "cost savings of 30% or more."

The real advantage

In an era when one day's delay in a clinical trial can cost a company $2 million in subsequent foregone revenue, speed to market is key for many small and medium sized pharmaceutical and biotechnology companies. The real advantage for a pharmaceutical company is to get to market and reach peak sales sooner, prior to patent expiration.

As Robert Maguire, MD, Wyeth's vice president of clinical development, shared in a CenterWatch Monthly interview, "Time is really the key thing...Phase II being where most drugs fail in the clinical process, it's important to do Phase II right."⁵ Dr. McGuire continued, "by reducing the number of sites, and focusing enrollment for certain trials in India, we believe enrollment times are going to be cut by half or better."

India not only provides rapid patient enrollment solutions, it has investigators who are highly motivated, project managers who are often well-trained MDs and PhDs, and a huge patient population that is treatment naïve and available for researchers to test novel therapies. In the aforementioned Sanofi trial, Dr. Mody stated that they "completed recruitment three months ahead of schedule."

Previously, when clinical trials were delayed due to enrollment, investigational sites in India were added to rescue the trial. Today, many companies include conducting trials in India as part of their clinical development plans.

Summary

Conducting clinical trials in India has become a strategic imperative for many pharmaceutical companies. Speedy patient enrollment, strong investigators, and cost savings are key draws. As of July 9, 2008, clinicaltrials.gov listed 721 ongoing trials in India.

Doug Cowart, PharmD, president of Therapeutics Development Consultants (North Potomac, MD), advises small and medium size pharmaceutical clients in the design and conduct of clinical trials. He states, "I am now advising my clients to look closely at India for patients. With English the native language, attractive regulatory and patient enrollment timelines, and motivated investigators, India can help my clients complete their trials more quickly and with strong quality."

As in any country, selecting the right outsourcing partner and investigators is fundamental to a trial's success. Several leading researchers trained in the United States have now set up their own companies or hold key leadership roles within Indian subsidiaries of multinational companies.

A decade ago most midsize and smaller pharmaceutical and biotechnology companies were reluctant to include investigational sites in Western Europe for the conduct of clinical trials. Today, they do this routinely. Similarly, in the coming years, companies will recognize the quality and value of conducting trials in India and other Asian countries. "I feel India has tremendous potential, and the concerns that most people express seem to reflect prejudice—likely historically based—which will be overcome soon," said Dr. Brown.

Munish Mehra, PhD, is managing director of Global Drug Development Experts, 910 Seventeenth St., NW, Suite 312, Washington, DC, 20006, email: mmehra@gddexperts.com.

References

1. Web site for Indian Council of Medical Research, http://www.icmr.nic.in.

2. Web site for the Ministry of Health & Family Welfare, http://www.mohfw.nic.in.

3. Web site for Central Drug Standard Control Organization, http://www.cdsco.nic.in.

4. P. Kenyon, Drug Trials: The Dark Side (BBC Documentary, 27 April 2006), http://news.bbc.co.uk/1/hi/programmes/this_world/4924012.stm.

5. The CenterWatch Monthly, "A New Era Begins for India's Clinical Research Market," 13 (7) July 2006.