Demystifying India

When people think of the world's best places to visit and conduct business, many would not include India on that list. What most people don't know is that India is as vibrant, diversified, and sophisticated a country as many of the world's most popular. Its people, culture, architecture, and cuisine all make visiting and working in India an amazing adventure, filled with hospitality, warmth, liberation of the mind, and expansion of the stomach!

Only in India would you arrive at the New Delhi International Airport late at night after a 14 hour flight and without a working cell phone only to have a taxi driver offer his cell phone so that you may call your ride. Only in India would you find yourself eating Biryani (a traditional Indian dish) in Hyderabad at midnight with your colleagues and a hundred others who have gathered to enjoy the local flavor at an odd hour. Only in India would your car be stopped in a busy traffic and exhaust filled intersection and have an elderly woman cut open the top of a fresh coconut with a machete and place a straw in it so that you can enjoy a cool refreshing drink.

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But India can be as confusing and slow as much as it seems simple and efficient. It can be scary and overwhelming as much as it is warm and traditional. India can mean faster, lower-cost clinical trials, but it can also mean 85 people sitting in the waiting room of a small eye clinic at 9:00pm hoping to get a visit with a doctor before he leaves at 10:00pm after putting in a 14 hour day. Most will have to go home and try again tomorrow—even though home may be two hours away.

India means understanding that to get across Mumbai (Bombay) during the day, you should plan to be in the car for at least 2 hours and that your client may or may not be mad about it if you arrive late. India means knowing that a nice hotel or international brand hotel in a major Indian city like New Delhi, Mumbai or Hyderabad can run you in the range of $350 to $600 per night. Only in India do you see a burgeoning middle class driving Honda Accords and Toyota Camrys navigating streets with people on bicycles and four and five person families crammed onto two wheel motorcycles.

These are some of the realities of India today and why India is such a fascinating place to explore and to do business. There are also many misconceptions and myths associated with conducting business in the BIG I.

This article identifies and explores some of the most common myths related to conducting clinical trials in India today. Understanding the truths behind each can make entrance and operation in India an enormous strategic advantage for your company. Failure to understand or getting caught up in the hype could result in a missed golden opportunity or a more difficult path through India than is necessary.

Myth 1: The Indian clinical research market is emerging and unstable

While the clinical research industry in India is small compared to many other markets and is experiencing rapid growth, it is very much an established market and a country being considered or utilized by hundreds of biopharmaceutical companies worldwide.

As is widely known, sponsors operating in mature drug development markets including the United States and Western Europe are facing difficult challenges in moving their compounds efficiently through the pipeline, whether it be a shortage of beds for Phase I units, delays in contracting and budgeting or patient recruitment challenges, the costs and timelines associated with bringing new compounds from the bench to bedside is greater than ever before. These issues have forced the industry out of its comfort zone, resulting in a rapid globalization process over the last 10 years. Likewise, regions and countries around the world have adapted to and benefited from this globalization, including India.

As it turns out, clinical research has been ongoing in India for more than 30 years. Though, in recent years, India has adapted its laws and regulatory guidelines to allow global biopharmaceutical companies access to and confidence in conducting clinical trials there. It may come as a surprise to many that most prostaglandin clinical trials were performed in India in the 80s to obtain global approval in post partum hemorrhage, second trimester termination of pregnancy, etc. Indian physicians participated in many global clinical trials of injectable contraceptives in the 80s. Strong national resources and advantages in medical education and practice, patient populations, and the prevalence of first- and third-world diseases have made India not only an open destination, but also an attractive destination.

Up until 2005, India was probably best known in the world of pharmaceuticals as a generic powerhouse. Due to poor laws around intellectual property, red tape, and long start-up times, most multinational biopharmaceutical companies did not seriously consider India as a destination for clinical trials. Numerous other challenges and roadblocks existed as well. But as the industry began to globalize rapidly throughout the 90s and early part of this decade, regulators, entrepreneurs, and businesses began to recognize the significant economic opportunity that they were facing, as well as the opportunity to gain new credibility in the world of medicine, science, and the international business community.

The response was a profound, and rapid changes in the regulatory landscape related to clinical research and intellectual property has created an inviting market, which is realizing true and sustained growth. Today, there are nearly 1000 physicians and nearly 800 hospitals and clinics that have either conducted trials or have been determined through a feasibility process to be capable of conducting trials that conform to U.S. FDA and ICH GCP guidelines.¹

Clinical trials are taking place throughout the country in all regions and in cities large and small. Thousands of people are now employed and are busy planning, running, and monitoring clinical trials for sponsor companies, CROs, and investigative sites. Major universities and new and expanding colleges are offering certificates and bachelor and master degrees in the field of clinical research.

Existing service providers are expanding rapidly and new players are entering the market daily. Over 40 global sponsors and CROs have established ambitious operations there during the past 4 to 5 years.² Thousands of patients have participated in global clinical trials and thousands more are being screened daily. It is an exciting time to be considering or conducting clinical trials in India.

These attractive aspects of the market translate into a growth spurt in the number of studies taking place (see figure 1). An analysis conducted by Excel Life Sciences identified a minimum of nearly 600 clinical trials taking place in India today, a number that is growing by double digits annually.³ This figure doesn't take into account non-U.S. IND studies, investigator initiated studies, and other studies taking place.

Figure 1. The benefits of the Indian market that have translate into an increase in the number of studies taking place.

You've most certainly heard that upwards of 90% of clinical trials are delayed at least one month due to enrollment delays at the investigative site. That data comes from an annual CenterWatch survey of investigative sites that examines the relationship between sponsors and sites and considers issues impacting drug development from the sites perspective. Recently this survey has been expanded to include Asia in its analysis.⁴

A significant number of sites included in the survey were located in India. When compared with other regions of the world, Asia actually registered the second most ontime study starts, ahead of Europe and the United States. Contributing to this trend, reasonable regulatory and IRB approval timelines, enthusiastic investigators and study staff, and because sites are largely new to clinical research and many don't have established business practices related to negotiating clinical research contracts, PI and site contracts can take as little as three to five weeks. While the sample size for the survey was smaller than other regions, this is still a very positive early sign reflecting the benefit of conducting studies in this region of the world.

A look at 1572 filings between 2002-2006—the form an investigator needs to submit in order to participate in a U.S. IND study—shows that a rapidly growing number of investigators are from India, far outnumbering growth rates seen in several other Asia-pacific countries. Sponsors are finding that the regulatory timelines, data quality, costs, and abundance of patients make India one of the most attractive countries in the Eastern world to run their studies.

Isolating growth between 2006 and 2007, the 1572 data shows strong year over year growth in India, Japan, Poland, and the Ukraine among others. India rose from 10th to eighth place, with 395 investigators signing up for FDA-regulated research—29% more than in the previous year. Other newly attractive markets that have received a lot of attention recently, such as China, did not see a significant increase, up just 5.7% from 2006, although China's ranking improved from 31st to 25th.⁵

Compared to other newer markets, the Asia Pacific region is growing at a strong clip, with the highest growth when compared with Asia, Central Europe and Russia, South America, and Middle East/Africa over the past few years—growing market share from 2.9% in 2005 to 4.2% in 2006 with similar growth expected for 2007.⁵

The well known consulting firm AT Kearney ranked the attractiveness of markets across the world using the U.S. market as the benchmark (see figure 2). India ranks second only to China on that scale and other than population size, ranks very closely to or better than China in a number of categories, including perhaps most importantly for many companies, the regulatory environment and timelines.

Figure 2. With the U.S. market as a benchmark, world markets are ranked on their attractiveness to conduct clinical trials.

By anyone's standards, India is still a small market but a market that can surely be considered established and here to stay. Given the number of trained physicians, the strong commitment being made by government and nongovernment organizations, the establishment and growth of university programs focused on clinical research, and the vast untapped patient population, the opportunity for India to quickly become a world leader in clinical research is a distinct and perhaps inevitable possibility.

Myth 2: The regulatory process is complex and review timelines long

Like any clinical research market, India has its own laws, rules, regulations, and guidelines that guide the conduct of clinical trials taking place in the country.

In addition to internal regulations put into place, the FDA has become more active in auditing clinical sites in India. The number of FDA inspections in India is still very low, but the agency is talking of more and receiving pressure to do the same. In addition, the globalization of clinical research has resulted in a doubling of the number of international FDA inspections from 50 in the year 2000 to over 100 in 2007; so India can probably expect to see more.⁶

The regulatory environment has improved dramatically in a short time period. These changes have resulted in a standardized and predictable regulatory review and approval process. There is also a growing number of FDA compliant IRBs. To some degree, the regulatory submission and review process can be even better than other parts of the world in that conditional IRB approval can precede Ministry of Health (MOH) approval in some instances.

A common misconception about India relates to the timelines associated with regulatory review and approvals. India is often lumped in with other emerging markets and the assumption is that the approval process is lengthy. In fact, regulatory approval timelines are very reasonable, ranking with some of the fastest in the world. The timelines for review and approval depend largely on the type of study that is to be conducted. All clinical trials in India are overseen by the office of the Drugs Controller General India (DCGI), a department of the MOH. There are two categories of clinical trials that have been established by the DCGI for the review process. Specifically, the categories, related stipulations, and typical approval timelines are as follows:

1. Category A:

1. Global clinical trials with India as a location

• U.S., Japan, Europe recognized (excludes EE)

2. Average of 20 applications per month

3. Typical DCGI Approval Time: 4-6 Weeks

2. Category B:

1. India and developing countries/market locations

2. India as the only location for Proof of Concept of a drug discovered outside

3. Two Types: (1) Global (2) Local

4. Typical DCGI Approval Time = 12–16 weeks

In either case, the steps involved and timeline for review and approval have become largely predictable. Typically it takes a maximum of six weeks for a global study, with some cases taking as little as three weeks. Some studies can have their first patient enrolled within three months, with the average being not much longer than that.

[Editors Note: At the time of printing for this article, the two category system was under review and expectations are that the system will be streamlined into a single guidance, including a possible shortening of the timeline associated with India as the only location or India and developing countries as the only location for trials.]

Myth 3: There are no central IRBs and site-based IRBs don't meet often enough

IRBs in India are set up remarkably similar to those in more mature markets, especially the United States. Like the Indian regulatory process, Indian IRBs are fairly straightforward in their make-up, submission requirements, review and approval times, and their expectations.

Most IRBs are associated with and reside in an individual research center. Although they exist, central IRBs are much less common than in the United States and are often established to review clinical studies related to a small group of investigative sites who lack their own IRB. Meeting frequency of IRBs is something that any sponsor planning a study in India should be cognizant of and include in their prestudy planning. Because demand for their services is far less than what IRBs see in more mature markets, most IRBs only meet once per month, some only every two or three months. Knowing when upcoming meetings are taking place and having the appropriate documents ready for approval is critical to an on-time study start.

The composition of Indian IRBs is also similar to those in other markets. The typical number of members is around five to seven people, with a maximum range of 12 to 15. Members typically include individuals from the local medical and nonmedical community, including the following:

• Chairperson

• One to two basic medical scientists (preferably one pharmacologist)

• One to two clinicians from various institutions

• One legal expert or retired judge

• One social scientist/from nongovernment organization

• One philanthropist/ethicist/theologian

• One lay person from community

• Member Secretary

Each IRB follows a strict set of standard operating procedures and has specific requirements related to the review of any new study. Knowing these requirements and preparing properly is important, as well as being prepared to address and resolve any queries as quickly as possible. The documents and other information required for IRB approval are fairly extensive and include the following items:

• Protocol with application proforma

• Investigational sites

• Approval of the head of the institution

• Informed Consent Process (ICF in regional languages)

• Case report forms and follow-up cards

• Ethical issues

• Preclinical animal data, clinical trial data and Investigators Brochure (IB)

• CV of investigators

• Regulatory clearances from DCGI/other regulatory bodies

• Source of funds

• Financial issues

• Agreement to report SAEs to IEC

• Statement of conflicts of interest

• Agreement to comply with GCP

• Compensation plans

• Indemnification Policy

• Significant previous decisions by others

• ECs/Regulatory authorities if any

• Publication of Results Policy⁷

As Indian research sites and service providers continue to work on a growing number of studies from the United States, the number of IRBs registered with the U.S. Office of Human Research Projection (OHRP) continues to grow. Today, there are over 60 IRBs registered with the OHRP located in major cities across India (See figure 3).⁹

Figure 3. The amount of IRBs registered with the U.S. Office of Human Research Projection (OHRP) across major cities in India.

Myth 4: Indian patients are not properly consented into studies

While there are failures in the consenting process in even the most established markets, the instance of poor or lacking consent is very rare in India and the Indian government and industry have put extensive measures in place to protect patients considering or participating in a clinical trial.

For example, to protect Indian patients from becoming the testing ground for first-in-man Phase I drugs, the Indian government does not allow such studies to take place for drugs discovered outside of India. Also, before a study can be approved all study related documentation including the informed consent document is reviewed by the DCGI and by the IRB at each site. In addition to the government regulatory bodies, IRBs act as a second safeguard for patients, ensuring that the study is ethical, patients are properly informed and consented, and that patient-facing materials are translated into the applicable local languages.

In addition to these safeguards, many sponsors are now hiring contract service providers to manage the investigative sites involved in their studies, often involving the placement of a full-time clinical research coordinator (CRC) at each site to help run the study. Indian sites are very busy places, where investigators can see more than 100 patients daily and existing CRCs are often spread across studies. The addition of a well-trained CRC from an external entity helps ensure that patients get adequate face-time with study staff, they're properly consented, and that their questions are answered.

An ongoing survey of more than 900 patients by Excel Life Sciences has led to some suprising findings; it relates to patient experiences in the informed consent process and their level of understanding with regard to study expectations and requirements. The survey draws parallels to some previous surveys conducted by CenterWatch in an attempt to compare the experience of Indian patients versus the experience of patients in the United States. Two interesting findings from the survey were:

• Only 8% of patients in India made the decision to participate on their own, versus 38% in the United States.^{9, 10}

• 97% of patients first found out about the study through a physician versus just 23% in the United States.^{8, 9}

The doctor–patient relationship is still the most important driving factor in patients participating in clinical trials in India, as it was years ago in the United States. While there could be suspicion that such a tight bond could lead to coercion on the part of the doctor, the fact that patients are making the decision with the help of loved ones might help to negate any negative influence that might exist.

Essentially, there is a natural safeguard built into the Indian culture as it relates to medical care, in this case clinical research. The vast majority of patients often attend the screening visit with an attendant, typically a loved one—from a single sibling to their entire immediate family. Unmarried women and younger men will often be accompanied by both parents, and in general the family, especially the father, weighs heavily into the patients decision to participate. Therefore, the process of properly educating a patient about clinical research and the specific study often has to be tailored to the patient's needs as well as the needs of the attendant. While this can make the screening and informed consent process more challenging, it is widely felt that the commitment to participate is taken much more seriously and patients are less likely to drop out.

Myth 5: Patient enrollment is easy in India

While it is true that in many cases, enrollment rates at investigative sites in India are faster than many other markets that might be involved in a global study, there are still challenges that occur. Faster enrollment in India often results in reduced costs, meeting two major objectives of sponsor companies who place studies there. Like anywhere though, slow patient enrollment can create havoc on a study and help spiral costs out of control. That is why proper planning and study feasibility are so critical for any sponsor considering entrance into India for a clinical trial.

While most clinical trials can be conducted successfully in India, India is not the right place for all clinical trials. For example, due to prevalence rates, awareness levels, and socio-economic factors, enrollment for a prostate cancer study would typically be much easier in the United States than in India. There are many other examples like this.

One thing that has to be understood is this: A bad protocol brought to India is still a bad protocol. Throwing 1.2 billion people at the problem can certainly help, but it won't necessarily mean success. To understand which studies will enroll in India, you have to understand disease prevalence rates first. Unfortunately, India does not currently produce wide ranging information via government or industry organizations that could provide an accurate assessment of disease prevalence and incidence. Instead, a more classic feasibility must be conducted directly through the investigative sites.

Many factors including newness of some sites, cultural customs, and trust require the feasibility questionnaire to be distributed in person and information to be gathered through an interview rather than simply sending along a form via fax or email. Using an organization with personnel across the country and with good contacts at each of the sites can make the process more efficient and often result in better data.

As in the United States, enrollment projections given by Indian investigators typically need to be scaled back considerably, but often the aggregate projections are usually still much higher. Good feasibility data will also include the meeting frequency of each site's IRB and the related fees.

This hands-on feasibility process typically results in the selection of better sites. But far greater in importance is the need for ongoing support of each site to ensure faster enrollment. As mentioned earlier, site management companies are now assisting sponsors with placement of a full-time, highly trained CRC at each site to work along side the investigator, conduct chart reviews, follow-up with potential patients, conduct screenings, and help administer informed consent among other things. This type of day-to-day support is essential to ensuring the right patients are enrolled.

In recent weeks and months there has been a clamor about the need for patient recruitment support in India and companies have been entering and deploying initiatives that are not appropriate for the market culturally, reflect a lack of understanding related to overall public awareness issues, or use inappropriate, ineffective information mediums to reach patients. The truth is, that if the feasibility process is thorough, the right type of study is placed, strong sites are selected, and proper site support is provided, then patient recruitment initiatives as defined in mature markets are not necessary. When used though, patient recruitment in India is probably reflective of patient recruitment in the United States ten to fifteen years ago, largely a matter of relationship building, grassroots information distribution, and elbow grease style follow up with patients and local physicians.

A dynamic Landscape remains

India continues to evolve and change and with that comes new myths and truths to be discovered. The growth of the clinical trials industry will allow for the realities of India to unfold to a growing number of clinical research professionals. There are an ever increasing number of stories being told in the form of articles such as this one and in presentations and news coverage. The drive for faster studies is forcing the industry to span the earth at breakneck speeds and that reality will require a significant albeit imperfect education process. New service providers are springing up monthly. Companies, universities, and scientists are racing to record and chart the epidemiologic profile of India. Investors are pouring money into clinical research start ups. The number of patients aware of research and enrolling in clinical trials is expanding from north to south and from east to west. These are exciting times to be forging new paths in the world of clinical research. If nothing else, the myths associated with clinical research in India will evolve...as it does in any market where industry continues to pursue the truth to successful clinical research.

Dan McDonald is vice president of business strategy for Excel Life Sciences, Boston, Massachusettes, email: dan@excellifesciences.com

References

1. V. Kumar, Globalization of Clinical Research Trials: India—The New Frontier presented at the Israel Life Sciences Conference, Tel Aviv, Israel, February 10, 2008.

2. Excel Life Sciences estimation based on analysis of industry trade publications, newswires, and interviews.

3. D. McDonald and V. Kumar, Understanding the Realities of Clinical Trials in India: More than Patient Pools and Cost Savings, presented at the FDANews and RxTrials Institute Audio Conference, May 13, 2008.

4. CenterWatch, State of the Clinical Trials Industry 2008 (CenterWatch, Boston, 2008).

5. Parexel, Bio/Pharma R&D Statistical Sourcebook 2008/2009 (Parexel, Waltham, MA, 2008).

6. J. Wechsler, "Global Trials Draw Regulatory Scrutiny," Applied Clinical Trials, September 2008, 28-32.

7. S. Das, Ethics Committees in India: Observations & GAP Analysis, presented at the Institute for Clinical Research India (ICRI)—Bangalore Campus, Workshop on Pharmacovigilance, April 14, 2007.

8. U.S. Office of Human Research Protections, 2001, 2005, 2007, 2008 via CenterWatch State of the Clinical Trials Industry 2008.

9. D. McDonald, "First Survey Made Public on the Understanding and Experiences of Clinical Research Volunteers in India," ArticleBase.com, February 3, 2009.

10. M.J. Lamberti and D. McDonald, Thomson CenterWatch 2006 National Survey of Study Volunteer Experiences, presented at the DIA 2006 Annual Meeting, Philadelphia, PA, June 2006.