COUNTRY FOCUS: INDIA

India’s place in the global
clinical development sector

Dr Nermeen Varawalla, PRA International

More pharmaceutical and biotechnology sponsors than ever before consider India to be an attractive location for conducting international clinical trials. Motivated by India’s potential to enrol large numbers of study participants, with data quality of an internationally acceptable standard, in a cost effective manner, international sponsors are keen to include India in their multi-country trials. This has resulted in a striking growth in the number of international clinical trials being carried out in India.

At the present time there are 240 international studies in India recruiting subjects which represents 1.2% of the total studies worldwide. A year ago 172 international studies were recruiting subjects in India, equivalent to 1.5% of the total studies worldwide. From a worldwide perspective, India’s contribution to global clinical trial activity is limited, however, there has been a 40% increase in clinical trial activity over the past year.

Currently there are about 350 investigators in India who are engaged in clinical trials intended for FDA submission. This represents a 49% increase over the past five years in the numbers of physicians in India participating as investigators in international clinical trials (Tufts CSDD Analysis of FDA’s Bioresearch Monitoring Information System File, 2007). It is estimated that 40,000 subjects from India have participated in international clinical trials to date. The above data portrays a nascent sector enjoying rapid growth from a low denominator, in response to relatively recent and escalating global interest.

Fundamentals Attractive to Sponsors

The fundamentals to support swift, meticulous and cost effective global clinical trial conduct in India have been in place for a long time. India’s large population with high prevalence of diseases of both the industrialised and tropical world forms a tremendous pool from which clinical trial subjects may be recruited. It is worth noting that it is the 350 million individuals residing in metropolitan India who predominantly form the population base for clinical trials. The lifestyles and healthcare practices of this group are more similar to urban populations in other industrialised countries than that of their compatriots in rural India.

India’s urban centric healthcare system comprising of both state subsidised and private healthcare offers investigative sites with much potential for clinical research. Hospitals in India’s cities and large towns, be they state managed, single specialty units or part of corporate healthcare groups, have the required patient attendance, motivated staff and equipment to serve as high performing clinical trial sites. India’s 500,000 English speaking physicians form a solid base from which clinical trial investigators may be recruited; however, only a fraction have the attributes to serve as investigators for global clinical trials. The number of GCP trained physicians keen to participate in global clinical trials is increasing. These physicians are IT savvy, often have completed their post graduate training in the USA or UK and hold appointments at hospitals well suited for clinical research.

Clinical trial sites in India have the ability to be more efficient in that they have the potential to recruit larger numbers of patients per site with relatively fewer sites being non or low recruiters. This enables a higher degree of operational effectiveness as more value is gained from every site visit – the most resource consuming aspect of a clinical trial – as monitors have the opportunity to review larger volumes of clinical data.

India offers the opportunity for up to 40% savings of clinical trial costs as compared to North America. Keeping in mind the labour intensity of clinical trial execution, lower labour costs for clinical operations personnel account for a substantial proportion of these cost savings. In addition there are lower costs for domestic travel and support services. Investigator fees in India are about 30 - 40% of those in the US and Western Europe.

However, it must be noted that rising staff costs and investigator expectations for higher grants are increasing the costs of clinical trial conduct in India. Whilst computing the costs of clinical trial conduct in India it is important to recognise the costs of training. In view of the nascent clinical trial environment, staff experience is limited and provision of intensive training is a pre-requisite. Training costs could include global travel for trainers and trainees, a reflection of the fact that global organisations seeking to build capabilities in India have realised the importance of investment in training to an international standard. Recent developments have addressed some of the concerns that international sponsors have about regulatory approval timelines, acceptability of clinical data and enforcement of Intellectual Property (IP) protection. This has contributed to the accelerated pace of growth being enjoyed by India’s clinical trials sector.

Regulatory Environment

India’s regulatory authority – the Drugs Controller General of India (DCGI)-has made good progress in streamlining the regulatory environment in India over the past few years. Regulatory approval times for obtaining permission to conduct clinical trials in India have reduced from 16 to four weeks. Furthermore, the uncertainty related to the approval process and timelines has been reduced. Hence, provided the prescribed approvals process is meticulously followed with careful compilation of the submission dossier, unexpected delays are becoming infrequent.

In early 2007, the DCGI implemented a step change in its processes, in that applications which have received regulatory approval or in selected cases, ethics committee approval from either of the US, Japan, UK, Switzerland, Germany or France, qualify for a “Track A” approval that could be obtained within four weeks. Such a fast track application needs to be supported by sponsor affidavits stating that the trial is ongoing in other regulated countries and that there have been no serious adverse effects requiring the trial to be withdrawn. Applications that are unable to meet these requirements fall in to the “Track B” category where the approval times can be as long as 16 weeks. The DCGI continues to refuse applications to conduct first in man studies in India unless the originator of the study molecule is an Indian company or a case can be made why development of that particular molecule would be particularly beneficial for India’s healthcare requirements.

Data Quality

Over the past five years clinical data from India contributing towards pivotal global clinical trials has been accepted by the FDA and EMEA on numerous occasions. The increasing volumes of data from India being submitted to the FDA prompted its first audit in India in 2005. Two clinical sites participating in a global study for an anti-infective were audited with no actionable findings. Since then further FDA audits have taken place, as yet none of the audits have passed the dreaded ‘OAI’ – Official Action Indicated – verdict.

All stakeholders in India’s clinical development sector, including the government, industry players, investigators and sites have realised the critical importance of data quality. To address this, numerous training initiatives have been implemented. These include sponsor delivered study specific training, formation of training institutes and a focus on “on the job” training delivered by sponsors and CRO s to their own and site related staff.

IP protection

Legislation to enforce IP protection of product patents in accordance with WTO standards, including TRIPS, was passed by the Indian Parliament in January 2005. However, Indian patent laws deny protection to drugs patented before 1995 or that are deemed to be modifications or new formulations of old medicines. Examples of such modifications include improved drug delivery mechanism, new isomers or alternate formulations. A government select committee has recommended to Indian Parliament to grant clinical data exclusivity for five years for pharmaceutical products. This is almost certain to be adopted within national law. India’s domestic generic pharmaceutical industry is visibly adapting to the evolving IP environment.

The ruling of the Chennai high court in August 2007 that dismissed the challenge from Novartis regarding dismissal of its product patent for imatinib mesylate (Gleevec) has attracted substantial international attention.

Via this ruling India has clearly declared its intention to adopt a patent regime that enables the country to meet its aspirations to ensure inexpensive access to medicines by prohibiting “evergreening” of patents, in keeping with the spirit of the WTO TRIPS agreement. India has demonstrated that is does have an effective legal process for patent grant, review and challenge; however, it has set a different – perhaps higher-standard of patent law for itself. International sponsors choosing to conduct clinical trials in India will be those who conclude that advantages of doing so outweigh the possible disadvantages of operating in a research and commercial environment with a higher bar to secure for a product patent.

Ethical Framework

The nascent clinical trial environment and marked disparity in access to healthcare resources has caused concerns about the robustness of the ethical framework within which global clinical trials are carried out in India. There have been concerns about the informed consent process, more so in view of the numerous languages spoken by the potential subject pool. As investigators play a critical role in ensuring the sanctity of the informed consent process, attention to their selection and management is very important.

Individual physicians, medical institutions and the state are keen for India to attract its share of global clinical trials as they believe that this will enable Indian patients access biomedical innovation as well as improve overall healthcare standards by emphasising the value of evidence based medicine, record keeping and patient communication. It is this belief that dismisses the notion that clinical trials are exploitative and promotes development of a GCP compliant ethical framework for clinical research.

Recognising the importance of a robust ethical framework for clinical research in India the ICMR (Indian Council for Medical Research) has set up initiatives to review the functioning, provide training and introduce an accreditation system for Ethics Committees. Furthermore, the DCGI has formally prescribed the roles and responsibilities of Ethics Committees, their composition and the format for their approval letter. Thus although the ethical framework for clinical trials in India remains an issue of concern it is reassuring that the various stakeholders are cognisant of this and seek to address the issues.

Staffing Paradox

The brisk growth of the Indian clinical development sector has resulted in a competition for trained and experienced resources. A paradox – since one of the key attractions of India is its large pool of English speaking, IT literate biomedical graduates. However, rapid growth from a modest base is causing an industry shortage of trained and experienced resources, particularly clinical trial monitors, project managers and site co-ordinators. This supply-demand imbalance has led to high staff turnover and rising compensation expectations.

The pool of suitable and keen graduates does exist to fulfill the needs of this resource intensive sector; however, time and patience are required as new entrants get trained and accumulate experience. Numerous programmes have been set up to provide training to biomedical graduates seeking to develop a career in the clinical development industry. These include degree courses established in collaboration with overseas universities; diplomas from institutes set up as collaborations between academia, the state and industry; sponsor and CRO delivered training – both “on the job” as well project related. In addition the increasing number of trials being conducted in India is expanding the resource pool with exposure to the conduct of international clinical trials. However, it will take some years to achieve a steady state between the available resource pool and industry demand.

Meanwhile employers seeking to attract and retain skilled resources must implement measures to differentiate themselves from their competitors. This challenge is a familiar one for global CRO s who also face resourcing challenges in the clinical development “hotspots” of the US and Western Europe. Not surprisingly the recipes for success are similar, namely, career development opportunities, work-life balance and generous compensation. Employers in India who are able to offer their staff superior career development, through training in international best practices, a global working environment and the opportunity to work on global clinical studies with innovative products, are at a distinct advantage.

Capacity Constraints at Investigative Sites

In view of India’s nascent clinical trial environment, investigators play a critical role in that they not only enable access to trial participants but also are custodians of the data’s scientific and ethical integrity. It is the investigator who provides leadership at the site and ensures that subjects are recruited, the protocol adhered to and data collated in a GCP compliant manner, in keeping with sponsor expectations.

Although there is still relatively limited competitor trial activity in India, this is rapidly changing at “first tier” sites that have developed experience and a track record. These sites are becoming increasingly busy with participation in numerous trials. Expectedly clinical sites with high potential to contribute subjects are those with heavy clinical workloads. In such a busy clinical environment dedicated resources to support clinical research are usually limited. As a result sites experiencing capacity constraints are hindered from delivering subject enrolment and the clinical data quality they could be capable of. Support at the site level by dedicated, trained resources either employed by the site or by a site management organisation is most valuable and is now being provided by most sponsors. Furthermore, there is a need to develop additional site capacity at “second tier” clinical sites. Often these sites are located within smaller cities – still large by most standards, with populations of around two million. They also provide healthcare services to populations from surrounding rural and semi-rural areas. Initiatives to train potential, often keen investigators based at these sites, allocation of funds for infrastructure and resources and a commitment to grow such a network of investigative sites will contribute to the development of much needed site capacity.

Although a tiny fraction of the population has private medical insurance, this segment is rapidly growing fuelled by an increasingly affluent middle class – estimated to be 300 million strong. To meet the healthcare needs of this segment corporate hospital groups are developing national, regional and local hospitals. These newly established and well furbished hospitals are keen to attract international clinical trials and to do so are investing in setting up clinical research secretariats to address the administrative and contractual requirements as well as hotel style beds to lodge clinical trial subjects and their families during their follow up visits. The motivations for this are not only grants and additional resources but also the associated kudos that will attract the more sought after physicians to be associated with these institutions.

Global Data Management

In recognition of India’s leadership position within the IT and business process outsourcing space, off-shoring global clinical data management to India is now considered to be a proven approach for sponsors seeking to reduce clinical development costs. The fundamentals to support efficient, high quality and cost effective global clinical data management, namely, the skilled workforce and IT infrastructure, have been in place for over a decade in India. In order to leverage this, both sponsors and CRO s have established data management capabilities in India and over the years have progressed from simply data entry services to programming, statistical analysis and medical writing.

Numerous successful business models have been established to achieve this, that include outsourcing in a piecemeal, project-by-project fashion; long-term functional outsourcing and building capabilities within the local operating companies of multinational pharmaceutical sponsors. The leaders in the field have built units with a few hundred resources working in multiple shifts thereby proving the efficacy of each of these business models.

Sponsors have deployed electronic data capture at Indian clinical sites with positive results. Indeed, not having to overcome legacy issues arising from previous experience with paper studies has been distinctly advantageous. Furthermore, large IT and business process outsourcing firms have muscled in on the Indian clinical data management space and secured multi-million dollar, long-term contracts with some of the world’s largest pharmaceutical sponsors that seek to outsource and off-shore clinical data functions to units in India staffed with many hundred resources. A variety of business arrangements have been struck to manage these ambitious contracts that seek more than cost savings, as sponsors have been promised business process innovation and transformation as well. Separating the global clinical data management function in this manner could well create opportunity for efficiency and process innovation; however, it remains to be seen how the interface with clinical operations will be effectively managed.

Conclusion: Globalisation Imperative

In order for global clinical development businesses, be they sponsors or CRO s, to successfully establish operations in India they will need to marry their international expertise, processes and systems to local knowledge, relationships and insights. Expertise and processes able to deliver clinical data to meet the requirements of international regulatory bodies is not enough for the successful inclusion of India within a global project. Understanding local healthcare practices, familiarity with India’s regulatory and bureaucratic processes and relationships with sites and investigators are equally essential.

Having made the investment to combine both the global and local pre-requisites as well as develop managerial, infrastructure and operational capabilities in India, organisations need to develop a culture able to translate the fruits of the “global-local marriage” to customer value, employee satisfaction and competitor advantage.

Dr Nermeen Varawalla,
PRA MD, DPhil (Oxon), MBA

Dr Nermeen Varawalla is Vice President, Investigator Relationships, Scientific and Medical Affairs, for PRA International. She contributes to the growth of PRA International’s operations in emerging countries with a focus on Asia. PRA International is a global CRO with 2,800 employees, covering 68 countries in all six continents. Nermeen is recognised to be an industry expert in the utilisation of emerging world countries for global clinical trials and has established PRA’s capabilities in Mumbai and Pune, India.

Dr Varawalla is well conversant with the Indian biomedical sector and in her capacity as Chair, OperationIndia, serves as an advisor to international organisations with an interest in the sector. Prior to joining PRA, Nermeen was the founder of PerinClinical, a niche India focused CRO. Before that she worked with Accenture’s Health & Life Sciences Business Consulting Practice in London. At Accenture, she specialised in drug development and has worked with pharmaceutical and biotechnology companies on drug development strategies, processes and systems.

Nermeen received her medical training at the KEM group of hospitals, Mumbai, India. She was awarded the Rhodes Research Fellowship to the University of Oxford where she conducted her doctoral research in Molecular Genetics. Nermeen practised as a specialist at two of the UK’s leading NHS Hospitals. She then obtained her MBA at INSEAD.

Dr Nermeen Varawalla
Vice President, Scientific and Medical Affairs
PRA International
Pacific House, Imperial Way
Reading,
Berks
RG2 0TD, UK
Email: varawallanermeen@praintl.com
Website: www.praintl.com

back