Global Clinical Trials

Global Clinical Trials – from Metro-centric to Multi-centric: A Herculean Task

Dr Umakanta Sahoo, Dr Vimal Sanghavi and Dr Arun D Bhatt give a brief review of the current scenario of clinical trials in India and the future challenges of patient recruitment

Dr A D Bhatt

Dr U Sahoo

Dr V Sanghavi

India is on the threshold of an exponential growth in clinical research business. This growth is based on India’s potential for fast recruitment of large number of treatment naive patients. However, this growth will pose a big challenge of large number of patients and the need for infrastructure and manpower. This article is a brief review of the current scenario of clinical trials in India and the future challenges of patient recruitment. Central and Eastern European countries boast of over 12,000 investigator sites, which can complete 300,000 subjects per year. India can take advantage of this opportunity if we make efforts to organise the clinical trial infrastructure for patient enrolment.

Indian Clinical Trial Scenario

India has 2-2.5 million cancer patients, over 35 million cardiac patients, 30-35 million diabetic patients and 3.8 – 4.5 million HIV/AIDS patients. These huge numbers are essentially estimates based on prevalence/ incidence rates, and do not reflect the number of patients attending hospitals.

Besides, the majority of patients – 70 per cent – are likely to be in rural areas. India has 14,000 general hospitals, of which around 150 have served as sites for clinical trials in the past. Most studies are done in academic institutions and only 30% of studies are carried out in private hospitals and clinics.

However, most global GCP trials have been successfully conducted in 20-25 public hospitals/ institutions located in 10-12 metros and class I cities. The number of allopathic doctors available in the country is around 572,000. Majority of them are graduates with no/ little knowledge about clinical trials, hence would not qualify as investigators for complex international clinical trials. The Medical Council of India (MCI) figures for number of postgraduate degree seats per year are: cardiology 75, neurology 62 and oncology 21.

Hence, in super-specialty areas, currently there are around 2500 cardiologists, 2000 psychiatrists, 500 neurologists, 500 oncologists and 400 diabetologists. In 2002, only about 5 per cent of these specialists were involved in global GCP trials.

In US, clinical research is losing its attraction for the investigators. By 2005, there will not be enough clinical investigators to handle the number of drugs in clinical development. CenterWatch estimates that against a 2005 demand for 56,000 investigators, only 48,000 will be available – a shortfall of 15 per cent.

In contrast, most Indian specialists, because of time pressure and because of ethical and scientific complexity of GCP trials, do not wish to take part in clinical trials. This situation requires tremendous efforts to attract the specialists to clinical research.

Challenge of Growth: Patient Numbers In 2002, the industry spent US $30-35 million on clinical trials, and there were 40-50 active ICH-GCP clinical trials and 200-250 investigators.

Considering 100 patients per trial, approximately 4000-5000 patients were enrolled in these trials. The 2010, projection for Indian clinical trials business ranges from US$250-300 million (CenterWatch) to US$ 1-1.5 billion (McKinsey). If we target the lower range estimates, the number of trials will need to increase 8-10 fold to 320-500, and number of patients would range from 32000-50000. At an annual enrolment rate of 25 patients, we will need 1600-2000 investigators to manage these patients. Even if the rate is doubled, the investigator number will be 800-1000.

This does not give a true picture of the efforts for enrolment of patients. We need to consider the proportion of patients 1) fulfilling the selection criteria and 2) willing to take part in the study. In randomized controlled trials, only 10-12 per cent of patients from general population are eligible to take part in the study. According to a US survey, only 13 per cent of the American patients take part in a clinical trial. A survey from JIPMER, Pondicherry suggested that about 30 per cent of the Indian subjects consent to participate in a trial.

Considering the impact of both these factors, the Indian investigators need to screen 30-fold higher number of subjects. If we want to recruit 50,000 subjects, we have to screen 1.5 million subjects. If the McKinsey estimates are considered, the number of patients will be 4-6 times larger i.e. 6-9 million and number of investigators required will be 6400-12000!

Estimates of Patient Recruitment in 2010 CenterWatch McKinsey Market Size US $ millions3001,500 Number to be enrolled 50,000250,000 Number to be screened (10 x of enrolled)500,0002,500,000 Number willing to consent (3 x of screened)1,500,0007,500,000 Investigators ( 50 enrolled patients / year)1,0005,000

Potential issues and solutions

The need to screen 1.5 million subjects suggests that the trials have to go beyond the urban metros and class I cities to smaller towns. The sponsor will have to change their strategy from metro-centric to multi-centric (small towns) trials! The sponsors have to focus on the following areas while organising clinical trials in small towns:

  • Patient population – recruitment and retention
  • Medical manpower – GCP trained investigators and clinical research coordinators, Ethics committees (EC)
  • Health care infrastructure – refrigerators, clinical laboratory, special diagnostic set up.
  • General infrastructure – electricity, air/ rail links, telecommunication, internet connectivity
  • Logistic support – central laboratory, cool chain couriers

Patient population

The available patient population in India, though huge, is highly disorganised. There are hardly any ready databases available to rapidly screen large number of patients. There is an urgent need to organise network of specialists and primary care physicians along the lines of National Cancer Institute’s Clinical Trials Cooperative Group.

About 7,925 physicians in the United States and Canada belong to these cooperative, and an additional 2,500 community cancer specialists and primary care physicians take part in NCI-sponsored trials through the Community Clinical Oncology Program. Similarly, UK’s National Health Services (NHS) and industry are developing UK Clinical Research Collaboration to increase the number of participants taking part in trials.

This collaboration, to be set up at a cost of US$ 44 million, will work in five areas- Alzheimer’s disease, stroke, diabetes, mental health, and children’s medicine. The sponsors/ CROs and institutions need to work together for such critical initiatives, which will smoothen the recruitment process. Besides, it is also essential to focus on education of society regarding the importance of clinical trials in drug research and health care, so that potential subjects develop positive attitude about taking part in clinical trials.

Medical manpower

Identifying and attracting potential investigators is the biggest challenge, requiring innovative approaches. As there are not adequate number of specialists in small towns, the sponsor will have to depend on non-specialist general physicians. One approach will be to select a metro town specialist as the principal investigator (PI) and the surrounding small town physicians with interest in the specific therapeutic area as the satellite site co-investigators.

The PI can guide these co-investigators in key aspects of selection, recruitment, follow-up and adverse event reporting and also train them in GCP and clinical research. Use of new technologies – telemedicine, web-based workshop- could help obviate the problems of distance and time. Another vital area is establishment of ECs.

According to an ICMR survey, there are about 200 ECs in Indian hospitals. ICMR is making efforts to educate and train ECs in all major hospitals. Till such time that all potential sites have their own ECs, we will have to depend on independent ECs to approve and oversee the clinical trials in small towns. This role can also be played by the EC of the PI’s institution. Another option is to have a National Ethics Committee, which could give overall approval to a large multi-centric trial and provide support to small institutions lacking EC infrastructure.

Healthcare infrastructure

Today’s multi-centric trials demand a whole range of tests and procedures. Hospitals in smaller town/ cities may have the facilities for standard care, tests and procedures, but may not necessarily have all the ultra modern equipments to support the clinical trial requirements. Some of the small towns like Cuttack have centers dealing with special conditions e.g. cancer.However, they may lack equipments to perform the crucial tests for a clinical trial. eg bone scan. If this is an essential requirement for the trial and can be managed by sending the subjects to the nearest center for test, then such centers may be considered. It is also likely that in next five years many small towns would develop such facilities in private or public hospitals and would be equipped to handle global trials.

General infrastructure

This is one of the many decisive factors in identification of the site. Most of the towns and smaller cities are not well connected by air. Monitoring costs increases if travel time is increased due to unavailability of the proper air link. However, the scenario is expected to change, as the market competition will force airline companies to cover small towns.

Similarly, in a few years, increasing telecommunication and Internet connectivity will cover most small towns. However, irregular electric supply can be a major issue when the trial requires the drug/ lab samples to be stored in refrigerator for a long period. The sponsors may have to depend on special couriers to handle such situations.

Logistic support

Central laboratory services form another key element in conduct of clinical trial. If the trial requires sending samples to a central lab outside India, then the issues of sample storage and timely shipment will be of paramount importance. In such a situation, the sponsor may be forced to avoid a town with limited air links. The recent news of NHS UK considering SRL Ranbaxy for analyzing samples of British patients, suggests that in future, India is likely to be a location of a central lab. This will also encourage opening of several such central labs in collaboration with global CROs. There are several labs, which have collection centers in many cities. However, they will have to cover many smaller cities and be ready to organise themselves to meet the challenges of multi-point logistics – sample collection, storage and desired reporting in time to become central labs.

Courier service providers also play an important role in conduct of the clinical trial. One important document lost in the transit may create a lot of hassle for the clinical trial. In some trials, there is a need of a specialized courier to handle transportation of clinical trial material under controlled temperature conditions. The specialised couriers will have to gear up to meet this challenge.

Conclusion

India’s market potential in clinical trials depends on the potential for fast recruitment. This potential can only be realized if we recognize the challenges of recruiting large number of patient, investing in training of medical manpower, the need for adequate medical and general infrastructure, and necessity of improving logistic support.

Dr Umakanta Sahoo Project Manager usahoo@clininvent.com Dr Vimal Sanghavi Medical Adviser vsanghavi@clininvent.com Dr Arun D Bhatt President arunbhatt@clininvent.com ClinInvent Research Pvt Ltd Mumbai