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(Clinical) Trials and (Regulatory)Tribulations

Unless the regulatory system of India rise to the occasion by being transparent and efficient, the country shall fail to seize the opportunities in clinical trials, says Dr Arun D Bhatt

In recent years, India’s potential as a major hub of international clinical has been recognised. The advantages of large patient pool of treatment-naive patients, well-trained investigators and reduced trial costs have made international pharmaceutical companies and contract research organisations (CROs) look at India favourably. In a regulatory situation where it takes 10-15 years and $500 million to develop one new drug, each day’s delay in obtaining an approval can result in a loss of over $1.5 million for the sponsor. Hence, their major requirement is rapid initiation and timely completion of clinical trial. One of the biggest hurdles in the clinical trial plans is uncertainty and time to obtain regulatory permissions. If the regulatory system of a country is not transparent and efficient, the international trials will go to other countries. Is our regulatory system responsive to this need?

Regulations in developing countries

A review undertaken by the Association of the British Pharmaceutical Industry in 2000 showed that most European countries have a two-step process for clinical trial permission -- Ethics Committee (EC) review and Health Authority (HA) review. (Table 1). Some countries require EC approval prior to HA approval while some others permit parallel processing of clinical trial application by both. The range of time for EC approval varies from two weeks in Finland to 12 weeks in UK and time for HA approval ranges from five days in Australia to 60 days in Italy. The overall time for both EC and HA approval ranges from 6-12 weeks. In France and Belgium there is no formal HA approval. In these countries, a sponsor after obtaining EC approval can initiate trial after notifying the HA with a letter of intent.

The UK has four-step process with a total time of 10-12 weeks for approval and is considered one of the slowest countries in Europe and world. There are concerns that UK is losing her competitive edge because of a slow clinical trial approval process.

In USA, an Investigational New Drug (IND) application goes into effect 30 days after FDA receives the IND, unless FDA notifies the sponsor that the investigations described in the IND are subject to a clinical hold. The IND can also begin earlier than 30 days, if FDA notifies the sponsor that the clinical investigation in the IND may begin.

Situation in Asia

In most Asian countries (Table 2), HA and Institutional Review Board (IRB) approval for protocol takes about three months. It is usual to obtain IRB approval followed by HA approval, a process that usually slows timelines. In Singapore this sequential process takes only three months. Philippines, Indonesia, Taiwan and Malaysia allow parallel submission to IRB and HA. However, the HA approval is dependent on IRB approval. Until recently, the protocol approval in Taiwan could take longer than six months. Taiwan has made significant efforts to reduce the time for protocol approval to attract international clinical trials.

Indian scenario

No official Indian survey of time for HA approval is available. Informal discussions with sponsors and CROs suggest a range from 4-6 months. Some claim to obtain approval in two months time. However, such short timelines are exceptions. Sometimes an international MNC turns to India, when the global trial is close to completion and it has not been able to recruit adequate number of patients. The challenge for the local subsidiary is to recruit patients within a short time of 4-6 months. As the HA timelines in our country are longer and unpredictable, the local subsidiary is unable to accept such a project. This means a loss of opportunity for India to participate in international trial!

The companies embarking on new drug research have complained about delays in getting approval for phase I. The timelines for approval have been 5-8 months or longer. In a world where international competition can get a phase I approval from USFDA in just 30 days, such delays are costly for these Indian companies! Most of the sponsors are concerned about uncertainty of the timelines, as it could take much longer than six months. There are hardly any technical queries from HA authorities on the protocol.

Most often the applicant receives some administrative queries or is asked to fulfil new requirements that are not part of Schedule Y or any other regulatory guidelines. If the HA authorities seek opinion of external experts or ICMR on the protocol, the timelines become much longer and unpredictable. The applicant dreads this scenario and makes all efforts to avoid this situation!

In 1999, the Pharmaceutical Research and Development Committee headed by Dr Mashelkar commented on this issue as follows:

‘‘Applications submitted to the DCG(I) for permission for clinical trials in respect of new drug applications (NDA) and abbreviated new drug applications (ANDA) are often referred to outside agencies like the Indian Council of Medical Research (ICMR) and the Department of Biotechnology, Government of India (DBT) for review. This arrangement often leaves very little control with regard to the time runs.’’

Besides HA approval, the international applicant also needs licence to import clinical trial samples and permission from Directorate General of Foreign Trade to export blood samples for analysis to a central laboratory. The EC approval can take from 1-3 months. However, some ECs review the application only after the HA permission is given. This means that a clinical trial can start in India almost 7-9 months after the protocol is submitted to HA and EC. This is criminal waste of time as globally acceptable approval time for clinical trials is just 3 months! Our regulatory system needs to change to meet this goal!

Potential long term solutions

There is a need to bring Indian regulatory system in line with international agencies. The Pharmaceutical Research and Development Committee has made several recommendations in 1999 to revamp the regulatory system. Some of the recommendations are:

• In order that the applicant is enabled to complete the investigations in the shortest possible time, it is imperative that adequate infrastructure for fast track clearances is created in the Central Drugs Standard Control Organisation (CDSCO).
• CDSCO is required to carry out multifarious functions but expertise in technical, administrative and vigilance functions is not sufficient. Full-time experts must be there with CDSCO for timely evaluation of the papers submitted by the parties
• The DCG(I) should have under his direct supervision a number of divisions/departments with officers and support staff adequate and competent for the job
• Full-time experts in key areas with adequate scientific and medical expertise and back-up support should be made available to the DCGI
• Responsibility and accountability for the decisions and their timeliness must rest on the shoulders of the DCG(I) and/or the divisional or departmental heads
• On a priority basis, the office of the DCGI should be provided with electronic networking nationally and internationally to facilitate and expedite decisions
• A time schedule for processing of application for different stages of clinical trials should be developed and made known by the DCGI along with the fees to be charged for different stages. Most HA in Asia have their own website and information regarding their policies and guidelines are available electronically. In contrast there is no website providing access to our regulatory agency!

The committee recommended a time-frame of one year to revamp and modernise the CDSCO. In spite of above recommendations, there does not seem to much progress in the direction of making our regulatory system efficient and transparent!

Alternative strategy

The above changes are desirable but are unlikely to happen in near future. There is a need for an alternative regulatory process to approve the clinical trials in a reasonable time of three months or less. In Asia, Taiwan and Malaysia have improved their HA system to complete the approvals in three months time. Our HA authorities can follow the system in other Asian countries and developed nations. The sponsor should submit the clinical trial protocol with approval letter of 1 EC. Based on this, the HA authorities could give their approval in two weeks. With this approach, the overall process of protocol approval is unlikely to exceed three months. This will make India an attractive country for clinical trials!

The Dream From Report of the Pharmaceutical Research and Development Committee, 1999: Here’s what the Economist may write on August 15th 2004 on India’s remarkable turn around Regulatory framework, ‘‘The most spectacular development has been the establishment of a professionally managed and transparent regulatory framework that competes in processing time with the best in the world.

A grand new steel and glass building heavily populated by computers gets approvals moving quickly and efficiently. The approval time has recorded a remarkable fall in the no of days to approval from two years to 30 days.’’

Will this dream (of efficient regulatory system) be fulfilled or the current nightmare (of regulatory unpredictability) will continue?

The writer is consultant, Pharmaceutical Medicine & Clinical Pharmacology. Email: arun—dbhatt@hotmail.com