Introduction:
The Clinical Research industry in India is about a decade old. The business has however gained momentum in the last three to four years. Now that India has subscribed to the TRIPS agreement and recognizes product patents, it is expected that the effect of this will be that the multinational industry will be more inclined to conduct clinical trials here, as the level of protection from generic copies has increased. This development should also stimulate more innovation within India’s own pharmaceutical industry as new molecules discovered will be protected.
The clinical research industry is touted by experts to be the next big outsourcing boom. The potential and pitfalls of India as a favored clinical trial destination is the subject numerous discussions in the Pharmaceutical and Clinical Research fraternity. Most articles on the subject focus on how India is an irresistible target for the Pharmaceutical and Biotech industry to conduct clinical trials.
Of course, not everyone shares this enthusiasm. Critics warn that venturing into India may be a risky prospect for Sponsors fraught with ethical issues. I shall however steer clear of this debate and attempt to provide via this article the framework within which clinical trials in India are conducted. I hope it will serve as road map to sponsors who are possibly - with much trepidation - considering taking the plunge and finding out if India truly lives up to its claims.
The key areas of concern to the foreign Sponsor while considering performing clinical trials in India are 1. Regulatory procedures 2. Functioning of Ethics Committees3. Informed Consent process4. Quality of Investigators5. Hospital Infrastructure
I have provided below a summary of each of these areas and attempted to highlight the difference in procedures as compared to those in the west.1. Regulatory Procedures: The Central Regulatory agency known as the DRUGS CONTROLLER GENERAL (INDIA) or the DCGI is responsible for all procedures related to New Drugs including Clinical Trial Application, Registration, and Import & Export.
All clinical trial applications are submitted to the DCGI office for approval. The documents required as part of the clinical trial application are detailed in Form 44 under Schedule Y of the Drugs and Cosmetic Act. Permission to conduct trials is granted in approximately 3 months from the time of submission. The approval process takes longer if the DCGI’s office decides to refer the application for expert feedback to agencies such as the Indian Council of Medical research (ICMR). If the drug falls under the category of “genetically engineered” or “biologics” then the application is passed through to the Department of Biotechnology (DBT) and is reviewed by the Genetic Engineering Approval committee (GEAC). This approval process usually take anywhere between 5-6months.
As per current regulations, Phase I trials for molecules discovered “outside” India are not permitted. Exceptions are made only when the drug being tested is of “relevance” to the health problems in India or if it is a repeat phase I study. Phase II and Phase III trials can be conducted in parallel with the trials in the rest of the world as long as data from earlier phases is submitted with the application.
Along with the clinical trial application, an application for Import License is made by completing Form 12 of Schedule Y. The application should accurately quantify the drugs imported accompanied with appropriate justifications for the quantities imported. An import license number is issued about 2 weeks after the clinical trial approval is provided. This import license number should appear on all the individual subject drug supplies.
If biological samples need to be shipped out of India, an application for export needs to be made to the Director General of Foreign Trade (DGFT)
The Central Drugs Standard Control Organization first issued the Indian Good Clinical Practice (GCP) guidelines in year 2001. These guidelines were subsequently amended and made the law in the year 2005. Not many countries can boast of this achievement. These guidelines can be readily downloaded from the website cdsco.nic.in.
There are also elements in Indian GCP that are not included in other GCP Guidelines, these include the following:
Research on Special Groups (Paediatrics, or Pregnancy),
The role of a foreign sponsor. A foreign sponsor may hand over responsibility to a CRO, and this transfer of responsibility must be documented. However, the sponsor is ultimately responsible for the drug and the trial
Clinical Trials on vaccines, contraceptives, surgical procedures/medical devices, diagnostic products and herbal remedies.
The Guidelines also include specific details about the format for submitting data for rDNA based vaccines, diagnostics and other biologicals.
Indian GCP is modified in the following sections in comparison to ICH-GCP:
Protocol- QC/QA methods, Finance and Insurance
Ethics Committee- Composition
Informed consent
Compensation for participation
Sponsors need to be aware of each of these differences and ensure adherence to Indian guidelines at all times.
2. Ethics committees: Almost every large hospital in India has an Institutional Ethics Committees attached. These committees are formed in line with requirements of the GCP guidelines. Submissions for approvals are made as per the format requested by the Ethics Committee. At a minimum, the documents submitted to committee are Protocol and Investigator Brochure including all amendments, Informed Consent Forms along with translations as well as details of payment or compensation to subjects, if any.Approval is received in maximum of six to eight weeks following submissions. Most ethics committees usually charge a fee of approximately 200 US$ or 170 Euros. Some ethics committees chose to provide conditional approval until regulatory approval is received. Once regulatory approval is received, a full approval is provided in a matter of few days.
In a reflection of the increasing number of clinical trials being performed in India, several Independent Ethics Committees have begun functioning in the last couple of years. Sponsors usually approach the Independent Ethics Committees when they need to work with potential investigators with a private practice that not attached to a Hospital or Institution
The regulatory and Ethics Committee approval process usually takes place in parallel. However, some Sponsors prefer to provide at least one Ethics Committee approval at the time of submitting the application to the regulatory authorities.
3. Informed Consent Process: Ever since the recent BBC documentary on clinical trials in India, the issue of informed consent has come under even more scrutiny than ever before. The “guinea pig” theory has been widely discussed in the national media as well. Illiteracy as well as the possibly blind acceptance of the doctor’s advice amongst semi-urban and rural populations naturally raises sponsors’ concerns about how truly “informed” the informed consent process is in India. A recent issue of the journal CRFocus published by the Institute of Clinical Research carried an article on this very topic. The authors who are auditors and have audited studies all across the globe concluded that that the informed consent process carried out in India is probably as good or bad as anywhere else in the world.
Most clinical trials are carried out in urban and semi-urban areas where the population is generally literate. India has a population of over 1 billion, and there are many languages spoken throughout the country. One source I found listed 387 living languages! The informed consent and patient information leaflet therefore need to be translated into the local languages.
Any informed consent document is translated into a minimum of at least 8-10 regional languages. Being a multi-lingual society, most site staff are conversant with the languages in which the Informed Consent Document is provided to the site. The Informed Consent Document is always explained verbally in a regional language the subject is most comfortable with. In cases where the subject is illiterate, the subject is asked to return with a relative who is literate and can serve as the Legally Acceptable Representative during the informed consent process. If the subject is illiterate, a thumbprint impression is obtained in the Informed Consent Form; it is also accompanied by signatures of the Legally Acceptable Representative, an independent witness and the site staff conducting the entire informed consent process. As per the Indian guidelines, the subject can refuse to allow his biological material to be stored and used for future evaluations. The Indian GCP guidelines clearly define the content and format of the Informed Consent document and must be adapted for all clinical trials being performed in India.
4. Investigators: India has the second largest pool of qualified doctors, (after the USA) and probably over 500 investigators who have been GCP-trained and have the experience of participating in clinical trials. It is anticipated that India will need to double this figure in the next 2 years in order to deal with expected load of clinical trials to be performed in India.
Sponsors and CROs will invariably have to expand this database by approaching investigators who lack GCP awareness or have no prior experience. However, based on my personal experience these novice investigators more than make up for their lack of knowledge and experience with sheer enthusiasm and commitment and have been known to perform as well if not better as the sites with experience.
In any case, most sponsors ensure that the investigator and site staff undergo basic GCP training prior to the start of a study. Doctors in India are very well conversant in English and familiar with the standards and practice of Western Medicine. Besides the obvious financial reasons, an opportunity to participate in global trials, possibilities of authorship in journals international repute as well as the ability to provide patients with free treatment are some of the driving factors for investigators to participate in clinical trials.
Access to latest treatment options and generous grant by sponsors by way of expensive equipments are compelling reasons as well.
5. Hospital Infrastructure: Most hospitals and Institutions have the minimum requirements necessary for a clinical trial to be undertaken. Specific equipment required for the study is usually provided by the sponsor and remains at site post-study as an institutional grant. Based on the requirements of the study the sponsor may need to provide the site with necessary equipment such as a refrigerator or deep freezer. At a minimum, a cupboard to store the study documents exclusively is requested by most sites.
In most hospitals, patient records are maintained with the medical records department. During the course of the study, these records are maintained with the study staff for the sake of convenience. Following the closure of the study, the original source documents are returned to the medical records department and photocopies of the source documents are placed with rest of the study documents such as Case Report Forms and Informed Consent document. These documents are not archived in the true sense of the word but rather stored in a secure locked metal cupboard for the required duration.
As opposed to the norm in the west, the pharmacies in the hospital do not play any role in the management and dispensing of study drug supplies. This activity is always managed by the study staff.
In general, the privately owned and run hospitals are better equipped as compared to government-run hospitals. However, it is the government hospital, which receives the bulk of the patient population. Sponsors should aim for careful balance of private, semi-private and government institutes while choosing sites in India.
With data generated to GCP standards, the quality of clinical trial data generated in India is on par with the rest of the world. The US FDA last year successfully audited two sites in Southern India and reported no serious findings. Clinical trials outsourced to India have so far performed well. The need of the hour is a collaborative effort the by the industry and regulators to position India as a global player in the field by ensuring quality in every aspect of clinical research.
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