Clinical trials are a set of practices performed to certify a new drug molecule as safe to be used. Rule 122 DAA of Drugs & Cosmetics Rules, 1945 (“D & C Rules”) defines clinical trials as a “systematic study of new drug(s) in human subject(s) to generate data for discovering and/or verifying the clinical, pharmacological (including pharmacodynamic and pharmacokinetic) and/or adverse effects with the objective of determining safety and / or efficacy of the new drug”.
Several factors have led to emergence of India as a preferred and sought after destination to conduct clinical trials. Some of the key factors are: (i) availability of a large and diverse population; (ii) availability of highly trained physicians, nurses and technical personnel; (iii) world class medical facilities; (iv) good information technology infrastructure; and (v) strong Intellectual Property Rights environment.
Until recently, very few clinical trials were conducted in India due to regulatory restrictions faced by foreign pharmaceutical companies. However, the Government of India (“GoI”) has realized the potential benefits of conducting clinical trials in India and has amended various provisions of the Drugs and Cosmetics Act, 1940 (“D & C Act”) in 2005 to ease the regulatory restrictions and facilitate clinical trials. For example, the amendments define the term ‘clinical trials’ as well as prescribe the procedure of conducting clinical trials. In addition, the amendments outline responsibilities of sponsors, investigators and the Ethics Committees and has provided guidelines and procedures for the import of drugs for clinical trials into India.
In addition to the D & C Act, the Medical Council of India Act 1956 and the Central Council for Indian Medicine Act 1970 also regulate the conduct of clinical trials in India. The Indian Council of Medical Research (“ICMR”), the apex regulatory body which regulates clinical trials in India, was set up in order to promote research culture in India and improve and develop the infrastructure for clinical trials.
To conduct clinical trials in India, approval from the Drugs Controller General of India (“DCGI”) is mandatory. Before the DCGI could approve companies to conduct clinical trials in India, it is compulsory for applicant companies to comply with the requirements for registration as provided by the ‘Pharmaceuticals for Human Use’, ‘International Conference on Harmonization’, and ‘Good Clinical Practices’. Based on the approval process of the DCGI, clinical trials are categorized into two types:
ICMR issued the ‘Policy Statement on Ethical Considerations involved in Research on Human Subjects’ in 1980 and thereafter revised this Policy Statement in 2000 and renamed it as the ‘Ethical Guidelines for Biomedical Research on Human Subjects’ (“Ethical Guidelines”). D & C Act and Medical Council of India Act, 1956 provides that all clinical trials in India must be conducted in compliance with the Ethical Guidelines.
The Ethical Guidelines require that all the research involving human participants must be conducted in accordance with four ethical principles including (i) respect for the participant; (ii) beneficence; (iii) non-malfeasance; and (iv) justice. Certain relevant provisions of the Ethical Guidelines are discussed below:
There is a general and positive duty on all persons conducting, associated or connected with any research entailing the use of a human participant to ensure that both the letter and the spirit of these guidelines, as well as any other norms, directions and guidelines which have been specifically laid down or prescribed and which are applicable for that area of research are complied with.
Apart from the aforementioned general principles, the Ethical Guidelines also provide for specific principles/guidelines to be followed while conducting drug trials, vaccine trials, trials on medical devices and trials concerning herbal medicine. The ICMR has formed a ‘Central Ethics Committee on Human Research’ which audits the functioning of Institutional Ethics Committee (“IEC”). IEC is generally formed at an institutional level and its main responsibility is to review the proposed research protocol and to monitor on a regular basis the approved programmes and to ensure that the guidelines issued by ICMR are being followed while conducting clinical trials.
With the object of making clinical data and reports available to the general public, ICMR has recently initiated an online registry, for registration of any clinical trial. Through such registration of clinical trial, the ICMR seeks to ensure (i) transparency and accountability; (ii) internal validity; (iii) compliance with ethical guidelines; and (iv) reporting of the results of such clinical trials. With time, Government of India has revised its own policies to dilute the regulatory hurdles faced by foreign pharmaceuticals companies conducting clinical trials in India and to bring the laws governing clinical trials in India at par with international standards. However, there is a need to upgrade the administrative system which monitors the conduct of clinical trials in India and to ensure that all the ethical guidelines framed under the ICMR Code are complied with by the investigators and all other persons associated with research on human subject.
Shravanti Bhowmik M.D. Medical Advisor-Clinical Research, Sun Pharma Advanced Research Company Ltd.
Clinical trials are essential for evidence based medicine. The question of whether an investigational treatment is effective in an indication is answered using validated evaluation tools with the resultant data being subjected to predefined statistical processes. For every drug or device being used, the indication(s)/dose/ duration/adverse effects and many details that go into the making of prescribing information for use by physicians come from clinical trials that have been conducted.
Clinical trial results form the basis of most practice-changing decisions.
Some of the significant challenges include lack of awareness of clinical trials among patients and doctors, especially in small towns and rural areas; misconceptions about clinical trials. Moreover, Ethics Committees that follow standard operating procedures need to take their reviewing responsibilities seriously.
Yes and no.
Yes, because there has been a considerable improvement in the (i) way clinical trial applications and approvals have been processed by the regulatory authorities over the last 10 years; (ii) manner in which guidelines and laws have been implemented; and (iii) the degree of transparency in function.
No, because the turnaround timelines for applications and approvals remains unpredictable despite there being timelimits set in documents available on official websites. Further, dialogue between regulators and industry is yet to evolve in terms of scientific content. Even the regulatory infrastructure does not seem adequate to cope with the increase in numbers of clinical trial applications and marketing applications.
There is no stop-gap initiative that can achieve this. Over a period of time, the importance of clinical trials needs to be given due importance in the academic curriculum of academia, primarily in the medical colleges. Regulators need to increase their work-force by recruiting personnel with appropriate qualification and experience, thus increasing their reach. Industry also needs to support academia in research endeavors. Lastly, scientific forums to discuss best research practice in various therapy areas could be of great help.
Dr. Yash Pal Munjal Medical Director, Banarsidas Chandiwala Institute of Medical Sciences , New Delhi
There is a spate of new drugs and molecules which are coming up in the market and these new drugs have been mostly tried on individuals and people from outside our country, belonging predominantly to the Caucasian race. The genetic background, the built of people of our country is very different from that in the Western world and in developed nations. Therefore, it is very important that any medicine which we want to use on our patients (of Indian ethnicity), should be tried on our patients so that we know their effectivity; the effective dosage level, and the sideeffects which emerge out of these therapies which are being introduced into the market.
There are few major issues involved. Now, the international agencies have put up good clinical trial practices and it is mandatory that we should also adopt those particular guidelines because they are reasonably good and are more useful in our country. There has to be an ethical committee before any drug is put to clinical trial. There should be adequate data of stage 1 and stage 2 trials as well as trial on animal model which should give adequate safety margin for the dosage level at which it is being now tried on human beings. One of the problems in our country is that people may not be educated to the level where they can understand this concept. So we need to tell them and make them understand. It is important that whatever clinical trials we conduct should be in the presence of a social worker.
After having done the trial in the animal models, and once the safety and utility of the drug has been established, then usually stage 1 involves healthy volunteers which are given this particular drug in varying dosages and the effect is monitored on them to see if there are any adverse outcomes or not. So at the level of stage 1, healthy volunteers are taken into consideration. Stage 2 is at the level when the patient has got that particular disease and the associated diseases are not a big problem when we do this; and again, it is a limited trial in which there is a ‘placebo’ element which consists of either healthy individuals or patients who are not being administered this drug or a similar drug.
The first level at which the legal community can get involved is at the level of ethics.Any company which plans to start a trial, has to first see that they have the data available, as well as all the safety parameters. To address any eventuality, there has to be a mechanism.Another issue is the confidentiality clause. I think one of the reasons why our country does not get too many clinical trials is that we cannot keep the confidentiality of a trial.When investing such a huge amount of money, a certain amount of confidentiality is needed before the results are available.
The other issue when the legal fraternity gets involved is when there is a problem with the individual; it is the drug company’s responsibility to see that their confidentiality has to be maintained at the individual patient level.
By informed consent, we mean that, we got to tell the patient about the drug which is effective in a particular disease, and that it is a new drug. It should be conveyed to the patient that the intention is to see whether it helps the subject as a patient and that there are certain side effects. You can be either in the active drug group because most of the trials have got a placebo on. Some will get the medicine and some will not have any active ingredient in the capsule though the two capsules will look exactly the same. If the individual agrees, he has to consent in the presence of 2 witnesses. This is called ‘informed’, and after understanding this information, he has given his consent.
‘Placebo’ has no medicine in it. It is just a shell of a capsule. It could have glucose, or some inert powder. It does not have any effect on the individual.
The main point is that, in India, there are too many hassles whenever a person has to start a trial.At the moment, we have only one agency i.e. the Indian Council of Medical Research, which can allow these research protocols to be carried out. Most drug trials that take place in our country are the pre-marketing surveillance trials i.e. the affectivity of the drug has been proven in some other part of the world. So, most of the times, our Drug Controller feels that when the foreign (US or European) agency has approved the drug, then it is okay to market the drug in our country and what he does is just a premarketing trial on a very small number of patients in India.
At the level of stage 2 and stage 3 trials, we have not got many numbers. However, in the last 5 years that number has started increasing. Our country has also been taken into confidence and some of the centres are recognised for carrying out such trials. Although such centres are not many in number.
One of the important aspects is that, any disease, most of the time, infections apart, is an interaction between the genetic backdrop and the environmental factors. It is a combination of the two. The genes load the gun and the environment fires it. So that is how the disease develops. Therefore the genetic background also has a great deal to do with the medication. There is a new wave of thought according to which, based on the understanding of the genetic background of the individual, we can administer a suitable medicine.
One aspect is that the pharma industry will have to interact with the medical profession. The other aspect is that we need to ask our Drug Controller to conduct a major trial before allowing the marketing of a drug in our country and only then can we have clinical research and our own data. India is one country where the health syndrome has improved very significantly. The standard of laboratories has also improved significantly. But some pressure has to be exerted on the pharma companies to conduct major rather than small trials. …as told to Avinash Mohapatra
A.B. Ramteke Joint Drugs Controller of India
“As far as initiatives between regulators and academia is concerned, there is an increased interaction between the two in the field of new drug research. I personally believe that this interaction has been quite significant ever since India joined the WTO regime in 1995. Further, with the amendment of the country’s patent laws in January 2005 bringing it in line with international laws, India has never looked back. The regulations too are adequate. Nowadays, at the time of granting permission for conducting clinical trial, applicants are being advised to get clinical trial registered at ICMR’s webbased clinical trial registry. Infact from 15th July 2009 onwards, Clinical Trial Registration has become mandatory.
More importantly, the Government has facilitated clinical trials by introducing a number of fiscal incentives, including exempting import duty on clinical trial supplies; exemption from registration requirements for clinical trial supplies; allowing export of clinical trial related biological specimens based on protocol approval; and exemption from service tax on new Drug testing.”
Abhayan Jawaharlal Legal Head (Biocon), Bangalore
Clinical trials are conducted to ensure the safety of a drug. From the point of view of an Indian pharmaceutical company, there are not many challenges except getting the right patient population for conducting the test. From an MNC’s point of view, they have to identify the right Contact Research Organization (CRO), and again getting the desired patient population.
The regulatory mechanism of India is more stringent as compared to other countries. Because of the Clinical Trial Registry, registration is a welcome step for those who want to conduct trials in India. The regulatory environment in India is not going against the progress of clinical trials in the country.We require optimal regulation and not excessive. The clinical data generated in India should have validity in foreign countries’ jurisdictions.
For the academia, one difficulty is that there is no proper interaction. The academia’s interaction with the other parties should be at a level where they are made aware of the regulatory mechanism and also of the Guidelines for Good Clinical Practice (GCP). It is always good to have interaction between regulatory authorities. Most clinical trials depend on the time frame which involves waiting for regulatory approval. Effective interaction can help reduce this time bracket. The Clinical Research Form should be made standardised. Most trials in India are already following GCP Guidelines.
Dr. B Ekbal National Convener (Jan Swasthya Abhiyan) and Former Vice-Chancellor of University of Kerala
Following the amendment to the Patents Act in 2005, the public and private sector can now make drugs by following both the product and process patenting. Indian companies are permitted to make drugs made by foreign companies using a different process and market it in India at a cheaper cost. Initially, we thought that the Indian drug community could now opt for serious drug research, but instead it started doing contract research and drug trials for MNCs from other countries.We demand that public sectors should use research facilities to do serious research. The second option should be to help the MNCs to do trials in India.
India is a big market for drug trials; it is almost like patient outsourcing. Reason being, in India a lot of poor patients are ready to do trials. In other countries, many patients may not agree. When you inform the patients that the drug will be given for free, they agree to undergo the trial. India is said to have many diabetic patients- many patients who are ill informed and thus will submit themselves for such trials. Secondly, drug trials are relatively cheaper in India than in foreign countries. You can do human drug trials in India with only 40-50% of the cost it takes to conduct it elsewhere. Because of this, MNCs are investing in India as a destination for clinical trials. Indian companies are paid a part of it. Clinical trials are coming up in a big way in India.
Our country has many ill-informed and poor illiterates who are vulnerable and will be easily submissive to any trials without knowing the proper consequences. The solution lies in educating these people and empowering them though campaigning.
We already have some regulations; like, we are required to register at the registry before we can conduct any trial. And there are many wavelengths issued for doing drug trials in human beings, but there must be a monitoring system of the ongoing trials despite these rules and regulations. I feel that the Indian infrastructure is insufficient to monitor all the trials. There should be a transparent monitoring system maybe by putting the trial results on a public domain under Right to Information Act. Monitoring can be bettered by forming a monitoring committee consisting not only of experts, but of socially committed professionals and public activists along with government officials.
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