The determination of the safety and effectiveness of medicines, diagnostic devices, diagnostic products intended for human use is made through clinical trials. Simply put, it is an experiment conducted to study the safety and efficacy of a medication in the treatment of a specific medical condition. Typically, the regulatory rigors around the conduct of clinical trials are higher, to ensure patient safety.
The Indian Council of Medical Research has stated that clinical trials are premised on the principle of essentiality, and they continue to be a robust determinant of efficacy of a new medication. Existence of clinical trials can be traced back to as early as the first recorded trial of legumes in the biblical times, and as referred to in the Book of Daniel, in The Bible1. The Canon of Medicine, compiled by Avicenna (also known as Ibn Sina) in 1025 AD also prescribed2 on the efficacy of several drugs and substances, and continues to influence the practices followed by the Unani practitioners. The year 1747, marks the conduct of the popular scurvy trial by JamesLind; evidencing several elements of a controlled trial. The 19th century saw the advent of placebo, which was an epithet given to any medicine more to please than benefit the patient. Over the years there have been prolonged debates concerning the scientific, regulatory, and, ethical implications of clinical trials. Modern clinical trials came in to supplement evidence-based medicine. More importantly, the first guidance on ethics in medical research was formulated in 1947, as the Nuremberg Code, in response to the horrific fate of the human guinea pigs during the World War II.
India stands as an attractive destination for clinical trials for a variety of reasons, inter alia, (a) diverse ethnic population; (b) drug naïve population; and, (c) variety of gene pool stands. All of this combined with low costs, should ideally result in India being treated as an R&D hub in the long term. However, lack of a proper regulatory framework has impacted this potential in the past. The recent introduction of New Drugs and Clinical Trials Rules, 2019, (Rules) is set to bring in more legal clarity.
Over the years, legislators have worked towards lending credibility to the sector. India amended its patent laws to extend protection to product patents for pharmaceutical products, in compliance with the Agreement on Trade Related Aspects of Intellectual Properties. Further, upon acknowledging the importance of clinical research for new therapies, Schedule Y was introduced as an amendment to the Drugs and Cosmetics Rules, 1945. Additionally, upon the incidence of foreign entities conducting researches in the country, the Indian Council of Medical Research issued the Ethical Guidelines for Biomedical Research on Human Subjects; and, the Central Drugs Standard Control Organization (CDSCO) issued the Indian Good Clinical Practice (GCP) guidelines in 2001. However, as the guidelines were not a mandatory requirement, clinical trials were conducted in absentia. Resultantly, data yielded was of low quality and companies were reluctant to rely and/or invest in clinical trials in the country.
Keeping up with the changing times, the CDSCO ensured that changes be made to Schedule Y to align the practices with international standards in 2005; and the successive amendment to patent laws in 2005 also brought in consistency and greater value to intellectual properties in India. Amendments were made to reduce incidence of service tax on clinical trials, remove phase lags3, and introduce responsibilities of invested parties. This led to an increase in the number of clinical trials in India.
Even with the changes brought into the system, there have been reports in the past which have established how informed consent is followed only on paper, and how children in developing countries are still being treated as the proverbial guinea pigs. Statistics demonstrate that 49 children4 died in six clinical trials conducted at the All India Institute of Medical Sciences between 2006-08 and this is from the best and premier medical institution in the country. An additional ethical challenge presents itself in case of children because adults are involved in decision making. Another appalling incident5 was where clinical trials concerning adults were conducted in a Kerala Regional cancer treatment center (John Hopkins University Hospital was the sponsor), where patients were not even informed about their participation in clinical trials. Moreover, there have been several incidents in the past where approvals for trials have been sought with incomplete information.
When a public interest litigation was filed in the Supreme Court by several women’s health activists, the CDSCO and the Ministry of Health and Family Welfare decided to strengthen the procedure for conduction of clinical trials. The consequent amendments required for the ethics committee to obtain registration from the Licensing Authority; deriving compensation vide a prescribed formula, et cetera.
In the past where it was seen that informed consent stood as a plaguing issue, the Drug Controller General of India issued an order in 2013 that made audio visual (AV) recording of the informed consent process compulsory for all clinical trials. The present Rules have taken due note of the need for informed consent and have entailed all the scenarios which may play out in practice; a checklist has been provided with the essential elements to be included in the subject’s informed consent document, as well as a format for the same. Owing to the higher sensitivity and social stigma attached to certain diseases like HIV and leprosy, only audio recording of the informed consent is required to be maintained by the investigator for record.
Increase in ethical concerns around clinical trials in the country led to onsite inspection of clinical trials by CDSCO teams. Several regulatory amendments led to the decline in the number of clinical trial approvals in the country. The CDSCO was not inclined to share results of onsite inspections to the dismay of the invested parties. While earlier the CDSCO did not have to reveal the results of such inspection, the current Rules require reasoned decision highlighting results of inspection to be provided to applicants/ Ethics Committee, lending transparency to the process.
Per the draft rules (circulated amongst stakeholders for consultation), the sponsor was mandated to pay an interim compensation of sixty percent of the derivative quantum, upfront in case of death or permanent disability of the patient. This has paved way for the present position which requires that the companies will pay the total amount once it is proven that the incident occurred because of the trial. Free medical management must be provided to the subject, in case of an injury caused during the trial, till such time it is established that the injury is not related to the trial, or as long as required, whichever is earlier. This, however, is subject to the determination of the investigator, as medical management will be met out to such subject as long as required as per the opinion of the investigator. The trial subject does not have the right to move against such decision of the investigator. This will require a greater deal of deliberation by the agencies, for this might result in misuse owing to ambiguity.
The mandated post marketing surveillance through periodic safety update reports are seemingly inspired from the Adverse Events Reporting System and Risk Evaluation Mitigation Strategies required by the US FDA. Desired implementation of this will go a long way in assessing patient safety in matters of clinical trials in the country.
As a relief to the applicants, pre and post submission meetings have been introduced which allow for applicants to seek clarity on several issues, and also facilitate the application process to a great extent. Further, conditions for the provision of free post-trial access of investigational drugs to patients have been outlined for the first time.
As a relief to the applicants, pre and post submission meetings have been introduced which allow for applicants to seek clarity on several issues, and also facilitate the application process to a great extent. Further, conditions for the provision of free post-trial access of investigational drugs to patients have been outlined for the first time. The Rules have qualified this provisioning to the conditions, where alternative therapy is unavailable, and, where the trial subject / legal heir have consented. However, as a setback to the patients, a declaration in writing will be obtained from the subject or their legal heir, stating that the sponsor shall have no liability for post-trial use of the new drug.
Efficient timelines include provisioning of approval or rejection of applications within 90 days from the date of application for drugs developed outside India. Further, with the approval of the Central Government, the Central Licensing Authority may from time to time specify the names of the countries, for waiver of local clinical trials for approval of new drugs. Pharmaceutical companies which intend to sell a new drug will no longer be required to conduct a Phase III clinical trial that tests for efficacy and safety of the drug on the Indian population, if it has been approved for sale in certain geographies. However, trials will have to be conducted after the drug has been marketed to evaluate long-term effects, known as Phase IV clinical trial.
The Rules have, for the first time, defined orphan drugs as drugs intended to treat conditions which do not affect a population larger than five lac persons in India and have also provided fee waivers for orphan drug trials. This will encourage the research in the field of rare diseases in the country.
Increasingly guidance documents are being made available on the official website allowing the stakeholders to understand and appreciate the implications of the laws better. The Rules will go a long way in rebuilding trust in the sponsors and welcome clinical trials in the country. The provisions have demonstrated realization of the discussions with several stakeholders, prior to the notification of the new rules. Nevertheless, as advances will continue to occur, new challenges concerning ethical and regulatory implications will continue to require vigorous responses.
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