The total cost for bringing a new prescription drug to market is about USD 2 to 3 billion (DiMasi et al.). A significant portion of this cost is incurred in conducting clinical trials. The global clinical trials market size is expected to reach USD 69.8 billion by 2027, exhibiting a 5.1% compound annual growth rate (‘CAGR’) during the forecast period. One of the important drivers for this growth is the increasing prevalence of chronic diseases and conditions. In 2019, the clinical trial market was dominated by North America with the largest revenue share (Grand View Research, Inc.). A large number of Contract Research Organizations (‘CROs’) specifically provide clinical-study and clinical-trial support for drugs and/or medical devices.
After the Agreement on Trade Related Aspects of Intellectual Property Rights (‘TRIPs’) kicked in in 2005, India was poised to become one of the biggest hubs for clinical trials. Various factors such as skilled medical, clinical, and IT professionals, large and diverse pool of patients, prevalence of chronic diseases, and health conditions as well as cost effectiveness, made India a favourable destination for conducting clinical trials. Thus, the clinical trial market in India witnessed enormous growth during 2005-2009. However, the lack of clear and stringent regulations and guidelines led to inadequate protection of the trial participants (subjects). During 2010-2013, several reports emerged about the falsification of trial data by investigators, the abuse of trial participants, the lack of informed consent from the participants and the lack of adequate compensation to the participants. A Public Interest Litigation (‘PIL’) was filed in 2012 by an NGO called Swasthya Adhikar Manch, in the Supreme Court of India, raising these issues. The 59th report of the Parliamentary Standing Committee also noted the failings of the regulatory system for clinical trials. The Supreme Court directed the government to stop all clinical trials in the country and amend the regulatory framework to ensure a foolproof system for the protection of the participants before any approval for a clinical trial was granted. These concerns about ethics, data quality and lack of robust regulatory framework led to a decline of the clinical trials market in India. From 500 in 2010, the number of clinical trial application approvals dropped to 150 in 2014, and to a mere 81 by the end of 2015.
RECENT HISTORY OF REGULATORY CHANGES
In response to the criticism, and in tacit acknowledgement of the low rates of clinical trials in the country, the Central Drugs Standard Control Organization (‘CDSCO’) and Ministry of Health and Family Welfare made a series of changes in regulations governing the clinical trials.
In 2010, the CDSCO had created a new entity, the New Drug Advisory Committee (‘NDAC’) and brought in a new review process. The new process meant prolonged timelines, even as long as 18 months, for the approval of clinical trials. Further, the process was unpredictable. This led to a sharp decrease in clinical trials.
Following recommendations by various stakeholders and the Prof. Ranjit Roy Choudhury Expert Committee, CDSCO brought in more changes.
In 2013-2014, the Drugs Controller General of India (‘DCGI’) implemented a three-tiered regulatory process to review clinical trial applications. As per the new process, an application for approval was required to be submitted along with an executive summary to the DCGI. The application was then reviewed in succession by the Subject Expert Committee (SEC), which replaced the NDAC and approximately 25 subcommittees, the Technical Committee, and the Apex Committee. At the same time approvals of the Independent Ethics Committees (‘IEC’) or Institutional Review Boards (‘IRB’) were also required. However, because of the stricter rules and too many changes that led to confusion, the industry still did not show significant signs of revival.
To give a further boost to the industry, CDSCO once again revisited and revised the regulations. The result was the implementation of the New Drugs and Clinical Trial Rules, 2019 (the ‘New Rules’).
THE 2019 NEW RULES: A BRIEF SUMMARY:
The New Rules comprise 13 chapters (including 107 rules), 8 Schedules, and 27 Forms. These rules supersede Part XA and Schedule Y of the Drugs and Cosmetics Rules, 1945. In the New Rules 2019, the timeline of the lengthy regulatory process for approval is significantly reduced. The definition of the ‘new drugs’ has been revised. The New Rules also address issues relating to orphan drugs, academic clinical trials and post-trial access. Orphan drugs are now relatively less stringently regulated, as compared with other drugs, for example, the application fees for orphan drug trials now stand waived. The New Rules have also differentiated the requirements for conducting phase IV clinical trials and post marketing surveillance for new drugs. The New Rules 2019 bring more clarity in terms of the following issues:
- Applicability: The New Rules are applicable to new drugs, investigational new drugs for human use, clinical trials, bio equivalence studies, bio availability studies and Ethics Committees.
- Central Licensing Authority (‘CLA’): The DCGI is the CLA under the New Rules.
- Online application: The application for conducting a clinical trial is required to be submitted to the CLA via SUGAM, an online portal managed by the CDSCO.
- Definition of a ‘new drug’: A ‘new drug’ defined to include
- a drug, including active pharmaceutical ingredient or phytopharmaceutical drug, which has not been used in the country to any significant extent,
- a drug approved by the CLA for certain claims and proposed to be marketed with modified or new claims,
- a fixed dose combination of two or more drugs, approved separately for certain claims and proposed to be combined for the first time in a fixed ratio,
- a modified or sustained release form of a drug or novel drug delivery system of any drug approved by the CLA,
- a vaccine, recombinant Deoxyribonucleic Acid (r-DNA) derived product, living modified organism, monoclonal anti-body, stem cell derived product, gene therapeutic product or xenografts, intended to be used as drug.
- Orphan drug: An ‘orphan drug’ has been defined as a drug intended to treat conditions which affect not more than five lakh people in India.
- Reduced timelines: The time for approving applications has been reduced to 30 days for drugs manufactured in India and 90 days for the drugs developed outside India.
- Deemed Approval: In case of no communication from DCGI, the application will be deemed to have been approved.
- Management of injury: In case of injury to participants, medical management will be provided as long as required as per the opinion of the investigator or till such time it is established that the injury is not related to the clinical trial.
- Compensation: The DCGI will decide the compensation in cases of death and permanent disability or other injury to a trial participant. Ethics committee will monitor the trials and decide on the amount of compensation in cases of adverse events. The quantum of compensation is required to be calculated on the basis of the formula specified in the New Rules.
- Waiver of requirement of local trial in certain cases: The requirement of a local clinical trial may be waived for approval of a new drug if it is approved and marketed in any of the countries specified by the DCGI with the approval of the government.
Phase IV clinical trial requirements are also relaxed if a drug is for a life-threatening condition or is of special relevance, or for a rare disease for which drugs are not available or available at a high cost.
The requirement of animal toxicology studies, reproduction studies, teratogenic studies, perinatal studies, mutagenicity and carcinogenicity studies is relaxed in the case of new drugs approved and marketed for more than two years in other countries.
Additionally, no permission is required from the CLA for conducting an academic clinical trial. The observations of such clinical trials however, should not be used for promotional purposes.
- Phyto-pharmaceutical drugs: New specific requirements have been provided for phyto-pharmaceutical drugs.
- Ethics Committee: An Ethics Committee is required to be set up and registered by anyone who intends to conduct a clinical trial or bioavailability studies or bioequivalence studies. The trial or the study can be conducted only after the approval of the Ethics Committee.
- Registration of clinical trials: It is mandatory to register clinical trials prospectively in the Indian Council of Medical Research -Clinicals Trial Registry India (ICMR-CTRI), before enrolling the first participant for the trial.
- Increase in fee: The application fee for conducting phase I to phase IV trials has been increased about six to eight times.
- Phase IV study: The Phase IV study would include studies related to drug-drug interactions, dose response or safety studies, trials designed to support use under the approved indications.
- Post-trial access of investigational new drug: Post-trial access of investigational new drug is to be provided by the sponsor to the trial participant after the completion of the clinical trial. The drug will be provided free of cost by the sponsor, if it is found to be beneficial and there is no alternative available.
- Post-marketing surveillance studies (PMS): Requirements for carrying out the PMS for a new drug have been laid out. As a part of requirement, Periodic Safety Update reports (PSUR) are required to be submitted every six months for the first two years after the approval for a drug is granted. Pediatric and geriatric populations are required to be included in the clinical trial study if the drug is intended to treat conditions that specifically affects such populations.
With the implementation of the New Rules, CDSCO has made sweeping changes in the regulatory framework governing the clinical trials in India. The New Rules provide for a predictable, clear and transparent system for regulation of clinical trials. The changes such as reduced approval period and online registry, are expected to revive and drive the growth of the clinical trials industry in India. The New Rules are expected to put the clinical trials industry back on track. The condition of waiving local clinical trials under the New Rules will help early access to drugs for patients in India. The faster approval process will also speed up the trial procedure and encourage local drug development.
- DiMasi, J.A., Grabowski, H.G., Hansen, R.W., 2016. Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics 47, 20–33.
- Clinical Trials Market Size, Share & Trends Analysis Report by Phase (Phase I, Phase II, Phase III, Phase IV), By Study Design (Interventional, Observational, Expanded Access), By Indication, And Segment Forecasts, 2020 – 2027, Market Search Report by Grand View Research, Feb 2020.