|Year : 2018 | Volume
| Issue : 1 | Page : 51-55
Paradigm shift in clinical trial regulations in India
Sandeep Lahiry1, Rajasree Sinha2, Shouvik Choudhury1, Ayan Mukherjee1, Suparna Chatterjee1
1 Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India
2 Department of Pediatrics, Medical College and Hospital, Kolkata, West Bengal, India
|Date of Web Publication||26-Feb-2018|
Prof. Suparna Chatterjee
Department of Pharmacology, Institute of Postgraduate Medical Education and Research, 244 A. J. C. Bose Road, Kolkata - 700 020, West Bengal
Source of Support: None, Conflict of Interest: None
India has the potential to contribute meaningfully to global clinical drug development. A critical enabler to achieve this potential is a balanced, predictable, and scientifically robust regulation involving clinical studies. In the past few years, the country's regulatory milieu has witnessed a positive transformation to favour ethical conduct of clinical trials, while appropriately supporting patient safety. Numerous amendments to existing policies governing the conduct of clinical studies are predicted to bring a paradigm shift in the overall regulatory scenario. In such view, it is important for us as academicians, to be abreast of such changes. We, therefore, discuss major regulatory highlights involving clinical research in India.
Keywords: Clinical trials, guidelines, India, regulatory environment
|How to cite this article:|
Lahiry S, Sinha R, Choudhury S, Mukherjee A, Chatterjee S. Paradigm shift in clinical trial regulations in India. Indian J Rheumatol 2018;13:51-5
| Introduction|| |
Over the last few years, a slew of legal litigations have surfaced pointing at poor enforcement of clinical trial (CT) regulations in India. Specifically, irregularities in reporting of CT-related data and violations of ethical guidelines have highlighted the need for amendments to existing regulations. Moreover, there were unnecessary delays in study protocol approvals (usually 6-7 months) which often lead to huge financial losses, particularly in the pharmaceutical sector, causing major investors to shy away from Indian markets. There was a need to bring in major overhauls to existing regulations, therefore; Government of India has recently brought several amendments in Schedule Y of Drugs and Cosmetics Act (1940), to address such issues. Timeline of such key regulatory changes has been summarized in [Table 1].
|Table 1: Timeline of important regulatory changes involving clinical studies in India|
Click here to view
To cater to the problem of unnecessary time lag in the approval process of CTs in India, starting February 2013, a “three-tier” review process has been implemented, wherein CT applications will now be reviewed by the “technical committee” followed by the “apex committee,” after an initial approval from a “subject expert committee” (SEC). Only on receipt of approval in all three stages, final approval will be granted by the Drug Controller General of India (DCGI). This new system will ensure faster dispensation of protocol approvals since previously it used to take 6–7 months for the DCGI office to arrive at an informed decision. Since August 2014, there exist nearly 25 panels of SECs across various therapeutic domains.
Clinical trial-related injury
Any Injury or death due of a subject to following reasons is considered as “clinical trial related injury,” (i) adverse effect arising out of usage of an investigational product(s); (ii) violation of approved protocol, scientific misconduct, negligence by the sponsor or investigator; or in case (iii) failure of investigational product to provide intended therapeutic effect where standard care, though available, was not provided to the participant as per CT protocol; or (iv) use of “placebo” in a placebo-controlled trial, where standard care, though available, was not provided to the participant as per CT protocol; (v) adverse effect due to concomitant medication excluding standard care, necessitated as part of approved protocol; (vi) injury to a child in utero for participation of parent in CT; or (vii) any CT-related procedures. In case of CT related injury or death, the participant or nominee is entitled to compensation.
Causality assessment of adverse events
Assessment of causality or relatedness of an adverse event (AE) due to a suspect medication(s) is commonly undertaken by the standardized World Health Organization-Uppsala Monitoring Center adverse drug reaction causality scoring system. India has adopted this scoring system, that takes into account temporality, biological plausibility, exclusion of other causes, and response to rechallenge or dechallenge of the suspect medication. Based on the above, they are categorized as “certain,” “probable,” “possible,” “unlikely,” “unclassified,” or “unclassifiable.” However, in regulatory CTs (premarketing trials), causality assessment categories are restricted mainly to “related” or “unrelated” or rarely “unassessable.” Causality assessment needs to be done independently by the investigator, sponsor, ethics committee (EC), and independent committee in case of serious AE (SAE) of death. Prompt detection, documentation, monitoring, and reporting of all SAE in regulatory trials within the stipulated timeframes to the respective stakeholders as per the Schedule Y are mandatory.
Provisions regarding SAE reporting and criteria to define study-related injury to decide eligibility for compensation were amended, wherein, in case of injury to CT participant, “free medical management” shall be provided “as long as required or till it is established that the injury is not related to CT, whichever is earlier.” However, in case the injury is related to CT, financial compensation shall include “over and above free medical management” (= no fault compensation). Moreover, in case of CT-related death, compensation will be provided to the nominee. However in case of failure to treat and/or provide compensation, CT will be cancelled, suspended, or restricted.,,,
It is to be noted that in the event where there may be a second SAE (during therapy for first SAE) occurring within the same study period, it will be treated as a “new” SAE. Hence, all the provisions regarding SAE reporting and criteria for eligibility for compensation as discussed previously will continue to be applicable. The timeline of the second SAE is an essential determinant, especially in situ ations where the therapy for the first SAE is long term and exceeds well beyond the study period. In such cases, eligibility may be decided on a case-to-case basis.
Guidelines on mandatory EC registration have been updated, wherein the registration granted to ECs will now be valid for a period of 3 years and subject to periodic renewal. Till date, >2000 ECs have been registered in India, and the number is ever increasing., However, as per the recent DCGI notification, CDSCO registered independent ECs can now give clearance for bioavailability/bioequivalence (BA/BE) studies only. In other words, it mandates all institutions to have a registered IEC in order to conduct and oversee clinical studies.
ECs of the country are now primarily responsible for recommending the compensation for any trial-related death/injury; thus, it is pertinent that the cause-effect relationship of the investigational product and AE is established. The EC's opinion to the expert committee or DCGI is only in the form of 'related' or 'unrelated'. Latter applies when it is definitely judged that there is no possibility of the trial intervention/procedure of having contributed to the event.
Recently, the Ministry of Health (MoH) and family welfare (FW) and quality council of India (QCI) has also mandated National Accreditation Board for Hospitals and Healthcare Providers (NABH) accreditation for ECs supervising CTs effective from January 1, 2018. The NABH was established in 2006. It is a constituent board of QCI certification, set up to establish and operate accreditation program for healthcare organizations in India.
Earlier provisions for mandatory audio-visual (AV) recording of informed consent had faced intense scrutiny in view of practical feasibility and social concerns impacting subject recruitment., Later, a new notification was issued clarifying the norm, which stated that AV recording of informed consent was mandatory only in cases involving “vulnerable” subjects and studies involving a new chemical entity. However, the definition of “vulnerable” is yet to be formally standardized.
Formulae for compensation
Formulae to determine the quantum of compensation in cases of CT-related injury have been proposed and implemented. This marks a unique feat of achievement, making India the only country in the world to have such a working compensation formula. The compensation would be decided by DCGI after consideration of reports available from EC and the expert committee constituted by DCGI using the following formulas:
- SAE causing death of the individual
- The formula for compensation is (B × F × R)/99.37;
- Where B = Base amount (i.e., 8 lakhs); F = Factor determined as per the age (based on Workmen Compensation Act); R = Risk factors (based on seriousness and severity of the disease, presence of comorbidity, and duration of disease of the individual at the time of enrollment), calculated as per predetermined scale for compensation (0.5–4):
- 0.5 – Terminally ill (expected survival <6 months)
- 1 – High risk (expected survival <6–24 months),
- 2 – Patients with moderate risk
- 3 – Patients with mild risk
- 4 – Healthy volunteers or patients with no risk.
It was decided that in case of patients whose expected mortality is 90% or more within 30 days, the compensation would be a fixed amount of 2 lakhs.,,
SAE causing permanent disabilityIn case of 100% disability, the quantum is fixed at 90% of the amount which would be due for payment in case of death of the individual., In case of < 100% disability, the amount would be proportional to the actual percentage of disability suffered and calculated as below:(C × D × 90)/(100 × 100);Where, C = Quantum of compensation in case of death and D = Percentage of disability.SAE causing life-threatening disease or reversible SAE in case it is resolvedThe quantum is calculated keeping in mind the number of days of hospitalization which results in wage loss of the patient as well as the attendant (thus double wage loss). The wage loss is calculated as per the minimum wage of unskilled worker (in Delhi).,,Compensation = 2 × W × N;Where, W = Minimum wage per day of unskilled worker (in Delhi) and N = number of days of hospitalization.SAE causing congenital anomaly or birth defectStill birth, early death due to anomaly, permanent disability (mental or physical), and no death but deformity which can be fully corrected through appropriate intervention are considered under congenital anomaly. If such congenital anomaly arises due to participation of one or both parent in a CT, then the compensation amount needs to be kept as fixed deposit or alike, so as to bring a monthly interest approximately equivalent half of minimum wage of unskilled worker (in Delhi).,,In case of deformities or disabilities, as highlighted above, the medical management needs to be provided by the sponsor over and above the financial compensation.
Timeline for disbursement of compensation has been updated, as shown in [Table 2]. Expert committee appointed by the DCGI would examine the report of SAE and would give its recommendation to the licensing authority within 30 days. The DCGI must determine the cause of injury or death due to the AE and make the final decision on the amount of compensation to be paid by the sponsor or his/her representative within 150 days of the occurrence of the AE. In case of CT-related injury or death, the sponsor or his/her representative shall pay the compensation as per the order of the DCGI within 30 calendar days of the receipt of such order.
|Table 2: Updated serious adverse event reporting timeline (in place from June 12, 2015)|
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As an impetus to academic research, investigator-initiated studies (IIS) on “new” indication for a marketed drug will not require a DCGI approval anymore. Institutional EC approval for IIS or academic studies shall now be sufficient in cases where an already marketed drug has a “new” or “off-label” indication and if the data generated are not intended for submission to licensing authority. However, IIS involving procedures such as intervention would still require an Institutional EC (IEC) approval and registration in the national CT registry. The ECs will have to inform the DCGI about the cases approved by it and also about cases where there could be an overlap between the clinical trials for academic and regulatory purposes. In case, the DCGI does not convey its comments within a period of 30 days from the date of receipt of communication from the EC, it shall be presumed that no permission from the DCGI is required.
Medical device legislation
In the past, there was no regulation specific to medical devices (including in vitro diagnostics) in India. Therefore, the MoH & FW notified the medical devices rule, 2017 (to be effective starting January 31, 2018), to regulate studies involving medical devices in the country. The rule now classifies medical devices primarily under two groups: (i) “investigational” medical devices and (ii) “registered or approved” medical devices. Chapter VII of this notification states that CT involving “investigational” medical devices will need both IEC and DCGI approval, while IIS (not intended for marketing) with the latter, need only IEC approval. A fixed timeline of 90 days has also been prescribed for the DCGI to provide permission to conduct the CT. After obtaining such approval, the first individual is required to be enrolled within 1 year. All government institutes have been exempted from payment of fees for conduct of clinical investigation.
Criteria for study conduct
Another major CDSCO notification on the requirement of EC approval for new trial sites now states that DCGI approval for the addition of new trials site or investigator will not be needed, and only IEC permission will be sufficient. There will no longer be a mandatory requirement of minimum 50-bedded hospitals to conduct clinical studies and all studies are to include at least 50% government institutes, with requirement for each site, to have “emergency rescue and care arrangements.”, A previous CDSCO directive that had a stringent norm of restricting investigators from conducting of ≤3 trials simultaneously was also revoked recently.
| Conclusion|| |
The regulatory authorities have now empowered ECs with a larger mandate, depicting that Indian regulations are evolving toward a “decentralized” approach for faster outcome delivery. However, India is expected to witness future amendments in existing regulations, which will hopefully ensure faster approval timelines and increased transparency making it more conducive for various stakeholders in academia and pharmaceutical industry to conduct ethical clinical research.
We thank faculty of Department of Pharmacology, IPGMER Kolkata for giving us important regulatory inputs during article preparation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]