The Central Drugs Standard Control Organization (CDSCO), India’s regulatory agency for clinical research, has made a series of announcements and corrections recently that moves India towards alignment with global clinical research practices. Reasonable direction is now available for regulatory review timelines, the role of ethics committees, the consent process, safety reporting process and the compensation process.
New and additional steps ensures a fair protection mechanism for all participating subjects and also enable a cleaner, transparent and easier decision-making process for Indian clinical researchers. This was possible because, in addition to the new guidance, the CDSCO framed several new processes and separate committees to manage a variety of approvals based on clinical specialty, and to oversee the safety aspect of the compensation process.
In addition, the regulatory mechanism is now geared up for on-spot inspections of clinical trial sites by local drug inspectors. This is expected to improve the environment for patients, researchers and industry equally.
In Jan 2013, legislation was introduced that required clinical trial sponsors to compensate for deaths in clinical trial irrespective of whether the death was related to the trial, and the amount depended on factors such as gender and income. This was one of the most controversial legislation that was introduced.
However, in July 2014, this was revised where compensation was required only for deaths related to the drug or trial intervention, and the amount clearly calculated based on subject age and risk factor of the disease. With this place, India is now a fair environment for clinical research.
Summary of corrections made by CDSCO
The corrections made by CDSCO relate to several different, but sensitive areas of the clinical trial process. They are summarized and discussed below.
- Mandatory registration of Clinical trials on CTRI (recommendation from WHO)
- Timelines and process of approval of global and local trial applications
- Spot inspections for safety data gathering and assessment of site facilities and capabilities
- Site SOPs and EC SOPs became mandatory
- Financial support provided to PI to be submitted to Institutional Ethics Committee and DCGI as part of Clinical Trial approval process
- Mandatory Ethics Committee registrations
- Audio-visual consenting process for all trials
- Compensation formulae for SAEs leading to outcome as death and non-death SAEs related to clinical trial procedure /drug/device
- Payment of reimbursement for medical management and treatment for all cases of SAE related to clinical trial procedure/drug/device
- SAE Expert Committee to review the SAE compensation and reimbursement to patients, based on a new SAE reporting mechanism
- Standard of care to be made available to patients, (where options are available) when use of placebo and the failure of treatment is to be justified
Registration of Clinical trials on CTRI database
The Clinical Trials Registry- India (CTRI) which is hosted at the ICMR’s National Institute of Medical Statistics, is a free and online and voluntary public record system for registration of clinical trials being conducted in India launched in mid-2007. However, since June 2009, trial registration in the CTRI has been made mandatory by the CDSCO. This must be completed as soon as DCGI provides approval for a clinical trial application, prior to first patient enrolment.
Timelines for regulatory approvals
The clinical trial approval process timelines range from two months for protocol amendments to 6 months for new drug protocol approvals. Similar timelines will apply for major changes to protocol that are already approved. All these approvals are also posted daily on the CDSCO website indicating a more transparent approval process. Associated processes, like import and export licences, require 1.5 months post- CT approval.
This has made the process of CT approval process timelines transparent and predictable.
On-spot inspections, Site assessments and EC registrations
Starting late 2012, over 300 on-spot inspections were conducted at very short notice or no-notice basis by local state FDA inspectors. This had led all sites and ethics committees at the sites to become more vigilant, introduce SOPs and also upgrade facilities to help manage trials in a more secure, confidential and transparent manner. It also helped the sites to improve source document keeping and training records for site staff involved in clinical research activities.
Sites were also importantly assessed in the way the drugs were stored and source documents were maintained. ECs at sites were also questioned in several cases as to how oversight of trials approved by them was regularly maintained and how they had dealt with cases of SAEs and deaths that may have occurred at the site. Compensations and reimbursement records were sought by the CDSCO during the inspection or via post-inspection observation reports.
Inspections of sites revealed that some of the smaller sites and consultation type hospital were not reviewing safety reports and ECs were either not in line with the GCP & ICMR requirements or facilities described in applications for registration were inadequate for safe conduct of new drug trials at the site. This resulted the process of EC registration which now includes over 740 sites, which are ready to be used for studies. Non-registered sites will not be allowed to conduct clinical trials.
These steps will ensure continued Ethical, Scientific and Safety standards at all the sites are up to highest acceptable standards.
Audio-Video consenting process
There have been some reports of impersonation as well as misrepresentation of personal details resulting in patients and NGOs claiming that they were unaware of being part of clinical trials and that they did not sign any consent forms or undertakings. There were also cases of patients who did not sign the forms in language that they could read and understand leading to questionable processes followed at sites.
As a result, the regulatory agency, under pressure from Supreme Court has asked for AV consenting process to be followed. General guidelines to follow for the AV process are available to the public at the above mentioned hyperlink.
This is presenting a new challenge at the site in getting patients to agree to get on to camera recording, especially where some indications and clinical conditions do not present the best of the opportunities for an on-camera consenting process. Hence, the sites need to train their social workers as well as study co-ordinators to help manage to convince patients about confidentiality as well as the purpose of this recording.
The sponsors generally would specify the minimum standards of the AV recording process and the site and IECs are responsible for maintaining confidentiality of these recordings.
This is one of the unique requirements in India, which no other regulatory agency in the world mandates for consenting for clinical trials.
Serious Adverse Event (SAE) compensation and medical reimbursements
This is one of the most controversial elements as previously, it meant biopharma and CROs were expected to have unlimited liability for SAEs and all medical management for participating patients. Since no clinical trial related causality was taken into account, the risk was unimaginably large for some indications or clinical conditions.
This was a major deviation from the global definitions where, reasonably, only trial related injuries are compensated. In addition, insurance companies also termed this as impractical as the premium and exclusion clauses are built based on certain risk conditions and not all conditions.
Currently, two compensation guidance for SAEs have been released. One addresses SAEs that lead to deaths and calculation of the compensation based on formulas and factors specified in the guidance. The other guidance addresses SAEs that do not lead to death but have caused other disabilities and long term effects that need to be managed under this guidance. Medical management reimbursements also follow detailed guidelines for compensation. As both are only applicable to clinical trial related injuries, it is now more practical and able to be covered under international clinical trial insurances.
In addition to the above, CDSCO has also formed an Expert Committee which will collate all the SAE information and reassess the cases to verify that appropriate compensations and reimbursements are made to the patients affected due to clinical trial related activity. Timelines for the submission and processing are now clearly defined so that they are practically possible to achieve. Previously, the timelines were short and were difficult to meet.
India is now the only country with such transparent and clearly drawn out with formulas available for calculations of compensation. However, one aspect regarding the SAE process still remains unaligned to global practices. CDSCO expects the site to report the SAE within 24 hours of its occurrence rather than its awareness. However, this is still accepted by the SAE reporting cell with an explanation on why it was not possible to report within 24 hours.
Standard of care in placebo controlled trials and inefficacy of treatment
The legislation introduced in 2013 also included a restriction on all placebo-controlled trials and additionally, the guidance seemed to indicate that all cases where there was no efficacy of treatment (including subjects whom the clinical trial intervention were not administered to) should be provided compensation and/or medical reimbursement, as applicable.
Current guidance that were released in early June 2014 have been amended to now include that “Standard of care” should be provided to all subjects taking part in placebo controlled trials. Where appropriate standard of care is provided, there is not an option to claim compensation for inefficacy of treatment.
Conclusion
With the changes above, the clinical trial environment in India is now transforming. In the past, a fractured environment that lacked oversight meant there were more opportunities for unethical practices. Although the clinical trial industry has been severely affected, it emerges now with increased transparency, objectivity and a clear understanding the roles required in upholding the integrity of the trial.
To get to where we are now, many parties and independent committees have met and worked together, thus unifying what was a divided field, driven by a common cause to elevate good clinical research practices.
