Over the last five years India has become a preferred destination for global trials. This globalization has brought challenge of compliance to global regulatory and ethical norms. To meet this demand, Indian regulatory system had been on an evolving mode for quite some time now. From an era of bureaucratic hurdles, delayed approval timelines and lenient attitude towards misconducts, it is rapidly moving to an era of fast- track approvals, active inspection of sites and mandatory registration of Indian trials in national trial registry in an attempt to meet global regulatory expectations of stringency and transparency.
Recent regulatory reforms initiated by the CDSCO
Fast-tracking approval timelines:
In September 2009, the CDSCO revised timelines for various regulatory processes. If application is complete, first response from DCGI office can now be expected within 30 days for T license and 45 days for approval of clinical trial applications. Moreover, one can check the status of their application since the approval letters sent out by the DCGI office are displayed in the CDSCO website under ‘Daily Dispatch’ section.
Single_- window clearance for export NOC:
The Indian regulators have recently introduced a single-window approval process through the DCGI for trial related biological sample export NOC. Earlier, upon getting permission to conduct a trial from the DCGI, an applicant had to apply separately to the Directorate General of Foreign Trade (DGFT ) for obtaining an export NOC. This process has been simplified and fast -tracked, since now an applicant can apply for trial permission as well as export NOC simultaneously to DCGI, without need for separate application to DGFT. As per revised timelines, export NOC can now be expected within 10 working days, in contrast to the previous 2-4 weeks timeline for DGFT approval.
Stringent pre-approval review process:
Fast- tracking of approval process does not imply the DCGI has become lenient and will approve any and all applications. On the contrary, for global trials, the US IND number and US IRB approval letters need to be submitted along with trial application; the ethical and scientific aspects are closely scrutinized by the regulators including protocol procedures, rationale for sample size etc. Queries are being raised more frequently by the DCGI office and in the scenario of lack of appropriate justification by the applicant trial might get rejected.
Compliance to GCP and ICMR guidelines:
The approval letter issued by DCGI does not give blanket approval; rather it requires the applicant to comply with principles of GCP and ICMR guideline, making these guidelines an important precondition for regulatory approval.
Importance of GCP in today’s scenario:
GCP, as we know, refers to a set of guidelines which ensures ethical and scientific quality standard in the conduct of a clinical trial, encompassing its design, conduct, monitoring, termination, audit, analysis, reporting and documentation. The basic aim of GCP is to ensure that studies are scientifically and ethically sound and the data generated is authentic and credible, thus acceptable globally. With the number of global trials outsourced to India increasing by day, the importance of compliance to GCP cannot be overemphasized, since without assurance to GCP compliance trial data will not be acceptable by global regulators.
SOPs—tool to implement GCP
An important tool to implement GCP is the Standard Operating procedures (SOPs) which refer to standard, elaborate, written instructions to achieve uniformity of performance in all the tasks related to the conduct of a trial. SOPs form the basis of a GCP compliant trial by allowing uniformity and standardization of tasks, and, more importantly by fulfilling regulatory requirements. All the stakeholders in a trial (sponsor, investigator, EC, regulators) are required to follow SOPs pertaining to their tasks. The sponsor is required to prepare, follow and document SOPs on the conduct of trial related activities, process of data management, record keeping, internal QA & QC processes; the investigator is required to comply with the sponsor SOPs while conducting the trial; moreover, the site is required to have its own SOP, in agreement with the sponsor SOPs for various activities related to study conduct such as source data management, screening, enrolment, IC process, subject management while on study, AE and SAE reporting and handling, specimen collection and dispatch, IP management, CRF management, archiving etc; the EC is required to prepare, follow and document its own SOPs on member selection process, duties of EC members, functioning and operation of the EC including frequency of meetings, review process, method of communication or notification etc. From a regulatory view point SOPs offer a written record for all trial related activities undertaken by all stakeholders, thereby facilitating audit and inspections by the regulators. This in turn assures quality of data generated and thus its global acceptance.
ICMR ethical guidelines for biomedical research (2006):
The 2006 revised ICMR guidelines, currently awaiting clearance by parliament to become law, incorporates issues such as registration of ECs under a national authority, tentatively termed as ‘Biomedical research authority’ which will evaluate and monitor functioning of ECs and develop mechanisms for ensuring transparency and accountability in the conduct of EC activities. The guideline also talks about training EC members on GCP and ethical issues of clinical trial in order to make them competent of reviewing trial proposals.
Mandadory registration with CTRI
The National Clinical Trial Registry at www.ctri.in launched by National Institute of Medical Statistics (NIMS) under the ICMR is now operative for the last two years (since July 2007). However, until recently the registration was voluntary, or at the most advisory. Since June 2009 prospective registration with CTRI has been made mandatory for all trials to be conducted in India. By making all important trial- related information (such as inclusion exclusion criteria, protocol summary, site details, name of contact persons, total sample size etc.) available in public domain, CTRI ensures accountability and transparency in conduct of trials, two essential demands of globalization. Once the mandatory fields are filled out by the applicant and the details are verified by the site administrator, a CTRI registration number is generated for the trial which needs to be notified to the DCGI before the first patient can be enrolled. Recently CTRI has mandated full contact details of each site and investigator, including their phone number and mail ids to be incorporated and also the DCGI and EC approval letters to be forwarded to the site administrator so that the trials can be verified before granting registration with the site. ICMR is currently working towards upgrading the CTRI registration system so that audit trails could be traced each time applicant makes changes in the data. Also, given the huge number of trials being sent to the site every day, authorities are considering automatization of the check process to verify data, replacing the current manual check process.
DCGI inspection of trial sites:
Another welcome initiative taken by the DCGI is to conduct inspection of trial sites. Recently the DCGI inspectors had visited an Indian site which reported death of an infant participating in a vaccine trial by a foreign company and halted the trial suspecting violation of regulatory norms. The process is expected to be on full swing by December 2009, with trained teams of inspectors visiting trial sites across India randomly. The DCGI, in collaboration with USFDA has recently concluded an initial training session of 25 members to be designated as potential inspectors.
Future plans (2010-2015):
DCGI is planning to initiate a system of registration and accreditations of CROs, in an attempt to quality check their activities. A draft guideline on the CRO registration process has already been made and is proposed to be incorporated as new Schedule Y1 to Drugs and Cosmetics Rules, 1945
● Registration of clinical trial sites
● Registration of EC/IRBs
● Opening doors to allow early (phase I) phase trails for foreign molecules in India
● Creating environment for Phase 0 or micro dosing studies in India
● Ensuring penal provision for fraud and misconducts in clinical research
● The CDSCO has a further futuristic plan of implementing e-governance program which would enable companies to file, track and review trial applications online.
Conclusion
In conclusion, Indian regulatory system has started adapting itself to the demands of quality, transparency and accountability of global trials. The recent initiatives underscore the fact that our national regulatory authority is in the process of becoming more pro-industry, more vigilant and more efficient, which translates to a more US FDA-like regulatory system that by all means is the need of the hour.
-Authors are working with Clininvent Research Pvt Ltd