The new amendments of regulations for clinical trials have shaken the pharmaceutical and clinical research industry. Most of the amendments are aimed towards reforming the clinical trial industry. The major impact is on the sites which eventually get translated to all the stakeholders like ethics committee (EC), contract research organization (CRO), sponsors, patients etc. Registration of EC, compensation & free medical management for any clinical trial related injury, serious adverse event (SAE) reporting guidelines, change in consent taking process, inspections etc. all are expected to improve regulatory and ethical compliance in conduct of clinical trials (CT).

EC registration
The first and foremost impact before undertaking any trial is compulsory registration of an EC. Unless registered with Drug Controller General of India (DCGI), no EC can review and approve any protocol of a CT. Only those sites that have a registered EC will be able to undertake any CT. This will curtail functioning of independent ECs, which were giving approvals without actually pursuing their roles and responsibilities. Small private clinics that would earlier approach such independent EC will not be able to undertake trials. Thus, the number of sites available for CT will be reduced as compared to earlier availability. And these limited sites may get over burdened with more number of trials; thereby affecting the quality of trial conduct.

Registration process will require ECs to get all their documents and processes in place and submit an application in a prescribed format. Along with preliminary details of EC and all members; training documents/certificates proving that members are conversant with all the applicable regulations; details about all the past trials and documents reviewed by them along with details of meetings and review of SAEs; all standard operating procedure (SOPs) and policies regarding vulnerable subjects, conflict of interest; details of previous audits or inspections of EC have to submitted when applying for registration. The chairman of the EC will also have to give an undertaking that EC will approve and conduct an ongoing review of trial as per regulatory requirements; analyse and opine on SAE; allow inspections and maintain records of trials for five years.

Thus, ECs will have to spend time, money and other resources to ensure that all the proceedings are in accordance with the new rules. Major implication is requirement of up- to- date knowledge of all the members about applicable regulations and ethical guidelines. All members of EC should be equipped with education and regular training to enable them to critically review and approve any protocol; analyse and give opinion on SAE causality and quantum of compensation to the licensing authority. EC members will also have to devote sufficient time and energy to be committed to their roles and responsibilities. They all should be available to have a timely meeting and ensure adherence to the SAE reporting timelines. The EC has to conduct continuing review during the trial conduct, by reviewing progress reports from the investigator, SAE reports and overall trial conduct at the site. Also, the facilities at the office should be conducive and equipped for all the administrative work like maintenance of records, effective communication and archival facility.

Compensation
As per new rules, the patients are eligible for free medical management and compensation for any trial related injury and compensation to the nominee in case of death; payable by sponsor. The DCGI office will determine the final quantum of compensation based on reports submitted by investigator, EC, sponsor and recommendations of expert committee. If the sponsor fails to pay the compensation within stipulated time, the trial may get cancelled. The expert committee has released the formula for calculating compensation, which takes into account the base amount (Rs 8 lakhs), the age of the clinical trial subject, and the risk for the subject. The compensation ranges from Rs four lakhs to Rs 73 lakhs. The sponsors will have to budget for this compensation amounts and also take adequate insurance to take care of compensation.

Informed consent
Informed consent form (ICF) should be amended to include information about free medical management and compensation; and details about subject and nominee. The investigator should make sure that this information is communicated clearly to the subject.

New proposed rules will require investigators/sites to have an audio-video recording of the consent process. Thus, a proper audio-video recording facility with a proper storage and archival facility of all such recordings will be required. Even though this may ensure documented consent from a patient, but he/she might not be comfortable being recorded. Also, maintaining patient’s confidentiality may be an issue; especially with technical staff who is recording and any translator or impartial witness present during the consent process.

Essential documents
Sites will have to make sure that all the essential documents are amended as per new rules, especially ICF, clinical trial agreement (CTA), Investigator and sponsor undertaking, revision of SOPs.

Inspections
All stakeholders especially sites should be ready for CDSCO inspection at a short or no notice. The usual inspection findings noted are on deviations in consent, non-compliance to protocol, lack of SOP, EC approval process, Investigational product management, discrepancy in CRF data, SAE reporting and compensation, inadequate infrastructure, documentation, archival facilities etc. The sites have to be trained to be ready for inspections.

SAE reporting
Any SAE has to be reported by the investigator within 24 hours and a due analysis report within 10 days to sponsor, EC and DCGI. The sponsor, the investigator and the EC also have to notify SAE report after due analysis to DCGI in prescribed manner and within stipulated time-frame. SAE reports will be analysed by the expert committee and licensing authority to arrive on the causality and the compensation quantum. Arriving at causality with sufficient and thorough analysis will be difficult, as the focus is on clinical trial related injury. Thus investigator, sponsor and EC members will need adequate training on various domains, to analyse the SAE and to arrive at causality.

Immediate impact on industry
The immediate visible impact is delayed process of obtaining approvals from DCGI to conduct CTs. In the past year or so, the number of approvals given by DCGI has decreased and time frame of receiving approval has increased. The industry faces challenge of selecting appropriate sites with registered EC, training of EC members and site staff on new regulations along with regular and in depth monitoring and audit to ensure compliance. Adequate compensation will require increased budget and insurance cover. These changes have increased responsibility, and accountability of all the stakeholders.

However, the questions are: The speed of conducting CTs in India was considered as unique selling point (USP) for global CTs. But now with increasing cost and decreasing speed and yet to be attained quality, does India still have a chance to attract global trials? Even after increased time and money spent by the industry, will it really improve the quality of CTs? This can only happen if all there is a paradigm shift from quantity to quality and cost to compliance!