Central institutional ethics committee needed to facilitate timely review of multicenter clinical trials.

A multicenter trial in India undergoes review by Institutional Ethics Committees (IECs) of all participating institutions. The failure to obtain approval even from a single institution's IEC creates a situation of inequitable access to clinical trials. The dichotomy in decisions of different IECs is attributed to lack of standardization and accountability in their functioning. The registration of IECs with Central Drugs Standard Control Organization notwithstanding, the current model of IEC review has failed to ensure uniformity in IEC decisions in multicenter trials. Alternative models that allow central review of multicenter clinical trials should be explored.

Context

We were approached by an Indian pharmaceutical company to conduct a bioequivalence study for liposomal doxorubicin, a complex generic formulation. The research protocol failed to receive a favorable decision from our hospital's Institutional Ethics Committee (IEC). Our IEC's decision certainly stood out in this regard because the study was approved by the Indian drug regulatory agency and the ethics committees of all participating centers. An appeal against this decision led to a series of correspondence between the IEC and PI, each interspersed by several weeks of review, and by the time the trial was eventually approved, it was too late to initiate the study. This brings us to wonder whether multicenter trials approved by Drug Controller General of India (DCGI) should only undergo IEC review for specific local issues which are unique to the center, or should it be subjected to a comprehensive review. Alternatively, should a centralized ethics committee be made responsible to discuss and approve the study protocol on behalf of all the participating centers?

Introduction

The function of ethical oversight of research involving human subjects is currently served by the IEC system, based on the prospective and ongoing local review of the proposed research. While clinical research has been around for decades, IECs are still evolving in India and other low and middle-income countries (LMICs).[1] Along with each IEC facing challenges within itself, there is lack of harmonization among IECs operating at various institutions, leading to onerous duplication of efforts to achieve ethics approval for multicenter research.[2] As multicenter clinical trials have become more common, it is pertinent to understand whether the goal of protecting research participants can be achieved by having a single comprehensive review by a central Ethics Committee to minimize the delay in initiating a study.[3]

Pluralism

Indian laws demand regulatory and IEC clearance before initiation of a clinical trial. In spite of this, both bodies seem to work in isolation.[4] Interaction of the two bodies is limited to procedures of IEC registration, serious adverse event (SAE) reporting, decisions on compensation for trial related death or injury and regulatory inspections. The all-important decisions of approval are conveyed directly to the Investigators or Sponsors by the DCGI, but the practice of apprising the IECs of such decisions does not exist, thus creating a potential situation for pluralism in decisions of both bodies. Furthermore, in the absence of a hierarchical oversight, the IEC decisions are mostly unchallenged raising concerns about their accountability.[4]

Harmonization: What Purpose does Registration Serve?

The Indian regulators mandated the registration of IECs since February 2013. However, it is debatable whether this rule has resulted in standardization of functioning among registered IECs. Disparity in training of members has led to differences in how each registered IEC functions, further hindering standardization. A country like India, due to its vast and diverse population, certainly demands a system to oversee the functioning of IECs.[5] Further, while more than 1000 IECs have registered with the Central Drugs Standard Control Organization (CDSCO), the actual impact on participants’ protection and safety of these new regulations still remains to be seen. Thus, a method to oversee all ECs, improved functioning of IECs including on site monitoring, central ECs for multicenter studies and the development of metrics to assess the performance of ECs are the chief priorities at present. As a minimum expectation, registration with regulatory agency should achieve standardization of IECs across the country, without which it cannot be called a successful initiative.

Bridging the Gap

The issue of variable IEC decisions on multicenter trials is the bane of clinical drug development in India. In addition to causing delays in initiating studies, it creates a situation of variable access to clinical trials to patients, thereby violating the principles of equitable distribution of healthcare. One may argue that selection of sites by the Sponsor is itself not equitable. However, it should be borne in mind that site selection by Sponsors is their prerogative and subject to feasibility assessments, and it is not the same as being denied access due to inconsistencies in ethical review. Ethics is not an exact science and differences in opinions related to research ethics cannot be wished away. However, alternate models should be explored to minimize inconsistencies in ethics review for multicenter trials. One such model is of a “central IEC”. The Clinical Trials Transforming Initiative (CTTI) has defined central IEC as ’a single IEC of record for the protocol. It has regulatory responsibility for assuring the protection of the rights and welfare of research participants from initial review to termination of the research, including review and approval of informed consent.[3] ’IEC of record’ is a group designated to monitor research involving human subjects for all sites involved in a research study. This group could be an institution's IEC or a private, independent IEC. “Central IEC” is commonly used to describe other alternative models, such as federated, consortium and facilitated models. Table 1 describes each model with their advantages and disadvantages.

Table 1

Central Institutional Ethics Committee (IEC) Models

IEC model	Description	Advantage/Disadvantage
Federated model	Incorporates a mechanism to establish a shared set of principles, processes, and performance metrics for the review of protocols at participating institutions.This model incorporates three options for IEC review: (i) reliance on a lead IEC (ii) shared IEC review (iii) local IEC review at each study site with access to IEC submissions approved by a lead IEC	Advantage:Maximum flexibility for institution to choose an IEC review process of choiceReduction in duplicative review by IECs across sitesReciprocal acceptance IEC reviews and decisions among organizations
Consortium-based model	This IEC is composed of representatives from each consortium member organization	Advantage:Reciprocal acceptance of IEC reviews and decisions among organizationsDisadvantage:Decision does not extend to IECs of institutions outside the consortium
Facilitated model	The outside IEC and local IECs share information; the outside IEC reviews the protocol first and shares its review with the IECs at the local institutions to facilitate their reviews.	Disadvantage:Still involves review by multiple IECs

The use of Central IEC will encourage more sites to participate in research, as they shall not be faced with the administrative and financial burden of maintaining an IEC. It will also speed up the review process and bring about the much-needed fertile landscape for growth of clinical research in India.[6] Local IECs can continue to exist so long as their responsibilities are decoupled from that of the central Ethics Committee. A guideline for institutions that can help to decouple institutional and central IEC responsibilities needs to be established to assist in the acceptance of centralized ethical review, which has the potential to result in more consistent and efficient reviews of multicenter clinical trials. Figure 1 shows the potential division and sharing of duties among the Institutional and Central Ethics Committees.[3] A charter that clearly spells out the duties, responsibilities and liability terms may be drawn, to rule out any ambiguity in the process. Setting up an alternative arrangement may take significant time and effort of the boards’ chairs, members and administrative staff, and other university staff. It is likely to be a costly endeavour due to the initial time and resource investment, which might deter boards from initiating these agreements.[7] In addition, an appellate mechanism does not exist in the proposed models which means that the ’IEC of record’ would have to make decisions taking into consideration the magnitude of impact it will have on human subject protection across the country. A rejection from the ’IEC of record’ would mean the trial will not see light of day.

Figure 1

Delineation of duties between Central and Institutional IECs. The overlapping portion enlists duties that should be carried out by both committees. *indicates duties that can be carried out by either committee. Execute IEC authorization #: exercise control on certain parts of research at the site. Example: Local IEC = site-specific aspects and Central IEC = science of the protocol

Alternate IEC models have been adopted in countries including USA, Australia, UK and Canada and have been successful at reviewing multicentre research more efficiently, cost-effectively and with reduced turnaround time of projects.[7] A similar system could be replicated albeit with minor customization to suit our requirements. For a start, a common application form for all IECs across India can be an important step to achieve uniformity in functioning of IECs. This would introduce harmonization in the IEC review process, benefitting the research industry as a whole.

Conclusion

We were in a predicament when a multicenter bioequivalence study failed to get approval from our Institutional Ethics Committee in spite of DCGI's approval. Such situations underscore the need for mechanisms to beget consistent decisions on clinical trial applications so as to ensure equitable access to trials across the country. Registration of IECs with CDSCO notwithstanding, the current model of IEC review has failed to ensure uniformity in EC decisions in multicenter trials. Alternative models that allow central review of multicenter clinical trials should be explored.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.