Projects not initiated by investigators: A retrospective analysis of the queries raised by the institutional ethics committees of a teaching hospitalSS Kuyare1, PA Marathe2, YC Shetty2, SK Kamat2, JV Katkar3, UM Thatte4
1 Department of Microbiology, Seth GS Medical College, Acharya Donde Marg, Parel, Mumbai, Maharashtra, India
2 Department Pharmacology and Therapeutics, Seth GS Medical College, Acharya Donde Marg, Parel, Mumbai, Maharashtra, India
3 Institutional Ethics Committee, Seth GS Medical College, Acharya Donde Marg, Parel, Mumbai, Maharashtra, India
4 Department of Clinical Pharmacology, Seth GS Medical College, Acharya Donde Marg, Parel, Mumbai, Maharashtra, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.128808
Source of Support: None, Conflict of Interest: None
Background: Some investigators on receiving queries from Institutional Ethics Committee (IEC), either leave the queries unanswered or withdraw their studies. The present study was conducted to assess the queries raised by two IECs after reviewing studies that were not initiated and to identify reasons for the same. Clinical Trials Registry-India (CTRI) website was checked to review approval status of these studies at other sites. Materials and Methods: A retrospective analysis of studies (submitted between January 2006 and December 2011) not initiated by investigators on receiving queries from IECs were identified. The nature of of these studies: whether sponsored (pharmaceutical industry (pharma)/government/investigator initiated), single-centre/multi-centric, and queries raised were analyzed. Status of multi-centric trials; not initiated at our site was checked at CTRI. Data was analyzed using descriptive statistics. Results: A total of 219/2075 (11%) studies were not initiated. The proportions in pharma sponsored, investigator initiated, and government sponsored were 33%. 7.4%, and 8%, respectively. Out of a total of 1676 queries, the maximum queries were related to ethics (42%) and the least were administrative (7%). The largest proportion of queries in the pharma studies was ethical (47%), whereas majority were scientific queries (45.5%) for the investigator initiated studies. Twenty-one of the 94 multi-centric studies not initiated at our site were found registered at the CTRI and were ongoing or completed at 2-55 sites. Conclusion: Inability of investigators to defend studies due to lack of good clinical research practice (GCP) and research methodology training or unwillingness of sponsors to comply with local IEC requirements could be potential reasons for studies remaining uninitiated. Continued GCP training of investigators and IEC members and development of uniform ethical review standards across IECs are strongly recommended.
Keywords: Ethical issues, informed consent document, institutional ethics committee, standard of care
The concept that there should be a peer review of a proposal by an Institutional Review Board (IRB) or Institutional Ethics Committee (IEC) was introduced in the Declaration of Helsinki, 1964,  as one of the mechanisms along with written informed consent (which was introduced in the Nuremberg Code, 1949)  to ensure research participant protection. In India, the Indian Council of Medical Research (ICMR) recommended for the first time the voluntary establishment of ethics committee in the "Policy Statement on Ethical Considerations involved in Research on Human Subjects"' issued in 1980.  Since then, clinical research has expanded, with the introduction of multi-centric, international studies, research on newer techniques/areas like stem cells, biologics, stored tissue samples, and devices and an explosive increase in genetic research. National and international efforts have tried to keep pace with this progress by developing and expanding guidelines for IRBs/IECs to function to meet the emergent challenges. ,,,,
While reviewing research studies, in addition to ethical concerns, an Ethics Committee raises scientific, administrative, and regulatory queries and provides recommendations to investigators keeping the best interest of study participants in view. The investigator is expected to provide an explanation to the questions raised by the IEC and comply with its recommendations.
While serving on the IEC, we observed that several studies were not initiated at our site following queries raised by the IEC. Some sponsors/investigators also withdrew their studies from the review process. We noted that some of these studies had been initiated at other sites in the country. In view of the fact that this raised potential ethical issues, we conducted this study of assessment of queries raised by the IEC in an attempt to identify whether these could have led to noninitiation of studies at our centre. Further, we made an effort to find out whether multi-centric studies, which were not initiated at our site had received IEC approval at other sites.
This was a retrospective study, which included an analysis of data over a period of 6 years (January 2006 to December 2011). Our institution has two IECs, working according to identical standard operating procedures (SOPs). Both are recognized by the Forum for Ethical Review Committees in Asia and the Western Pacific (FERCAP). Our study was initiated after obtaining approval and waiver of consent from the IECs. Confidentiality was strictly maintained and all authors were members of the committees at the time of doing the study.
From all the proposals received by the IEC Secretariat (which are then farmed out to the two IECs for review as per our SOP), we identified studies not initiated by the investigator following queries raised by the IECs. We excluded studies that were not initiated by investigators even though they had received approval from the IEC. The minutes of the meetings, which discussed these projects were reviewed and the following data extracted: sponsor [pharmaceutical industry(pharma)/government/investigator initiated], single-centre/multi-centric, and the queries raised by the IEC during the meeting. These queries were grouped under different headings namely, scientific (e.g., rationale for the study, study design, adequacy of sample size), ethical (e.g., withholding of standard of care, risks vs. benefits, provision of compensation for research-related injury, modification of compensation-related clause in informed consent document, provision of compensation for participation), regulatory (e.g., DCGI approval of drug, intellectual property rights issues), and administrative (e.g., nonsubmission of essential study-related documents, issues related to interdepartmental approvals, issues related to study team).
The status of multi-centric clinical trials, which were not initiated at our site because of either unanswered queries or termination of the study by the sponsor at our site, was reviewed at Clinical Trials Registry-India (CTRI) at www.ctri.in. 
Data was expressed as median, range, and proportions using GraphPadInstat 3.0 (Windows 95, GraphPad Software, San Diego California USA, www.graphpad.com)
The IEC Secretariat received a total of 2075 research proposals during the study period, of which 258 (12%) were pharma sponsored, 65 (3%) were government sponsored, and 1752 (85%) were investigator initiated. Of the 258 pharma sponsored projects received, as many as 85 (33%) were not initiated. A small proportion of the investigator initiated (129/1752, 7.4%) and government sponsored studies (5/65, 8%) were not initiated. Thus, a total of 219/2075 (11%) studies were not initiated; of which about 2% (37/2075) studies were withdrawn by the investigator while the remaining 9% (182/2075) did not respond to the queries in any way.
A total of 1676 queries were raised for the 219 studies not initiated by investigators, and these are summarized in [Table 1]. Of the four categories into which the queries were classified (scientific, ethical, regulatory, and administrative) the largest proportion were of an ethical nature (711/1676; 42%), followed by scientific (528/1676; 32%), regulatory (321/1676; 19%), and administrative (116/1676; 7%).The number of queries raised per project ranged between 1 and 23 (median 7). The maximum queries per project were generated in government sponsored studies (median; range: 12; 4-17), followed by pharma sponsored (median; range: 8; 1-23), and investigator initiated studies (median; range: 7; 1-17).
Pharma sponsored studies received a total of 723 queries, of which the maximum were ethical (340/723; 47%) for a total of 85 projects. The largest proportion of queries in the 129 investigator initiated projects, in contrast, were of a scientific nature (406/892; 45.5%). Although the number of government sponsored studies that were not initiated at our site was small (n=5), the maximum proportion of queries generated were ethical (31/61; 51%).
Pharma studies contributed to the maximum proportion of regulatory queries raised (214/321; 67%) while investigator initiated studies led to the maximum proportion of scientific queries (406/528; 77%).Both pharma and investigator initiated studies led to approximately half the number of the total ethical queries raised (340/711; 48% each).
Issues that may have led to noninitiation of studies could not be identified with certainty as there were multiple queries raised per project, which could have led to this. However, some of the issues that may have been responsible are summarized in [Table 2]. Queries about sample size, eligibility criteria and inappropriate study design were the major scientific issues raised. More than half the ethical issues that were largely left unanswered were related to the informed consent document or process. Other commonly raised issues included the lack of provision of free investigations or treatment with study-related medications, recommendation of additional tests requested by the IEC for the safety of the participants, and concerns about an unfavorable risk benefit ratio. Administrative queries were mostly related to an inappropriate study team (including not having dedicated study coordinator) for pharma studies and lack of appropriate administrative approval for investigator initiated studies.
Regulatory queries were the most common in pharma studies. The major road block was regulatory approval (35/85 proposals; 41%), which was asked for by the IEC. In one case, the IEC insisted on regulatory approval as the total dose and regime of an approved drug being investigated was changed and it therefore became a Phase III study. The sponsor withdrew the study at our site saying that only notification was needed in this case. A survey of the CTRI website revealed that this study was completed at three other sites in the country. Nine investigator initiated studies were not started as the IEC asked for regulatory approval as the drug under trial was to be administered with for a new indication (8) or change of route (1). Lack of training in good clinical research practice (GCP) of study team (a requirement of the IEC) was the most common issue with investigator initiated studies.
Of the 219 studies not initiated at our site, 94 were multi-centric studies (81 pharma, 4 government, and 9 investigator initiated studies). As registration of clinical trials at CTRI was made mandatory by Indian regulatory authorities from June 15, 2009,  the studies were further classified into studies submitted before or after this date. Of the 58/81 pharma sponsored studies submitted before June 15, 2009, 6 were found on CTRI. Of the 23/81 pharma sponsored studies submitted to the IEC after June 15, 2009, 14 were found registered. None of the 3/4 government studies submitted before June 15, 2009 were registered while the only one submitted after June 15, 2009 was registered. None of the investigator initiated studies was found on the CTRI website.
Thus, a total of 21 of 94 multi-centric studies that were not initiated at our site (including 9 global studies) were found registered at CTRI and were either ongoing or completed at 2-55 other Indian sites per study. The sponsor had either deleted the name of our site in 14 studies or mentioned the status of the study at our site as 'under review'.
A sub group analysis of the queries that IEC had raised to these 21 studies revealed that of the total 157 queries these studies received, the maximum were ethical (84; 54%), followed by regulatory (45; 29%), scientific (21; 13%), and administrative (7; 4%).
One of these global studies had generated a query related to using a placebo and withholding standard of care. The IEC was not satisfied with the justification given in the protocol and therefore a query was raised. Subsequently, the sponsor withdrew our site stating lack of patients at our site, but we found that the study had not only received DCGI approval but also started at four other Indian sites.
This study found that as many as 11% of the submitted studies were not initiated at our site following queries raised by the IEC, the major proportion of these being pharma sponsored. The largest proportion of queries raised in investigator initiated studies were of a scientific nature, while pharma and government sponsored studies generated the most ethical queries. Pharma studies contributed to the maximum proportion of regulatory and administrative queries raised while both pharma and investigator initiated studies each led to approximately half the number of the total ethical queries raised. These results need to be appreciated against the fact that our study did not review the decisions of the IEC but rather focused on the queries raised, which the sponsors/investigators were given ample time to respond to.
Earlier, Boyce reported that of the 353 studies submitted to an IRB in London, 330 were approved, 1 was rejected, 9 were conditionally approved but not pursued by the researcher, whereas the remaining 13 studies (3.7%) were withdrawn.  Interestingly, in our study although 11% of the studies submitted were not initiated, only 2% studies were withdrawn by the investigator. Investigators and sponsors often look on IRBs as obstacles and when queries are raised, prefer to change the research topic (in case of investigator initiated) or the site (in case of pharma sponsored) rather than defend their project. ,,
Of the total investigator initiated studies submitted to our IEC, only 7.4% were not initiated at the site. Fifty-six (of 129) were dissertations of postgraduate students and it was not surprising that these studies had received the most science-related queries. Training in research methodology is often lacking at both postgraduate and undergraduate level and this is reflected in the observation that investigators were unable to defend their studies in response to queries raised by the IEC. That training in research methods is inadequate and needs to be incorporated in the curriculum has been stated earlier.  However, disturbingly, as many as 73 studies were academic initiated by faculty members and reflected the lack of training or the commitment to follow up on queries related to their projects. Here again, the need for ongoing training is highlighted among senior and junior faculty. Further, 26 investigator-initiated projects were not initiated after Principal Investigator (PI) was asked to submit evidence of GCP training of the study team reflecting either a lack of awareness or apathy toward need for continued training. There is also a need to have more easily available "approved" on-line GCP training courses to encourage students and faculty to get trained.
Interestingly as many as 33% of the submitted pharma sponsored studies were not initiated after we raised queries. The type of issues raised in these studies were ethical and regulatory, and included an inappropriate risk-benefit ratio, issues in the informed consent document and process, as well as lack of DCGI approval. Pharma sponsors, especially of global studies, are often loathe to make locally recommended informed consent document (ICD) changes (except, e.g., name of IEC or person to contact). Compensation for research-related injury and simple and accurate vernacular translations, as well as complexity in the ICD have been the most common bones of contention. 
The issue of placebo-controlled studies has always generated a huge amount of global debate. , As stated in the results, the study in which the IEC had raised objections to withholding standard of care and administering placebo instead, was withdrawn by the sponsor rather than defending their protocol. This observation illustrates that there is variability in ethical review when multiple review boards examine one protocol. Menikoff has commented on this issue earlier where he states, "…there is reason to believe that not only do these duplicative reviews provide relatively few benefits, but the current framework may actually reduce the likelihood that studies are in keeping with relevant ethical standards".  As the study in fact was actually conducted at the other sites, it would perhaps have been useful to communicate our concerns with the other IECs,  a practice not very popular with IECs as yet.
The variable interpretation of regulatory requirements is another aspect that needs to be addressed as was seen in our study. We found that one sponsor had initiated a study at three sites, although our IEC had asked for DCGI approval for change in dose and schedule of the investigational agent. This highlights the need for continued training of IEC members especially regarding new regulatory and ethical requirements as well as improved communication between ethics committees in over-seeing multi-centric studies.
Because of the availability of the CTRI, and more so because of registration becoming mandatory after June 2009, we were able to find 21 studies not initiated at our site ongoing at other Indian (315 sites) and global (90 countries) sites. One of the recommendations in view of this variable review process in IRBs in multi-centric studies has been the use of a central IEC for such studies. ,
Our study is limited by the fact that the concerned investigators were not interviewed to find out reasons for noninitiation of their studies. It can be argued that the review of the protocols by the IECs was considered "restrictive" by the investigators or sponsors, which led to the withdrawal or noninitiation of their studies. Questions have been raised about the "effectiveness" of protocol review by IECs especially with respect to participant protection  and hence it is important that there is oversight of functioning of IECs with a regular audit of their performance and periodic training of IEC members. The practice of IEC shopping is common among sponsors and may be allowed when a sponsor asks many sites simultaneously to obtain local IEC approval for a muti-centric study. However, engaging in IEC shopping by submitting protocol to a new IEC if rejected by first  and not informing the new IEC of previous IEC disapprovals is unethical.  We did not have information regarding why a study was not initiated or was withdrawn at our site and whether the sponsor approached the other IEC after receiving our queries or simultaneously. Therefore issues such as "ethics committee shopping"  by sponsors could not be identified with certainty as being the raison d'etre for withdrawal/noninitiation.
The present study showed that investigators or sponsors withdraw studies or leave queries unanswered at a site after receiving IEC queries for ethical, scientific, regulatory, and administrative reasons. Unwillingness of the pharmaceutical industry to comply with local IEC requirements and inability of investigators to defend studies due to lack of GCP and research methodology training could be potential reasons for studies getting stalled. Continued GCP training of investigators and IEC members and development of uniform ethical review standards across IECs are strongly recommended.
The authors acknowledge with gratitude the contribution of Dr Kannan Sridharan in the statistical analysis of the study data.
[Table 1], [Table 2]