Ensuring patient safety is an essential requirement for clinical trials. This aspect has been neglected in most of the clinical trials conducted in developing countries such as India. Even in the developed countries like US also, as reported by McCarthy M (1), failure by the researchers to stick to their stated plans, to protect the safety of trial participants, and to maintain good records, have been cited as common reasons for warning letters issued by the US Food and Drug Administration (FDA) to clinical investigators.
Shetty UC (2) reviewed the content of 84 first warning letters issued by the United States Food and Drug Administration (USFDA) following site visits to 46 trial sponsors, 20 lead researchers, and 18 institutional review boards, which assess and monitor safety, between 2005 and 2012. They have found that the most common concern raised among clinical trial sponsors was a failure to monitor progress according to the stated schedule (58 per cent), followed by a failure to obtain the agreement of the principal investigator (35 per cent).
Under such circumstances, what could be done to ensure patient safety during clinical trials ? The Government of India has notified some changes in the context of clinical trials in India (3). Notification of the Government of India provides provision for compensation to the client in case injury or death resulting from participation in the clinical trial in the following ways: (i) free management as long as required in case of injury occurring to the clinical trial subject, (ii) financial compensation as per order of the Licensing Authority to the subject if injury, to the nominee in case of death of the subject, (iii) bear medical management expenses by the sponsor of the clinical trial. Compensation in case of injury or death related to the trial should be granted because of the following reasons:
(a) adverse effect of investigational product(s);
(b) any clinical trial procedures involved in the study;
(c) violation of the approved protocol, scientific misconduct or negligence by the sponsor or his representative or the investigator;
(d) failure of investigational product to provide intended therapeutic effect;
(e) use of placebo in a placebo-controlled trial;
(f) adverse effects due to concomitant medication excluding standard care, necessitated as part of approved protocol;
(g) injury to the child in-utero because of the participation of parent in clinical trial.
Steps for ascertainment of the injury or death has been incorporated in the notification. It involves reporting of adverse effects, injury or death by the sponsor to the Chairman of the ethics committee who has granted ethical clearance to the trial, from the ethical committee to the Licensing Authority which will constitute an Expert Committee to look into the matter for appropriate compensation within a specified time frame.
Researchers have been critical about the provision of free treatment to the injured since there is no clear information on the nature of injury, whether related to the trial or not since injury can happen to anybody which may or may not be related to the effects of the clinical trial such as road traffic injury, murder etc. Shukla S (4) has raised the issue of negative impact on the pharmaceutical industry due to the changes in the regulatory requirements. However, the changes are necessary with clear information on the provisions of the notification for providing adequate safety and compensation to the participants of clinical trials.
Measures for patient safety should include formation of “reference groups” or “safety committees” to provide advice on the adequate course of action in situations that may develop during patient safety research (5). The committee may regularly monitor the trial through site visits, patient interaction, review of periodic patient information and reports by the investigators etc. In addition, if patients are hospitalized, a close monitoring and observation by dedicated nurses for the clinical trial could provide the much needed information on adverse effects of the drugs or intervention. The role of the trial subject and his/her close associates or relatives need to be emphasized. They should be educated and motivated to report any effect they have observed in their body during the participation in the study to the investigators so that appropriate safety measures can be undertaken.
References
1. McCarthy M. Failure to adhere to study plans is the most common
research error among US investigators. BMJ 2014;348:g4245
2. Shetty UC, Saiyed AA. Analysis of warning letters issued by the US Food and Drug
Administration to clinical investigators, institutional review boards and sponsors: a
retrospective study. J Med Ethics June 23, 2014. doi:10.1136/medethics-2013-101829
3. Notification of Government of India, Ministry of Health and Family Welfare (Department of Health). G.S.R. 53(E).The Gazette of India Extraordinary, part II-Section3-sub-section (i), New Delhi, 30th January, 2013. Available at http://cdsco.nic.in/writereaddata/GSR%2053(E)%20dated%2030.01.2013.pdf (accessed 23.7.14)
4. Shukla S. India's amended trials regulations spark research exodus. The Lancet 2013;382:845. doi:10.1016/S0140-6736(13)61833-4 (Published Online: 05 September 2013).
Rapid Response:
Ensuring patient safety is an essential requirement for clinical trials. This aspect has been neglected in most of the clinical trials conducted in developing countries such as India. Even in the developed countries like US also, as reported by McCarthy M (1), failure by the researchers to stick to their stated plans, to protect the safety of trial participants, and to maintain good records, have been cited as common reasons for warning letters issued by the US Food and Drug Administration (FDA) to clinical investigators.
Shetty UC (2) reviewed the content of 84 first warning letters issued by the United States Food and Drug Administration (USFDA) following site visits to 46 trial sponsors, 20 lead researchers, and 18 institutional review boards, which assess and monitor safety, between 2005 and 2012. They have found that the most common concern raised among clinical trial sponsors was a failure to monitor progress according to the stated schedule (58 per cent), followed by a failure to obtain the agreement of the principal investigator (35 per cent).
Under such circumstances, what could be done to ensure patient safety during clinical trials ? The Government of India has notified some changes in the context of clinical trials in India (3). Notification of the Government of India provides provision for compensation to the client in case injury or death resulting from participation in the clinical trial in the following ways: (i) free management as long as required in case of injury occurring to the clinical trial subject, (ii) financial compensation as per order of the Licensing Authority to the subject if injury, to the nominee in case of death of the subject, (iii) bear medical management expenses by the sponsor of the clinical trial. Compensation in case of injury or death related to the trial should be granted because of the following reasons:
(a) adverse effect of investigational product(s);
(b) any clinical trial procedures involved in the study;
(c) violation of the approved protocol, scientific misconduct or negligence by the sponsor or his representative or the investigator;
(d) failure of investigational product to provide intended therapeutic effect;
(e) use of placebo in a placebo-controlled trial;
(f) adverse effects due to concomitant medication excluding standard care, necessitated as part of approved protocol;
(g) injury to the child in-utero because of the participation of parent in clinical trial.
Steps for ascertainment of the injury or death has been incorporated in the notification. It involves reporting of adverse effects, injury or death by the sponsor to the Chairman of the ethics committee who has granted ethical clearance to the trial, from the ethical committee to the Licensing Authority which will constitute an Expert Committee to look into the matter for appropriate compensation within a specified time frame.
Researchers have been critical about the provision of free treatment to the injured since there is no clear information on the nature of injury, whether related to the trial or not since injury can happen to anybody which may or may not be related to the effects of the clinical trial such as road traffic injury, murder etc. Shukla S (4) has raised the issue of negative impact on the pharmaceutical industry due to the changes in the regulatory requirements. However, the changes are necessary with clear information on the provisions of the notification for providing adequate safety and compensation to the participants of clinical trials.
Measures for patient safety should include formation of “reference groups” or “safety committees” to provide advice on the adequate course of action in situations that may develop during patient safety research (5). The committee may regularly monitor the trial through site visits, patient interaction, review of periodic patient information and reports by the investigators etc. In addition, if patients are hospitalized, a close monitoring and observation by dedicated nurses for the clinical trial could provide the much needed information on adverse effects of the drugs or intervention. The role of the trial subject and his/her close associates or relatives need to be emphasized. They should be educated and motivated to report any effect they have observed in their body during the participation in the study to the investigators so that appropriate safety measures can be undertaken.
References
1. McCarthy M. Failure to adhere to study plans is the most common
research error among US investigators. BMJ 2014;348:g4245
2. Shetty UC, Saiyed AA. Analysis of warning letters issued by the US Food and Drug
Administration to clinical investigators, institutional review boards and sponsors: a
retrospective study. J Med Ethics June 23, 2014. doi:10.1136/medethics-2013-101829
3. Notification of Government of India, Ministry of Health and Family Welfare (Department of Health). G.S.R. 53(E).The Gazette of India Extraordinary, part II-Section3-sub-section (i), New Delhi, 30th January, 2013. Available at
http://cdsco.nic.in/writereaddata/GSR%2053(E)%20dated%2030.01.2013.pdf (accessed 23.7.14)
4. Shukla S. India's amended trials regulations spark research exodus. The Lancet 2013;382:845. doi:10.1016/S0140-6736(13)61833-4 (Published Online: 05 September 2013).
5. World Health Organization. Ethical issues in patient safety research: interpreting existing guidance. Available at http://apps.who.int/iris/bitstream/10665/85371/1/9789241505475_eng.pdf. (Accessed on 23rd July 2014).
Authors
Mongjam Meghachandra Singh
Professor,
Department of Community Medicine
Maulana Azad Medical College, New Delhi
Reeta Devi
Assistant Professor,
School of Health Sciences,
Indira Gandhi National Open University, New Delhi
Competing interests: No competing interests