CASE STUDY RESPONSES
Knowledge vs ethics in clinical research in resource-poor settings: a clinician’s perspective
B Subha Sri
This case study of the 1970s (1) no doubt raises several ethical questions. I will however try to look at the case study from the perspective of a gynaecologist and primary care physician attempting to establish a community-based cervical cancer screening and care programme in rural Tamil Nadu.
There is enough knowledge today that cervical cancer is caused by the Human Papilloma Virus and progresses through stages of cervical intraepithelial neoplasia (CIN), carcinoma in situ (CIS) to invasive cervical cancer. This knowledge determines the modalities of screening and treatment recommended today for cervical cancer and its precursors. However, while attempting to analyse the case study to draw lessons for current practice, one needs to start from the scientific evidence that was available regarding cervical cancer precursors at the time of the study, to consider whether a study to understand the natural history of cervical cancer was necessary, and whether the study was justified in its design of following up women with proven dysplasia without any intervention, given the evidence available at that time.
Since I have no personal knowledge of the clinical scenario in the period of the study, I looked through literature on the history of cervical cancer treatment and also spoke to two senior gynaecologists who were working in premier medical institutions in India at that time. I understand that the progressive nature of cervical dysplasias (as they were called then) to cervical carcinoma was well known by the early 1970s. In 1968, Richart (2) indicated that all dysplasias have the potential for progression. However, there seems to have been a lack of clarity on how exactly each grade of dysplasia behaved and what proportion actually progressed to invasive cancer. This was an important issue, especially while evolving guidelines for treatment in high disease-prevalent resource-poor settings like India. Based on existing understanding, while carcinoma in situ was most often treated with hysterectomy, severe forms of dysplasia were often treated with an excisional cone biopsy of the cervix. Treatment for mild and moderate dysplasia did not seem to have any standard protocol and varied between individual facilities. Answers to questions regarding the natural history of dysplasia would therefore, at that point, definitely have helped in evolving context-specific guidelines for clinical decision making.
Also, there seems to have been a widely held view that since cervical cancer was highly prevalent in the developing countries of south Asia, and there was a possibility of ethnic variations in disease pathology, studies on South Asian women were needed. While these arguments may be used to justify planning a study to understand the natural history of dysplasia and cervical cancer, how does one decide if such studies are really needed? How does one decide when the evidence generated in “developed” countries is relevant to the question at hand, and when indigenous studies are in fact needed?
Moving on, even if one were to accept that the study was indeed justified, was the methodology planned appropriate and ethical? First, did the institutions carrying out the study have the necessary infrastructure to take on a study of this magnitude? The study involved following up women with possible cancer precursors with the potential of developing into a serious, life-threatening disease. Were the institutions capable of the stringent recall and follow-up required in such cases? Given that they could not handle the final disease if it developed, were they even justified in taking on the study? Given the significant false negative rates of Pap smears, well known in the 1970s, were they justified in relying on Pap smears alone to reach an end point of CIS to begin treatment when it was likely that this already meant foci of invasive carcinoma were present in the woman? This was a time when modalities like colposcopy were being used in other countries (3 , 4). Other technologies were thus known and available to evaluate women with cervical dysplasia, while this study relied solely on Pap smears. Was it okay to agree on CIS as the end point for follow-up when it seems to have been common knowledge then that severe dysplasia or CIN III and CIS were part of the same continuum? Should there not have been systems for interim monitoring of such a long-term study so that changes in global clinical practice, such as those influenced by the other study published in the North American journal, would have been taken into account? If the questions that the study had set out to achieve were already answered by another study, should this study not have been terminated? Shouldn’t women in this study have been given the benefit of knowledge gained from that study and offered treatment?
There are also some other questions that I would pose as a clinician. How does one balance the roles of a clinical caregiver and researcher, especially when these may be in conflict? In this study, the researchers were mostly clinicians whose primary responsibility was patient care. Shouldn’t the basic principles of clinical ethics of beneficence, non maleficence and patient autonomy apply in these settings too? Aren’t these also ethical principles guiding research? If one accepts this, then, in view of the long-term nature of the follow-up and the implications of not intervening, the women should have been consulted at every stage in decision-making regarding their care, regardless of their initial consent to be part of the study. In this particular case, the initial consent also seems to have glossed over several important facts well known to the researchers at that time, such as the lesions’ potential to progress to invasive cancer. Patient autonomy cannot be overridden even if the clinician believes in good faith that what s/he is doing is best for the patient – though even this does not seem to have been the case here. Also, the least the clinicians could have done was to expedite treatment for these women once they developed carcinoma. That they failed to do so reveals a total lack of concern for the women in the study as compared to the research outcomes.
Then, what about public health ethics? How does one strike a balance between clinician and public health researcher? What if, truly, this study had uncovered a different pattern of progression of dysplasias in south Asian women? Would it then have been justified in its design and methodology? Would the larger good of understanding cervical dysplasia in south Asian women to benefit women in the future have been justification enough for following up women with dysplasia in this study without intervention? I do not think so. Even if the study were justified in terms of the larger public good, adequate safeguards should have been built in, so that women in this study also received the benefits of existing and emerging knowledge, whether from this study or elsewhere. Interim monitoring of results, terminating the study in the face of the results of the other study, expediting treatment for women whose dysplasias progressed in severity – all of these should have been necessarily built into the study.
This case study brings up several concerns on the regulation of research studies in developing countries including India. While the situation now is vastly changed from the era of this study, it is also true that there is an explosion of clinical trials happening now in India. Questions such as what kinds of trials may be carried out in developing countries like India, and what kinds of problems they should address, gain relevance. Even if one were to accept that certain problems relevant to our country need clinical research based here, how does one safeguard the interests of trial participants? This gains significance especially given the large scale poverty, marginalisation, and lack of literacy and information in countries like ours. How does one ensure that the marginalised are not exploited and are in a position to negotiate safeguards for their benefit in a research setting?
Research priorities in developing countries need to be driven by the sometimes unique clinical needs of these countries. However, carrying out research studies in resource-poor settings can be challenging. This can very often result in compromises in ethical standards for reasons of “practicality”. The role of regulation and regulatory bodies is, therefore, crucial in such settings. This is all the more critical given that, most often, research subjects in these settings are the very marginalised.
I wish to acknowledge the contributions of Dr Asha Oumachigi, Retired Professor of Obstetrics and Gynaecology, JIPMER Pondicherry; Dr Lakshmi Seshadri, Retired Professor of Obstetrics and Gynaecology, CMC, Vellore, and Dr Rakhal Gaitonde, Public Health Researcher, Chennai, during the development of this comment.
- Cash R, Wikler D, Saxena A, Capron A, editors. Casebook on ethical issues in international health research. Geneva: World Health Organisation 2009;124-5.
- Richart RM. Natural history of cervical intraepithelial neoplasia. Clin Obstet Gynecol. 1968:10:748-84
- Coppleson M. The value of colposcopy in the detection of preclinical carcinoma of the cervix (Three years’ experience at King George V Memorial Hospital, Sydney). BJOG: An International J Obstet Gynaecol Br Emp. 1960 Feb; 67:11 – 23. doi:10.1111/j.1471-0528.1960.tb06945.
- Navratil E. Colposcopy. In: Gray L A, editor. Dysplasia, carcinoma in situ and microinvasive carcinoma of the cervix uteri. Springfield, IL: CC Thomas; 1964. p. 228-83.