JOIN USBusiness of medical research
Two multinational observational studies on Covid-19 were retracted by The New England Journal of Medicine (NEJM) and The Lancet recently. While the NEJM study had concluded that the risk of mortality was higher in Covid-19 patients with cardiovascular co-morbidity, the disputed Lancet study reported that there were no benefits of treating Covid-19 patients with Hydroxychloroquine (HCQ) or Chloroquine and that the risk of mortality would increase with such treatment. Concerned by the safety of the treatment regimen, the WHO had discontinued its HCQ trials; the retraction of the studies led to its resumption.
Adding to the prevailing ambiguity over the efficacy and safety of HCQ in treating Covid-19 infection, these retractions have also cast doubts on the credibility of clinical research. At the centre of the ongoing academic storm is a little-known clinical data analytics company called Surgisphere Corporation. Formed in 2008, its business is to use patient interaction data to help hospitals become more efficient healthcare providers. However, for The Lancet study, it managed to get health records of more than 96,000 patients across 671 hospitals, working though complex medico-legal structures of six continents. The fact that a company with 11 employees managed to do it in less than four months should have got the investigators using the data curious. That the investigators also missed the uncanny similarity in the mean age, body mass index (BMI), and male/female ratio of the study populations across continents raises serious questions.
However, it would be erroneous to assume that mishaps like these are a new or rare occurrence. ‘Research misconduct’ has been a cause of concern in the scientific community for a long time and the Surgisphere episode has brought much-needed public scrutiny on medical research. In the eagerness to achieve desired results and to be recognised and celebrated by their peers, researchers sometimes compromise on the rigour of medical research, a field of enquiry which has come to be dominated by the biomedical industry for the past several decades. With the rise of contract research organisations, site management organisations and data analytics companies like Surgisphere, the research landscape has become more complex and vulnerable to misconduct. The Surgisphere fiasco reaffirms that industry involvement needs to be looked at more carefully by scientists, reviewers, readers and policymakers.
Leading journals have been grappling with dissipating rigour in clinical studies themselves. Richard Horton, Editor of The Lancet, wrote in 2015 that “much of the scientific literature, perhaps half, may simply be untrue.” He rued that, led by bad research behaviour and flagrant conflict of interest, science has taken a turn towards darkness. Former editor of NEJM, Dr Arnold Relman, had almost prophetically warned about the rise of the ‘medical-industrial complex’ and how it could erode a clinician’s credibility. Jonathan Quick, former director of the essential drugs and medicine policy of WHO, had also expressed similar concerns on the reliability of clinical trials. He wrote that they are under threat from investigators’ conflict of interest, inappropriate involvement of sponsor institutions in study design and management and bias in publishing and disseminating results.
Systematic analysis of clinical trial publications have reported significant association between positive results of such trials and manufacturer funding. Studies have also reported that industry-sponsored research is eight times less likely to report unfavourable conclusions than those sponsored by non-profits. The point is, there is no dearth of review literature that demands caution while studying published clinical research. Not everything that is printed in a high impact journal is scientifically rigorous, especially if the research is industry-led.
The Surgisphere-HCQ study should be a global wake-up call as hundreds of observational studies and clinical trials are ongoing to either find a cure or a treatment for Covid-19. In India, NITI Ayog is advocating faster approvals for such trials in the light of the current pandemic. That would lead to increased pressure on the Indian Council of Medical Research (ICMR). Other than being government’s apex biomedical research institution, ICMR also formulates guidelines, maintains the clinical trials registry, and grants ethical clearance for clinical research in India. So, its role becomes crucial in maintaining the ethical and clinical standards of medical research.
Unfortunately, the ICMR itself has a history of violations that does not evoke much confidence. In the 1980s, ICMR was testing contraceptives on women violating the ethical norms of the Helsinki Declaration. Women from underprivileged socio-economic backgrounds were recruited from family planning clinics and obstetric wards and administered injectable contraceptives without consent. In the trials of a sub-dermal contraceptive implant called Norplant, ICMR not only failed to obtain informed consent from the participants, but they were not even offered follow-up health services. Further, the adverse events were not recorded – a serious violation of general clinical trial norms.
ICMR’s collaboration with pharma companies, global philanthropies and international non-profits have further compromised its credibility as a research institution and a regulator. One of the recent examples of its dereliction is the HPV vaccine trials conducted in collaboration with PATH in 2009. Two vaccines, manufactured by Merck and GSK were administered on 30,000 adolescent girls in Gujarat and Andhra Pradesh, a majority of them tribal children. A series of ethical violations and research misconduct were reported from the study. Informed consent was not taken from the parents, follow-up care was not provided, and deaths following administration of the vaccine were not categorised as adverse events. A Parliamentary Committee that probed the violations condemned ICMR for unethical research behaviour and promoting the interests of the manufacturers of the HPV vaccine.
The Covid-19 crisis has given ICMR an opportunity to make amends for its past violations. The repercussions of such violations, if continued, would be catastrophic in the case of Covid-19. It would be wise to not overlook the ethics and the rigour of medical research in the rush to find a cure. People readily accept and trust scientific research published in reputed journals, without acknowledging that scientific knowledge is not absolute and is contingent on several factors. With the lure of billions of dollars, contingencies are many in the Covid-19 studies. The need for critical vetting of the robustness of scientific evidence was never needed as much as it is now. We can choose to ignore it at our own peril.
(The writer is a doctoral student at the Centre of Social Medicine and Community Health, JNU)