Randomized Clinical Trials Face Practical and Ethical Challenges

The high cost of conducting biomedical research in the U.S. has drawn intense scrutiny in recent years as to the efficiency of clinical trial operations, effectiveness of research oversight and the value of more flexible strategies for tapping new data sources. While the placebo-based randomized clinical trial (RCT) has long been the “gold standard” for obtaining objective, unbiased information on the safety and efficacy of medical products, the need to revise the design, performance and interpretation of clinical research to reflect changing methods and standards has drawn serious attention. Recent analyses have cast doubt on the value of highly controlled and regulated research, as seen in difficulties with patient recruitment, concerns about informed consent, and demands for more transparency in research data and results. 

One sign of progress is the shift to greater reliance on a single institutional review board (IRB) to oversee multi-site clinical studies, as outlined in a recent final policy from the National Institutes of Health (NIH). The hope is that central IRBs will eliminate duplicate ethical reviews of human subject protections, an approach now common in commercial research programs.

Efforts to update the “Common Rule” governing the protection of federally funded human subject research may get a fresh start based on a June report from the National Academies of Sciences, Engineering and Medicine. A blue-ribbon panel criticizes the current effort to revise these policies, particularly a proposal for requiring informed consent on future uses of de-identified residual biospecimens.

The value of randomized trials in providing evidence on the efficacy of SSRIs and other anti-depressants is revisited in a new book by the author of the 1993 blockbuster Listening to Prozac amidst the continuing debate over whether these drugs are no better than placebo. Now in Ordinarily Well: the Case for Antidepressants, Peter Kramer examines the limitations of clinical trials, but concludes that Prozac and other similar therapies are useful despite their flaws. 

RCT operations and standards face further scrutiny with the approval of more breakthrough therapies based on limited clinical trial data. Sponsors also find new challenges in conducting traditional studies to test new cancer therapies, as rapid changes in standard of care often make a clinical trial outdated by the time a sponsor has gone through study design, site identification and patient enrollment. 

These developments are driving efforts to augment initial research findings with more real-world evidence (RWE) found in health system and insurance claims data systems. FDA Commissioner Robert Califf says a top priority is to better leverage RWE to inform FDA decision-making, a goal also outlined in a recent report from the Bipartisan Policy Center. Pharma companies are looking more to RWE to confirm efficacy and to track safety issues and rare events following new drug approval and to support added indications for marketed therapies. 

At the same time, much RWE appears highly variable and incomplete compared to RCT results, and, thus, not yet considered sufficient to document safety and efficacy for a new therapy. Even so, both regulators and researchers are looking to broader use of RWE in the future to supplement post-market research, identify novel outcomes and avoid clinical studies that could expose more patients to less efficacious treatment. 

A tricky issue for clinical research sponsors is to decide which individuals should have priority access to drugs in limited supply, a situation that emerges related to compassionate use requests for experimental therapies and for critical marketed drugs in short supply. Continued supply disruptions for medically necessary treatments, particularly those used in emergency care and for treating cancer, often force hard decisions, particularly in caring for children with cancer where treatment routinely involves older generic injectibles often hit hard by shortages. 

The research community has long recommended that participants in clinical trials should be first in line to receive a critical new therapy in order to reward their altruism and to further encourage trial enrollment. Now a task force looking to establish ethical standards for allocating scarce life-saving pediatric cancer drugs says that patients participating in clinical trials should not necessarily top the priority list. 

The recommendations from the Working Group on Chemotherapy Drug Shortages in Pediatric Oncology, published in the February 2014 issue of the journal Pediatrics and examined further in an article published online in January by the Journal of the National Cancer Institute, note that such preference could smack of coercion to enter a study and also undermine their effort to base priority access on where a critical therapy is most likely to save lives and improve prognosis. An overriding goal is to avoid “bedside rationing” that leaves critical allocation decisions to conflicted physicians.