In the published medical literature supporting off-label cancer treatments, the prevalence of COI and funding disclosures was low, at 33% and 58%, respectively. Time trends showed some improvement between 2002 and 2007, but in 2007, only 60% of studies had disclosures, and reporting frequency had leveled off between 2005 and 2007, likely showing the limitations to voluntarily reporting despite the increased emphasis. Larger studies, those published in journals with higher impact factors, and those with more complex regimens were more likely to have statements, as were studies performed in the United States, perhaps as a result of the influence of FDA policies regarding off-label therapies and the fact that US studies were conducted by more mature organizations and/or investigators.13
COI and funding disclosures do not prevent conflicts, but they help to mitigate their impact and allow users of the information, such as clinicians and publishers of compendia, to make independent judgments about the source and potential impact of sponsorship and financial bias. Recent studies showed that research funded by pharmaceutical companies was more likely to be published, more likely to be associated with restrictions on data sharing and publication, and more likely to have outcomes favoring the sponsor than studies funded by another source.14,15
The role of conflicts has also recently been illustrated in the case of a delay in the publication of adverse drug reactions and a case of modification of end points that resulted in obscured results.16,17
Users of the medical literature must acknowledge that not all COI is financial; COIs might result from a desire for the prestige of authorship or for academic promotion. Given these dangers, it is important for the reader to at least be aware of potential COIs through author disclosure statements.
Increased reporting of COIs and funding sources fits well with the movement already underway, as an element of the Physician Payments Sunshine Act, to require reporting of “transfers of value” between industry and both physicians and teaching institutions.18
As outlined in a recent editorial by Carpenter and Joffe in New England Journal of Medicine
, unique identifiers that match individual physicians to industry payments could be used to make COI reporting more robust and could be implemented across settings, from grant applications to regulatory findings to manuscripts.19
If improved reporting in the literature is not done voluntarily, similar legislation may ultimately be passed to require it.
The impact of off-label prescribing of anticancer therapies is beneficial to patients (through access to new treatments for advanced illness), but is also very costly. Targeted therapies are now the fastest growing segment of cancer care, with numerous FDA-approved agents11
This class accounts for substantial costs to the US health care system. In a study of a monoclonal antibody treatment conducted at a single institution, on-label prescribing increased after the drug's introduction but quickly leveled off, whereas off-label prescriptions exhibited a near-exponential increase.10
Between 1998 and 2001, direct drug costs for off-label use at that single institution exceeded $1.1 million, whereas costs for its FDA-approved use totaled $355,000. Scaled to the national level, and to the full armamentarium of cancer drugs, the cost of off-label prescribing is staggering.
The legislative action that has allowed the compendia to be the authoritative source for reimbursement decisions provides both an efficient mechanism for care and a pathway to promote off-label prescribing outside the purview of the FDA. Given the substantial market for these drugs, the potential for a COI among the compendia is substantial, and public concerns about these conflicts often play out in the news.20–22
For example, a 2009 New York Times
article argued that the system leading to off-label prescribing was fraught with hidden conflicts and called for reconsideration of the compendia-based reimbursement system for off-label prescribing in oncology.22
More transparent disclosure of potential conflicts and funding by the compendia was highlighted as the top priority, with the need for researchers whose studies support off-label prescribing to disclose their conflicts a close second.11
As a clinical research community, we should monitor our own activity, before the lay press, regulatory bodies, and the public demand changes that may not be consistent with quality cancer research and care. The editors of medical journals should also require disclosures, so that a high standard is maintained in the medical literature.
This study is limited by the small number of articles, drugs, and indications in the analysis, and the potential publication bias among the included articles. COI reporting in all venues is becoming more commonplace. However, the study was only conducted through 2007 to avoid summarizing evidence for or against any particular off-label treatment in use today. The goal instead was to outline the trends in reporting standards.
To ensure transparency and to establish confidence in the results of off-label studies, routine COI reporting needs to become standard. Defining appropriate benchmarks for metrics is always hard, but in this case the expectation for COI and funding disclosure should be that it occurs with every publication expected to influence care. We suggest that guidelines require this change. Investigators, authors, and journals need to demand a high level of accountability and consistency in this task. It is important to underscore that the intention of such a guideline would not be to expose any suspected wrongdoing, nor would it be to punish those who proceed with research and publication despite conflicts, as such a requirement would significantly limit evidence development. The intention is instead to create a body of literature in the off-label space that is credible and dependable because conflicts are transparent.