Life Science Compliance Update

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32 posts from March 2011

March 31, 2011

JAMA Disclosure of Interests in Meta Analyses

Metaanalysis 
A recent article from the Journal of the American Medical Association (JAMA) noted that, “disclosure of conflicts of interest (COIs) from pharmaceutical industry study funding and author-industry financial relationships are sometimes recommended for randomized controlled trials (RCTs) published in biomedical journals.” However, “authors of meta-analyses, are not required to report COIs disclosed in original reports of included RCTs.” 

Background 

Over the past several years, “conflicts of interest (COIs) related to the funding of biomedical research by pharmaceutical companies and financial relationships between researchers and pharmaceutical companies have come under increased scrutiny.”

According to the authors, “COIs may influence the framing of research questions, study design, data analysis, interpretation of findings, whether to publish results, and what results are reported. 

 

For example, the authors pointed to various studies, which showed that “results from positive trials and from favorable analyses are more likely to be published than results unfavorable to sponsors. In addition, they cited studies, which found that “compared with nonindustry-funded trials, pharmaceutical industry–funded studies more often yield results or conclusions in support of the sponsor's drug, and authors' relationships with drug manufacturers have been linked to favorable assessments of drug efficacy and safety.” 

To address this issue, the Consolidated Standards of Reporting Trials (CONSORT) guidelines require disclosure of study funding sources in trial reports. Moreover, the International Committee of Medical Journal Editors (ICMJE) guidelines recommend disclosure by authors of study funding sources and also of author-industry financial ties. However, as noted above, “there are no guidelines for the reporting in meta-analyses of COIs disclosed in included randomized controlled trials (RCTs).”

 

While the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement requires meta-analysis authors to report the funding source of a meta-analysis, it does not address the reporting of COI from included RCTs.”  

This concerned the authors because “meta-analyses are cited more than any other study design and prioritized in grading evidence for practice guidelines.”In addition, the authors noted that “without documentation in meta-analyses of COIs from included RCTs, users of meta-analyses may not have access to important information that could influence their evaluation of the risk of bias in the evidence reported.” As a result, the authors decided “to investigate whether meta-analyses of pharmacological treatments published in high-impact biomedical journals report COIs disclosed in included RCTs.”

The objective of the study was to investigate the extent to which pharmaceutical industry funding and author-industry financial ties or author employment disclosed in published reports of RCTs of pharmacological interventions are transparently reported in meta-analyses published in high-impact general and specialty medicine journals and the Cochrane Database of Systematic Reviews.

Methods

The study, entitled “Reporting of Conflicts of Interest in Meta-analyses of Trials of Pharmacological Treatments,” looked at 3 recent meta-analyses of patented pharmacological treatments published January 2009 through October 2009 in each general medicine journal with an impact factor of at least 10; in high-impact journals in each of the 5 specialty medicine areas with the greatest 2008 global therapeutic sales (oncology, cardiology, respiratory medicine, endocrinology, and gastroenterology); and in the Cochrane Database of Systematic Reviews.

 

Then, two investigators independently extracted data on disclosed study funding, author-industry financial ties, and author employment from each meta-analysis, from RCTs included in each meta-analysis, and on whether meta-analyses reported disclosed COIs of included RCTs. 

Results 

 

Of 29 meta-analyses reviewed, which included 509 RCTs, 62.5% (318 of 509) of included RCTs reported funding source. In addition, only 2 meta-analyses (7%) reported RCT funding sources; and 0 reported RCT author-industry ties or employment by the pharmaceutical industry. Of 318 meta-analyzed RCTs that reported funding sources, 219 (69%) were industry funded; and 91 of 132 (69%) that reported author financial disclosures had 1 or more authors with pharmaceutical industry financial ties. 

In 7 of the 29 meta-analyses reviewed, 100% of included RCTs had at least 1 form of disclosed COI (pharmaceutical industry funding, author-industry financial ties, or employment), yet only 1 of these 7 meta-analyses reported RCT funding sources, and 0 reported RCT author-industry ties or employment. Additional findings included:

 

  • At least 1 author of 16 of the 29 meta-analyses (55.2%) reported at least 1 financial tie to the pharmaceutical industry,
  • All of the authors of 12 of the meta-analyses (41.4%) reported 0 financial ties to the pharmaceutical industry
  • Author financial ties were not reported in 1 meta-analysis (3.4%), and
  • Only 1 of the 29 meta-analyses listed authors employed by the pharmaceutical industry.37

Author financial disclosures were reported in only 25.9% (132 of 509) of included RCTs. Among these, 68.9% (91 of 132) reported 1 or more authors having financial ties to the pharmaceutical industry. Author affiliations were reported in 94.7% of included RCTs (482 of 509), including 26.1% (126 of 482) with at least 1 author employed by the pharmaceutical industry.

 

Discussion 

The main finding of the study was that with few exceptions, information on COI disclosed in RCTs is not reported when RCT data are combined in meta-analyses. Based on these results, the authors asserted the “need for complete and transparent disclosure of COI in biomedical research.” They recommended that the PRISMA statement be updated to “require authors of meta-analyses to report funding sources of included RCTs or report that funding sources were not disclosed.” In addition, they recommended that the PRISMA statement consider recommending that meta-analyses report author-industry financial ties disclosed in included RCTs or report that there was no disclosure statement.

 

The authors did note that “the proportion of RCTs reporting author-industry financial ties will likely increase with the recent introduction of ICMJE disclosure guidelines.” The authors also recommend that, “meta-analysis authors should document that they have evaluated all potentially relevant sources of bias, whether or not a particular source of possible bias is present in the studies reviewed and whether or not the magnitude of bias is expected to be large in comparison with other likely sources of bias.”

The authors also stated that “meta-analysts should evaluate the potential for bias due to pharmaceutical industry study funding and author-industry financial ties as part of their standard risk of bias assessment,” and that the Cochrane Collaboration should consider formalizing the requirement to assess potential bias from COIs.

One of the limitations from this study is extremely significant. Specifically, while authors asserted the potential problem created by the lack of reporting, “the study was not designed to assess whether reporting of COI from RCTs included in meta-analyses was related to the quality of meta-analyses or whether COIs from included RCTs influenced the results of the meta-analyses reviewed.” In other words, this study had no indication or conclusions about whether the COI’s affected the quality of the studies. Without this information, the value of this study is merely informational.

Ultimately, transparency in all aspects of medical research is important. However, this study did not show that industry involvement or lack of disclosure led to negative quality of meta-analyses. Accordingly, the recommendations contained in this article should be further discussed to meet modern standards of transparency and disclosure to ensure that medical research is conducted at the highest standards to ensure that physicians are given all the information necessary to make informed decisions that will improve patient care.

March 30, 2011

FDA Regulations Doubles Review Time and Quadruples Trial Size for Diabetes Therapies

FDA Green 
Cardiovascular safety issues with a number of drugs led the Food and Drug Administration (FDA) in late 2008 to introduce new regulatory guidelines for type 2 diabetes drugs and more recently to recommend a risk assessment and mitigation strategy for rosiglitazone. Consequently, as a recent article in the Journal of Contemporary Clinical Trials noted, the “immediate effect of the guidelines was a pathway to approval fraught with greater challenges.”

Accordingly, the authors of the study, Viereck and Boudes, examined the impact of FDA's 2008 guidelines for addressing cardiovascular risks of new therapies for type 2 diabetes on clinical trials.  They focused on the new class of incretin-modulating drugs, exenatide, sitagliptin, saxagliptin and liraglutide, which were approved in 2005–2010.

They then contrasted these findings with those from 2 different groups: 1) diabetes drugs approved in the same timeframe but with a non-incretin mechanism of action (colesevelam HCl and bromocriptine mesylate) and 2) diabetes drugs with NDAs delayed and not yet approved within the same timeframe (vildagliptin, alogliptin, insulin inhalation powder, and exenatide long acting release).

Based on their study, the authors concluded that, “the new guidelines have had an important impact on clinical development.”  Specifically, they found that the drug “review time has increased over 2-fold,” and “the increase is seen even if a drug with the same mechanism of action has been already approved.”  In addition, “the number of randomized patients and patient-years in NDAs increased more than 2.5 and 4 fold, respectively since the guidelines.”

Ultimately, through rigorous methodology, Viereck and Boudes quantitate for type 2 diabetes drugs what many have intuitively thought: huge increases in clinical trial size, NDA  and review times as a result of new cardiovascular guidelines for drugs in type 2 diabetes.  The increased regulatory burden relative to the EU is stifling innovation in the US.  Accordingly, the authors concluded that, “the significant cost increases and negative publicity because of rare adverse reactions will adversely affect future clinical research in type 2 diabetes and not address its burgeoning health care impact.”

 

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