Is there transparency in clinical trials on endometriosis?

By Lone Hummelshoj

Despite mounting pressure on more transparency of clinical trials, the current state of transparency, or lack thereof, of clinical trials on endometriosis is worrisome and does not benefit the trial sponsor or women with endometriosis.  We need to change this!

Professor Sun-Wei Guo, Fudan University, China

In the last decade, about half dozen books have been published that are very critical of the pharmaceutical industry, some of them scathingly. They include Merrill Goozner’s The $800 Million Pill, Jerry Avorn’s Powerful Medicines, John Aramson’s Overdosed America, Jerome Kassirer’s On the Take, Marcia Angell’s The Truth About the Drug Companies, and, very recently, Ben Goldacre’s Bad Pharma.

From different vantage points, these books provide an unflattering—sometimes disturbing—but consistent portrait of drug companies’ behaviours.

Why this deluge of books chastising pharma?

The seemingly deluge of these books on a similar topic cannot be simply dismissed off-hand as merely a pharma-bashing fad, since these books appear to be well-researched and based on credible and documented sources.

A few of them are actually written by former editors of some prestigious medical journals, who witnessed first-hand some high-profile cover-up cases of clinical trials sponsored by the industry, such as the Vioxx saga.

One troubling behaviour is the selective publication and the suppression of “negative” information arising from clinical trials funded by drug companies.

The mounting pressure on the transparency of clinical trials

Clinical trials used to be cloaked under secrecy, in the name of proprietary or privileged rights. The public was kept in complete darkness, totally unaware of their existence, let alone of any significant adverse effects of a trialled compound.

Believing that this situation was not in the best interests of the American people, the US Congress decided to encourage openness by enacting Section 113 of the Food and Drug Administration Modernization Act (FDAMA 113) in November 1997. Section 113 ultimately led to the creation of ClinicalTrials.gov as an Internet-based public depository for information on studies of drugs, including biological compounds, that are conducted under the FDA’s investigational-new-drug regulations [1].

In September 2004, the International Committee of Medical Journal Editors (ICMJE) announced that its journals would not publish the results of any clinical trial that had not been appropriately registered at ClinicalTrials.gov or another qualified public registry by 13 September 2005 [2].  Human Reproduction also enforced this rule. The ICMJE announcement prompted a surge of registrations at ClinicalTrials.gov, especially from industry [3].

Clinical trials investigating new treatments for endometriosis were no exception [4].

Echoing these requirements for more openness, the World Health Organization (WHO) also launched in May 2007 a new web site that enables researchers, health practitioners, consumers, journal editors and reporters to search more easily and quickly for information on clinical trials. On September 27, 2007, the US Congress enacted the FDA Amendments Act of 2007 (FDAAA), or Public Law 110-85.

On the same day, the FDA Revitalization Act was signed into law, which aims to improve the FDA’s ability to ensure the safety of the nation’s drugs and medical devices. Section 801 of FDAAA mandates the expansion of ClinicalTrials.gov and provides for the first federally-funded trial results database.

As specified by the law, the data elements include:

• participant demographics and baseline characteristics;
• primary and secondary outcomes and statistical analyses;
• disclosure of agreements between sponsors and non-employees restricting researchers from disseminating results at scientific forums.

Generally, some important outcome data would be available to the public within 12 months of trial completion or within 30 days of FDA approval (or clearance) of a new drug, biological, or device.

Clearly, the pressure is mounting for more transparency of all clinical trials, to the benefit of those who research disease pathogenesis, and ultimately to those who suffer from conditions such as endometriosis. These legislatures and trial registries are intended primarily to encourage and promote openness in clinical trials.

Selective publication and the suppression of “negative” information arising from clinical trials: Old and bad habits die hard

The pharmaceutical industry produces medicines and there is no doubt that these medicines have saved countless lives worldwide. Unfortunately, it also acquired bad habits of selective publication and the suppression of negative results from clinical trials [5].

Examples abound: Avandia, Vioxx, Seroxat, Reductil/Meridia, just to name a few. The more recent example would be the tamiflu, which has been highlighted by a few articles published in the BMJ [6,7].

In fact, the UK’s House of Commons Science and Technology Committee are currently calling for evidence for a new hearing into the implications of missing clinical data to the NHS and patient safety, and the BMJ is launching an “Open Data Campaign”, calling for scientists to report any obstruction, from any researchers or companies, in the releasing of data from clinical trial and fill out quick online form, and the BMJ will collate the details and publish in a publicly available spreadsheet.

Indeed, reading that spreadsheet can be quite disheartening.

Non-publication of trial results

When a few industry-sponsored trials did not publish their results well after the trials were completed, it could have been interpreted as an idiosyncratic phenomenon.

However, when it is clear that the completed industry-sponsored trials have a lion’s share of unpublished trials even though it is equally clear that these trials had more resources, it is evident that, at very least, industry-sponsored trials are less likely to publish the negative results than those sponsored by non-industry.

Whether it is the executives’ decision or the company scientists’ decision not to publish, is beside the point: non-publication of clinical trials may hold the field of endometriosis back and put patients of endometriosis unnecessarily at risk.

Lack of transparency of clinical trials on endometriosis

As elaborated by the half-dozen books on drug-markers, the selective reporting and the suppression of “negative” data are quite ubiquitous and pervasive across the entire industry.

Not surprisingly, endometriosis trials are no exception.

In a survey conducted 4 years ago, it was found that 57 endometriosis-related clinical trials were registered at ClinicalTrials.gov [8].

Among 15 completed phase II or III trials that evaluated the efficacy of various promising compounds, only three (20%) had published their results but the remaining 12 (80%) did not.

In other words, most endometriosis trials were shrouded in secrecy even when completed.

Four years have since mercilessly elapsed. A recent analysis of trials registered at ClinicalTrials.gov found that the situation has changed very little [3].

Specifically, it reports that among 35 completed trials on endometriosis, only 11 (31.4%) published their results, which is well below the 66.3% reported in a recent survey of non-endometriosis trials [9].

More disturbingly, trials sponsored by pharmaceutical industry were about 4 times less likely than those sponsored by non-industry to publish the results, even though they were typically larger in size and faster to complete likely because of more resources. Industry-sponsored trials that did get published were those that led to the regulatory approval for marketing.

Conspicuously, no “negative” trials sponsored by industry have ever been published. Such an abject failure to publish and selective reporting pose a serious threat to professional access to all trial results and to the validity of evidence-based medicine.

It also flies in the face of mounting pressure around the globe for more transparency of clinical trials.

The implications of the lack of transparency

One can argue that the ultimate goal of disease-focused research such as endometriosis research is to provide better clinical care to patients through better diagnosis, treatment, or even innovative ways of prevention.

Towards this goal, one important intermediate linking basic research and clinical practice is randomized clinical trials that evaluate the safety and efficacy of compounds deemed to be promising in preclinical research.

Clinical trials are also known to contribute to our knowledge base in evidenced-based medicine.

Yet this hinges critically on the timely public release and dissemination of findings from such trials, which are considered to be key principles in the proper conduct of clinical research [10].

Indeed, clinicians, policy-makers, and even patients learn of evidence-based medicine primarily through peer-reviewed biomedical journals. The apparent opaqueness of endometriosis trials is certainly a disservice to the entire endometriosis research community and the public at large.

Non-transparency may contribute to slow progress in treating endometriosis

At the time when there is a palpable disappointment over the slow progress in developing novel therapeutics for endometriosis [11], this opaqueness is an added hindrance to drug development, since it impacts negatively on basic research scientists.

When everybody is holding their cards close to their chests, nobody will benefit from hard-earned lessons and everybody will be condemned to repeat others’ mistakes, miscalculations, or missteps.

It also exposes trial participants to unnecessary risk of receiving inferior treatment or having adverse effect since different drug companies may test slightly different drugs that belong to the same class of drug (such as selective progesterone receptor modulators).

Above all, it betrays the wish implicitly or tacitly expressed by the trial participants that their participation will generate generalisable medical knowledge that might benefit not only themselves but also other and future patients, scientists and physicians so that collectively the trial and other scientific research will ultimately improve patient care.

Full disclosure of clinical trials is needed

Full disclosure of clinical trials ensures unbiased systematic assessments of the drug of interest, and can help also uncover serious safety issues even after the drug has been approved for marketing.

The rise and fall of rosiglitazone, an antidiabetic drug, is a prime example. Approved by the US FDA in 1999 despite concerns expressed by its reviewer about adverse lipid effects, edema, and myocardial ischamia [12], it was successfully launched and marketed afterwards. Immediately after its launch, a prominent endocrinologist publicly voiced his concerns about its cardiovascular safety, yet the drugmaker intimidated him and eventually silenced him [12].

Yet more reports of adverse effects surfaced afterwards, prompting the FDA to order a revision of the rosiglitazone label noting “rare reports of unusually rapid increases in weight” [10]. No one at that time, except the FDA, had any access to rosiglitazone trial data, which were considered to be drugmaker’s proprietary information.

In 2004, as part of the a settlement with the New York state suing GlaxoSmithKline (GSK), the maker of rosiglitazone, for consumer fraud through deliberate and systematic suppression of data on increased suicide risk among teenagers taking GSK’s antidepressant paroxetine (Paxil), GSK agreed to put all its recent clinical studies on a website. It is this website that permitted Nissen et al, in 2007, to perform a meta-analysis of all 42 clinical trials of rosiglitazone, 35 (83.3%) of which were unpublished, and reported increased risk in cardiovascular events in patients taking rosiglitazone [13].

This led to the addition of a “black box warning” by the FDA to the rosiglitazone label for ischemic events. The rosiglitazone story epitomises the important role that publicly available trial data can play.

Lack of transparency affects R&D in endometriosis

The lack of transparency in endometriosis trials may also add another hurdle to drug R&D in endometriosis.

Without full transparency, the lessons learned from apparently unsuccessful trials will be lost and there will be repetition of other investigators’ assumptions and mistakes, miscalculations, or missteps in target choice, subject selection, and untoward side effects.

New patients will be included in new trials of which the outcome might already have been known, had appropriate disclosure of the outcome of previous trials occurred. Data obtained from medical studies are arguably not private property of the investigators; rather, they constitute a public resource for the benefit of medical science and future generations of patients [14].

What should we do?

Given the current opaqueness in endometriosis trials, pressure needs to be kept on to change this situation.

More transparency not only is a moral imperative to researchers, sponsors, reviewers, and journal editors alike, but also should help researchers, healthcare providers, policy-makers, and, eventually, the drug companies and, above all, women with endometriosis.

We should call upon all academic and industrial sponsors of endometriosis clinical trials to openly and voluntarily disclose their trial results within a reasonable timeframe (within which data collection, analyses, and dissemination can be done adequately).

We call on journal editors and reviewers to encourage the publication of negative trials, and on researchers who designed and conducted trials on endometriosis to publish trial results even though they may be negative.

We also call for the use of trial identifiers when publishing trial results and for the proper disclosure of major trial outcome in the trial registry. In this electronic age, online disclosure of trial results on the Internet, accessible to the public, entails minimal costs. And there are many options for disclosing trial results, even for full disclosure of raw, but anonymised, data [15]. This, if implemented, should greatly reduce the possibility of suppressing unfavourable trial results, and provide “the ultimate test and promoter of statistical quality”, and allow for public scrutiny.

This action awill lead to more accurate systematic reviews, better clinical decision making, improved patient care, and improved research efficiency and safety [16], and benefit the drug makers and women with endometriosis.

Isn’t this what we are about?
Improving the care of our patients!

References

1. Drazen JM, Wood AJ. Trial registration report card. N Engl J Med 2005;353:2809-11.
2. De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R et al. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. N Engl J Med 2004;351:1250-1.
3. Zarin DA, Tse T, Ide NC. Trial Registration at ClinicalTrials.gov between May and October 2005. N Engl J Med 2005;353:2779-87.
4. Guo SW, Evers JHL. Lack of transparency of clinical trials on endometriosis. Gynecol Obstet 2013;121(6):1281-90.
5. Guo SW, Olive DL. Two unsuccessful clinical trials on endometriosis and a few lessons learned. Gynecol Obstet Invest 2007;64:24-35.
6. Jefferson T, Doshi P, Thompson M, Heneghan C; Cochrane Acute Respiratory Infections Group. Ensuring safe and effective drugs: who can do what it takes? BMJ 2011;342:c7258.
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10. Prayle AP, Hurley MN, Smyth AR. Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study. BMJ 2012;344:d7373.
11. Vercellini P, Crosignani P, Somigliana E, Vigano P, Frattaruolo MP, Fedele L. ‘Waiting for Godot’: a commonsense approach to the medical treatment of endometriosis. Hum Reprod 2011;26:3-13.
12. Nissen SE. The rise and fall of rosiglitazone. Eur Heart J;31:773-6.
13. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-71.
14. Vickers AJ. Making raw data more widely available. BMJ;342:d2323.
15. Wager E. Publishing clinical trial results: the future beckons. PLoS Clin Trials 2006;1:e31.
16. Wood AJ. Progress and deficiencies in the registration of clinical trials. N Engl J Med 2009;360:824-30.

The author

Lone Hummelshoj is the publisher/editor of www.endometriosis.org. She works globally to raise awareness of the impact of endometriosis, and to secure funds for research to improve knowledge of the disease so that targeted treatments can be developed - with prevention as the ultimate goal!