Industry Voices: Clinical trial transparency--time for some carrot as well as more stick?

By David Grainger

Clinical trial results are seldom reported in a form that is accessible to the public. To many people that is unacceptable for several reasons: it allows drug companies to selectively marshal the evidence base surrounding their drugs (if not to subvert the regulatory process, then to spin the story to support adoption in the clinic); it is also morally questionable given that the public are essential participants in trials and in return deserve to see the results.

High-profile commentators, such as Ben Goldacre and his AllTrials movement, have brought this issue to the center stage and are leveraging public opinion effectively to shame pharmaceutical companies in particular into adopting the principles of comprehensive transparency.

Pharmaceutical companies are much less popular than they should be. Sometimes it feels like these corporations rank only a little above politicians and bankers in the affections of the wider public. The huge gains in public health they have brought about get less attention than the profits that they make in the process. And the most powerful legacy of a decade of socialist government in Britain is disdain for success.

That makes pharmaceutical companies easy targets to subject to the power of public opprobrium, coordinated through the glue of modern social networks.

But there are genuine concerns about transparency. It costs money to generate data, and controlling the output of expensive research efforts is an essential part of having commercial operations investing in research and development. Forcing complete disclosure may increase comfort levels in the customers but risks making pharmaceutical R&D economically unsustainable.

It would not be to the benefit of the public at large to hobble commercial investment in clinical research and development--putting at risk future health gains of the magnitude delivered by medicines such as statins, which have reduced deaths from heart attacks and strokes by almost half in just 15 years.

If we accept that comprehensive transparency of clinical trials is a goal worth fighting for (and DrugBaron believes that it is), is there a way of achieving it other than by force? Is there a way of encouraging the wider pharmaceutical industry to embrace full public disclosure of clinical trial data rather than offering the minimum possible standards of transparency necessary to placate their enemies?

DrugBaron believes there is: offer a carrot whose value is at least as great as the penalty associated with loss of proprietary knowledge. A carrot that makes disclosure preferable. A carrot that eliminates the open-ended liability associated with launching a new drug and keeping it on the market.

A new pact between the public and drugmakers could deliver these benefits. In return for complete disclosure, the state should take on the liability for harm the drug may do in the future which could not be predicted from the data used to support the approval.

Provided the drugmaker complied with these new requirements for complete disclosure of all information (whether deemed relevant or not), they no longer need fear mass tort litigation of the kind that followed the realization that Cox-2 inhibitors increase the risk of heart attacks, or that certain powerful anti-inflammatory biologics cause PML.

Pharmaceutical companies stand to gain substantially from the certainty that, once drugs are approved, they are no longer responsible for events that they could not predict. That such protection is invalidated by failing to disclose data provides a powerful carrot for full disclosure. A carrot that, together with the stick of public opinion, could usher in a utopian new world of complete transparency of clinical trial data.

The consumer is right to demand full transparency of all clinical trial data (whether commercial or academic, although it is the industry-sponsored trials that elicit the greatest concern when the results are withheld). Understanding how to use drugs safely and effectively requires a "weight of evidence" approach that uses all data, without selection.

Bald use of statistics to determine significance of an effect on a primary endpoint is appropriate for determining regulatory approval but stifles proper understanding of the profile of efficacy versus side effects in the longer term. After all, modern meta-analysis yields powerful insights even by combining studies that were, individually, nonsignificant. And the greatest enemy of meta-analysis is selective publication of data.

There is also a moral contract between researchers and the wider community: by participating in a clinical trial, you help your fellow man even if you gain nothing (or even lose) yourself. Most people participate in such trials with precisely this community spirit--rather than to line the pockets of the trial sponsor or further the career of the principal investigator. Yet, in the absence of full disclosure, the latter rather than the former occurs in too many cases.

The argument, then, for requiring disclosure of all clinical trial data, taken up with vigor by the AllTrials movement, is compelling.

The "demands" of the activists are straightforward: all trials, past and present, should be registered, and full methods and results reported. Simple.

But like any shiny coin, this one has two sides. Clinical trials require more than just willing participants; they also take cash. For academic trials, funded publicly, that only adds grist to the mill for the pro-disclosure camp. If "we" paid for it and participated in it, surely we should see the results too. But for industry-sponsored trials, it's not so clear-cut. The justification for paying for a trial is that you own and control the emerging data.

The transparency lobby argues, with some justification, that the commercial benefit comes from owning the molecule about which the data is collected rather than owning (and restricting access to) the information about that molecule.

That seems too black and white. Many clinical studies generate "understanding" of an area that has value over and beyond its application to the development or use of any one particular molecule. Indeed, many clinical studies are as much about understanding the disease as they are about understanding the treatment. Forcing disclosure of such information significantly impairs the incentive to pay for its discovery.

For example, at Funxional Therapeutics (FXT) we paid for a trial to examine the profile of changes that occurred in individuals with different diseases treated with several anti-inflammatory drugs with different mechanisms of action, looking to identify matches between the biomarker signature of a disease and a drug that together yielded clinical benefit. This study did not use any FXT compounds, just approved medicines from other companies. The value of the resulting study was the insight into mechanism of action that was obtained--value that would have been eroded by forced reporting of the results. At least in this instance, the study would never have been funded if full publication of the output had been mandated.

Like every other "good," complete transparency has a cost. Pharmaceutical companies can only sustain themselves through knowledge asymmetry--they must know things that are not obvious to everyone else. Transparency puts that competitive advantage at risk, and it is this concern (rather than a desire to deliberately manipulate the public view of their products to increase sales) that drives pushback from industry.

And there is pushback. Despite some high-profile and commendable support from GlaxoSmithKline ($GSK) and Roche ($RHHBY), which have accepted at least the principles of disclosure set out by AllTrials, the rest of the industry is considerably less enthusiastic. In July, EFPIA and PhRMA, the two largest industry bodies in the world, published a set of joint principles governing responsible sharing of clinical trial data, based around institutional boards considering requests for access to the data and publishing synopses of clinical study reports that have formed part of a marketing authorization (though only after approval).

The principles, which the signatories will adopt in January 2014, fall far short of comprehensive transparency. Ben Goldacre rightly described them as "weak and full of loopholes," falling well short of the levels of disclosure the European Medicines Agency, and GSK and Roche, had committed to.

Tellingly, in marked contrast to the AllTrials principles, EFPIA and PhRMA included "maintaining incentives for investment in biomedical research" as one of the three main objectives. If AllTrials are interested in achieving the best for patients, then they should be concerned about this too. It would not be good for patients (at least in the longer term) if pharmaceutical R&D investment fell significantly.

All this begs the question: is there a solution that offers something in return for the "cost" of transparency, the vast majority of which must be shouldered by the industry (and "cost" in this context refers to the loss of competitive advantage through disclosure rather than the administrative cost of actually making the information publicly available).

Better still, is there a way to make the industry players enthusiastic about disclosure? Without that, it seems likely that the disclosure that will be achieved under the threat of public opinion will be wider than current practice but still fall well short of the scenario dreamt of by activists who see the benefit of a comprehensive public record of clinical trial data. The real utility in these clinical data sets lies in the details--a terse summary of a clinical study report is likely to raise as many questions as it answers.

To answer this question, DrugBaron cast around for anomalies in the regulatory system that harm companies.

One of the most striking is the concept of indefinite liability associated with use of a marketed drug in accordance with this approved label. While it seems appropriate that if a company sells you a product that harms you, you should have the right to seek redress, that simple situation is complicated by the intervention of the state in the form of regulatory approval. Once you have such a complex burden as modern drug approvals legislation, the decision to launch a drug belongs as much to the regulator as to the company.

Is it reasonable, if the company has complied with all the requirements of the regulator to demonstrate the safety of its product candidate, that--in the unfortunate event that it proves not to be completely safe--those harmed can seek damages from the company but not the state (represented by the regulator)?

The argument for corporate liability often boils down to disclosure: the regulator did not necessarily see all the data and as a result may have been misled into the approval by a company eager for sales. Only the company has all the information, so they must decide (alone) whether they are willing to take the risk associated with launching the drug once approval to do so has been given.

The damages (financial and reputational) can be immense: Bloomberg reported that Merck paid out in excess of $8 billion to settle civil and criminal damage cases related to Vioxx between 2004 and 2006. Arguably, the company has never recovered from the affair nearly a decade later.

Equally, even with the benefit of hindsight it is far from clear that the company knew such risks existed prior to launching the drug. Even with the sharp discovery powers in the U.S. legal system, a complete picture of what the company did and did not know was difficult to piece together.

How much better (for the company and for the patient) would it be to live in a world of complete disclosure? With all the data in the public domain, the company is at once released from the charge of suppressing information to mislead patients and doctors into using its drugs. And the responsibility for interpreting that data passes, in large part, to the regulators and physicians.

This then represents a real incentive to adopt comprehensive disclosure. The challenge is for the transparency lobby to leverage this gain to their advantage. Perhaps the easiest way to do so is to seek a new pact between pharmaceutical companies and the state (represented by its regulators). This new pact in effect makes an explicit transfer of liability from the company to the state for harms that emerge from the use of a drug in accordance with its approved label once it has been approved--but only on the proviso that all the data the company has collected about the drug candidate has been disclosed.

Fortunately for patients and companies alike, mass tort cases against drugs are rare and seem to be getting rarer (perhaps because the safety bar required to garner approval is higher than it has ever been, but also perhaps because the number of truly innovative medicines launched has declined substantially in the last decade). But while the absolute risk of damaging liabilities from marketed products is seemingly small, the open-ended nature of those liabilities is nevertheless worrisome. Completely removing that risk--in return for comprehensive disclosure--undoubtedly has value to the industry. Enough value, DrugBaron argues, to make disclosure an enthusiastic preoccupation.

As with any plan, there are difficulties. On a practical level, the amount of information created over the decade or so it takes to get a product to market is immense. And defining what is relevant data is even more burdensome. There will always be discretion--and one must rely on the mantra that the more that is disclosed the lower the risk of future liability.

On a purely theoretical level, there is a moral hazard concern. Freed from liability, companies might become more cavalier with their launches. That seems unlikely--liability for manufacturing defects would clearly remain with the company, and the strict requirements for approval keep the companies on their toes. Only in the area of postmarketing surveillance might stronger legislative imperatives be required if state liability was to be accepted as DrugBaron proposes.

In the end, full transparency of clinical data is highly desirable. But before applying the stick of public opinion too aggressively, we have to remember that it also has a cost. If we can also find carrots, to encourage enthusiastic rather than reluctant compliance with the principles of comprehensive disclosure, we are likely to be much more successful. A formal transfer of liability from company to state on approval of a new drug, conditional on full transparency, is one such carrot society should seriously consider.

David Grainger, Ph.D., who is the author of DrugBaron, serves as a biopharma consultant and venture partner at Index Ventures. Read his blog.

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