Governance of conflicts of interest in postmarketing surveillance research and the Canadian Drug Safety and Effectiveness Network.

There has been surprisingly little research in the public domain on the long-term safety and effectiveness of postmarket drugs—drugs that have been approved by regulators and are being used by consumers—even though this information is needed by regulators, policy-makers, health care providers and consumers. The establishment in Canada of the national Drug Safety and Effectiveness Network (DSEN)1 and its first call for applications for postmarketing studies are therefore positive developments for consumer and patient safety. Established and largely administered by the Canadian Institutes of Health Research (CIHR), the DSEN will fund independent and scientifically rigorous real-world studies on the safety and effectiveness of postmarket drugs in Canada and will connect to the research being conducted through a virtual network of Canadian centres of excellence in postmarketing pharmaceutical research. These centres will have a common research agenda and strategic direction set by a DSEN steering committee. In addition, the DSEN will assist in coordinating a national research agenda based on decision-makers’ priorities. The federal government has made a financial commitment to the DSEN of $32 million over the first 5 years and $10 million per year thereafter.1

We believe it is essential for the DSEN to secure the public’s confidence quickly, which has been shaken in recent years by a series of scandals related to postmarket drugs. Many medical journals made urgent calls for better reporting of adverse events, more active postmarketing surveillance and better designed studies2,3 particularly in the wake of the highly publicized withdrawal from the market of rofecoxib (Vioxx),4,5 a now infamous drug that has been associated with major adverse events, including myocardial infarctions or strokes in “tens of thousands of patients.”4 Other controversies include the promotion of hormone replacement therapy6 and the off-label promotion of arthritis drug valdecoxib (Bextra), epilepsy drug gabapentin (Neurontin), and the schizophrenia drug olanzapine (Zyprexa). The latter three resulting in criminal prosecutions, fines and settlements of hundreds of millions of dollars, and, in the case of valdecoxib, a record-setting settlement of US $2.3 billion.7-9

In Canada, drug manufacturers are required to report postmarket adverse drug reactions. They are not, however, currently required to conduct new efficacy or safety studies, or studies on therapeutic effectiveness.10 In Canada and the United States, questions have been raised about the legislative authority of drug regulatory agencies to mandate such studies. In the US, before the Food and Drug Administration (FDA) Amendments Act of 2007,11 it was unclear whether the FDA had the legislative or regulatory authority to request postmarketing surveillance studies12 other than in cases where a drug had received accelerated approval.13 Unfortunately, despite encouragements to conduct postmarket studies and to comply with postmarket commitments, there is evidence that drug manufacturers fail to do so and that drug regulators are not adequately monitoring postmarketing surveillance commitments.4,13,14 In Canada, Health Canada believes it does not have the regulatory authority to explicitly impose postmarketing studies as a condition for further sales of a pharmaceutical product.10 To address this and other issues related to drug regulation, Health Canada has been working for some years on a progressive licensing framework that, among other things, will give the government authority to require drug manufacturers to conduct postmarket studies and to submit the resulting data for review.10,15,16

As important as a progressive licensing framework will be to Canada, it is crucial to keep in mind that many have questioned the wisdom of relying on drug manufacturers to conduct postmarketing studies of their own products.17 Studies indicating a statistical correlation between study outcomes and funding source, reports of misleading selection of trial designs, and the exposure of instances of data suppression, data misrepresentation, ghost authorship or research articles by industry-funded writers and other related practices have added fuel to this concern.18,19

Enter the DSEN. Although drug manufacturers will continue to have mandatory obligations to report adverse drug reactions (and possibly in the future to conduct postmarket studies), the DSEN will fund “independent research on the safety and effectiveness of postmarket drugs.”20 Having CIHR operate the DSEN could strengthen public confidence in the independence of the network since CIHR is not involved in drug approvals—as Health Canada is—and has no direct financial interest in drug development—as pharmaceutical companies have. CIHR has the status and connections to secure the commitment of qualified researchers who are independent from the products and the drug manufacturers. In their 2006 commentary on reforming US drug regulation, Ray and Stein19 call for the establishment of an independent, specialized centre for postmarketing studies with a mandate to promote the unfettered conduct of postmarketing studies by independent researchers. Before amendments were made to the US Food and Drug Act in 2007, several commentators argued that there was a need for a fully independent US agency or centre for postmarket studies.19,21 This would avoid the conflict that arises when the agency that approves new drugs is also in charge of conducting postmarket studies on those same drugs, the results of which can lead to their withdrawal and could suggest a failure in the approval process. However, although the FDA Amendments Act (2007)11 gave the FDA authority to, among other things, order drug manufacturers to conduct postmarketing studies, it stopped short of creating an independent agency for postmarketing drug trials or imposing fully independent post-marketing surveillance research.

We believe that a fully independent agency with postmarketing surveillance as its core mandate would be ideal, but having the CIHR operate the DSEN moves Canada forward, provided that some conditions are fulfilled. Box 1 provides a summary of our key recommendations.

Box 1

Key recommendations to ensure the independence of the Drug Safety and Effectiveness Network (DSEN)

First, a DSEN good governance framework (characterized by the existence of a well-defined operating structure, clear lines of operational accountability and high standards for integrity and openness) must be instituted that is based on an effective approach for avoiding and mitigating conflicts of interest. Dealing appropriately with conflict of interest will provide researchers with the necessary environment for producing credible, honest, timely and scholarly research that can withstand academic and public scrutiny. Stringent conflict-of-interest rules and other measures to ensure the independence of researchers are essential in this context because postmarketing surveillance research can have huge financial implications. The potential need to withdraw a blockbuster drug from the market, and potential legal liability related to findings of serious side effects, create serious incentives that may affect behaviour. Stocks in Merck Frosst tumbled by 30% the day after Vioxx was withdrawn from the market, decreasing the company’s market value by an estimated US$26.8 billion; this is a stark reminder of what interests are at stake.22

Strong and enforceable conflict-of-interest rules for all those involved in the research, its reportage and knowledge translation (e.g., researchers, centres of excellence and their staff), and measures to protect researchers’ independence are in our view crucial. Such rules and measures are needed because of the very significant public health implications of this type of research and the reasonable concern that the financial interests of industry sponsors in an already marketed product can lead to significant pressure on investigators, institutions and those working directly under contract with pharmaceutical sponsors. This is not to say that such pressure always affects researcher or institutional behaviour, but it is a reasonable expectation that such pressure can have this impact and can affect public trust.

Our support for CIHR establishing and largely administering the DSEN is also conditional on the expectation that CIHR will be sufficiently funded and strongly independent from both Health Canada’s Therapeutic Products Directorate and drug manufacturers since this is crucial for a public funding agency that has a mandate through the DSEN to promote independent drug surveillance research. The commercialization mandate embedded within the statutory role of CIHR and the growing emphasis on CIHR–industry partnerships do, in this context, create a tension. A major step forward for CIHR would be the adoption of an ethics policy on partnership with the for-profit private sector, as discussed at a 2007 CIHR workshop,23 which takes into account CIHR’s role with respect to the DSEN.

In the spring of 2009 we presented a governance framework at a DSEN workshop on potential legal and ethical risks24 to address conflict-of-interest issues. We recommended that the DSEN governance and operational standards should be such that they promote five intertwined principles: transparency and openness, accountability, independence, commitment to scientific integrity, and freedom of action. Boxes 2 and 3 (which are reproduced largely from our presentation) elaborate on the five key principles in the context of the DSEN governance and as applied to DSEN-funded researchers.

Box 2

Elaboration of the five principles for good governance of the Drug and Safety Effectiveness Network (DSEN)

Box 3

Principles for avoiding and mitigating conflict of interest (COI) among researchers and researchers’ host institutions involved with the Drug Safety and Effectiveness Network (DSEN)

Although details of the governance system are not yet available, we did obtain some information about the general oversight structure. The DSEN’s steering committee, which will provide strategic direction to the DSEN and set priorities for research, will be appointed and chaired by Dr. Ian Graham, vice-president of knowledge translation and public outreach at CIHR (Krissy Davidge, DSEN, Ottawa, personal communication, Feb 2010).

There are many stakeholders who have a legitimate and material interest in the DSEN’s research priorities, and their involvement can strengthen the DSEN. Thus it is important that the DSEN engage these stakeholders, who include, for example, patient or consumer groups, provincial health ministries, drug manufacturers, Health Canada and other policy-makers. We believe the five key principles should set the stage for stakeholder engagement about research priorities. Although having stakeholders contribute their views about research priorities will help inform the DSEN, membership on the DSEN steering committee should be carefully chosen to avoid situations of conflict of interest. Members of the steering committee should not have financial interests in marketed products or have financial ties with those who do. Although having the DSEN operating from within Health Canada would not have allowed for adequate independence, it is important that Health Canada provide input about research priorities, which will be possible through DSEN’s role in assisting with the coordination of a national research agenda based on decision-makers’ priorities.Finally, the DSEN should also be set up so that it is structurally independent within the CIHR from those who are involved in the creation and promotion of CIHR–industry collaboration.

We believe the DSEN and CIHR can play a major role in securing the public’s trust in postmarketing studies, but respect for and realization of the five core principles will be vital. The appointment of Dr. Bernard Prigent, vice-president of Pfizer Canada, to CIHR’s governing Council—the first pharmaceutical representative to be so appointed25-29—and statements by CIHR president Dr. Alain Beaudet in the context of this appointment, emphasizing the need to intensify collaboration and even to align CIHR’s “agenda” and “vision” with the pharmaceutical industry,30 do raise the question whether CIHR remains sufficiently independent from industry to operate the DSEN. As one of us (TL) suggested at a hearing of the House of Commons Standing Committee on Health related to this appointment, Dr. Beaudet’s justifications provided in support of this appointment are worrisome rather than reassuring.31 Steven Lewis has remarked on this appointment that “Pfizer has an obvious interest in the flow of CIHR funds to science that may lead to drug development, and an obvious interest in diverting CIHR funds away from science that may reveal the comparative ineffectiveness of one of its drugs or challenge the pharmacological therapeutic paradigm.”28 We therefore recommend that CIHR and the minister of health, to whom CIHR reports, carefully evaluate the impact of such appointments and of increased collaboration with industry on the DSEN, and ensure its continuing independence.

We commend the CIHR in co-hosting, with Health Canada, the DSEN workshop on potential legal and ethical risks24 and look forward to the release of the final DSEN governance structure and policy documents to see how they fit with the core principles for building public trust we have described here. Canadians deserve scientifically rigorous real-world studies on the safety and effectiveness of postmarket drugs; these can happen only when those with conflicts of interest are not permitted to unduly influence the DSEN’s strategic direction, research agenda, research sponsors or the researchers themselves. The appearance of conflict of interest matters,28 and therefore in terms of promoting public trust it is crucial that the DSEN operate from the core principles of transparency and openness, accountability, independence, commitment to scientific integrity and freedom of action.