By David Tuller, DrPH
*April is crowdfunding month at UC Berkeley. If you like my work, consider making a tax-deductible donation to Berkeley’s School of Public Health to support the Trial By Error project: https://crowdfund.berkeley.edu/project/31347
*Note: To give credit where it’s due, Magical Medicine: How to Make an Illness Disappear, an exhaustive investigation from Malcolm Hooper and Margaret Williams, first mentioned the PACE team’s violations of the Declaration of Helsinki 20+ years ago.
The PACE authors and their allies routinely cite the UK’s Health Research Authority as having given this boondoggle of a trial a clean bill of health. The HRA, which oversees research ethics processes and procedures, conducted a review of PACE and issued its findings in January, 2019. The agency assessed PACE as having been conducted properly, but it noted that its purview was limited to “whether the study was properly approved by the Research Ethics Committee (REC),” and questions about the “quality of the study” were beyond its scope.
Even within its remit, the report was deficient in multiple respects. It has therefore had the unfortunate effect of obscuring some of the trial’s unacceptable flaws.
These deficiencies are apparent in the report’s section on “conflicts of interest” and its analysis of whether the PACE investigators should be held to account for not disclosing their advisory and/or financial ties with major insurance companies to prospective trial subjects.
To recap. In the PACE trial protocol, the investigators included a paragraph on “compliance” that featured this sentence: “The trial will be conducted in compliance with the Declaration of Helsinki, the trial protocol, MRC Good Clinical Practice (GCP) guidance, the Data Protection Act (1998), the Multi-centre Research Ethics Committee (MREC) and Local Research Ethics Committees (LREC) approvals and other regulatory requirements, as appropriate.”
The item mentioned first, the Declaration of Helsinki, was developed after World War II as an effort to protect human research subjects. This document is very explicit about disclosures: Researchers must inform prospective participants about “any possible conflicts of interests” and “institutional affiliations of the researcher.” These mandates were already part of the Declaration of Helsinki years before the 2005 launch of the PACE trial. In promising to adhere to it, the PACE investigators committed themselves to adhering to all of its provisions—including the specific requirement that they disclose “any possible conflicts of interests” and any “institutional affiliations” to prospective trial participants.
At the time of the PACE trial launch, the lead investigators maintained advisory and/or financial ties with major insurance companies. For years, they had advised companies that the interventions being investigated in PACE could get claimants back to work and off social benefits. Could there really be a dispute over whether these insurance industry ties would qualify as “any possible conflicts of interest” and/or “institutional affiliations” under any reasonable interpretation of these phrases from the Declaration of Helsinki?
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The HRA analysis of “conflicts of Interest,” paragraph by paragraph
Below, I have included the section of the HRA on “conflicts of interests,” which includes discussion of the Declaration of Helsinki. I have highlighted the especially problematic passages and have provided a response after each paragraph.
HRA REPORT: “Critics of the trial raise concerns that there was a failure to comply with the standards contained in the Declaration of Helsinki over the disclosure of conflicts of interest. One issue concerns the involvement of the Department of Work and Pensions (DWP) as one of the funders. The information that all participants received included this fact and we therefore conclude that this was transparent and must be taken as acceptable to those who chose to take part. Concern has also been raised about potential conflicts of interest on the part of investigators. The trial protocol notes more extensive ‘competing interests’ than were included in the Patient Information Sheet (PIS). The differences concerned the advisory roles of the researchers. These were noted in the protocol but the PIS records only the sources of funding.”
MY RESPONSE: This description of critics’ concerns fails to mention a salient point—the PACE investigators themselves promised to adhere to the Declaration of Helsinki. The main objection—at least my main objection—was not simply that there was “a failure to comply with the standards contained in the Declaration of Helsinki over the disclosure of conflicts of interest.” The objection is that the PACE investigators received funding and approval based on their protocol, and in their protocol they listed the Declaration of Helsinki as first among the ethical codes they intended to follow. Investigators invoke the declaration in their protocols to assure funders and reviewers that a study will be conducted in accordance with internationally agreed-upon provisions designed to protect human research subjects.
The proper question for the HRA, therefore, was not whether the investigators violated the Declaration of Helsinki but whether they violated their protocol promise to abide by the Declaration of Helsinki–and whether the REC should have approved their consent forms without the disclosures of “any possible conflicts of interest” and “institutional affiliations.” Absent their own promise to follow the declaration, they would have been under no particular obligation to abide by it, as far as I can see.
In short, the PACE investigators agreed to inform prospective participants of “any possible conflicts of interest” and “institutional affiliations”—but they did not. It is understandable that the they might have felt it unnecessary or intrusive to provide this level of detail about their other activities. But no one forced them to mention the Declaration of Helsinki, and it is unclear why they should not be held to it.
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HRA REPORT: “This process was probably consistent with the contemporary understanding of when a ‘competing interest’ should be regarded as a ‘conflict’ of interest for the purposes of research ethics approval. This was understood at the time as a matter of personal benefit. The WHO (2011) definition is: Conflict of interest: In the research context, scientists have a conflict of interest if they stand to achieve personal gain (money or the equivalent) by failing to discharge professional obligations, either to protect the welfare of participants or to uphold the integrity of the scientific process.“
MY RESPONSE: The ”contemporary understanding” of what would warrant disclosure is irrelevant in this matter, and it is unwarranted for the HRA to cite or rely on it. The PACE investigators had already declared themselves bound by the stricter policies outlined in the Declaration of Helsinki. Investigators do not get to pick and choose from among the provisions of international human rights documents they endorse in their protocols. Given the trial’s enormous price tag, the public had a right to expect that the HRA would hold the PACE investigators to the standard they themselves had chosen. HRA failed fully in this regard.
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HRA REPORT: “Critics of the trial have raised concerns that the researchers were conflicted because they were advocates for the therapies that were being investigated. From the evidence we have identified, this is based primarily on presentations they have given to insurance companies and to government. However, it should be noted that the treatments that were being discussed were the therapies that NICE recommended, so all expert advisors would have been expected to explain them to such bodies. It is not clear what ‘personal gain’ the investigators stood to make from the trial and, in particular, it is not clear how any remuneration they received from advisory roles would have been different depending on the outcome of the trial.“
MY RESPONSE: This interpretation of the situation is so ridiculous that it seems almost willfully stupid. It is true that the treatments in question were recommended by NICE and incorporated into the agency’s 2007 guidance. The HRA report didn’t mention, however, that the PACE investigators were among the core group that created this treatment paradigm in the first place and helped ensure its hegemony, so they’ve obviously had a great deal invested in preserving the status quo. Moreover, their pre-PACE work inspired and informed the 2007 NICE guidance. As pioneers in this domain, they should certainly not be portrayed as run-of-the-mill “expert advisors” blindly following NICE in their provision of services to the insurance industry. The HRA’s argument here is disingenuous and cannot be taken seriously.
The same can be said of the HRA’s apparent confusion over whether the investigators “stood to make” some form of “personal gain” if they reported positive results for the treatments they had long promoted. Of course they did, and these forms of ‘personal gain’ are easy to list: reputational enhancement, academic vindication, and opportunities for professional advancement, for example. The investigators had spent years advising insurance companies that the treatments in question would get claimants back to work and off benefits. I presume it would have negatively impacted those professional relationships had they been forced to inform insurers that PACE had now disproved what they’d been asserting as fact for years.
It is perplexing that the HRA sees no problems here. Again, willful stupidity or ignorance seems like a possible explanation.
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HRA REPORT: “Given that the REC was aware of the competing interests that are regarded by some critics as giving rise to a conflict of interest, and that they approved the trial including the PIS [patient information sheet], it is not appropriate to criticise the researchers for non-disclosure. However, this is an area where greater clarification of expectations would be helpful. The Academy of Medical Sciences has recommended that further consideration and guidance is needed in relation to problems of conflicts of interest. The Health Research Authority is currently revisiting its guidance in this area.”
MY RESPONSE: The presence of an REC does not alleviate investigators of their responsibility to be honest and straightforward in their disclosures. In this case, the REC members might have been “aware of the competing interests,” as the HRA noted, but might not have been aware of the specific provisions of the Declaration of Helsinki that required the disclosure of “any possible conflicts of interest” and “institutional affiliations.”
However, the PACE investigators knew of this provision—or they should have, since they promised to abide by the declaration. The fault for the omission of key disclosures lies squarely on the decision by the PACE investigators themselves to violate their protocol in this consequential and unethical manner. There should have been zero confusion about this matter. The phrases “any possible conflicts of interest” and “institutional affiliations” are not ambiguous to anyone with an understanding of English–and that includes HRA report author Professor Sir Jonathan Montgomery, who was chair of the agency at the time.
In sum, by not providing key information to trial participants, the PACE investigators failed to obtain fully informed consent–at least per the promises they made in their own protocol. And the most powerful players in the UK medical and academic establishments, including the HRA, have let them get away with this. This systemic, high-level pooh-poohing of the serious ethical breaches that marred the conduct of the PACE trial is a shameful spectacle.