Mark and Barb and Eric and Carole

May, 30, 2022 | 13 Comments

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If North Americans don’t know much about Asterix cartoons – see The Harmed, Europeans don’t know about MAD. This image was adapted by Nina Otulakowski from a front cover image in Mad, see below, featuring the 1969 Bob, and Carol, and Ted and Alice movie.

Born in the USA

Multi-Regional Clinical Trials (MRCT) was born in the USA in 2009. Pfizer had just resolved a case with the US Department of Justice for $2.3 billion, then one of the biggest resolutions of an action against a corporation.

The company convened a meeting of other pharmaceutical companies, contract research organizations (CROs), institutional review boards (IRBs) (ethics committees in Europe) and lawyers, especially Ropes and Gray, a Boston law firm, later involved in GSK’s defense against a Department of Justice action, resolved in 2012 with a payment of $3 billion. This meeting created MRCT.

A later MRCT website listed Mark Barnes and Barbara Bierer as its founders. Barnes is a lawyer variously linked Ropes and Gray, Harvard, and Pfizer. Bierer is a professor of medicine (haematology) at Brigham and Women’s hospital.

It seems clear that industry and its advisors/consultants were aware that transparency was a coming issue. A fraud action taken by New York State against GSK in 2004, centered on the mismatch between a company publication and the underlying Study 329 trial data, demanded an industry answer to the transparency problem.

Responsible Access

In early 2013, MRCT convened a meeting with 36 people present. One third were company people, one third lawyers or regulators and the remainder a mixed group of Brigham and Women’s staff, MRCT staff, along with Jeffrey Drazen editor of the NEJM, a business consultant, and a patient advocate (if that is the right name for someone from a company whose business involved selling patient conversations about drugs to pharmaceutical companies). It is difficult to know if there were even two people at the meeting in regular clinical practice.

Later in 2013, the New England Journal of Medicine (NEJM), which in the form of Drazen was party to MRCT, published a paper on Responsible Access to Clinical Trial data that advocated the same model of clinical trial data sharing as AllTrials (see below).

Preparing for Responsible Sharing of Clinical Trial Data, the 2013 NEJM article, had six authors – four lawyers, Michelle Mello JD, Jeff Francer JD, Mark Wilenzick JD, Mark Barnes JD, one doctor Barbara Bierer MD, and one business consultant. All had been present at the earlier meeting.

In 2014, MRCT held a meeting on access to clinical trial data. There was a general enthusiasm for the idea. Bierer was the only medical author on the Responsible Sharing of Clinical Trial Data papers. Her take on data sharing was that:

I don’t think most people appreciate how much we know as a result of clinical research. To gain that knowledge – to determine treatments that are safe and effective – we are dependent on people who volunteer for clinical trials. If you get a therapy today that was based on years of study, you’re the beneficiary of other people’s volunteerism. We’re all in this together.,

Presentations at this MRCT meeting talked about data generators, a term that broadly speaking includes industry and non-industry trials. Some presenters (academics) at these meetings argue for the same set of rules for all data generators, as would be appropriate for science.

A neutral term like data generators conceals the conflicting interests data generators can have. Barnes above made this conflict explicit:

We need to remember the role of directly involved commercial interests as funders. It may be great to share data – let a thousand flowers bloom – let’s share everything. This may be true for academic research but if commercial funders believe their commercial interests will be affected the funding will dry up. The capital will go elsewhere. They won’t fund it.

MRCT Special Missions

Between 2009 and 2014, key MRCT players were grappling with Pfizer’s growing difficulties in Nigeria over Trovan and other problems.

All Western pharmaceutical companies were faced with problems in India, which had become an important center for clinical trials. In 2010, the deaths of 7 girls in HPV vaccine trials led the Indian government to clamp down on clinical trials and introduce a stricter code of practice.

This new stricter code of practice led to a 2014 MRCT workshop in India, a central feature of which was to review what could be said about causality assessments in the event of adverse effects. This will be outlined in a forthcoming Harmatology post.

MRCT materials from 2014 emphasize that clinical trials have become global and different jurisdictions can throw up issues ‘investigators’ and companies have never confronted before. The use of ‘investigators’ in texts like this refers to clinicians like Stephen Thomas, first author of the Pfizer vaccine trial in adults but it is as ornamental as having a ‘patient advocate’ at an MRCT workshop. Other than rhetorically, no medical academic has been an investigator in a company trial for decades.

On one level what was at stake in 2014 was the outsourcing of an industrial development process to India, China and Africa. The more recent development of virtual trials opens up a path to ignoring these countries.

In 2017, MRCT launched Vivli, notionally a Center for Global Data Sharing. Company trials however had been run in Africa, Latin America and Asia for two decades before Vivli, so running trials outside the US was not new. What was new was the idea of responsible sharing of trial data, as was an embrace of data sharing more generally, which a decade earlier companies resisted and then reluctantly tolerated.

There was another factor – which will run as a separate post ‘Harmatology’.

Responsible Access to Clinical Trial Data sounds as difficult to object to as motherhood and apple pie. Suspicions that Responsible Sharing of assay data, if supported by pharmaceutical companies and their lawyers, cannot be as good for us as motherhood and apple pie have, however, some basis.

RCTs necessarily have a primary outcome, without which the statistics do not make sense. This outcome is only one of more than a hundred things a drug may be doing, and quite often the effect of commercial interest will not be the most common effect.

Focusing on one uncommon and uncertain effect often renders other effects invisible. In the case of antidepressant RCTs, for instance, the benefit is uncertain compared with the effect of these drugs on sexual function, which is immediate, and close to universal, but the intense focus of an RCT means that these sexual effects vanished in antidepressant trials.

This focus on one effect means that, despite rhetoric claiming RCTs offer gold standard knowledge, they are not a good way to evaluate a drug. See The Fault Lies in our Stars and Fawlty Stars.

The focus also means that the entire RCT is primarily structured to provide certain datapoints. An emphasis on responsible access with an approved analytic plan means any subsequent investigators can essentially only come to much the same answer as the company already has.

It is possible, as in Study 329, that a new set of investigators might find a benefit claimed in the original publication doesn’t stack up, but, if so, responsible access to assays can come to the rescue. Quite predictably, when all 30 RCTs done of antidepressants in children who are depressed are negative, stacking them all together can pull out a positive effect, which can then be used to claim these drugs work, despite every single trial being negative.

The current proliferation of meta-analyses on pediatric antidepressant trials shows just this, which is ironically being sold as precision medicine.

It will come as no surprise then to find that MRCT-Vivli aim to facilitate data sharing across comparable trials.

The Pfizer input on data sharing to the Vivli platform needs to be read against this background. The company will support data sharing and will evaluate proposals under the following heads:

Is the research question clearly defined with a scientifically valid rationale?
Is there a well-documented and rigorous statistical analysis plan?
If the proposal includes combining data across different Pfizer trials, is there a clear plan to standardize data sets to ensure they are comparable?

There is little here about Vivli making trials possible in non-Western settings and everything about data-sharing as optimizing the assay function of company trials.

Translating what is being said for lay people, you are being told you can access this data for efficacy purposes but if you are interested in treatment harms forget it.

The New England Journal of Misinformation under Drazen and now Rubin, Eric Rubin Boston Strangler, has essentially devolved into an outlet for efficacy studies. Eric made this point clearly in a lecture he gave on March 29 2022, for the Berkshire District of the Masachusetts Medical Society.

What has happened is perhaps best caught in this screenshot of a recent NEJM initiative.

NEJM is dragging the Massachusetts Medical Society along with it – see So Long and thanks for all the Fish, which brings Carole Allen into the frame. She was then the President of the MMS, which has some responsibility for the NEJM – although insiders say very little influence.

Shared DNA or Shared mRNA?

MRCT shares DNA (Do Not Access), or perhaps mRNA (messenger Responsible Non-Access), in common with AllTrials.

All Trials began in the UK in 2013, immediately after GSK, defended by Ropes and Gray resolved a Department of Justice case for $3 billion.

AllTrials was a coalition involving BMJ, the Cochrane Collaboration, the Centre for Evidence Based Medicine, GSK and Sense about Science. Sense about Science set up in 2002 and is effectively an outsourced PR department for the pharmaceutical and other industries. See SaS 1, SaS 2, SaS 3, SaS 4.

All sorts of people normally critical of the pharmaceutical industry signed up and donated money to AllTrials. The BMJ put the CEO of GSK on its front cover as the acceptable face of the pharmaceutical industry – just 3 months after the then biggest resolution payment in corporate history.

With AllTrials input fronted by Ben Goldacre, a UK House of Commons Select Committee stated that:

We are not in favour of placing anonymized individual patient-level data (IPD) in the public domain in an unrestricted manner… specific individuals should be provided with controlled access to IPD through carefully managed and secure “safe havens”.

Access should be facilitated by an independent “gatekeeper” responsible for insuring that the data … makes a useful contribution to scientific understanding.

This is identical to the MRCT position. AllTrials is blind and deaf to the idea that medicines might cause harms. Its leading figures went out of their way to rubbish efforts to restore Study 329 – as did the New England Journal of Medicine.

AllTrials is not heard of so much now but Vivli actively promotes itself as a global data-sharing platform, supported by all major pharmaceutical companies.

The Originals

The images in the post come from Nina Otulakowski, from an original Dr Pedro idea.

Which was in turn adapted from the promotional material for the 1969 movie, billed as a comedy. In c 1970 Ireland, a ‘sophisticated’ image like this, in the Tom Lehrer sense of this word, was beyond shocking – which is perhaps part of some Divine or other Comedy.