‘The Strange Case of Dr Jekyll and Mr Hyde’ was an 1886 novel written to contrast public and private lives of a reputable gentleman. Duplicity is a constant failing, but often what’s revealed is just an iceberg’s tip above massive issues. Thanks to the only mandatory Pfarma reporting in Oz, Medicine Australia’s Education Events, we know that Pfizer spent an average of $12k on each of the 23 rheumatologists they recently sent to European and American conferences EULAR and ACR. The full reports give an insight into specialist’s lives outside the surgery, as $43.3m was spent on them in the 6 months to Sept 2015. Worse still in 2010 pharmaceutical companies reported $637m expenditure on research, but nobody knows who received the money *. There is monumental potential for conflict-of-interest as the scope of new-gen bio-agents increases (monoclonal antibody drugs, hereafter referred to as the _mab drugs).
Amgen sponsored 799 events in the last 6 months. Focusing in more closely, we really can’t be sure just how safe is their anti-inflammatory _mab for arthritis, Enbrel. Regulatory authority TGA advises physicians under Adverse Effects: “In placebo-controlled trials, no increase in the incidence of serious infections (fatal, life-threatening, or requiring hospitalisation or intravenous antibiotics) was observed“. Uhuhh.
Allegations it caused Eagles frontman Glenn Frey’s death due to pneumonia can’t be verified. In the latest EULAR journal ‘Annals of Rheumatic Diseases’ Winthrop & Smolen et al suggest it’s a good idea to track outcomes of _mabs. ‘Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases’ reveals the shortcoming that “no consistent OI [Opportunistic Infection] definition was identified across  studies“. Hence a list of OIs was drawn up, topped by the pathogen responsible for pneumonia. The best evidence for their recommendations was the publicly accessible meta-analysis by Kourbeti, Ziakas, & Mylonakis which put the odds of infections 1.8 times higher for _mab recipients than controls (usually patients on frontline med, methotrexate) in Rheumatoid Arthritis (RA) trials – a small but significant risk. But note that RA doubles that risk over healthy comparators already.
That’s short term though, a trial median of around 6 months for the drug to prove its worth. Aust Rheumatology Association’s Rachelle Buchbinder established the ARAD tracking database a decade ago to determine _mab safety. It’s paid for by Pfizer, BMS and AbbVie. The few reports published in journals thus far inform us of customer satisfaction such as subjective Quality of Life surveys, and that no increased risk of cancer occurs, and that herpes/shingles virus infection rates are 1.7 times higher. Specifically for Enbrel, this result came after a median of 3 years followup. So the longterm prognosis is much like the brief studies would indicate. A worsening, but hardly deadly. Glenn’s manager wisely declares he has taken legal advice to limit his accusation.
This drug inhibits TNF, a cytokine messenger that augments our innate immunity system. As understanding of the molecular basis of many diseases improves, an inflammatory aspect is a recurring theme. The prospects for treatment with anti-TNF therapy look promising, but for the fact that the body needs to be regulated by internal controls. And not shareholders, salesfolk, or Jekyll. Interestingly, a trial for Enbrel in Alzheimers found that TNF levels rose. Feedback systems are adaptive.
Future studies could well heed the EULAR belief that their “… list of infections should be considered potential indicators of alterations in host immunity, and that this list and the associated case definitions should be used to standardise reporting of OIs in future biologic and other disease modifying antirheumatic drug clinical trials“. It’d also be helpful if an outcome tracking registry reported on all OIs, instead of the trickle of data from ARAD. But unease over industry manipulation of research is fuelled by the doctors themselves. When a weakened version of the US Sunshine Act for disclosing contents of the unmarked envelope was being considered by the Aust Competition and Consumer Commission, the AMA submission sought a deferral: “A twelve month delay in implementing the ACCC’s condition would allow health practitioners to think about and plan for their ongoing relationships with pharmaceutical companies.”
EULAR 2016 is in London. The UK has an Office of Research Integrity, let’s hope some fresher ideas than creative accounting are brought home.
* Source: College of Psychiatry submission to the ACCC. They’re concerned: “Clinical research should be included in the transparency model. All payments above the threshold that are made to individual researchers, or research institutions, including hospitals, should be publicly reported. This would better enable doctors and other health professionals to interpret the research outcomes while taking into account their funding sources.”