Krentz, Andrew J.
Many doctors would probably readily concur that, in the relationship between clinicians and clinical researchers on the one hand and the pharmaceutical industry on the other, trust is not symmetrically distributed. Pressed a little further, they might agree that aspects of drug development and marketing leave something – possibly quite a lot – to be desired. The same doctors might confess to feelings of unease when confronted with the sometimes astonishingly unsophisticated ads directed at them in medical journals. The thought might also cross their minds that perhaps they shouldn’t be quite so reliant on ever-so-nice sales representatives and glossy brochures for their continuing medical education.
They are right to feel uneasy. Clinical medicine is a serious game. It is complex, expensive and imprecise. The consequences of poor decisions can be unnecessary suffering, even death. Optimal prescription of potent medications can only be assured if the requisite information is available on which to ensure a favourable balance of benefits to risks. Yet, so often the process of selecting powerful pharmacotherapy for an individual patient relies on inadequate data derived from large clinical trials performed on homogenous groups of unrepresentative individuals. When treading their way through this daily minefield, clinicians need to be able to trust what they have been told concerning expectations for a new drug. Of necessity, the busy nonspecialist doctor looks to respected peers – considered as ‘thought leaders’ – to provide unbiased guidance that complements their own reading of the literature. Regrettably, as a profession we have perhaps been too ready to accede to what has become an opaque landscape of filtered data and commercial spin in which the salient facts can be difficult to discern.
At this point let’s acknowledge that it’s easy enough to knock Big Pharma. However, the industry only has itself to blame for a poor image, which stands in conspicuous contrast to the scientific excellence and expertise of the many dedicated people who work within its ranks. In his recently published book ‘Bad Pharma’ 1, British physician and academic Dr Ben Goldacre provides a timely and troubling assessment of some of the less salubrious activities of the pharmaceutical industry. Much of what is contained in this well-researched and comprehensive book will be familiar, at least to some extent, to most doctors. Nonetheless, this doesn’t materially detract from the impact of being presented with the dysfunctionality of the interactions between the pharmaceutical industry, physicians and regulators in its dispiriting entirety. Indeed, there’s plenty of uncomfortable reading here, not least for those who sit at the pinnacles of our professional societies and medical schools.
Dr Goldacre's book exposes the quality of some of the information that guides doctors in their daily prescribing decisions as being alarmingly suspect. All doctors are at least aware that clinical trials are often flawed – sometimes unforgivably from a scientific perspective – and not infrequently are selectively quoted. That’s bad enough, but we can deal with such problems when we see it. Worse, others – how many? – never reach the light of day to become accessible by the medical science community. There is an unforgiveable information void that we cannot quantify. The recent news 2 that GlaxoSmithKine has pledged to publish clinical trial reports for all of its medicines once they have been approved or discontinued from development and the results published is welcome. GSK has signed up to the http://www.alltrials.net campaign, set up by Goldacre and colleagues, including the Editor of the British Medical Journal, to ensure that all clinical trials are registered and reported.
Where, we might ask, are the authorities that police what remains a rather unsatisfactory state of affairs? The major regulatory authorities have become adept at presenting themselves as less than convincingly competent – and rather too often. Adding to this general sense of disquiet is the indefensible lack of transparency on the part of those who run the European Medicines Agency (EMA). Who do they serve? Within the biopharmaceutical industry, meticulous scrutiny of individual principal investigators [who are publicly named and shamed by the US Food and Drug Administration (FDA) when standards are not met] keeps minds focussed on clinical safety. It is less apparent that similar rigour is exercised at all levels of the drug approval process.
In recent years cardiometabolic medicine has had its share of discomforting experiences with novel drugs. Rosiglitazone was touted as potentially cardioprotective by virtue of its insulin-sensitizing actions, a claim that was ultimately revealed (by a cardiologist to an initially disbelieving diabetes community) to be spectacularly ill founded 3. Worse still, the rosiglitazone debacle came hard on the heels of the calamitous hepatoxicity of the first-in-class thiazolidinedione troglitazone, which, despite deaths and liver transplants, survived in the US market for several years. Rimonabant and sibutramine are other high-profile drugs that have shared the ignominy of being withdrawn from clinical use because of risk–benefit profiles that were eventually deemed unacceptable. How many patients were harmed along the way? For senior company executives, leaving behind such debacles to move on to better things seems a fairly well-trodden path. Interested observers (that’s, all of us of course) might be forgiven for thinking that this seems a bit one-sided.
Just recently, in the wake of the negative Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial, Merck, with the approval of the European Medicines Agency, sent a letter to UK doctors. The company recommended that no new patients be started on Tredaptive (a combination of extended-release niacin and laropiprant). After a median follow-up of 3.9 years, the drug had not significantly further reduced the risk of the combination of coronary deaths, nonfatal heart attacks, strokes and revascularizations compared with statin therapy, according to Merck. Moreover, there was ‘a statistically significant increase in the incidence of some types of nonfatal serious side effects in the group that received Tredaptive and statin compared with the group that received only statin’. Even though Tredaptive had not shown a benefit, the recommendation was that patients who were already taking the drug did not need to stop. However, this was followed shortly afterwards by a decision to withdraw Tredaptive (also known as Cordaptive) from all 40 countries in which it was available, not including the USA where it had failed to win FDA approval. Regulators continue to draw wildly differing conclusions from the same data.
We need better and safer drugs to manage public health challenges such as the epidemic of obesity-associated disease – no question. Total new drug approvals by the FDA hit a 16-year high in 2012. Of these, a disproportionate number (eight of 39) were approved in December – something of an FDA tradition according to Goldacre. Good news for patients? Time will tell. Novo Nordisk’s insulin degludec (Tresiba) is poised to give insulin glargine (Sanofi’s Lantus) a run for the proverbial money ($billions), having been granted marketing authorization by the European Commission. Overall, neither of these expensive insulin analogues has overwhelming advantages over well-established (and much cheaper) human insulin preparations, and both have fallen under a cloud of safety issues. The FDA has voiced concerns about the cardiovascular safety of insulin degludec, whereas the major concern – far from proven, it should be clearly stated – in the case of insulin glargine has been an increased risk for cancer. Yet, somehow we find ourselves in blockbuster sales territory. In February 2013 the FDA stunned Novo Nordisk by requiring a new cardiovascular safety study on Tresiba. This decision came only weeks after the drug had been given the green light in Europe, and just as Tresiba was poised to launch in Japan. The FDA’s decision has been seen as evidence of the agency’s new stringency that followed the rosiglitazone experience.
Returning to the issue of interpreting trial data clearly it is unrealistic to require that prescribers read all the relevant clinical trials before venturing to use a new drug. Summary data are necessary; trustworthy guidance is required. Given that such a large part of ‘Big Pharma’s’ budget is spent on marketing, we might ask whether today’s medical school graduates are prepared to critically appraise the selective and well-crafted claims of a manufacturer seeking to maximize sales? Where is the training for young doctors who will spend their careers exposed to material designed to persuade rather than educate in a balanced and objective way? To return to the aforementioned biologics it is widely perceived that the huge success of Lantus was in no small part due to a highly effective marketing campaign. To borrow a phrase from another well-known multinational corporation – this stuff matters. On a more positive note, at least stories of unduly lavish entertainment of doctors in anticipation of prescribing favours have faded in recent years.
All these considerations need to be set in the context of determined campaigns by governments to bring universities and the pharmaceutical industry closer together. Each has much to learn from the other, and such collaboration has the potential to facilitate the translation of preclinical observations to the clinic.
As for the reliability of the scientific literature, what responsibility should medical journal editors assume for the lamentable state of affairs concerning ghost written articles? For far too long the provenance of articles bearing the names of guest authors, whose contribution in extreme cases may have been minimal, has remained concealed from readers. The medical publishing community still has some way to go. As far as Cardiovascular Endocrinology is concerned, the journal was launched in alignment with current international recommendations, including guidance for papers generated by the pharmaceutical industry. The journal welcomes suggestions about how we might strengthen our safeguards against misleading publications. Our vision for the journal is that it will function as a trusted forum for the exchange of sound scientific data through robust peer review and transparency. However, vigilance is required. If any articles raise cause for concern, the journal will investigate and, where indicated, take appropriate action.
As doctors we must ensure that the pharmaceutical industry, the regulators, medical schools and bodies charged with postgraduate education provide clear, unbiased and accessible guidance for doctors. ‘Bad Pharma’ is a timely book that everyone involved in medical practice or medical education should embrace. Although the contents make for dispiriting reading, Dr Goldacre offers many practical suggestions for action. It is surely within our collective capability to improve on the unsatisfactory state of affairs that we have collectively allowed to develop. It is perfectly reasonable to demand the transparency that will ensure that patient safety is the paramount consideration during the development and implementation of new drugs. Indeed, we should demand nothing less. We have a duty to honour the trust that patients are obliged to place in our hands. The senior editors of Cardiovascular Endocrinology will endeavour to play our part in this process as best we can. Accordingly, we will be reviewing the journal’s requirements concerning authorship to try and ensure that the process is as transparent and rigorous as possible. Please send any suggestions you may have to us at firstname.lastname@example.org. If you haven’t already, do get hold of a copy of ‘Bad Pharma’. And please encourage your colleagues – senior and junior – to do the same; this book is essential reading for the medical profession.
The views expressed are those of Dr. Krentz in his capacity as Editor-in-Chief and do not necessarily reflect those of other members of the editorial board, Lippincott Williams & Wilkins or any other commercial or academic institution. Dr. Krentz has contracted as either a consultant, advisor, speaker and/or has received research funding from pharmaceutical companies including Abbott, Astra Zeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Halozyme, Johnson & Johnson, Merck, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, Servier, Takeda. Dr. Krentz holds no personal stocks or shares in these companies or any other pharmaceutical manufacturers.