Top 5 reasons why medical associations should maintain ties with industry

In the April 1st issue of JAMA, Rothman, et al. spelled out a proposal for controlling conflicts of interest that calls for professional medical associations (PMAs) to cut all ties with industry. PMA conferences, continuing education and practice guidelines often set the standard for patient care.

The proposal seems reactionary, albeit understandable given how quickly a handful of high-profile cases—particularly those involving failure to disclose—both blackened the eyes of science and eroded public trust.

But should a few bad apples be allowed to spoil the bunch? I say no. And here are the top 5 reasons why I propose just cutting all the bad apples loose and continuing to reap the best possible fruit.

1. Together, PMAs and industry actually do more good than harm. I could go on and on about all the good new drugs and devices have done for patient care, but we don’t have the space. I will say that I once had a 40-plus year old former patient stop me on the street to thank me for helping save his life. In my opinion, the kudos should have gone to the makers of the intra-aortic balloon pump that kept him alive while his heart recouped. Back in the day, he would never have survived that event regardless of how good the care was.

2. Industry doesn’t have as much power as you think. Industry’s power is diluted by nurses, patients and grass-roots patient advocacy groups, who together wield big clubs called prescriptive pressure and noncompliance: if a drug or device doesn’t work, nurses won’t give it, or patients won’t use it. And don’t forget the 800-lb. gorilla in the room—third-party payers—who have more power than drug and device companies over treatment guidelines and who gets what and when.

3. Industry is on the same side of the fiduciary coin as PMAs. Industry wants to save lives, too. They also want safe and ethical care. If you don’t believe that take a look at how pharma manufactures have come together to police themselves. Visit http://www.phrma.org/ and click on their outline for a revised marketing code.

4. Physicians are business people too. Physicians can’t cut ties with industry; they are industry. We like to believe that pure professionalism lies at the heart of medicine, but the drivers of treatment guidelines, namely the individual physicians and their associations, are in business. Profit isn’t a palatable word, so let’s call what they do “earning a living.” Besides, physicians can cross the line without help from the drug and device part of the industry, as evidence by anti-kickback laws that have more to do with unethical patient referrals than branded pens and notepads.

5. Together, PMAs and industry are on the ethically right path. In the Association of American Medical Colleges’ “The scientific basis of influence and reciprocity: A symposium” the authors show how self-interest can unconsciously bias even those of us who have the best of intentions, but they also demonstrate how just being reminded of an honor code stops cheating completely regardless of the amount of reward. Full transparency is a kind of honor-code reminder, and a huge step in the ethically right direction for all parties involved.

Sources:
Rothman DJ, McDonald WJ, Berkowitz CD, et al. Professional Medical Associations and their relationships with industry. JAMA 2009; 301: 1367–72
Korn D, Ehringhaus SH. Association of American Medical Colleges, The scientific basis of influence and reciprocity: A symposium. 2007. Available at: www.aamc.org/publications Association of American Medical Colleges, Industry funding of medical education: report of an AAMC task force. 2008. Available at: www.aamc.org/publications


Written by Terri Metules.

The value of in vitro data in metabolic disease: Editorial Board member Keith Suckling comments on a review by Clapham et al.

It is not unusual to read at the end of a paper presenting new biology that the novel mechanism or process being described may be a target for pharmacological intervention. The data may well have been obtained from studies in cell culture, perhaps of an immortalised human cell line, perhaps from cells genetically manipulated, and the basic picture (given the rigours of the reviewing process) may be very convincing. But there is always a strong doubt in the reader’s mind. This is because the pathway from a novel and potentially relevant piece of biology to a new drug with demonstrated clinical value is long and hazardous. At this early stage, the relevance to human disease may be little more than a hypothesis, and data of all kinds will be required as drug discovery and development takes place to validate the target.

It has been recognised for many years that one of the major problems to address is how to develop sufficient confidence in a target or agent to allow the major financial commitment that is required to be made. We need confidence that the cell culture models are relevant to an intact animal, and that the data we obtain in a pre-clinical species has relevance to the situation in the patient. Such confidence is hard to obtain, particularly for novel biology. In this review [1], Clapham and colleagues lay out the ground for metabolic disease. Apart from offering a very clear analysis of the issues involved, they make a very useful contribution by illustrating the value of data on drug activity obtained from cell culture studies and from parallel studies in laboratory animals, both in relation to the observed effects in patients. This kind of information is not readily available: it is mostly held in the experience of specialised scientists, an asset that is all too easily lost in the major reorganisation of drug companies.

A central point in the problems clearly illustrated by Clapham et al. is the proper understanding of what a cell culture model or an in vivo model can be expected to achieve. The question has been addressed for animal models in the closely related area of dyslipidaemia [1], but, probably because the relevant data are very widely scattered in the literature, the aligning of in vitro, in vivo and human data has not been widely done. The analysis of Clapham and colleagues is a welcome example of what could be done. But we need to go further. As I have noted recently [3,4], I believe we need to be much more critical of what our models can achieve and what their limitations are. Only then, as Clapham et al. clearly illustrate, will we be able to offer a rigorous scientific foundation for the difficult investment decisions that have to be made.


1. Clapham J.C., Hallén S. (2009), Cell based in vitro and ex vivo models in metabolic disease drug discovery: nice to have or critical path?, Expert Opinion on Drug Discovery, 4: 417-428.

2. Suckling K.E. (2006), The ideal model in atherosclerosis and dyslipidaemia - does it exist? Expert Opinion on Drug Discovery 1: 507-511.

3. Suckling KE (2007), Top down meets bottom-up. The critical interface for drug discovery. International Atherosclerosis Society Commentary.

4. Suckling KE (2008) Animal research: too much faith in models clouds judgement. Nature (letter) 2008, 455, 460.

By Keith Suckling, PhD, Editorial Board member of Expert Opinion on Therapeutic Patents

Open repositories VS the Publisher

On March 18th the MIT introduced a policy requiring all scholarly articles written by its faculty members to be made freely available in an open access repository. While researchers understandably applaud the free and open dissemination of data, there are questions that should be considered with regards to the impact of a growing number of open repositories on the value added by Publishers, and how this value would be retained if in the long term the open access journal turns out to be unsustainable.

How important is the value added by the Publisher (and this is not an open access versus non-open access journal debate)? While the peer review process is certainly not without its failings, to any Publisher or Editor worth their salt, the integrity of the peer review process is paramount. To quote a previous blog post on this site, an author of a CMRO article on receiving his peer review comments said "I have never received 58 referee comments on a manuscript less than 3000 words long, but the referees' comments and the revision definitely improved the paper." An author of a recent paper submitted to Expert Opinion on Medical Diagnostics fed back "a comment about the reviewers: it was clear that they read the manuscript carefully. Regardless of whether they agreed with some of our arguments, their comments reflected readers that thought about what they read. This is how peer review is supposed to work. Excellent reviewer selection on your part, and a thorough job on theirs." Aside from assisting the author in critically reviewing their work and ultimately leading to a better paper, without the peer review process how do we ensure no dangerously inaccurate information is published that is indistinguishable from high calibre scientific research?

And it’s not just in the peer review that value is added by the Publisher. Who checks references are cited correctly and terms are not misspelled - will the institutions running their own open access repositories employ copyeditors? Who will ensure the figures are legible and of good quality – will the institutions employ production editors who lay the work out in such a way that it is easy on the eye and doesn’t give readers a headache? Will there be any independent quality check before the research is published? With a limitless amount of potentially unqualified freely available literature, how will the busy physician who only has 5 minutes in his/her day to digest the most important findings even know where to start? These are just a few of the questions that would need to be answered.

Ok, I’m playing devil’s advocate a little here. I do not envisage a world where the peer-reviewed journal ceases to exist, but the open access model of publishing is widely debated, both in terms of quality and sustainability. So what is the future of publishing? Even if the open access, pay to publish model is viable in the long term, does the scientific community agree to paying to publish all of their work in the future, rather than pay to read the work of others? The fact is, publishing a journal is a costly business and the money has to come from somewhere. Publishers are accused of placing scientific research behind ‘commercial barriers’, but surely the same argument could be applied to the pay to publish model. Is it fair that only authors with funding can afford to have it published? Will this lead to a bias in the literature towards sponsored research, not even so much through the choices of the Editor, but through the fact that only authors who can pay can publish? Or is there an alternative, free to publish, free to read, sustainable model for open access publishing that still maintains high standards of peer review and editorial quality?

While Publishers undoubtedly need to take steps to ensure the advancement of science through the widest possible dissemination of research, with respect to the whole principal of open access, how do we do this for free? Surely someone, somewhere has to pay something?

In summary:

• How important is value added by the Publisher?
• How will high calibre research be distinguished?
• How will the reader filter the wealth of freely available literature?
• Does the scientific community want to pay to publish all of their work in the future?
• Could this lead to bias in the literature?
• What if the pay to publish model doesn't work?
• Is there an alternative, free to publish, free to read, sustainable model for open access publishing that still maintains high standards of peer review and editorial quality?

By Anna Heinink, Publisher, Expert Opinion

Informa Pharmaceutical Science’s policy on NIH-funded research can be found here http://www.informapharmascience.com/page/resources/authors#nihfundedresearch

Expert Opinion on Therapeutic Patents and Journal of Medical Economics selected for indexing in MEDLINE

Informa Pharmaceutical Science is delighted to announce that Expert Opinion on Therapeutic Patents (EOTP) and the Journal of Medical Economics (JME), have been selected for indexing in MEDLINE.

A widely used bibliographic database compiled and maintained by the US National Library of Medicine, MEDLINE is freely accessible via the PubMed search engine. It is worth noting that the decision by MEDLINE to index or not a journal is based on a review by the Literature Selection Technical Review Committee upon application. The main criteria for selection, which go beyond sound science and thorough peer review, are listed here.

We are very pleased by this decision which will deservedly increase the visibility of JME and EOTP articles.

Reuben’s Research: A Pain In The Analgesia

Research on multimodal analgesia took a hit when one of its leading proponents, Scott S. Reuben, MD – aka the Medical Madoff - was caught fudging his data. Baystate Medical Center’s internal review board launched a full-fledged investigation into Reuben’s work last May when he appeared to be conducting studies on humans without approval. The investigation, completed in January, uncovered some 21 published articles—dating as far back as 1996—in which Reuben made up some or all of the data. Baystate's chief academic officer is quoted as saying that in many cases, "there was no clinical trial because there were no patients." Whew!

At least it looks like nobody got hurt. But the incident raises questions in our industry that beg for answers:

Where Were The Peer Reviewers? In my opinion, that’s an unfair question some people are asking. Peer reviewers, and editors for that matter, can only work with the data they’re given. We can’t be expected to show up on every study site to make sure a prospective author’s data is pure before we decide to accept it for publication.

Why did it take 13 years to catch him? We can only speculate on why it took so long to uncover Reuben’s fraud, but it may have been because, like the Piltdown Man, nobody was taking his research all that seriously—nobody else could replicate his findings. Replication, albeit slow, is the surest way to keep fraud in check.

What was Industry’s role? Outside of partially funding some of Reuben’s research—and there’s nothing inherently wrong with that--Pfizer is not suspected of any wrongdoing. However, Reuben’s relationship with Pfizer, at least in the papers I was able to fully access, was not properly disclosed in most cases.

Would full disclosure have mattered? I think so. Knowing the financial ties an author has to a study’s sponsor alerts readers to the potential for biased results.

What Can Be Done About It? Reuben’s case is every Editor’s worst nightmare. Patient care is ultimately affected by erroneous data. While CMRO has never published a Reuben paper, something like this could happen to us. But rest assured that we are doing everything within our power to prevent such a thing from happening.

All CMRO articles undergo such a stringent peer review process that caused one author recently to say, “I have never received 58 referee comments on a manuscript <3000 words long, but the referees' comments and the revision definitely improved the paper.” We will also be introducing new measures soon to stay at the forefront of ethical publishing - keep your eyes open for more news soon.

By Terri Metules, US Deputy Managing Editor, Current Medical Research and Opinion

Further Reading

Good publication practice guidelines for medical communications agencies: a MedComm perspective Bareket-Samish et al. CMRO 2009;25(2):453-61

Working with compliance - the role of healthcare communications agencies Cairns & Yarker CMRO 2008; 24(5): 1371-78

International Society for Medical Publication Professionals (ISMPP) Position Statement Norris et al. CMRO2007 23(8): 1837-40

Phospholipases may not be targets of choice for medicinal chemistry, but two inhibitors are now in clinical development for atherosclerosis

By Editorial Board member Dr Keith Suckling

Phospholipases do not appear high on the list of major druggable target types. There are significant challenges in medicinal chemistry to provide specificity and in enzymology to generate data that can support chemistry for reactions that take place at a lipid-water interface at which active concentrations of compounds are difficult to define. So it is perhaps surprising that there are now two phospholipase inhibitors in clinical development for the treatment of atherosclerosis - surprising because of the chemical challenges but also because the final proof of efficacy in patients requires extended outcome studies in around 16,000 subjects.

The first of these compounds is darapladib (GSK) for which Phase 2 results were presented last year [1]. Darapladib inhibits the enzyme known as lipoprotein-associated phospholipase A2. As the name suggests, this phospholipase is found in the circulation associated with LDL and is thought to catalyse the hydrolysis of oxidised phospholipids. The products of the hydrolysis promote the expression of adhesion molecules on the artery wall and chemokines in macrophages and so promote the development of the vulnerable plaque. Inhibition of this process would therefore be expected to be of benefit and recent studies in a pig model support this concept [2] and some of the Phase 2 data are consistent with it too. This mechanism would be expected to have a similar overall effect on the pathogenesis of atherosclerosis to a chemokine receptor antagonist, for example CCR2. Importantly this approach does not reduce plasma LDL, and is not expected to.

Other forms of phospholipase have been implicated in atherogenesis in recent years and in particular those known as secretory phospholipases [3], of which the Group V enzymes have been of particular interest. Animal data also supports a role for these enzymes in atherogenesis [4], but the mechanism is different. In this case the phospholipase modifies HDL and LDL particles making the former less able to support reverse cholesterol transport and the latter more susceptible to oxidation. Very recently Phase 2 data have been reported of the effects of an sPLA2 inhibitor, varespladib (A-002, Anthera Pharmaceuticals) [5]. This compound inhibits a range of sPLA2 s (sPLA2-IIa>sPLA2-X>sPLA2-V) and, in contrast to darapladib, does have an effect on plasma LDL concentration and also on hsCRP. Recent animal data are consistent with an effect of varespladib on atherogenesis in the mouse [6]

It is important to recognize that the effects of these two phospholipase inhibitors on the process of atherogenesis are quite different and as a result, at least in Phase 2, they require different end points to be studied. If this is not borne clearly in mind there is a danger of serious confusion amongst non-experts. In this respect we should no more talk about phospholipase inhibitors as a class than we might about PPAR agonists: there are so many differences. Nevertheless, for both mechanisms, it is necessary to show that they improve outcomes in patients, and at this point the differences are not important. A large outcome study is beginning for darapladib (STABILITY) with around 15,000 patients [7].

By Keith Suckling, PhD, Editorial Board member of Expert Opinion on Investigational Drugs

Reference List

1. Serruys P.W., Garcia-Garcia H.M., Buszman P., Erne P., Verheye S., Aschermann M., Duckers H., Bleie O., Dudek D., Botker H.E. et al. (2008). Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 118: 1172-1182.
2. Wilensky R.L., Shi Y., Mohler E.R., III, Hamamdzic D., Burgert M.E., Li J., Postle A., Fenning R.S., Bollinger J.G., Hoffman B.E. et al. (2008). Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med 14: 1059-1066.
3. Kimura-Matsumoto M., Ishikawa Y., Komiyama K., Tsuruta T., Murakami M., Masuda S., Akasaka Y., Ito K., Ishiguro S., Morita H. et al. (2008). Expression of secretory phospholipase A2s in human atherosclerosis development. Atherosclerosis 196: 81-91.
4. Boyanovsky B., Zack M., Forrest K., and Webb N.R. (2009). The Capacity of Group V sPLA2 to Increase Atherogenicity of ApoE-/- and LDLR-/- Mouse LDL In Vitro Predicts its Atherogenic Role In Vivo. Arterioscler Thromb Vasc Biol ATVBAHA.
5. Rosenson RS, Hislop C, McConnell D, Elliot, M, Stasiv U, et al. (2009). Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretory phospholipase A2 (PLASMA study): a phase II double-blind, randomised, placebo-controlled trial. Lancet 373: 649-658.
6. Fraser H., Hislop C., Christie R.M., Rick H.L., Reidy C.A., Chouinard M.L., Eacho P.I., Gould K.E., and Trias J. (2009). Varespladib (A-002), a Secretory Phospholipase A2 Inhibitor, Reduces Atherosclerosis and Aneurysm Formation in ApoE-/- Mice. J Cardiovasc Pharmacol.53, 60-65
7. GSK Press release: http://www.gsk.com/media/pressreleases/2008/2008_pressrelease_10144.htm

Drug-drug interactions in oncology: from mechanisms to patient perception

Drug-drug interactions in oncology represent a highly problematic issue to resolve. The events that give rise to clinically significant drug-drug interactions are inherently driven by cancer patients that are often being medicated by more than one drug. Polypharmacy in oncology can result in alterations of chemotherapeutic pharmacokinetic profiles via multiple mechanisms affecting the pharmacodynamics of drugs that are closely related to their pharmacokinetic profiles. In their review article,Mani and colleagues critically analyze the mechanisms by which drug-drug interactions in oncology alter pharmacokinetics and also explore the emerging field of transcriptional control of enzyme/transporter action and its impact on altered drug clearance. Adding another layer of complexity to drug-drug interactions in oncology is the patient’s perception of the definition of a “drug”. Cancer patients undergoing treatment with chemotherapeutics who also consume over-the-counter medications, herbal remedies or supplements without informing their physician run the risk of unknowingly exposing themselves to potentially dangerous drug-drug interactions. In her Editorial article, Professor Marie Hanigan highlights the dangers of patients taking treatment advice from unreliable sources or misinterpretation of the scientific literature and calls for a more in-depth inquiry by the physician into the consumption of non-prescription medicines and other supplements by cancer patients. Professor Hanigan describes the lack of knowledge and confusion among cancer patients regarding the dangers of drug-drug interactions and addresses the challenges facing this large and complex field.