Forum

• 1. Call for Greater Global Dissemination of Clinical Science

• 2. Investment in Genetic Research Pays Off

• 3. Reviving Serendipity in Drug Discovery a “Utopian Fantasy”?

• 4. Pharma Industry Less than Healthy

• 5. MACE an Unreliable Endpoint in Cardiovascular Studies

• 6. Ethics of Clinical Trials called into Question

• 7. Mandatory Trial Results Disclosure has Implications for Journals

• 8. UK Yellow Card Scheme: Pharmacists to Encourage Patient Reporting

1. Call for Greater Global Dissemination of Clinical Science

“There is more need for clinical science of international interest to be globally disseminated”, conclude researchers from Greece and the US.

The researchers evaluated data concerning the country of origin of studies published in 11 leading medical journals over a period of 35 years.

The Lancet demonstrated the most diversity regarding the origin of published studies; between 1971 and 1975, 62.6% of studies published in this journal were from the UK, whereas between 2001 and 2005 only 43.2% of published studies were from the UK. For the remaining journals, the proportion of articles published that originated from the country in which the journal is based ranged between 71.7% and 95.1%, for the period 2001–5.

“We strongly believe that further efforts to boost the globalisation of the research published in the major biomedical journals will be a service to the global biomedical community as well as the public”, contend the researchers.

2. Investment in Genetic Research Pays Off

“Landmark genetic discoveries yield positive randomized, controlled trials and approved treatments frequently enough to justify investments into genetic research”, conclude researchers from Canada and the US.

To determine the rate at which genetic discoveries resulted in randomized trials and approved treatments, the researchers evaluated data for genetic determinants of human diseases that were published between 1975 and 2000; they subsequently searched for trials which resulted from each genetic discovery.

A total of 53 genetic determinants for human disease were identified in this study; the median follow-up time for potential translation was 14 years. Twenty of the 53 genetic determinants had randomized trials, of these, 15 were positive and 5 were not, resulting in a rate of translation to randomized trial of 28%. Overall, eight (15%) of the genetic discoveries had been translated into approved treatment options.

3. Reviving Serendipity in Drug Discovery a “Utopian Fantasy”?

“Given the distressing decline in pharmaceutical innovation”, should serendipity in drug development “continue to atrophy?” asks Dr Donald F. Klein, in JAMA.

He notes that the pace of discovery of “entirely new classes of psychotropic drugs” in the 1950s and 1960s was “dizzying”, and included chlorpromazine, clozapine, haloperidol, lithium and lysergide. These drugs were all discovered “serendipitously”, says Dr Klein, but such generative serendipity seems to have been “stymied” in the last 40 years. He suggests the following “antiserendipity factors” may have played a part.

• • The expectation that serendipity would be replaced by rational drug design, fostered by translational research.

• • The radical compression of clinical time by cost-control measures.

• • The adoption of the parallel-group, placebo-controlled, double-blind trial as the sole method for demonstrating drug efficacy.

Dr Klein quotes Louis Pasteur, who mused that “chance favors the prepared mind”. However, Dr Klein points out that “there must be proper environments that foster chance observations”, to allow prepared minds to pursue promising leads. He contends that the current clinical trial model “contributes to anti-serendipity”, and suggests a new model of an “imaginative objective study” of the successful specific treatment of patients to determine “how treatments work”.

Of course, such measures would be “difficult to support”, initially, and reversing the constrictions on clinical discovery time, “is probably a utopian fantasy”, Dr Klein comments.

4. Pharma Industry Less than Healthy

‘Big pharma’ companies appear healthy, writes Financial Times pharmaceuticals correspondent Andrew Jack in the BMJ, but their current low share prices reflect concerns over their long-term prospects. Jack says that the pharmaceutical industry’s problems are set to intensify due to the following issues:

• • generic substitution: over the next 5 years, the pharmaceutical industry’s collective annual revenue is set to drop by about $100 billion due to the expiry of patents for existing drugs;

• • a lack of new drugs: despite recent substantial advances in scientific knowledge, there has been difficulty in translating this into new drugs. Jack suggests that this is due to a lack of understanding of how to apply this knowledge effectively, technical difficulties, and stricter regulation that reflects ‘risk averse’ public opinion. Moreover, bringing a new drug to market is suggested to cost >$1 billion;

• • increasing pressure on pricing: resistance to new drugs’ high prices and suspicion of their benefits over cheaper generics is reflected by the introduction of organisations such as the UK National Institute for Health and Clinical Excellence, which recommends medications based on their cost effectiveness as well as clinical efficacy;

• • negative perception: “drug companies seem often to be viewed … as 19th century snake oil salesmen”, comments Jack. For example, European competition commissioner Nellie Kroes recently launched an antitrust investigation into the industry, making unannounced raids on companies.

Jack concludes that “drug companies may still be posting profits for now but they are likely to suffer much more pain ahead”.

5. MACE an Unreliable Endpoint in Cardiovascular Studies

A group of US researchers recommends against the use of the composite endpoint of major adverse cardiac events (MACE) in cardiovascular research, based on their findings.

Wide Variation in MACE Definitions …

The researchers assessed the definitions of MACE, both in a sample of randomized controlled trials with a clearly defined research question (bare metal stents versus drug-eluting stents; 20 trials), and in clinical studies in general that were published in the Journal of the American College of Cardiology in 2006 (27 studies).

Even among trials specifically comparing stents, there was substantial variation in which outcomes were included in MACE. In 2006 studies as a whole, the variation was even greater.

• … and Results Depend on which one is Used

Based on these results, the researchers constructed three MACE definitions, and evaluated MACE in 6922 drug-eluting stent recipients in the US DEScover registry, based on these definitions. They reported the following MACE rates:

• • 362 events/year for safety outcomes (death, myocardial infarction [MI] and stent thrombosis) alone;

• • 674 events/year for safety outcomes plus target vessel revascularization;

• • 868 events/year for safety outcomes plus any revascularization.

Furthermore, the inclusion of revascularization in MACE determined whether increases in MACE with acute MI or multilesion intervention were significant or nonsignificant.

6. Ethics of Clinical Trials called into Question

The ethical guidelines regulating clinical trials are to be revised in light of mounting international concern over “drug trial horror stories”. The World Medical Association is seeking input regarding their proposed revisions to the Declaration of Helsinki, which was last revised in 2000. “Since 2000 there have been so many scandals that have been unleashed that the need for ethical principles, and regulations and laws as well — first of all to be formulated, and second to be applied — is stronger than ever”, contends Dr John Williams, the former ethical director of the World Medical Association who is coordinating the revision process.

7. Mandatory Trial Results Disclosure has Implications for Journals

Trish Groves, deputy editor for the BMJ, has written an editorial reporting on the implications of a new US law that will require public disclosure of results from all clinical trials.

The US FDA Amendments Act mandates the registration of all ongoing clinical trials of any FDA-regulated drug, biological agent or device at clinicaltrials.gov. From 27 September 2008, the results of these trials will also need to be registered at this site. Failure to comply will incur fines of $US10000 per infringement, with no upper limit, and online listing of trials’ ‘responsible parties’.

Disclosure of trial results is required to take place within 1 year of the final data collection date, and there is no allowance for delay while awaiting publication in a peer-reviewed journal. Groves raises the possibility that editors could view this disclosure as a prior publication of results and, on this basis, refuse to consider such trials for publication.

Journals Urged to Adapt

The International Committee of Medical Journal Editors, having already recommended that journals only consider registered trials for publication, has made the further ruling that its member journals would consider trials with registered results, notes Groves — provided that no more than one results table or an abstract of ≤500 words is made publicly available. However, the FDA has now mandated the disclosure of a substantially greater amount of information than this, which presents problems for editors and researchers.

However, “the BMJ will consider disclosed trials and urges other journals to do the same”, says Groves. She comments that, unlike the FDA results registry, the journal peer-review process provides added quality assurance for published results. However, she questions whether a journal would still wish to publish study results whose prior disclosure has already resulted in widespread public debate, and wonders, “in the long run, will the role of peer reviewers and medical journals as the gatekeepers of new medical evidence become redundant?”

Groves encourages researchers who are submitting important trial results to the BMJ to request that their submission undergoes a fast-track review, in order to facilitate its publication prior to disclosure on the FDA site.

8. UK Yellow Card Scheme: Pharmacists to Encourage Patient Reporting

In February, the UK MHRA launched a 6-week campaign to get pharmacists to mention the Yellow Card scheme to customers. Pharmacists received an information pack with updated Yellow Card reporting forms, posters and information leaflets. The Yellow Card forms have been made easier to use and the online system updated to make reporting suspected side effects to the MHRA quicker and easier. Director of Vigilance and Risk Management of Medicines at the MHRA, Dr June Raine, advises customers “[i]f you suspect that you have had a side effect to your medicine, please tell us about it via the Yellow Card Scheme”.

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