Welcome to the August issue

By Robert Hand (robert.hand@rxcomms.com )

In recent years, pharmaceutical research has placed growing importance on patient-reported outcomes (PROs), defined as any outcome based on a patient's perception of a disease and its treatment(s), scored by the patient. PROs include a broad range of measures, from the purely symptomatic (e.g, change in headaches) to much more complex concepts such as quality of life (QoL). PRO data can enhance the understanding of the burden of specific diseases and the impact of intervening in those diseases.

But one problem so far has been the lack of a single, central repository for information on PRO data in approved drug labels. The PROLabels database, developed by the Mapi Research Trust, now offers a possible solution. This database, accessible at www.mapi-prolabels.org (for a fee), presents essential information about medicinal products for which PRO claims have been granted in the label. It also indicates information on products for which marketing approval has been withdrawn or discontinued. PROLabels is derived from postings on the EMEA website since 1995 and on the FDA website for new molecular entities (NMEs) since 1998. Mapi also offers PROQOLID, at www.qolid.org, which aims to aid researchers identify and gain access to appropriate PRO and QoL instruments.

What about standards for using PROs? In 2006, the US FDA issued draft guidance for using PROs to support drug label claims (available at http://www.fda.gov/cder/guidance/5460dft.pdf ). The agency encourages drug sponsors to identify the end point measurement goals early in product development, before beginning clinical studies, to allow for identifying or developing of appropriate PRO instruments. FDA recommendations include the use of questions that rely on current status rather than patients' memory, and the development of a user manual for PRO measures in clinical studies. Regulatory submissions must demonstrate the sensitivity, reliability, and reproducibility of the PRO instruments.

In response to the FDA guidance, the Mayo Clinic, working with the FDA, established the Mayo/FDA Patient-Reported Outcomes Consensus Writing Group. This group, including FDA personnel and experts from academia, industry, clinical research, and clinical practice, drafted a series of manuscripts to aid in discussing, disseminating, and implementing the FDA guidance document. The manuscripts were discussed at a meeting in 2006, and the final documents are now available, published in a supplement to the journal Value in Health (Volume 10, Supplement 2, 2007).

The documents cover five major themes: conceptual issues; PRO instrument selection; PRO instrument development issues; validation of PROs; and analysis, interpretation, and reporting results based on PROs.

The Writing Group's publications are intended to expand on the FDA guidance by describing methods for dealing with the challenges of including PROs in FDA-related clinical trials and submissions. Those involved in producing the articles concluded that “while the goals of assessing and analyzing PRO elements of clinical practice and research are challenging, there now exists a scientific foundation that makes achieving these goals feasible and the results credible.”

The FDA has not yet released a revision of its guidance, but readers who wish to explore issues related to PROs should refer to the information sources cited here.

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By Mary Gabb ( mary.gabb@rxcomms.com )

A negative result is defined as one that shows evidence of absent (or no) effect of an intervention; it is not due to absence of evidence, i.e, inconclusive results due to an underpowered study. Traditionally, negative clinical results were considered ‘uninteresting' and so were not published, or were not submitted for publication. In experience as a biochemist, a result was not ‘good' or ‘bad', ‘positive' or ‘negative'; it simply was. But a doctoral student could not obtain a PhD with only negative results, published or not. So, if we only strive for positive results, is this really rigorous science?

Dr Trisha Groves, Deputy Editor of the British Medical Journal , says that ‘we're keen to publish negative studies when they illustrate important points. Specifically, our policy is that if a research question is important, original, and relevant to the decision making of our general medical readership, and if that question is answered with the right study design and sufficient power, the answer should be published, whether it's positive {or} negative. We often publish negative results'. In fact, two of the BMJ's top 10 research papers published in 2006–2007 were negative studies (‘top' being defined by a combination of cites, hits, downloads, letters, pick-ups in evidence-based medicine journals, email alerting services, and media coverage).

How do negative clinical trial results affect economic analyses? Are they even used? One assumes that negative clinical trial data affect HE outcomes (e.g, assumptions made about the study population or efficacy of study drug, utilization rates, rates of adverse effects).

Christopher Carswell MSc, MRPharmS, Editor of PharmacoEconomics , feels that the effect of limited published clinical trials with negative results on HE research ‘is a very interesting research question, which to my knowledge has not been investigated and would probably be context specific. It undoubtedly leads to biased estimates of cost effectiveness but by how much and whether it is enough to affect decision making is an interesting question'. When asked whether health economists actively look for negative clinical trial results in their economic analyses, Carswell says, ‘If so, I have rarely seen authors make an effort to search for anything other than major published clinical trials, which I find very disappointing. A related point – rarely do authors employ formal methods to combine evidence from disparate sources, e.g, meta-analyses, mixed treatment comparisons, meta-regression – which is also disappointing'.

Both editors agree that negative clinical trial results are an important part of decision-making – for both efficacy and cost-effectiveness. As Christopher Carswell notes, ‘I don't like the term “negative [result]” as I think such studies should still be viewed in a positive light – they have shown a technology is not cost effective which helps with future decision making. In other words, we have added to the evidence base, which is not a negative thing'.

“ We go about curing a substantial number of ailments. But there is another part of the mystique. It's the great secret of doctors, known only to their spouses but still hidden from the public. Most things get better by themselves; most things, in fact, are better in the morning.”
Lewis Thomas (1913-1993) American physician and author

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By David Woods (david.woods@rxcomms.com)

Journal editors reject submitted manuscripts because they are:

• Inappropriate for their audience
• Poorly designed studies
• Poorly written
• Seen to have been submitted elsewhere
• Suspected of conflict of interest

When your manuscript is rejected, there are ways to handle the issue... principally by not taking rejection personally. There may be factors well beyond your control. For instance, the British publication, New Statesman , ran a competition whose first prize would go to the entrant who could produce a piece of writing that most closely resembled the style of acclaimed author, Graham Greene. Greene entered the competition – and came second!

A second way of handling rejection is by not attacking the editor. Editors are kindly and sensitive folk (I know it) and are just doing their job. Be ready to accept their constructive feedback. This you can do in a civilized way by addressing each suggestion for revision, by following instructions... and by being scrupulously objective.

As Dr. Edward Huth puts it in his excellent ‘How to write and publish papers in the medical sciences:' Rejection may be fully justified from the editor's point of view. Keep in mind how authors are competing for limited space in journals.” But Huth, a former editor of Annals of Internal Medicine does offer a Plan B of sorts for the rejectee: Send the manuscript somewhere else. “The paper may be readily accepted by a journal of lesser reputation,” he suggests. “But before you send the paper to a new journal,” he advises, “do what you can to improve the odds that it will be accepted.” That means giving careful consideration to the reasons why the first journal gave you the thumbs down.

Don't let rejection get you down. There are scores of examples of ultimately hugely successful works that were turned down multiple times. And remember the five Ps of effective writing: Passion, Patience, Perseverance, Pachydermia, and Parsimony. More on these in future issues of HOC .

This is one topic in David Woods's talk ‘Getting Published' which includes segments on overcoming writer's block; a handy checklist for writers of nonfiction; the classical article format; how to produce editorials, reviews, and abstracts; plagiarism, conflicts of interest; copyright – and those five Ps of effective writing.