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Should drug companies conduct their own clinical trials?
- (see full text of 3 BMJ articles below following this summary report.
 
 
 
 
30 November 200p pharmatimes.com

As new guidance on the standards required for communicating company-sponsored medical research is published, today on bmj.com two experts debate whether drug firms carrying out clinical trials on their own medicines creates an unacceptable conflict of interest.

Vincent Lawton, a healthcare consultant and non-executive director at the UK Medicines and Healthcare products Regulatory Agency (MHRA), argues that having invested billions of pounds in medicine development, it is unrealistic to expect the drug industry to "surrender its intellectual property." He adds that taking away research from pharmaceutical companies will lead to delays, inefficiency and a lack of innovation.

Doctor and writer Ben Goldacre disagrees, arguing that "it is hard to see any justification" for allowing the current situation to continue. Increasing evidence points to a conflict of interest for the drug industry which "results in bad evidence, which distorts medical decision-making and harms patients," says Dr Goldacre. One of the problems is that the industry can choose which data to publish and which to leave unavailable, he adds, pointing to the difficulties in getting clear information about the number of suicide attempts in industry trials of selective serotonin reuptake inhibitor (SSRI) antidepressants or the number of heart attacks in individuals taking Merck's anti-inflammatory drug Vioxx (rofecoxib)

The current situation, Dr Goldacre concludes, "is dangerous and absurd." Doctors who are making treatment decisions "need access to good-quality trial data, presented transparently, and all of it, not just the positive findings that drug companies choose to share," he says.

However, Prof Lawton believes that it is acceptable for the drug industry to make a profit and still undertake rigorous clinical trials that stand up to regulatory scrutiny. He points out that, in January 2005, the industry made a commitment to increase the transparency of clinical trials by registering its trials in central, publicly- accessible databases, and that most major companies also publish trial results, whether positive or negative, on their own websites.

It is unlikely that publicly-sponsored academics would have the infrastructure to conduct all clinical trials on all new medicines leading to regulatory approval, he concludes.

Dr Goldacre and Prof Lawton faced each other on the same issue recently as opposing speakers at PharmaTimes's Great Oxford Debate in September, when Dr Goldacre told drugmakers that, by withholding or distorting data, "you shoot yourself in the foot, you undermine your own credibility and mine as a doctor."

Prof Lawton reminded the Debate that pharma is the world's most regulated industry and that there are now unprecedented controls on clinical trials. Any interference with the right of industry to conduct its own clinical trials is "at your peril," he warned.

Meantime, an accompanying paper also published on bmj.com today sets out new guidance for communicating company-sponsored medical research. Written by the International Society for Medical Publication Professionals (ISMPP), the good publication practice (GPP2) guidelines have been updated in response to changes in the environment in which authors, presenters and other contributors work together to communicate medical research. They include guidance on defining the roles of authors, sponsors, and other contributors, recommendations about reimbursement, and confirmation of the role of professional medical writers, and apply to peer-reviewed journal articles and presentations at scientific conferences.

Lead author Chris Graf says the guidelines "make recommendations that will help individuals and organisations maintain ethical practices and comply with current requirements when they contribute to the communication of medical research sponsored by companies."

By Lynne Taylor


Head to Head

Is the conflict of interest unacceptable when drug companies conduct trials on their own drugs? Yes


Published 29 November 2009, doi:10.1136/bmj.b4949

Cite this as: BMJ 2009;339:b4949

Ben Goldacre, doctor and writer

1 Nuffield College, Oxford OX1 1NF

ben@badscience.net

doi:10.1136/bmj.b4330

Ben Goldacre argues that the financial interests of drug companies lead to distorted evidence, but Vincent Lawton (doi:10.1136/bmj.b4953) believes that adequate safeguards exist to keep bias in check and says below: "Competition and investment drive innovation and are dependent on the right environment. Companies should continue to work closely with academia and regulators to identify weaknesses or shortcomings and find ways to address them. Appropriate safeguards of transparency, scientific integrity, and regulation should ensure that different interests do not become unacceptably conflicted. Having invested an average of $1.2bn (£724m, {euro}802m) and 10 years to bring a medicine to the market, is the drug industry expected to surrender its intellectual property? A third party's lack of infrastructure, expertise, and resources would inevitably lead to delays, cutting into patient access and the patent life of the medicine. This seems to be a sure way to drive away the incentive to innovate.13 At present about 75% of the funding for clinical trials in the United States comes from industry14 and total industry spending on research is greater than that of the National Institutes of Health.12"

The practice of medicine is based on evidence. We need this evidence base to be complete, and of the highest quality, so that we can make the right decisions, but at present, drug companies produce most of the evidence we use. There is no doubt that these companies have a conflict of interest when they conduct trials: they want to sell their products, and so naturally they want a positive result from the trials they sponsor. But there is now good evidence from systematic reviews, meta-analyses, and case studies that this conflict of interest results in bad evidence, which distorts medical decision making and so harms patients.

We will start with a tangible story, from a single field. Rochon1 analysed the literature on non-steroidal anti-inflammatory drugs (NSAIDs), and found all the studies that had ever been published where one NSAID was compared to another. In every single trial, the sponsoring company's drug was either equivalent to, or better than, the drug it was compared to: all the drugs were better than all the other drugs. Such a result is plainly impossible.

A systematic review2 found 30 studies investigating whether industry funding is associated with outcomes that favour the funder: studies sponsored by drug companies were more than four times as likely to have outcomes favouring the funder, compared with studies with other sponsors.

How does this systematic bias come about? One answer is questionable trial design. Studies are conducted, for example, where the competitor drug is given at an inadequate dose, or worse, at a higher dose, increasing the risk of side effects, and so making the sponsor's drug appear to be preferable.3

Another common problem is that the industry can choose which data to publish, and which to leave unavailable. Much has been written on eye-catching stories, such as the difficulties in getting clear information about the number of suicide attempts in industry trials of SSRI antidepressants4 or the number of heart attacks in patients on rofecoxib (Vioxx).5

Equally concerning is the routine grind of publication bias, where disappointing negative results on the benefits of treatments quietly disappear. This phenomenon has been demonstrated in many fields, notably that of SSRIs,6 and in some areas of medicine its scale is staggering. Ramsey and Scoggins7 went to clinicaltrials.gov and found all the trials on cancer: 2028 in total. Only 17.6% of these trials could be found published on PubMed, but 64.5% of those that were published reported positive results. Restricting their analysis to only industry sponsored trials, these results became even more extreme: just 5.9% were on PubMed, but of those trials, 75.0% gave positive results.

And while disappointing results lie unpublished, positive results may be published repeatedly, in ways that are hard to spot. One group conducting a meta-analysis on the efficacy of ondansetron8 made a striking discovery: data from 3335 patients in nine trials had been published more than once, in 14 further reports. None of these duplicate publications used a clear cross reference, so there was no easy way for a casual reader to see that each was not a new trial. Crucially, and perhaps inevitably, data showing a greater benefit from ondansetron were significantly more likely to be published twice.

It is inevitable that publishing positive results more than once will cause doctors to think a drug is better than it really is, since doctors are busy, and cannot each conduct forensic checks on every trial they read. One study estimated that for physicians to read every published article relevant to primary care alone would take more than 600 hours a month.9 Duplicate publication and dubious methodological tweaks will be missed, and an illustration of how much these practices may cause doctors to overestimate a drug's efficacy can be seen in the ondansetron meta-analysis, where including the duplicated data led to a 23% overestimation of the drug's antiemetic efficacy.8

The problems I have described are not new, and they have been described on many previous occasions. They could be fixed, without taking research out of the hands of industry altogether, but to do so would require that the drug companies recognised the scale of this scandal, and campaigned themselves for more effective regulation: demanding full mandatory publication of all trial data from themselves and their competitors, for example.

Instead we see inertia, and the failure of regulators to engage adequately with these serious problems. In medicine, bad information leads to bad decisions: we prescribe one drug where an alternative would have been more effective, or had fewer side effects; or we prescribe an expensive drug, unnecessarily, when a cheaper alternative was equally effective, and so we deprive the community of limited healthcare resources. This is dangerous and absurd. Doctors who are making treatment decisions need access to good quality trial data, presented transparently, and all of it, not just the positive findings that drug companies choose to share.

Cite this as: BMJ 2009;339:b4949

doi:10.1136/bmj.b4330

Based on the Great Oxford Debate on 23 September 2009 at the Oxford Union, Oxford University, sponsored by PharmaTimes.

Competing interests: BG has written newspaper articles and part of a book criticising questionable activities in the drug industry, and has a Clinical Research Training Fellowship from the Wellcome Trust.


Head to Head

Is the conflict of interest unacceptable when drug companies conduct trials on their own drugs? No


Vincent Lawton, healthcare consultant and non-executive director

1 Medicines and Healthcare products Regulatory Agency, London

Vincent.Lawton@btconnect.com

doi:10.1136/bmj.b4330

Ben Goldacre (doi:10.1136/bmj.b4949) argues that the financial interests of drug companies lead to distorted evidence, but Vincent Lawton believes that adequate safeguards exist to keep bias in check

The drug industry is sometimes accused of finding it difficult to reconcile the difference between the strict disciplines of ethical science and its responsibility to its shareholders to return a healthy profit. Proposals to move control of this critical process in drug development into the hands of an "objective" third party need to be critically examined. Clinical trials are properly managed by a rigorous system of regulatory scrutiny throughout. Potential for conflict of interest, when clearly identified and controlled, is not unacceptable.

The industry develops medicines through years of painstaking research by some of the best scientists in the world, often in collaboration with academic researchers. Clinical trials are an essential part of developing safe and effective drugs, and after the drug is introduced to clinical use more is discovered about its effects. Further trials, which can involve academic collaboration, are done to provide further information and study whether new indications can be added to the drug's use—for example, as in the landmark 4S trial.1

Trial designs and protocols are assessed and endorsed by regulators2 who assiduously guard against inadequate trial design, insist on good clinical practice standards,3 and ensure high quality analyses. Ethics committees, who are fully independent (normally established and funded by the NHS in the UK through health authorities), do not countenance a substandard study design.4 They frequently intervene before a study is allowed to proceed. An impartial data monitoring committee (funded by the trial sponsor)5, comprising distinguished academic clinicians, monitors the analyses and trial results and protects the safety of participants, the credibility of the study, and the validity of results. Indeed, some evidence suggests that industry sponsored studies have higher methodological quality than those funded by other bodies 6.

No system is perfect, so it is important to keep enhancing the safeguards. To eliminate bias, the industry has developed various transparency measures. Companies often design studies with the input of regulatory agencies and the academic community. No matter how the study is designed, it cannot start until approval has been granted from both the regulatory bodies (the US Food and Drugs Administration and the European Medicines Agency) and the independent ethics committees,7 The analyses and methods must be in place and agreed by the regulatory agencies before the trial begins.

Trials not conducted by drug companies can and do deviate from these standards. For example, the Women's Health Initiative study in 2002 was conducted by National Institutes of Health sponsored investigators and looked at effects of hormone replacement therapy.8 The original focus of the study was coronary heart disease, but the investigators found that breast cancer—which had a low incidence, leading to results that were not statistically significant—got more media attention. The significance level was, therefore, changed post hoc in order to re-focus on breast cancer, causing alarm in concerned women.

Open access to clinical trial information is becoming increasingly important to policy makers, healthcare professionals, patients, and the general public. The drug industry actively worked to change the public's negative perception of clinical research and their lack of trust in science, which is directly related to the lack of clear information freely available to them. In January 2005,9 the major drug industry trade associations from Europe, Japan, and the United States announced their commitment to increase the transparency of clinical trials sponsored by their member companies. The commitment was for the industry to register its trials in central, publicly accessible databases. Most major companies also publish trial data, whether positive or negative, on their own websites. The databases usually have data on registered medicines, which are available in at least one country. However, companies or academics may judge that trial results for an investigational product that has failed in development have substantial medical importance. In such cases, study sponsors are encouraged, principally by the trade associations, to publish these results too. Data are intended to be published no later than a year after the medicine is first approved, although a backlog exists.10 The International Federation of Pharmaceutical Manufacturers and Associations has recently updated its position on disclosure of clinical trial information.11 This extends the range of trials that member companies should provide information on to include all clinical trials in patients, as a minimum. The scope of this new joint position will include early stage safety trials of medicines for life threatening conditions, which are usually done in healthy volunteers.

The notion that a super cadre of publicly sponsored academic researchers would be capable of conducting all clinical trials on all new medicines, leading to regulatory approval, requires a stretch of the imagination. Even assuming it was possible, it would take many years and enormous cost to establish an infrastructure to conduct these trials. Furthermore, academic investigators sometimes report drug adverse events less comprehensively than drug companies 12

Having invested an average of $1.2bn (£724m, {euro}802m) and 10 years to bring a medicine to the market, is the drug industry expected to surrender its intellectual property? A third party's lack of infrastructure, expertise, and resources would inevitably lead to delays, cutting into patient access and the patent life of the medicine. This seems to be a sure way to drive away the incentive to innovate.13 At present about 75% of the funding for clinical trials in the United States comes from industry14 and total industry spending on research is greater than that of the National Institutes of Health.12

The better way for patients, health care, and innovation is to continuously improve what we have, despite potential competing interests. Competition and investment drive innovation and are dependent on the right environment. Companies should continue to work closely with academia and regulators to identify weaknesses or shortcomings and find ways to address them. Appropriate safeguards of transparency, scientific integrity, and regulation should ensure that different interests do not become unacceptably conflicted.

Cite this as: BMJ 2009;339:b495

doi:10.1136/bmj.b4330

Based on the Great Oxford Debate on 23 September 2009 at the Oxford Union, Oxford University, sponsored by PharmaTimes.

Competing interests: VL is a non-executive director of the Medical and Healthcare Products Regulatory Agency and a non-executive director of Addex Pharmaceuticals. He was for 26 years an employee of Merck pharmaceuticals, latterly managing director MSD UK and vice president Europe (until 2006).


Research Methods & Reporting

Good publication practice for communicating company sponsored medical research: the GPP2 guidelines


Chris Graf, associate editorial director 1, Wendy P Battisti, associate director, scientific and medical publications2, Dan Bridges, group programme director3, Victoria Bruce-Winkler, medical publications consultant4, Joanne M Conaty, senior director, clinical strategy and planning5, John M Ellison, senior manager, scientific publications6, Elizabeth A Field, president7, James A Gurr, director, publication planning and development8, Mary-Ellen Marx, senior manager, medical education9, Mina Patel, senior director, medical communications10, Carol Sanes-Miller, global publications manager, scientific communications5, Yvonne E Yarker, senior vice president, medical communications11, for the International Society for Medical Publication Professionals

1 John Wiley & Sons, Wiley-Blackwell, Oxford OX4 2DQ , 2 Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ, USA, 3 Excerpta Medica, Elsevier, London, 4 Dunblane, 5 AstraZeneca Pharmaceuticals, Wilmington, DE, USA, 6 LifeScan, Milpitas, CA, USA, 7 Field Advantage Medical Communications, Chapel Hill, NC, USA, 8 Pfizer Collegeville, PA, USA, 9 PharmaWrite, Princeton, NJ, USA, 10 Cephalon, Frazer, PA, USA, 11 Knowledgepoint 360 Group, Newtown, PA, USA

Correspondence to: C Graf chris.graf@wiley.com

In response to changes in the environment in which authors, presenters, and other contributors work together to communicate medical research the International Society for Medical Publication Professionals has updated the good publication practice guidelines

Authors and presenters are responsible for how medical research is interpreted and communicated. Often their work is the product of collaborations with other individuals (such as clinical investigators, biostatisticians, and professional medical writers) from around the world. Some or all of the people who contribute to this collaboration may be employees of research sponsors, contract research organisations, or medical communications agencies that may be funded by pharmaceutical, medical device, or biotechnology companies. The authors, collaborators, and organisations share responsibility for developing articles and presentations in a responsible and ethical manner.

The good publication practice (GPP2) guidelines presented here make recommendations that will help individuals and organisations maintain ethical practices and comply with current requirements when they contribute to the communication of medical research sponsored by companies. These guidelines apply to peer reviewed journal articles and presentations at scientific congresses.

What's new?

GPP2 updates earlier good publication practice guidelines.6

New elements include:

* An extensive consultation process was used to write the guidelines

* Authorship guidance recommends assignment of a lead author and guarantor

* Contributorship guidance recommends describing the role of the sponsor

* Recommendations about reimbursement

* Recommendations for specific types of articles and presentations

* Recommendations for publication planning and documentation

Updated elements include:

* Guidance on defining the roles of authors, sponsors, and other contributors

* Guidance on establishing a publication steering committee

* Confirmation of the role of professional medical writers

Evolving standards

The conduct and communication of medical research, including that sponsored by companies, continues to be criticised.1 2 3 4 5 Since 2003, when the original good publication practice guidelines were published,6 the environment in which medical research is reported has evolved. The Declaration of Helsinki, updated in 2008, places accuracy and completeness among the primary ethical obligations of individuals communicating medical research, and suggests that "reports of research not in accordance with [its] principles should not be accepted for publication."7 Information about clinical trials, including results, is being made accessible in new ways driven by regulations and guidelines from around the world.8 9 10 11 12 13 14 15 Standards for the accurate publication and presentation of research have also evolved,16 and new or updated codes of practice have been developed (table 1Go). The International Society for Medical Publication Professionals (www.ismpp.org) has been established and certifies the practice of individuals developing articles and presentations sponsored by companies. These guidelines were written in light of these developments.

Methods

The International Society for Medical Publication Professionals invited members with over 10 years of experience in biomedical publishing to develop these guidelines (figure Go). The 14 members named as contributors to this article responded to the invitation and formed the steering committee. The steering committee reviewed the original guidelines,6 discussed items to be included in the revised guidelines (GPP2), and wrote the draft guidelines.

he steering committee recruited an international consultation panel by direct invitation and multiple open requests for volunteers. The draft guidelines were circulated to the 193 people who agreed to be part of the consultation panel for comment. The consultation process was conducted in confidence (table 2Go).

The 116 sets of comments submitted were blinded and collated, and members of the steering committee assessed and ranked them on:

* The frequency of comments received on a particular line number

* The critical or beneficial rating given by members of the consultation panel

* The steering committee member's interpretation of the importance of the comments.

Ranked comments submitted by steering committee members were combined into a composite rank, which was used to create the final guidelines.

Guidelines and recommendations

Roles and responsibilities


Written agreement

We recommend that companies describe obligations for good publication practice in written publication agreements with authors of articles or presentations and with members of writing groups or publication steering committees. We recommend that the written agreement confirms the sponsors' responsibilities to:

* Grant authors full access to study data

* Confirm the authors' freedom to make public or publish the study results

* Provide authors with copies of the sponsor's publication policy.

We recommend that the written agreement confirms the authors' responsibilities to:

* Plan and produce articles or presentations that are accurate and complete in a timely manner

* Avoid premature publication or release of study information

* Avoid duplicate publication

* Make decisions about practical issues concerning presentation and publication (for example, choice of congress or journal)

* Disclose potential conflicts of interest in all articles and presentations

* Identify funding sources in all articles and presentations

* Ensure authorship is attributed appropriately

* Acknowledge in all articles and presentations all significant contributions made by individuals and organisations

* Provide the sponsor with copies of publication policies from the authors' institutions

We recommend that the written agreement confirms the shared responsibilities of all contributors, including authors and sponsors, and that it:

* Confirms that sponsors will work with investigators, authors, and contributors to report and publish studies in a timely and responsible manner

* Defines the criteria that will be used to determine authorship for articles and presentations

* Confirms that the sponsor and the investigators will be informed about the publication process

* Provides protection to parties with intellectual property rights, and establishes a reasonable period before study results are made public for intellectual property rights to be protected

* Establishes the right of the sponsor to review, in a timely manner, articles and abstracts before they are submitted, and to share scientific comments with the authors

* Describes what, if any, support for the development of the article or presentation will be provided

* Establishes a process founded on honest scientific debate as the means to resolve scientific differences in interpretation of findings or study presentation

* Establishes that all articles and presentations will conform to good publication practice and other recognised standards (table 1Go)

We recommend that written agreements for articles and presentations from research studies are made at the earliest opportunity—for example, when the protocol is finalised. Written agreements for other articles and presentations (for example, meta-analyses, sub-analyses, review articles) should be made before the authors begin work.

Written agreements must respect the institutional policies of authors, investigators, and other contributors, as well as those of the sponsor. Individuals must not be asked to violate the policies of their institutions.

Access to data

Sponsors have a responsibility to share the data and the analyses with the investigators who participated in the study. Sponsors must provide authors and other contributors (for example, members of a publication steering committee or professional medical writers) with full access to study data and should do so before the manuscript writing process begins or before the first external presentation of the data. Information provided to the authors should include study protocols, statistical analysis plans, statistical reports, data tables, clinical study reports, and results intended for posting on clinical trial results websites. Sufficient time should be allowed for authors and contributors to review and interpret the data provided and to seek further information if they wish (for example, access to raw data tables or the study database).

Reimbursement

It may be appropriate for companies to reimburse reasonable out of pocket expenses (for example, travel expenses) incurred by contributors or pay for specialised services such as statistical analysis. Details of this reimbursement must be disclosed. We recommend that no honorariums are paid for authorship of peer reviewed articles or presentations.

Publication steering committee

It may be useful to form a publication steering committee of authors and contributors to oversee and produce articles and presentations from a research study. This committee should be a small working group of individuals; its composition may change over time, and it may include:

* Members of the study steering committee and the protocol development team

* Investigators and other individuals who have expertise in the area and who are willing to interpret the data and write or review articles and presentations

* Employees of, or contributors contracted by, the sponsor company who are involved in the study (for example, clinicians, statisticians, or professional medical writers)

Members of the publication steering committee may become authors, but membership of the committee does not automatically confer authorship. For any given study, we recommend that:

* The publication steering committee is formed early (for example, when the protocol is finalised or at the end of enrolment)

* All study investigators are informed of the committee's membership and responsibilities

* Authors and contributors agree to their roles in the development of an article or presentation before writing begins.

Authors

Recognised criteria should be used to determine which of the contributors to an article or presentation should be identified as authors.

We recommend using the criteria for authorship described in the International Committee of Medical Journal Editors (ICMJE) uniform requirements (box 1).8 Guidance regarding authorship is also available from the World Association of Medical Editors17 and the Council of Science Editors.18 Criteria used to define authorship may vary among journals and congresses, and we recommend following individual journal and congress requirements when these differ from ICMJE criteria. ICMJE criteria allow assignment of authorship to individuals who have contributed to the analysis and interpretation of a study but who may not have contributed to its conception and design. In these instances, or if authors differ from initial plans, particular care should be taken to attribute authorship and to acknowledge contributions appropriately.

Box 1 International Committee of Medical Journal Editors criteria for authorship8

Authors "should have participated sufficiently in the work to take public responsibility for relevant portions of the content" and should meet all three conditions below:

* Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; and

* Drafting the article or revising it critically for important intellectual content; and

* Final approval of the version to be published

We recommend that authorship criteria are applied consistently to all contributors to an article or presentation, including investigators, sponsor employees, and individuals contracted by the sponsor. All authors listed on an article or presentation must fulfil authorship criteria, and all those who fulfil the criteria must be listed as authors. All authors should agree on the order in which they appear in an article or presentation (if possible before writing begins) and should agree on any changes in authorship (for example, to ensure authorship reflects actual contributions made) before submission. Before writing begins one author (a lead author, who may also be guarantor) should take the lead for writing and managing each publication or presentation. One author (identified as guarantor) should take overall responsibility for the integrity of a study and its report.

Contributorship and acknowledgments

Contributorship and contributors

Interpretation of authorship criteria varies, and using a contributorship model to describe who did what helps to remove ambiguity.8 19 20 21 We support this approach and recommend that clear, concise descriptions of the role of each contributor during preparation of the article or presentation (including but not limited to the authors) are made in an acknowledgment within the article or presentation.

Individual contributions to an article or presentation that should be acknowledged include study conception and design, conceiving the idea for an article, conducting or managing a study, collecting data, performing statistical analysis, interpreting data, analysing published literature, drafting a manuscript, critically reviewing a manuscript, and approving a manuscript. Permission should be obtained from each individual acknowledged.

Acknowledgments

We recommend that all articles and presentations include an acknowledgment, even if not requested by the journal or congress, to describe:

* Author contributions—for example: "A and B designed the study. C was the study statistician. A and C analysed and interpreted the study data. A reviewed the literature. A, B, and C critically reviewed the manuscript and approved the final version for submission. A accepts overall responsibility for the accuracy of the data, its analysis, and this report"

* Contributions to the article or presentation from people who are not listed as authors, including name and affiliation or employer—for example: "The authors would like to thank D, YZ Pharmaceuticals, for overall management of the trial and E, WX Medical Writing, for drafting the manuscript"

* The role of the sponsor in the study and its reporting, including how the sponsor was involved in the "study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication."8 For example: "In collaboration with A and B, YZ Pharmaceuticals, designed the study, analysed, and interpreted the data, and edited the report. Data were recorded at participating clinical centres and maintained by YZ Pharmaceuticals. All authors had full access to the data. The authors had final responsibility for the decision to submit for publication"

* Funding sources, if any, for the research and for the article or presentation, such as for the work of a professional medical writer. For example: "The study was funded by YZ Pharmaceuticals, the manufacturer of drug F. Medical writing services from WX Medical Writing were funded by YZ Pharmaceuticals."

When journal or congress submission requirements do not allow inclusion of this information within the article or presentation, we recommend that it is included in a letter that accompanies the submission.

Professional medical writers

Professional medical writers work with authors to prepare abstracts, posters, slides, and manuscripts. They should ensure that authors control and direct writing and that disclosures of funding, potential conflicts of interest, and acknowledgment of contributions are made. They are required to have a good understanding of publication ethics and conventions, and ensure, in part through their collaborations with authors, that their work is scientifically appropriate.21 22 23 Professional medical writers are not ghostwriters. The Association of American Medical Colleges states "transparent writing collaboration with attribution between academic and industry investigators, medical writers and/or technical experts is not ghostwriting."24 This is echoed by the US Institute of Medicine.25 We recommend that authors and professional medical writers working with authors use a published checklist to discourage ghostwriting.26

We recommend that particular care is taken to ensure appropriate acknowledgment of the contributions made by medical writers and to describe their funding. Companies funding the work of medical writers should ensure that writers follow good publication practice. We refer readers to guidelines from the European Medical Writers Association.23

Working with authors

Professional medical writers must be directed by the lead author from the earliest possible stage (for example, when the outline is written), and all authors must be aware of the medical writer's involvement. The medical writer should remain in frequent contact with the authors throughout development of the article or presentation. The authors must critically review and comment on the outline and drafts, approve the final version of the article or presentation before it is submitted to the journal or congress, approve changes made during the peer review process, and approve the final version before it is published or accepted for presentation. Authors may delegate to the medical writer (or to an assistant) the administrative tasks associated with submitting the article or presentation to a journal or congress.

As authors

Professional medical writers, depending on the contributions they make, may qualify for authorship. For example, if a medical writer contributed extensive literature searches and summarised the literature discovered, and by doing so helped define the scope of a review article, and if he or she is willing to "take public responsibility for relevant portions of the content"8 then he or she may be in a position to meet the remaining ICMJE criteria for authorship.

Conflicts of interest

We recommend that authors disclose financial relationships (for example, any financial relationships or obligation to the research sponsor or other companies, including contractual relations or consultancy fees for scientific, government, or legal services, or equity in the company) and non-financial relationships (for example, personal relationships, including those of immediate family members, and participation in litigation) that could inappropriately influence or seem to influence professional judgment. We recommend that these disclosures are made in all articles submitted for publication in peer reviewed journals, as well as in abstracts and posters submitted to congresses at the time of submission, if space requirements allow, and that they are included in oral presentations and posters at the time of presentation, regardless of whether disclosure is requested by the journal or congress.

For example: "A is a member of a speakers' bureau, has been a consultant for, and has received research grants from YZ Pharmaceuticals. C is an employee of YZ Pharmaceuticals. B has stated that she has no conflicts of interest."

There is no universal standard applied by journals and congresses for disclosure of potential conflicts of interest. Until discussions about how to address conflicts of interest are resolved,25 27 28 29 we recommend authors favour greater, rather than lesser, disclosure.

Recommendations for specific types of articles and presentations

Primary and secondary publications


A primary article is the first full report of a study. We recommend that all articles and presentations include statements to indicate whether they are the primary article or first presentation from a study, including for randomised clinical trials; epidemiological, observational, and descriptive studies; non-clinical outcomes research studies; and health economics studies.

Authors preparing secondary articles and presentations (including those that describe exploratory secondary analyses, national or single centre data taken from international or multicentre studies, and alternative analyses or pooled analyses of already published data) must avoid duplicate publication. All post-hoc and exploratory analyses must be clearly identified as such.

Authorship of secondary articles and presentations may differ from that of primary articles and presentations from the same study, depending on, for example, the topic of the article or presentation. We recommend that one or more authors of the primary article from a study contribute to the secondary articles and presentations from the same study.

Duplicate publication

We recommend that the same study results are not published in more than one peer reviewed journal article unless:

* The results are substantially re-analysed, re-interpreted for a different audience, or translated into a different language; and

* The primary publication is clearly acknowledged and cited; and

* The article is clearly presented as an analysis derived from the previously published primary results or is a translation, is not presented as reporting the primary results, and respects copyright law.

Presentations

Congress guidelines should be followed for presentations that describe study results that have been presented at an earlier congress. We recommend that, at the time of submission, authors disclose whether the same results will have already been presented at the time of the congress. With approval from the authors of the primary article, research submitted for presentation at national or local meetings may include authors who do not appear on the primary article (for example, to enable accurate presentation in the appropriate language).

Review articles

We recommend that review articles are comprehensive and that the methods for searching, selecting, and summarising information are clearly stated. We recommend that discussions in review articles founded principally on opinion are clearly identified as such. We also recommend that care is taken to ensure appropriate description of contributions from professional medical writers and other contributors, particularly when they may have contributed to the design of a review article or when they may have suggested the idea for the article. We refer readers to the BMJ's "Who prompted this submission?" guidance (box 2).20

Box 2 BMJ's "Who prompted this submission?" questions20

We may ask authors submitting or offering unsolicited articles, particularly reviews and editorials covering topics with related commercial interests, several questions before proceeding. Even if the answers to all of these questions were "yes," we wouldn't necessarily reject the proposal or article. We appreciate that companies can commission some excellent evidence based work and that professional writers can present that evidence in a particularly readable and clear way that benefits readers and learners. We would, however, expect such companies' and writers' contributions to be mentioned in the article. And we would want to know that the BMJ article did not overlap by more than 15% with any similar publications or submissions written by the same authors elsewhere. Here are the questions:

* Has anyone (particularly a company or public relations agency) prompted or paid you to write this article?

* Would/did a professional writer contribute to the article, and to what extent?

* Would the BMJ article be original, or would it be similar to articles submitted or published elsewhere?

Reporting standards

We recommend that authors follow established reporting standards such as CONSORT, CONSORT for Abstracts, STROBE, PRISMA, MOOSE, and STARD.16 We offer the following brief recommendations:

* Articles and presentations should be complete, balanced, and clear

* Reference to the unique trial identifier should be included in all articles and presentations that report research from applicable clinical trials

* Interpretation of results should be unbiased, based on findings, and relevant to the audience

* Discussion of results should be unbiased, placed in the context of other relevant literature, and the evidence cited should be balanced

* Limitations of the study design and methodology should be described

* Studies with related findings should be cited, especially when previous results conflict with the results being reported.

Planning, registering, posting, and documenting

Publication planning

Publication plans can help study sponsors ensure that clinical trial results are communicated by presentation or publication to the scientific and medical community in an effective and timely manner. They can also enable sponsors to identify the timelines and resources necessary to meet their obligations for reporting and publishing clinical trial results. Authors retain responsibility for decisions about articles and presentations from individual studies, which may be described in a publication plan.

A publication plan should support authors and publication steering committees (if they exist) in their efforts to ensure appropriate, efficient, and complete communication of results by:

* Identifying submission deadlines for relevant congresses and determining which studies are appropriate to present and might have data available in time

* Identifying areas for new publications (for example, subgroup analyses, topics for pooled data analyses, post-hoc analyses, systematic reviews) and the resources required for them, such as statistical analyses

* Avoiding premature release of results

* Avoiding duplicate publication.

Before publication

Research sponsors must register and post all applicable clinical trials according to the definitions and timelines required of them by relevant legislation and guidelines.8 9 10 11 12 13 14 15 Posting clinical trial results according to the US Food and Drug Administration Amendment Act of 200710 and the Joint Position on the Disclosure of Clinical Trial Information,11 whether before or after submission to a peer reviewed journal, should not preclude consideration for publication.8

Authors may present clinical study results at congresses before publication in a peer reviewed journal. Authors and other parties with access to study results should avoid further and more detailed public reporting before publication in a peer reviewed journal, unless the circumstances are exceptional.

Authors should not submit their work for consideration by more than one peer reviewed journal at any one time. All parties should respect embargoes set by journals, congresses, and other media. For example, authors should follow journal instructions when articles are "in press" or published online ahead of print.

Documentation

We recommend that companies, and the organisations or individuals working for them, document how publications are initiated and developed. We recommend that companies implement policies detailing the types of documentation to be retained, including:

* Agreements to participate in the writing process (for example, signed and dated letter, email)

* Details of intellectual input, direction, and contributions, including comments on drafts (emails, notes from teleconferences) or drafts that contain revisions

* Main versions of the draft, to document how comments on previous versions were incorporated

* Workflow and timelines that were used to develop the document, including time taken to review and revise the document

* Approval from authors of the final version to be submitted

* Lists of participants other than authors who were allowed to review or comment on the document.

We recommend that this documentation is maintained for a period defined by the sponsor company's retention policy.

Checklists

Articles and presentations following good publication practice will show the characteristics described in table 3Go. Written agreements using good publication practice will cover, at a minimum, the items described in table 4Go.

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The International Society for Medical Publication Professionals initiated the development of these guidelines. The opinions expressed here do not necessarily represent those of the authors' employers. We thank the consultation panel for their comments. We thank Elizabeth Wager, Sideview, for her work on the original guidelines6 that GPP2 updates (some of the earlier guidance remains in these new guidelines) and for her willingness for ISMPP to sponsor the authors to write GPP2. We thank Sheema Sheikh at Excerpta Medica, Elsevier for compiling comments from the consultation.

Contributors: Jane Moore, Medtronic, and John Draper, Peloton Advantage, were members of the steering committee and contributed to discussions about the recommendations made in this document (JD in particular on managed care, pharmacoeconomic, and health outcomes). CG wrote the first and final draft; WPB wrote the draft sections on publication planning, documentation, and conflict of interest; DB, EAF, CSM, and MP contributed to outline, intermediate drafts, and revisions; VBW wrote the draft sections on authors, contributorship, acknowledgments, and medical writers; JMC the draft duplicate publication section, JME the draft review articles section, JAG the draft publication steering committee section, and YEY the draft access to data section. MEM compiled steering committee comments after the consultation, and contributed to outline, intermediate drafts, and revisions. All the authors contributed to the literature analysis and review before writing these guidelines. All the authors contributed to the outline and to the first and subsequent drafts, to interpretation of the comments gathered during the consultation phase, and reviewed the final draft. All the authors approve this document and CG is the guarantor.

Funding: The International Society for Medical Publication Professionals provided the contributors with meeting and teleconferencing facilities and web conferencing technology.

Competing interests: All authors are members of the International Society for Medical Publication Professionals a not for profit organisation with membership comprising pharmaceutical, biotechnology, and device industries; medical communications agencies; publishers; and independent medical writers. The society is funded by its membership. WPB and JME have stock in Johnson & Johnson; VBW has stock in Novo Nordisk and Parexel; JMC has stock in AstraZeneca; JAG has stock in Wyeth; and MP has stock in Cephalon. CG is a council member of the Committee on Publication Ethics. JAG was an employee of Wyeth, which was acquired by Pfizer in October 2009. VBW was previously employed by Novo Nordisk to work with publications.

Provenance and peer review: Not commissioned; externally peer reviewed.

 
 
 
 
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