Industry and Clinical TrialsRobert M Califf MD Director, Duke Clinical Research Institute Duke University Medical Center Durham, NCSalim Yusuf MDProfessor of Medicine, McMaster University Hamilton, ON, CanadaFrans J Van de Werf MD Professor and Chairman, Department of Cardiology University Hospital Gasthuisberg Leuven, BelgiumValentin Fuster MDDirector, Cardiovascular InstituteMount Sinai Medical CenterNew York, NY
Who controls the evidence for evidence-based medicine?The medical products industry?The academic community? Is all this being done On behalf of patients Or to generate profits for the medical products companies?
The "era of evidence-based medicine"
Who is generating this evidence, and what is the motivation? How are studies designed?How are they presented to the public? Is there a fair balance between patient interests and sponsor interests?Rob Califf
20 years of success20 years ago, we had almost no treatments in cardiology that were shown to save livesResearch has made huge strides in cardiology by validating those ideas in large clinical trialsSalim Yusuf
Trials funded by industryIndustry trials are fine if Studies are done independentlyResults are presented fairlySalim Yusuf"We have to be very careful that we work with industry rather as opposed to working for industry."
Industry independenceWe are now more dependent on industryIndustry is less dependent on academia Most important trials are performed correctlyFrans Van de Werf
All important new agents have been made by industry
You need to have an industrial partner for large-scale production of important agentsNo real alternativeFrans Van de Werf "We have to work with industry but it can be done in a correct way."
Overemphasis on drug and device trials We have no clinical trials informing us about diet Industry is designing trials based on the products they want to sell Still, industry research has achieved much in the fieldValentin Fuster
Public-private partnerships We need to link industry more with the federal government Trials should focus on the patient, not solely on pharmacology and devices The problem is trials are very expensive It would be ideal to bring industry and federal organizations together to share the cost of trialsValentin Fuster
The system Much of the advance in cardiovascular medicine is due to developing new medical products Rob Califf"I would certainly be a strong advocate that the capitalistic system is an effective system, obviously within certain bounds."
Fundamentals overlooked Clinical trials of lifestyles Clinical trials of alternative medicine Long-term outcomes Combining therapies in the same patientRob Califf
Decoding journal articlesIt is sometimes difficult to learn how a trial was conductedImportant trials should be clear aboutThe structure of the trialWho developed the study and where was the data analyzed Frans Van de Werf
Collaborating with industryIndustry people may know the drugs or devices better than any of the investigators. Investigators must maintain editorial independence while collaboratingInvestigators must maintain editorial independence while collaboratingIndustry should recognize the benefit of collaborating with a strong, independent academic groupSalim Yusuf
Editorial independenceData management should be run independently of industry Must maintain editorial controlWe wrote a draft manuscript before industry even knew the results of the studyThey could comment but we had the final word. Salim Yusuf
The ideal is symbiosis with the final word with the academic group
Industry can find subtle ways to put pressureSymbiosisA tough and strong academic group on one hand and a sensitive industry on the other hand can strike the right balance"Salim Yusuf
Outside cardiology Independent steering committees and data safety monitoring committees are relatively new ideas Academic communities often have little sayRob Califf
Supplements Ghostwritten articles are worrisome Supplements should not relate to a single product Focus on a single disease state to an end point Discuss all the possible strategies involvedValentin Fuster
Ghostwritten articles The non-writing author, non-author writer syndrome If the editors at a journal are familiar with the subject matter, it should not be hard to detect ghostwritten articles We will do our best to identify these articles, I can promise you."Frans Van de Werf
Primary manuscripts are usually written by the researchers
The problem lies in secondary publications, summaries, and supplementsSecondary publications"I would be happier if we had 20 or 30 percent fewer publications but each of those publications were more substantive"Salim Yusuf
In the US, sales forces cannot talk about off-label claims but can present off-label research
Supplements are big money-makers for journalsMotivating factorsRob Califf
If an article is ghostwritten, the ghostwriter should be first author
It should be clear that the article was not written by the researchersClear authorship"I might say my suggestion has not been embraced by people who are sending these articles in"Rob Califf
If the government can create the playing field for clinical trials, industry would respond
Government consortia could reduce cost and provide a balance between the public need and the private needPublic-private partnershipsRob Califf
Generic questionsWe have to answer generic questions in addition to product-oriented questions2 solutionsJoint partnership between academic, industry, and governmentFactorial designs in studies, which are not utilized enough
Useful approaches In every instance, propose a factorial design with an important generic question Half the companies accept this Epidemiological studies linked in with the trialSalim Yusuf"Government can also bring into the picture certain checks and balances that keep us all on the straight and narrow."
Government bureaucracyGovernment trials require years of reviews and committee meetings so it is hard to get things doneTrials are designed with political considerations in mind instead of focusing on answering a single questionRob Califf
Striking a balance Investigators must judge if it is worth the effort to go through the government In Canada, we get little money, but also very little interference Some flexibility is needed on the part of government, because it's in everyone's interest to cooperateSalim Yusuf
Public pressureGovernment agencies are moving in the direction of partnering with industryThese agencies are taking a lot of time in terms of the processPublic pressure to test promising therapies and devices should create systems that will be probably less bureaucratic and much more expeditiousValentin Fuster
Review Process Pool of qualified reviewers is extremely small and very busy We must bring the young generation of scientists into the review system with the help of more senior people Valentin Fuster
European PerspectiveLess of a tradition of cooperation between government and industry in Europe Multiple countries mean additional bureaucratic hurdles involved in trialsHopefully in the future a more unified Europe will make it easier to get funding from European organizations for industry-sponsored trials Frans Van de Werf
Cardiovascular medicine a leader in academic independence while working with industry Ensuring independence requiresThe presence of an independent steering committeeManagement of the data and analysis independently of industryPublication certified by the investigators, with industry having input but not the final say Summary academic independenceRob Califf
Summary - partnershipsGovernment infrastructure with industry funding will be a critical step in the futureGhostwriting should be discouraged but acknowledged when it happens so readers are aware of the source of the messagePublic pressure can help move public-private partnerships to answer questions of public health beyond medical productsRob Califf
"Whenever possible, consider factorial designs so that we will not just move the drug agenda forward, well also move the broader agenda of improving patient outcomes."
Factorial designSalim Yusuf
Eligible patients were men or women aged 5580 years with previously treated or untreated hypertension and electrocardiographically documented LVH. Patients had trough sitting diastolic blood pressure mean readings of 95 to 115 mmHg or sitting systolic blood pressure mean readings of 160 to 200 mmHg at weeks 1 and 2 of the placebo run-in period. LVH was diagnosed by standard 12-lead ECG, and was defined according to criteria based on the product of Cornell voltage (RaVL + SV3) x QRS duration product criteria: >2440 mm x msec in men product of QRS duration x Cornell voltage + 6 mm exceeding the same value in women. Alternatively, the Sokolow-Lyon voltage combination (Sv1 + RV5 or V6) >38 mm was accepted as an alternative criterion for LVH in men and women. The exclusion criteria included certain cardiac and non-cardiac conditions that may limit the long-term survival of patients or increase nonadherence to study medication.
Eligible patients were men or women aged 5580 years with previously treated or untreated hypertension and electrocardiographically documented LVH. Patients had trough sitting diastolic blood pressure mean readings of 95 to 115 mmHg or sitting systolic blood pressure mean readings of 160 to