Industry and Clinical Trials

Robert M Califf MDDirector, Duke Clinical Research InstituteDuke University Medical CenterDurham, NC

Salim 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 MD

Director, Cardiovascular InstituteMount Sinai Medical CenterNew York, NY

•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?

Who controls the evidence for evidence-based medicine?

The "era of evidence-based medicine"

Rob Califf

• 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?

20 years of success

• 20 years ago, we had almost no treatments in cardiology that were shown to save lives

• Research has made huge strides in cardiology by validating those ideas in large clinical trials

Salim Yusuf

Trials funded by industry

Industry trials are fine if

•Studies are done independently

•Results are presented fairly

Salim Yusuf

"We have to be very careful that we work with industry

rather as opposed to working for industry."

Industry independence

• We are now more dependent on industry

• Industry is less dependent on academia

• Most important trials are performed correctly

Frans 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 agents

No real alternative

Frans 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 field

Valentin 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 trials Valentin Fuster

The system

Rob Califf

• Much of the advance in cardiovascular medicine is due to developing new medical products

"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 patient

Rob Califf

Decoding journal articles

• It is sometimes difficult to learn how a trial was conducted

• Important trials should be clear about

The structure of the trial

Who developed the study and where was the data analyzed

Frans Van de Werf

Collaborating with industry• Industry people may know the drugs or

devices better than any of the investigators. Investigators must maintain editorial independence while collaborating

• Investigators must maintain editorial independence while collaborating

• Industry should recognize the benefit of collaborating with a strong, independent academic group

Salim Yusuf

Editorial independence

• Data management should be run independently of industry

• Must maintain editorial control

We wrote a draft manuscript before industry even knew the results of the study

They 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 pressure

Symbiosis

“A 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 say

Rob 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 involved

Valentin 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 supplements

Secondary 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 journals

Motivating factors

Rob Califf

• If an article is ghostwritten, the ghostwriter should be first author

• It should be clear that the article was not written by the researchers

Clear 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 need

Public-private partnerships

Rob Califf

Generic questions

• We have to answer generic questions in addition to product-oriented questions

• 2 solutions

Joint partnership between academic, industry, and government

Factorial designs in studies, which are not utilized enough

Salim Yusuf

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 trial

Salim Yusuf

"Government can also bring into the picture certain checks and balances that keep us all on the straight and

narrow."

Government bureaucracy

• Government trials require years of reviews and committee meetings so it is hard to get things done

• Trials are designed with political considerations in mind instead of focusing on answering a single question

Rob 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 cooperate

Salim Yusuf

Public pressure

• Government agencies are moving in the direction of partnering with industry

• These agencies are taking a lot of time in terms of the process

• Public pressure to test promising therapies and devices should create systems that will be probably less bureaucratic and much more expeditious

Valentin 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 Perspective

• Less of a tradition of cooperation between government and industry in Europe

Multiple countries mean additional bureaucratic hurdles involved in trials

• Hopefully 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 requires

The presence of an independent steering committee

Management of the data and analysis independently of industry

Publication certified by the investigators, with industry having input but not the final say

Summary – academic independence

Rob Califf

Summary - partnerships

• Government infrastructure with industry funding will be a critical step in the future

• Ghostwriting should be discouraged but acknowledged when it happens so readers are aware of the source of the message

• Public pressure can help move public-private partnerships to answer questions of public health beyond medical products

Rob Califf

"Whenever possible, consider factorial designs so that we will not just move the drug agenda forward, we’ll also move the broader agenda of improving patient outcomes."

Factorial design

Salim Yusuf