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Current Controversies in Pediatric Research Ethics: Day Two Notes

July 23, 2005

The following are unedited notes taken by conference participants. They are designed for information purposes only.

The following are unedited notes taken by conference participants. They are designed for information purposes only.

F. Bruder Stapleton, MD, Pediatrician-in-Chief

Dr. Stapleton welcomed the attendees, thanked the conference planning staff, and thanked Dr. Kassirer for donating his book, On The Take, to the first 150 attendees today. Today’s topic is the relationship between industry and research.

The SSRI Story: A Cautionary Tale

Norman Fost, MD, MPH

Dr. Fost opened by confirming the need for perspective regarding the relationship between the pharmaceutical companies, physicians, and consumers.

Issues to consider include:

  • Trials are designed by pharmaceutical companies (pharma);
  • Publication decisions by pharma;
  • Authorship of articles commonly by pharma;
  • Physician education dominated by pharma;
  • Off label use becomes major profit center;
  • Profits used primarily for marketing.

In Sept. 2004, the FDA Pediatric Drug Advisory Committee met to consider changes in the labeling of SSRIs for children. These meetings were triggered by the UK’s decision to revoke approval of almost all SSRIS for the treatment of depression in children. This public meeting was the largest in FDA memory in terms of the number of people who asked to speak (more than 100), many of whom were parents of children who died after use of SSRIs, often within one week of starting the drug. In addition, numerous professionals contributed comments that suggested SSRIs are safe and effective. However, 85 percent of treatment effectiveness can be attributed to a placebo effect.

Dr. Fost provided examples regarding the use and effectiveness of SSRIs. He noted that many of the drugs that have shown no benefit are those that are prescribed most and that the adverse event that the drug was intended to prevent is still highly prevalent. He also commented on the studies, their incompleteness, and their limited quality. Some of this is due to the influence of pharma control on studies, including the control they exert over the design of clinical trials, which results will be published, medical evaluation, marketing, and other parts of the process.

In one particular area, they exert great control. A Medical Education and Communication Company (MECC) puts on conferences and 90 percent of them are supported by pharma. Therefore, the meetings are planned and managed by the MECC and they offer to help pharma companies build product sales.

Within the conference, pharma supports half of the CME. Dr. Fost shared an example of the effects of pharmaceutical firm enticements on physician prescribing patterns based on pharma company-sponsored symposia. Some of program is dedicated to the promotion of off-label use of drugs and physicians are paid well to serve as “consultants” to these programs.

Another area in which pharmaceutical companies have influence is in the “ghost writing” of articles. Pharma pays MECC to write articles, and the MECC pays physicians to “author” the articles, which often appear in prestigious journals.

Direct-to-consumer advertising is another powerful tool used by pharma to promote drug use.

Dr. Fost concluded by noting that “this is a serious problem.”

Conflicts of Interest – Facts and Friction

Catherine DeAngelis, MD, MPH
Editor in Chief, Journal of the American Medical Association (JAMA)

Conflicts of interest:

  • Perceived or real, potential or actual;
  • Ubiquitous and inevitable;
  • Differ from conflict of commitments (competing demands on person’s time and resources).

Why do people have conflicts of interest?

  • Career advancement;
  • Peer recognition;
  • Competing research interests;
  • Competition of research grants.

Financial Conflict of Interest: Any paid affiliation or financial connection involved with any entity with an interest in the subject of, or materials in, a study. Examples of financial conflicts of interest include payment, remuneration, materials, financial interests, affiliation, consultancies, and competing interests - current, recent, remote, and future.

Increased scrutiny is warranted:

  • Skeptical public;
  • High profile lapses of business ethics;
  • Transformation of research enterprise;
  • Prioritization of biomedical research;
  • Financial self interest of investigators;
  • Increased awareness and attention on biomedicine.

Total US promotional spending has increased from $9 million in 1996 to $21.4 million in 2002, and up again to about $25 million by 2003. Most of the growth is in sample distribution ($12-$16.4 million in one year). Direct-to-consumer advertising is also growing, but at a slower rate.

Journal Advertising: Dr. DeAngelis stated that she would like to do away with this all together, but it is against the law and subscription rates would rise. So given that journal adverting is a reality, JAMA has a restrictive policy – no cover tips, no bellybands, no “advertorials”. The editor approves all advertising and does not allow advertisers to buy only one ad in a particular issue.

Leaders of the Lobby Push (includes lobbying expenses and campaign contributions): Drug companies are at the top of the list, followed by insurance companies, telephone companies, electric companies, commercial banks, auto manufacturers, tobacco and food processors, and manufacturers.

Industry research and development: This represented $60 billion in 2001. US federal spending was $27 billion in 2001. The cost for developing a new drug is $300 to 800 million, according to the drug companies.

Public and private sector biomedical R & D spending: This totaled $94 billion in 2001. Large pharmaceutical companies lead the way in terms of spending ($47 billion), followed by US/NIH funding ($27 billion), and biotech firms (about $12 billion).

The new trend is the development of CROs - Community Research Organizations. CROs are sponsored by pharmaceutical companies, which pay doctors for each patient they enroll in a study.

Conflicts of Interest - Why do they matter?

  • Affects what research gets conducted and published;
  • Scope of financial interests: 1 in 4 investigators have industry affiliations;
  • Study conclusions can be skewed based on author’s affiliation with pharmaceutical companies;
  • Delay of publication to give companies time for patent applications, marketing strategies, etc.;
  • Suppression of results – Oliviere case – company was able to delay publication for 3 years because of negative results;
  • Sponsor termination of research - Convince Trial - the sponsor terminated the clinical trial for “commercial reasons” two years early. JAMA published the study, along with an editorial stating this was a violation of the Pact with Patients and Investigators.
    Guidelines & Regulations on Conflicts of Interests: Several organizations and agencies have been involved in trying to develop guidelines and regulations. The policies and guidelines vary in the details, but agree on the following:

“The key to maintaining integrity in research and scientific publications with regard to conflicts of interest is DISCLOSURE.

The International Committee of Medical Journal Editors (formerly the Vancouver Group), made up of editors of the leading medical journals in the world, defines conflict of interest as: “Conflict of interest for a given manuscript exists when a participant in the peer review process and publication process – author, reviewer, or editor – has ties to activities that could inappropriately influence the outcome of the study, study design, collection or analysis of the data, and the conclusions.”

Authors, when they submit a manuscript, must disclose any financial conflict of interest or affiliation - past, present, or future. Any conflicts must be transparent to the reader. Most of the major medical journals publish the financial disclosure statements of the authors along with the articles.

JAMA also looks at industry-investigator relationships:

  • Who designed the study?
  • Who controls the data?
  • Who performs the statistical analysis?
  • Who are the authors?
  • Who controls the publication?

If the person who did the statistical analysis of the data is employed by the company who sponsored the study, then JAMA will only accept the study for publication if a second data analysis is done by an independent, academic institution. No other major medical journal does this.

Publication of Industry-Sponsored Research:

  • Funding source must be clear and complete;
  • Role of the sponsor in the study;
  • Disclosure of relationships with investigators.

Conclusions:

  • Financial interests are ubiquitous;
  • Involve researchers, authors, reviewers, and editors;
  • Policies on disclosure are essential and must ensure transparent reporting;
  • Managing conflicts of interest appropriately is essential to ensure the public’s trust.

Industry-Related Biases in Medical Information

Jerome P. Kassirer, MD
Distinguished Professor, Tufts University School of Medicine

How financial conflicts of interest endanger our profession.

Dr. Kassirer began by asking the audience to consider the use of drugs and guidelines in treating high cholesterol. He discussed the process and people (an expert panel) involved in developing and/or revising the guidelines, noting the recommendation of use of the drugs by one group, but not by another. He shared financial disclosure information related to the first panel, highlighting the fact that pharmaceutical companies paid seven of the nine people involved in the panel.

He commented on the role of the drug industry’s marketing, noting that most of the marketing dollars are directed at physicians, including trips, promotional items, etc. He said that even small gifts often influence physician behavior but financial considerations should never compromise a doctor’s decision-making.

While doctors believe that they are not influenced because they are trained in the scientific method, he believes this is “self-deception”. As an example, he cited a study at UCSF in which 39% of the physicians asked said that they could be influenced - but said that 84% of their colleagues could be influenced. Citing de Cervantes, Dr. Kassirer noted that those who receive a benefit show they are grateful and that not all incentives are financial.
Do financial incentives translate to bias? In a study published in Academic Radiology, a group of readers representing lawyers and a group of independent readers came up with completely different results when reviewing almost 500 films.

Those paid by the attorneys for industry showed results supporting the lawyer’s case. Dr. Kassirer further illustrated his point by showing data related to the COX-2 inhibitors (i.e., Vioxx). He again showed that those on the FDA advisory board with financial ties to pharma wanted to return these drugs to the market. Numerous other examples were also cited by Dr. Kassirer.

Dr. Kassirer went on to talk about CMEs and the influence of pharma on CME presenters and attendees as well as their influence on communication to the public. For example, Amgen pays for the website and publication of a brochure related to Epo.

Dr. Kassirer sees this as “a shameful marketing tool” for the off-label marketing of this drug. Not only is there no data to support the claims made by the company, but such use could be harmful. More examples were provided that Dr. Kassirer said were “sickening”. He noted that the conflicts of interest are prevalent and “shocking.”
He rhetorically asked if people should be getting treatment based on which doctor they go to or should it be the best treatment? Examples here include treatment of fibroids and heart failure.

The support of trainees was examined, including fellows who are directed to run drug trials or travel to conferences on drug company money. Unrestricted grants are not unencumbered.

Gifts can influence medical decision-making – and they will bias clinical treatment. Marketing promotes the latest and most expensive treatments and can endanger patients’ welfare. This damages trust. Physicians should NOT accept anything – from reprints to directed research dollars – from drug representatives. Dr. Kassirer recommends removing pharma involvement in CMEs.

Dr. Kassirer outlined some promising signs, including conflict of interest guidelines being developed at several medical schools, removal of those paid by industry from FDA panels, and movement by the House and Senate to look at conflicts of interest.

When conflicts of interest can exist, the issue of credibility is raised. In addition, those who are paid by industry are going to think alike. Instead, studies should look for those without conflicts of interest relative to that particular study, and involve a more varied group to review the results.

Panel Discussion

Drs. Kassirer, DeAngelis, and Fost

Q: When physicians are paid by drug companies to give CME presentations, they must adhere to certain limits (i.e., not mention specific drug names). Do drug companies plant members in the audience to allow the presenters to refer to the drug?

A: Yes!

Q: As long as healthcare is an industry, we are never going to fix this. How do you feel about this?

A: Dr. Fost noted “the best is the enemy of the good.” He said that while we can’t fix everything, we can make some inroads. For example, “ghost writing” should be considered fraud. There should be complete prohibition of any payment to write articles or editorials.
The profession should pay for its own education. This would not lead to less medical education, but less propaganda. Residents should not be allowed to meet with pharma because that influences their prescribing.

Dr. DeAngelis suggested that the health industry has always been an industry, but it has been a matter of degree. She commented on her experiences speaking to medical school graduates who are committed to serving the needs of people vs. those who have been in the profession longer and deal with the affects of pharma on the profession. “Take back our profession” she says. Dr. Kassirer added that there is no incentive-free system, but the goal is to align the incentives appropriately.

Q: Could you comment on the movement away from academic to community-based research and how that reflects the restrictions you are recommending?

A: Dr. DeAngelis responded that the journals must take a stand by not publishing research that is paid for by industry or is questionable. Dr. Kassirer commented that unless the restraints we have recommended take hold, this will be a problem. Dr. Fost, however, said that many research projects or clinical trials are marketing tools, not ways to identify new treatments. Some academic institutions are not pursuing research because it is a significant cost, and does not always serve science or humanity.

Q: Increase objectivity and reduce conflict of interest – why have you not done anything or plan to do anything to eliminate advertising?

A: Dr. DeAngelis noted she has done some incremental reduction of advertising and has restricted some advertising (costing JAMA $2 million last year). She reiterated that eliminating ads would increase the price of the journal, affect their ability to provide free issues to residents, and the ability to provide CME free to subscribers. Dr. Kassirer noted that when he was editor of NEJM, eliminating the pharma ads completely could have paid for the NEJM, but not make it as profitable as the “owner” wanted.

Q: Comment on SSRI – A lot of inappropriate prescriptions are no longer being written. Studies show that interpersonal therapies are important to treatment, along with medication. The speaker urged caution and suggested that SSRIs are not, in and of themselves, bad.

A: Dr. Fost responded that SSRIs are still not prescribed appropriately.

Q: Many of us are likely to be on IRBs, and many of the multi-center trials are paid for by drug companies. How can we help?

A: Dr. Fost responded that while you can’t review the publications, the institution could establish rules around publication. Each faculty member, for example, could disclose their involvement, and attest to the independence of the trial or project from influence. Dr. DeAngelis suggested you look at where projects are registered (clinictrials.gov).

Q: Is there evidence that financial incentives affect access to healthcare?

A: Dr. Fost mentioned that the pricing of pharmaceuticals is outrageous, particularly in the US, noting that the ROI is 18-20% vs. 3-5% in other industries. The pharmaceutical companies spend an overwhelming amount of money on marketing, not on R&D as they claim.

Q: How will free access to medical journal articles on the internet, suggested by government, affect your ability to decrease advertisements?

A: Dr. DeAngelis noted that JAMA and NEJM, as well as others, already provide key articles or anything with a public health implication, free to the public. If you put the information on others’ sites, however, it is not protected by copyright and could be changed by anyone. In addition, the journals put a lot of effort into what they publish (checking facts, revising conclusions, etc.) versus what is commonly accepted. Articles that are submitted elsewhere may not be accurate.

Dr. Kassirer said that the problem with publishing immediately is it requires the authors to pay for editing and reviewing, and where will they get the money to do that? Dr. DeAngelis added that by switching the process, there is the risk of favoring those who can pay as opposed to those who cannot.

Q: Congress is trying to direct research around children. What’s next?

A: Dr. Fost said that some well-designed studies are in place around pediatric drug use and many improvements in labeling and dosage have been made.

Q: Are there any efforts to educate residents, scientists in training, or others, to avoid these problems?

A: Dr. Fost notes that there is very little mandatory education around conflict of interest, primarily due to the influence of pharma money on university curricula. The bioethics community is increasingly being bought by pharma as well. Dr. Fost said that this conference is notable for its commitment to the discussion of this issue as well as the lack of non-university funds supporting the conference.

About Seattle Children’s

Consistently ranked as one of the best children’s hospitals in the country by U.S. News & World Report, Seattle Children’s serves as the pediatric and adolescent academic medical referral center for the largest landmass of any children’s hospital in the country (Washington, Alaska, Montana and Idaho). For more than 100 years, Seattle Children’s has been delivering superior patient care while advancing new treatments through pediatric research. Seattle Children’s serves as the primary teaching, clinical and research site for the Department of Pediatrics at the University of Washington School of Medicine. The hospital works in partnership with Seattle Children’s Research Institute and Seattle Children’s Hospital Foundation. For more information, visit www.seattlechildrens.org or follow us on Twitter or Facebook.

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