An Ethical Framework for Clinician/Industry Interactions Michael D. Jibson, M.D., Ph.D. Clinical Associate Professor of Psychiatry University of Michigan This curriculum is outlined as a three-session interactive experience with residents. It can be readily adapted to fewer or more session based on the amount of time set aside for discuss of each issue. I have also presented this material as a 1-hour CME program, largely in lecture format.

Course Objectives Residents will become familiar with APA guidelines for physician-industry contacts Residents will understand the basic functions of the pharmaceutical industry Residents will be able to characterize the various types of interactions between physicians and the pharmaceutical industry Residents will discuss an ethical framework in which to evaluate physician interactions with industry The purpose of this curriculum is to introduce the APA guidelines regarding physician-industry contacts to the residents, to teach them about the functions of the pharmaceutical industry, and to present an ethical framework to evaluate physician-industry contacts.

Readings Lexchin J. Interactions between physicians and the pharmaceutical industry: What does the literature say? Can Med Assoc J 149:1401-07; 1993 Rosner F. Pharmaceutical industry support for continuing medical education programs: A review of current ethical guidelines. Mt. Sinai J Med 62:427-63; 1995 Wazana A. Physicians and the Pharmaceutical Industry: Is a gift ever just a gift? JAMA 283:373-80; 2000 These are among the more scholarly and balanced papers from an enormous literature. Although I also have a much longer list available, I reserve it for interested residents who ask for additional readings.

Clinician-Industry Interaction Session I: Background

AMA Ethical Guidelines Any gift should benefit patients Gifts should be of minimal value and related to the physician’s work No gifts should be accepted with strings attached AMA Guidelines may be found on the AMA Website at http://www.ama.org/ama/pub/article/4001-4236.html under the title “E-8.061 Gifts to Physicians from Industry.” The AMA guidelines are applicable to a wide variety of situations, but they do not include an explicit ethical framework to explain why these standards were chosen, or to assist the physician in sorting through the issues involved in some novel or complex situations. They are also focused specifically on the issue of gifts, rather than the full spectrum of interactions that occur.

AMA Ethical Guidelines Support for legitimate conferences or meetings (including faculty honoraria) is permissible Subsidies for individual physicians to attend meetings are not permissible Scholarships for residents and fellows must be assigned by the training program It is noteworthy that although the FDA has guidelines governing industry’s interactions with physicians, the agency does not require industry to observe the AMA guidelines, and currently there is no particular correspondence between what industry may legally do and what physicians may ethically do.

PhRMA Ethical Guidelines Dinner programs should be limited to a “modest” meal, without guests CME programs should be planned and conducted by academic and clinical centers Consultants must provide legitimate services for reasonable fees Speakers’ training may include reimbursement for time, travel, and expenses In June 2002, the Pharmaceutical Research and Manufacutrers' Association (PhRMA) posted recommendations for its member organizations to follow in marketing contacts. For the most part, these guidelines are based on those of the AMA. These guidelines are voluntary, and manufacturers have been variable in their acceptance of them.

PhRMA Ethical Guidelines Scholarships should be for major scientific and clinical conferences, and should be awarded by the sponsoring academic institution Gifts should be of modest value (<$100), and should benefit the physician’s practice No gift, scholarship, or contract should compromise the clinician or academician’s independence of decision making

FDA Guidelines All marketing materials must be FDA approved, and information shared during marketing contacts may not exceed the boundaries of approved packaging information Sponsored speakers may answer questions, but may not initiate or perpetuate discussion of “off-label” drug uses The FDA regulates the availability of drugs and the content of advertising. FDA guidelines for how pharmaceutical companies market drugs are legally binding. The goal of the FDA guidelines is to limit information presented by the company to empirically-based data regarding the manufacturers' products, with some leeway for expert opinion even when sponsored by the company.

FDA Guidelines Sponsored speakers may only discuss information derived from accepted research methods or recognized expert consensus opinion Research studies involving a competitor’s drug must follow packaging guidelines for the drug The FDA also regulates some types of industry-sponsored research, specifically that involving a competitor's drug.

ACCME Guidelines for CME Programs Potential or perceived conflicts of interest regarding the topic of the presentation must be disclosed Presentations must include specific learning objectives The speaker’s qualifications must be appropriate to the topic covered The Accreditation Council for Continuing Medical Educations (ACCME) sets guidelines for CME programs. These guidelines are binding for the bestowal of CME credit for a program, but say little about the content of programs.

Economic Issues 2001 Sales of Prescription Drugs $122 billion domestic sales $5.8 billion export sales $128 billion total sales This slide simply illustrates the magnitude of the financial stakes involved in the pharmaceutical industry. With stakes as large as these, a full range of ethical and unethical practices are likely to be in play. Pharmaceutical Research and Manufacturers of America (PhRMA)

Economic Issues Research and Development Costs $24 billion spent on research and development in US, $7 billion abroad 24.2% of total sales are spent on research and development This is an extraordinarily high percentage of sales spent on research and development. Few other industries, even in fields dependent on aggressive innovation (e.g.,computers) are remotely close to this. Pharmaceutical Research and Manufacturers of America (PhRMA)

Economic Issues Promotional Costs $15.7 billion = 12.9% of sales (PhRMA) vs $27 billion = 22% of sales (Nofreelunch.com) PhRMA is a lobbying and public relations organization to which most major pharmaceutical manufacturers in the US belong. Many of the financial figures they present are derived from legal documents, such as financial statements and tax reports. Thus, the numbers are probably accurate, but are determined by legal definitions of categories such as “Promotional Costs.” Nofreelunch.com is a reputable advocacy group opposed to interactions between the pharmaceutical industry and the medical profession. Its numbers are also probably accurate, but are based on different category definitions. The discrepancy may be due in part to the fact that education grants are charitable donations. Thus, industry legitimately deducts them from their promotional costs (and from their taxable income), despite their obvious promotional value. Not surprisingly, pharmaceutical companies are among the most liberal providers of corporate “charity.” Even with the tax advantages that this confers, the pharmaceutical industry claims, probably accurately, to pay a higher percentage of sales in taxes than any other major industry. Unrestricted education grants are tax-deductible charitable contributions, not promotion costs

Economic Issues Are Medicines Too Expensive? Research and development costs are high A single lawsuit can be catastrophic Patent protection is time-limited One implication frequently invoked in the numbers game is that promotional costs should not exceed research and development costs. There is no obvious reason why this should be the standard, and it is not the standard in any other major industry. The real issue is if medications are too expensive. This debate can go on through endless iterations. Each of the above statements is unequivocally true, but...

Economic Issues Are Medicines Too Expensive? but Pharmaceutical stocks are considered among the most profitable and consistent investments available It is also true that the pharmaceutical industry is extremely profitable, to a degree enjoyed by few other industries.

Economic Issues Are Medicines Too Expensive? but High profitability is essential for the maintenance of an aggressive research and development program On the other hand, it is questionable if the current level of research and development could be sustained in a less profitable environment. The debate does not end here, but these few slides are intended to illustrate the perspectives of the opposing sides, each of which makes strong and legitimate points.

Contacts with industry are unavoidable Physician Desk Reference Why Do We Do It? Contacts with industry are unavoidable Physician Desk Reference Prescription of proprietary drugs Sponsorship of professional meetings Advertisements in professional journals Response to academic activity Contact with the pharmaceutical industry is inevitable. Every time a physician opens the PDR, writes a prescription for a proprietary drug, or reads a professional journal there is an interaction with industry. Most information on newly released drugs originates with industry. Academic reviews may rework this information, but it remains only one step away from its commercial source. For those who work in academics, these contacts may also occur in response to scholarly activity. For example, if a faculty member publishes an opinion favorable to one drug, both its manufacturer and its competitors are likely to respond. Invitations to speak at conferences, offers to review proprietary information, or opportunities to engage in large-scale research projects may result.

Contacts with industry are desirable Why Do We Do It? Contacts with industry are desirable Sponsorship of educational programs Sponsorship of professional organizations Sponsorship of research Notification of product availability Exposure to proprietary information Academic input into research and marketing Many of these contacts are desirable and useful. Unrestricted education grants underwrite innumerable valuable educational programs. About one third of APA funding is derived from industry. Only industry has the resources to fund large-scale direct comparison studies of competing drugs. Participation in industry programs allows physicians access to proprietary information that might not otherwise be available. Service on regional and national advisory boards allows academic and clinical input into research and marketing decisions by pharmaceutical companies. The heading “Notification of product availability” deserves special attention. It is essential that industry tell clinicians that new drugs are available. Advertising is the most direct way to do this. Dissemination of information by academic psychiatrists is not fundamentally better - that information ultimately originates with industry as well. By extension, it is desirable for physicians to get periodic reminders of the full range of medication options available. This is the goal of pens and sticky pads with product names. No one serious believes that the physician will be so grateful for a 79 cent pen that an inappropriate prescription might result. Instead, the name serves to remind the physician of the availability of the product, so that when the time comes to make a treatment decision, that product will be among those considered.

But... Industry’s priorities differ from those of clinical and academic medicine Is it possible to benefit from industry contacts without compromising the integrity of clinical and academic medicine? Even so, physicians must never lose sight of the fact that industry operates on a fundamentally different basis than clinical or academic medicine. The goals, standards, and means involved differ, in some cases quite dramatically. The ideal outcome is for clinical and academic medicine to enjoy the benefits of industry interactions without compromising their goals or standards. Whether this is possible or not is a subject of heated, on-going debate.

Clinician-Industry Interaction Session II: An Ethical Framework Rules of conduct, such as the AMA guidelines, do not arise in a vacuum, but are the product of ethical considerations applied to actual situations. This session will outline an ethical framework in which to understand the implications of physician-industry contacts, evaluate the AMA guidelines, and assess the ethical propriety of different types of interactions.

Primary Aims As noted previously, the primary aims of clinical medicine, academic medicine, and industry are fundamentally different. At this level, the beneficent goals of medicine contrast sharply with the crass commercialism of industry.

Positive Practices At the next level, however, their activities begin to overlap considerably, and the moral distinction between them blurs. In fact, industry best achieves its goals by the appropriate marketing of a safe and effective drug. That not all drugs meet this standard is rarely the result of inept or conspiratorial decisions by manufacturers, but the inevitable consequence of the use of medications by patients in the community, rather than in carefully controlled research centers.

Negative Practices Negative practices also exist in each of these areas. Industry is frequently guilty of intentional bias in research and education, and sponsor speakers known to have favorable opinions to specific drugs, lobby influential academicians for positive opinions, and so forth. Pricing of drugs is also a sensitive issue, and the profitability of the pharmaceutical industry suggests that some products may be overpriced, and some profits excessive. By the same token, clinical medicine has negative practices of its own, one of which, financial concerns, deserves special attention. Physicians are paid for their services. How they are paid should make no difference in decisions they make, but the risk is always there. In many settings, financial incentives are intentionally used to influence physician practice. In academic medicine, “career development” may be corrupting. Criteria for academic promotion were designed to identify faculty whose work is widely known, influential, and respected. Like a jaded lecturer “teaching to the test,” faculty run the risk of developing the trappings of academic excellence without the substance. I have repeatedly been advised at all stages of my career to make myself known for a particular stance or point of view. Whether that opinion is correct is less important than that it be widely known. Fame, not excellence, may sometimes become the criterion for advancement.

Oversight As a reflection of their ethical standards, legal oversight of these areas of medicine differs significantly. Clinical and academic medicine depend predominantly on internal regulation, while industry is intensely scrutinized by government agencies. The weaknesses of internal regulation are that it may be compromised by self-interest, and it is minimally open to outside perspectives. The weakness of dependence on government regulation is that it is excessively open to popular and political pressure,may be operationally weak, and may set up an ethos of “getting away with” whatever the regulators don’t catch. It could be argued that there is an inevitable weakening of moral rectitude when standards are enforced from outside.

Industry Interactions with Physicians Contract Services Scientific advisory boards Marketing advisory boards Speakers bureaus Research design, participation, and publication Legitimate interactions between physicians and industry include contract services, in which a physician agrees to perform a specific service for a company in exchange for a defined fee. Ideally, these services should be in keeping with the physician’s recognized area of expertise. It is essential that the fact of a contract, including financial reimbursement, be disclosed in the performance of these activities.

Industry Interactions with Physicians Educational Programs Unrestricted education/research grants Industry-sponsored symposia Patient education materials Journal sponsorship Educational programs are legitimate and useful at a variety of levels.

Industry Interactions with Physicians Marketing Contacts Physician detailing Lunch/dinner meetings and presentations Advertisements Marketing contacts are also a legitimate means of making physicians aware of the availability and characteristics of medications. These contacts should be clearly identified as advertisements.

Marketing and Clinical Practice Factors in clinical decision-making Evidence-based clinical data Clinical experience Nonclinical complicating factors financial reward academic interest It is worth a moment of reflection at this point on how physicians make clinical decisions. Clearly one factor is available data on treatments. In the best of all worlds, all decisions would be made based on data. The infinite variety of clinical presentations of real-world patients makes this impossible, and only the earliest and most general decisions fall into this category. Clinical experience allows attention to diagnostic and therapeutic nuance not addressed in large-group studies. Unquestionably, experienced clinicians make better therapeutic choices than novices. A variety of nonclinical factors may also enter in. The significance of financial incentives must be addressed. Consider the following scenario: A psychiatrist in private practice diagnoses a patient with mild-moderate depression and outlines the pharmacologic and psychotherapeutic treatment options. The patient asks the doctor which option is better. If the psychiatrist recommends medications, billings for this patient for the next year will probably total less than $500. If the answer is psychotherapy, billings will probably be around $5000-7000. Will this affect the psychiatrist’s opinion about the relative merits of the therapies? If the same psychiatrist works in an HMO, time rather than money will be the deciding factor, and the opinion of management may enter in, as well. Another, less appreciated factor is academic interest. This may range from personal curiosity to a formal study in progress, for which the patient may be recruited.

Marketing and Clinical Practice Legitimate marketing factors Notification of availability Clinical trials data Cumulative experience data Cost effectiveness data In marketing a medication, it is legitimate for the pharmaceutical company to tell both physicians and the public that the drug is available. Provision of clinical trials data is also appropriate. These data are prepared for the FDA, and are the basis on which the drug is approved for clinical use. It is harder to assess the value of cumulative experience data. In contrast to premarketing clinical trials, these data are not subject to FDA review. Companies may choose to selectively release findings, and unfavorable data may be suppressed. Anecdotal information may be misleading or incorrect. Nevertheless, some of this information is accurate and valuable. Critically examined, it is useful to the clinician. Cost comparisons are similarly subject to marketing bias, but may be useful to the clinician. Certainly, price lists from a manufacturer should be examined. More difficult to assess are comparisons of the value of a specific medication relative to its price.

Marketing and Clinical Practice Illegitimate marketing factors Personal relationship with physician Incentives to decision-makers Gifts Other aspects of marketing have no place in clinical or academic medicine. Personal relationships with pharmaceutical representatives should never influence treatment decisions. Incentives to decision-makers, financial or otherwise, are clearly in violation of both ethical and legal limitations. Gifts are more ambiguous. AMA guidelines permit gifts of nominal value that benefit patients. Gifts of minimal value may serve other functions, such as reminders that a drug is available. Many studies have shown, however, that even minor gifts have an impact on clinical decisions, and that physicians are not always aware that they are being influenced in this way.

Confusion of Boundaries Problems arise when boundaries of these categories are blurred or crossed. Among the most common violations are marketing contacts and promotional literature masquerading as educational programs. Speakers bureaus, papers distributed by manufacturers, and books distributed by companies may (but don’t always) cross these boundaries. Similarly, some contract services may be extravagantly reimbursed, raising the possibility that some element of the reimbursement is actually a gift.

Major Dangers Clinical compromise Research bias Academic corruption Specific negative consequences can be expected when categories of contact are confused.

Inaccurate or biased information Biased clinical judgment Clinical Compromise Inaccurate or biased information Biased clinical judgment Financial incentive Receipt of gifts Personal relationship with pharmaceutical representative Compromise of clinical practice may arise from any of these factors.

Sponsorship strongly predicts outcome in industry-sponsored research Research Bias Sponsorship strongly predicts outcome in industry-sponsored research Industry is not required to divulge all study results Research questions can be framed to favor a specific outcome Data can be framed to accentuate specific outcomes The reading of industry sponsored research studies requires special attention. Most of these studies are conducted by reputable academicians according to rigorous standards. Even so, studies almost invariably highlight the positive aspects of the sponsor’s drug. Some sources of bias include selective release of data, carefully structured research questions intended to accentuate the positive qualities of one study drug, and framing of data to highlight specific findings. Ironically, one source of bias is the FDA requirement that direct comparison studies sponsored by only one company use the comparator drug exactly as described in the package labeling information. Some of this information differs from what is now accepted as optimal practice, causing the competitor’s drug to perform less well.

Selective input into research Research driven by financial incentive Academic Corruption Selective input into research Research driven by financial incentive Education biased by financial incentive Industry support of favorable opinions Academicians have a special responsibility to maintain objectivity and avoid scholarly compromise. Financial incentives are a particular problem, and care must be taken to keep the nature of interactions clear. The possibility of a faculty member "selling out" is very real.

Clinician-Industry Interaction Session III: Practical Applications Residents' interest is invariably piqued when I promise to tell them exactly what we get paid for contract services. It is not clear if this is driven by voyeurism, moral outrage, or anticipatory excitement.

Required Disclosure 2001 Speakers’ Honoraria Pfizer AstraZeneca This is what I am required to disclose to meet CME standards.

Full Disclosure Contract Services Promotional Talk - $750-1500 Grand Rounds - $500-1500 District Advisory Meeting - $1000-2000 APA Symposium - $3500 A more realistic disclosure is broader and more explicit. This shows the range of honoraria I received for these activities during 2001 and 2002.

2001 Honoraria (direct payment) Pfizer Full Disclosure 2001 Honoraria (direct payment) Pfizer CME programs Promotional programs District Advisory Board AstraZeneca I received direct payments from two companies for the contract activities noted.

2001 Honoraria (indirect payment) Full Disclosure 2001 Honoraria (indirect payment) AstraZeneca Publications Pfizer CME program Janssen CME programs Eli Lilly CME program I received honoraria from other sources (hospitals, CMHs, universities, etc.) that represented indirect payments from pharmaceutical companies. In each case I was aware of which company sponsored the program, and my travel arrangements were generally made by the pharmaceutical representative, not the medical or academic institution.

Full Disclosure 2001 Gifts and Meals ~ 100 Lunches ~ 25 Detail visits ~ 20 Pens ~ 20 Sticky pads ~ 5 Dinners ~ 5 Toys 2 Z-Packs But no: Theater tickets Resort junkets Golf excursions Turkeys or hams During detail visits or educational activities underwritten by pharmaceutical companies, I received the items on the left. I was offered, but turned down, the items on the right.

2001 Donors (gifts and meals) Full Disclosure 2001 Donors (gifts and meals) Abbott AstraZeneca Bristol-Myers Squibb Forest Glaxo-Wellcome Janssen Eli Lilly Novartis Organon Scios Searle SmithKline Beecham Wyeth-Ayerst This is a list of the companies that provided the gifts on the previous slide. I am not really sure that I listed them all.

Percent of income derived from each source Full Disclosure Percent of income derived from each source Here is the total breakdown of the income I derived from pharmaceutical contract services in 2001. Clearly, the required disclosure does not include all the pertinent information.

Observe AMA Guidelines What We Can Do Observe AMA Guidelines Be clear about the nature of our interactions with industry Disclose everything Limit gifts and personal contacts There are specific steps we can take to maintain personal and professional integrity.

Be aware of sponsorship of research and educational programs What We Can Do Use peer review and consultation to detect diagnostic and therapeutic “drift” Be aware of sponsorship of research and educational programs There is no substitute for constant attention to personal integrity and professional rigor “Diagnostic drift” refers to the tendency to get into a rut with regard to diagnosis and treatment. Peer review and consultation serve the purpose of broadening the clinical experience of the individual physician. The final point is that personal integrity is essential for any ethical framework to be useful.

Case Scenario 1 During a detail visit by a pharmaceutical representative, a psychiatrist is congratulated on being the top prescriber of the company’s product in that area. In recognition of this, the psychiatrist is given a gift certificate for dinner at a popular restaurant. What APA guidelines apply to this situation? What ethical issues are involved? At least two AMA rules may apply in this case, and these programs represent a clear violation of the guidelines. The first rule is the prohibition on accepting gifts with strings attached. In this case the strings preceded the gift, but are there nonetheless. Second is the requirement that gifts must benefit patients. From an ethical standpoint, these programs are perilously close to kickbacks.

Case Scenario 2 An academic psychiatrist with an interest in antidepressant medications is offered $1000 to speak at a symposium on treatment of depression. What ethical issues must be considered if a. the symposium is sponsored by an unrestricted education grant to the hosting institution? b. the symposium is industry-sponsored? This is a legitimate contract activity irrespective of sponsorship, with a standard honorarium. Ethical issues include the speaker's responsibility to present objective and balanced information, and to disclose the financial arrangement.

Case Scenario 3 A psychiatrist is invited by a pharmaceutical representative to hear a speaker at a popular restaurant. Afterward, attendees are invited to a performance of an award-winning stage production. What APA guidelines apply to this situation? What ethical issues are involved? Dinner speakers are standard practice. AMA guidelines specify that the meal must be of moderate expense, a requirement that is routinely violated. Theater tickets afterward are a gift unrelated to the dinner presentation, and should be considered separately. It is difficult to imagine that the physician's attendance at the theater will somehow benefit patients.

Case Scenario 4 A psychiatrist is invited to participate in a regional advisory board for a pharmaceutical company. The meeting is for one day at a major hotel in San Francisco. The psychiatrist will be paid a $1000 honorarium for participation. What APA guidelines apply to this situation? What ethical issues are involved? This is a standard honorarium for this activity. Financially, it is comparable to what a psychiatrist in private practice would collect in billings during the period of the meeting and the travel. Regional advisory meetings are, however, ambiguous activities. Most of them consist of extended presentations on a sponsor’s drug, with little opportunity for the attendees to provide feedback. It is not clear just who is advising whom at these meetings. They nevertheless provide attendees with extensive proprietary information, which may be of clinical or academic value.

Case Scenario 5 A psychiatrist is invited to attend a CME conference in Hawaii at the expense of a pharmaceutical company. The meeting includes two hours of workshops each morning for three days. What APA guidelines apply to this situation? What ethical issues are involved? AMA guidelines forbid a drug company from directly sponsoring a physician’s attendance at a conference. In addition, the proportion of time spent in CME activity at this particular conference raises the suspicion that this is more about a vacation in Hawaii than a CME program.

Case Scenario 6 A psychiatrist attends a dinner talk on a new antipsychotic medication with which he is unfamiliar. The following day the psychiatrist prescribes that medication for a newly diagnosed schizophrenic patient. What ethical issues are involved? What legitimate marketing factors may be involved? What illegitimate factors may by involved? There is nothing inherently wrong in this scenario. A physician learning about an unfamiliar medication, persuaded by legitimate research data, should make adjustments in practice to accommodate the new information. On the other hand, the change may have simply been a response to a good advertising pitch, in the context of an expensive meal. Peer review may be useful to sort out these issues.