other extreme, managed care reimbursement systems reward physicians in such a way that underuse of diagnostic and therapeutic interventions is a possible pitfall. To simplify a complicated matter, in such systems, the physician stands to financially benefit when the care provided to patients covered by the plan is minimized.2 In such a system, there may also be an incentive by the physician to avoid sick patients, as they will require more care with financial penalties incurred by the physician caring for the patient. Conversions between fee-for-service and capitation systems for paying physicians have been shown to produce behavioral changes in patient encounters and referral patterns in the physicians affected.17–19

15.5 Interactions with Medical Industry

Ophthalmologists who take care of patients with diabetic retinopathy have frequent occasions to interact with representatives of pharmaceutical and medical technology companies who spend an estimated $57.5 billion annually in the United States ($61,000/ physician/year) to influence physician behavior, an amount larger than their research and development budgets.20–22 The interactions come in several forms. Most frequent are encounters with representatives who leave samples of new and expensive topical medications, but never inexpensive generics, in return for a few minutes of the target physician’s time to listen to a sales pitch in the guise of physician education.23,24 Usually, the sales representatives have little science background and work from practiced scripts honed to produce a closing commitment from the

physician to write prescriptions of the touted product.23,25 Simultaneously, there may be gifts given,

such as post-it notes, pens, computer memory sticks, a choice of textbooks, silk ties, or umbrellas. More recently, the industry has deployed increasing numbers of ‘‘medical science liaisons,’’ who are often physicians or pharmacists and can mention off-label uses for drugs that the sales representatives cannot in their interactions with practicing physicians.26

Another tactic companies employ is to invite ophthalmologists to expensive restaurants to listen to an opinion leader speak on a topic relevant to a

product the sponsoring company sells. The invited speaker is paid a fee, thus there is influence purchasing at the audience and speaker level in these cases.27 Sometimes a drug company will invite physicians to an expensive hotel for a retreat, ask them their opinions about the company’s drugs, call them ‘‘consultants’’ thereby, and pay them a fee in addition to the expenses for the retreat.28 In another variation, the office staff of an ophthalmologist may be invited to a catered lunch or dinner at which a speaker from the company talks about a topic related to a product sold by the company. Free lunches and gifts to physicians and staff are not random, but are targeted to those with the potential to cooperate with the company’s efforts and boost their sales.29

At a different level, pharmaceutical companies invite ophthalmologists to be investigators for com- pany-sponsored clinical trials of investigational drugs or devices.30 The reimbursements to the physician for encounters of patients enrolled in these

studies are higher than the reimbursements for patients not in these studies.31,32 Besides the richer

reimbursements paid for subjects enrolled in studies, pharmaceutical companies will pay for the engaged

ophthalmologists to travel to expensive locations to give or hear talks at meetings.21,30,33 Patients are not

informed that their participation in pharmaceutical research is associated with differentially favorable remuneration to the enrolling physician compared to remuneration associated with care outside of pharmaceutical research, although surveys indicate that many participants in clinical research would like to be informed of financial conflicts of interest.34 In some cases a proposed research study is not validly designed, and the payment to the physician is a veiled inducement to use the drug.35

Financial arrangements often exist between physicians who invent or help develop medical devices

and the companies that produce them. Universities may be a third party in these relationships.34,36,37

The patents, royalties, and compensation paid by companies to these physicians can potentially bias the relationship of the physician and patient, as when a surgeon recommends a medical device to a patient in which he has a financial interest or alters research data in a study for the same reason. In the United States in 2006, the average medical industry

support for medical school departmental activities was 2.1 – SD $5.6 million.38 Medical industries provided financial support for a wide range of activities to many medical school departmental chairmen: personal compensation for involvement in CME courses (28%); personal equity or stock options in exchange for professional services (6%); royalties, license payments, or milestone payments (11%); free or subsidized travel and expenses to meetings and conferences (16%); and research funding (21%).38 Yet in the same survey, 25% of medical schools had no institutional conflicts of interest policy or were not working on one.37

Questions have been repeatedly raised about the ethical basis of these interactions.20,39,40 They have

been identified as conflicts of interest at a minimum and as bribes by some.12,20,21,29,35,41 A conflict of

interest occurs when reasonable observers of a situation could conclude that the temptation for economic gain compromises the physician’s responsibility to place the patient’s interest first.41 There seems to be little doubt that the industry samples, gifts, and perks are effective from the perspective

of the companies, whether the targeted physicians believe it or not.2,21,23,29,33,41,42,42–45 The many ways

that physicians attribute moral vulnerability to others but not themselves and rationalize their attitudes toward accepting free lunches, gifts, and sam-

ples-for-face-time have been studied and characterized.43,46,47 Physicians who believe that nominal

gifts are ineffective in inducing reciprocity and

therefore less unethical are in error based on social science research concerning gifts.12,29,33,47 Targeted

physicians tend to change their prescribing habits

and use of medical devices, and the result is higher cost for medical care.21,33,25

Historically, the response of the ophthalmic community has been to institute a policy of disclosure of financial conflict of interest. The assumption has been that the audience can factor this disclosure into its reception of the speaker’s content and properly calibrate its granted credulity. However, there are problems with this response to the situation.21 Counterintuitively, there is social science evidence that disclosure perversely exacerbates the effects of bias rather than ameliorating them.12 Appraisers who disclose that they are paid based on the size of their appraisals have been found to produce

inflated appraisals compared to appraisers who do not disclose.12 This is not an argument to omit disclosure, but rather one that it is an inadequate response. Some physicians ignore disclosure rules or interpret their involvement in such a way that they think the rules do not apply. A survey of medical experts who write clinical practice guidelines found that 9 of 10 had financial ties to the pharmaceutical industry but rarely disclosed them.48 Financial involvements and disclosures have become so widespread and the time spent on them at meetings and in publications so cursory and without detail on magnitude of financial benefit that they are ignored. Moreover, the forms of disclosure have become more opaque. For example, here is the wording of a financial disclosure of an ophthalmologist from the Johns Hopkins School of Medicine (name removed):

The author has no financial interest in any of the material discussed. Dr [X]’s employer, the Johns Hopkins University, but not Dr [X], receives funding for research and other sponsored projects from Eyetech Pharmaceuticals, Inc, New York, NY, Genentech, Inc, South San Francisco, Calif, the National Eye Institute of the National Institutes of Health, Bethesda, Md, the US Department of Health and Human Services, Washington, DC, Novartis Pharma AG, Basel, Switzerland, QLT, Inc, Vancouver, British Columbia, and Carl Zeiss Meditec AG, Jena, Germany. The terms of these institutional consulting agreements are managed by the Johns Hopkins University in accordance with its conflict of interest policies.49

In the arrangement here, the money from the recipient’s work flows to the employing medical school. It sounds less likely to be ethically questionable inasmuch as the potential benefit to the recipient is indirect. Yet without knowing what the cited policies of the university are, the reader cannot assess how likely the recipient is to be influenced by the money. If the university policy is a direct pass-through to the faculty member, then the potential for bias is higher than if his compensation is completely disengaged from the funding the recipient brings into the university through his involvement with the companies. The disclosure is in fact no disclosure, because it is opaque. Few if any readers will spend the effort to pierce the veil of this disclosure statement, although technically, with enough digging, they could do so. As Brennan

and colleagues note, ‘‘Because declarations of conflict are usually unverified, their accuracy is uncertain.’’41 Many authors argue that disclosure is a halfmeasure response to the apparent ethical challenge; avoidance is the more appropriate ethical response.2,50 As an analogy, when someone embezzles money, we wish for them to stop it, not to disclose that they are embezzling. In a different profession – the judiciary – disclosure is not an option; if a judge has a conflict of interest, he must recuse himself from the case.23

The growing proportion of continuing medical education expenses underwritten by pharmaceutical companies that view the practice as good marketing has been noted and deprecated.50 Relman asks, ‘‘Does anyone really believe that medical educators are properly doing their job when they allow the pharmaceutical industry not only to subsidize their educational costs but also to help prepare the curriculum, recommend and pay the speakers, indirectly pay students and residents to attend, lavish free meals and favors on attendees, and then promote the company’s products at the meetings?’’50 Calls to physicians to refuse to attend industry-sponsored continuing medical education events (CME) have been published.20 Others have suggested that accreditation for offering CME be restricted to member institutions of the Accreditation Council for Continuing Medical Education and be denied to industry-sponsored public relations firms.51 Recommendations to eschew gifts and samples from industry representatives have been published.41 There is insufficient evidence to conclude that any of these recommendations has gained traction.

The conflicts of interest discussed herein are not abstract. They are concrete and occur on a daily basis in ophthalmic practice. Physicians have repetitive chances to affect the ethical landscape of the profession by their choices. Historically, the American Medical Association has issued guidelines in which the ethical propriety of gifts is determined based on type and monetary value.47 Gifts with a benefit to patients (e.g., samples) and related to a physician’s work (e.g., a pen) have received a pass, despite evidence that these are intended to affect and do affect prescribing practices.47 Based on history, pessimists contend that physicians and their professional societies are unlikely to change

their behavior internally and that federal regula-

tion with penalties for infractions lies in the future.24,46

In managing patients with proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME), the ophthalmologist has the discretion to choose among a menu of injectable intravitreal drugs in many cases. Reviewing the actions of drug companies in this environment is relevant to the discussion. For example, Genentech makes both bevacizumab, an oncological antivascular endothelial growth factor (VEGF) drug widely co-opted for off-label use by ophthalmologists,

and ranibizumab, an anti-VEGF drug specifically designed for ophthalmic use.52,53 Both drugs show

a biological effect in PDR and DME.54 The potential profit margin for Genentech is much greater for ranibizumab with a retail price over 20 times that of bevacizumab. The company has spent and continues to spend large sums of money supporting clinical trials to demonstrate efficacy of ranibizumab for diabetic retinopathy indications, but not for bevacizumab. This financial support has been a factor in the selection of ranibizumab, and not bevacizumab, by the National Institutes of Health-funded Diabetic Retinopathy Clinical Research Network for its phase 3 clinical trials with an anti-VEGF drug component. The logic presented to the Network investigators by the Network leadership for this choice goes as follows. By accepting the Genentech subsidy of free ranibizumab other valuable research can be conducted with the dollars not spent on bevacizumab. This logic perhaps underweights the expected future argument by Genentech that should anti-VEGF therapy with ranibizumab be shown to be valuable in PDR and DME, it would be an act based on faith rather than evidence to extrapolate the results to the untested, less-expensive bevacizumab, even though the mechanism of action of the two drugs is the same. At present, well-funded pharmaceutical representatives of Genentech assiduously court retina specialists by the methods listed previously to tilt their decision making in anti-VEGF therapy for neovascular macular degeneration. They would not do so were their efforts fruitless. In the future, they will undoubtedly expand their efforts to diabetic indications should the diabetic clinical trial results turn out in their favor.

A frequent component in the care of patients with diabetic retinopathy is the injection of intravitreal drugs and application of focal/grid and panretinal photocoagulation. In 2008, these procedures were added to the list of approved procedures that can be doneinambulatorysurgerycenters(ASC)intheUnited States. There are differential rates of reimbursement for these procedures when done in an ASC or in an office setting. Generally speaking, the reimbursement is higher when they are done in an ambulatory surgery center because a facility fee is generated that does not apply to the office setting. If the ophthalmologist is an investor in an ASC and directs his patient to that setting to receive the treatment, the issue of conflict of interest arises, especially if the patient is left to pay a higher out- of-pocket expense in an ASC setting compared to the office setting. As Tonelli has written, ‘‘arrangements thatbothincreasephysicianremunerationandimprove the care of patients are theoretically possible, and if patient care can be demonstrated to improve, would beethicallypreferred.Butsucharrangementsdemanda high burden of proof demonstrating that patients, and not simply clinicians, are benefited.’’2

15.7 Comanagement of Patients

Comanagement of patients with diabetic retinopathy has not been an issue in the management of patients with diabetic retinopathy as it has been in the management of patients undergoing cataract surgery; however, related concerns have begun to arise.55 For example, networks have been developed in which primary-care physicians take nonmydriatic fundus photographs to screen for diabetic retinopathy (see Chapter 14).56 These are graded by ophthalmologists, and if DR is detected, the patient is sent to an ophthalmologist. If the patient has an ophthalmologist, they are directed there, but if not, relationships between the grading ophthalmologist and the screening ophthalmologist may exist that direct referrals. These relationships may be influenced by external factors, including affiliation with hospital networks that own physician practices. Referrals may be governed by concerns such as emergency room coverage.

Perhaps no month goes by without an e-mail requesting an ophthalmologist to participate in a survey or a conference call sponsored by an investment firm in which money is offered for expert opinions on the prospects of drugs and devices used to treat diabetic retinopathy. Many ophthalmologists participate in clinical research networks and know the results of clinical research before they are published in peer-reviewed journals. Inside information from unpublished clinical trials is sought and used by investment firms to make money for the firms and their clients. Is it ethical to participate in and receive fees from these activities? Recommendations have ranged from disclosure alone to nonparticipation in such activities.57,58

15.9 Summary of Key Points

Daily clinical care of patients with diabetic retinopathy involves practical issues with an ethical dimension that are rarely covered in textbooks about diabetic retinopathy.

Theseissueshavethe commonthread of professionalism – the duty of the ophthalmologist to abjure self-interest and to act in the interest of the patient and, to a lesser and poorly defined extent, society.

Specific examples are presented and used as a springboard for discussion.

There are instances where the ophthalmologist’s actions are immediately relevant, and instances where the issues are broader and involve the social organization of health care.

15.10 Future Directions

Studies that determine if value is added by expensive ancillary testing in the management of diabetic retinopathy may be coming in an environment of decreasing financial resources. The ophthalmological groundswell of commentary regarding ethical aspects of physician relationships with drug companies and in the conduct of research is likely to grow. The prospect of