50

Ethical Issues and Conflicts of Interest

NOTE: The comments in this chapter represent those of the author and not of the organizations of which he is or has been a member or employee.

The ethical issues of business and medicine have become complex and difficult. Years ago, before medicine was thought of as “big business,” the ethics of medicine were somewhat cleaner (at least on paper). Physicians adhered to the Hippocratic Oath, which said, in regard to drugs, “I will neither give a deadly drug to anybody who asked for it, nor will I make a suggestion to this effect.” It is not so simple now that we know almost all drugs can be deadly. See “The Hippocratic Oath Today: Meaningless Relic or Invaluable Moral Guide?” at Web Resource 50-1.

The physician’s obligation for most of the years since Hippocrates was primarily to the individual patient. The physician had little in his or her armamentarium that was effective in diagnosis or treatment. Diagnosis relied on the physician’s brain, without laboratory tests or other investigations. Real medications were few, and often useless, adulterated, or impure. Clinical research dates only to the eighteenth century and serious use of clinical research to the nineteenth century. Surgery was, at least until anesthesia was developed also in the nineteenth century, crude and painful at best and fatal at worst. The physician comforted and predicted and often did little else.

How that has changed! Physicians (plus nurses, physician assistants, nurse practitioners, midwives, and many other healthcare providers) now have an extraordinary array of diagnostic and therapeutic choices available. There are far more choices than the practitioner is able to keep up with and use appropriately.

But the cost of this great improvement in diagnosis and therapeutics has been the introduction of complexity and conflicting agendas, as healthcare professionals now have obligations to society, employers, governments, insurance companies, partners, and hospitals. The days when the patient paid his or her $5 cash for an office visit (and $8 for a home visit) are long gone. The world of big business has now caught up with big medicine. Costs of physician and other healthcare provider services, procedures, surgeries, laboratory tests, medications, and devices have skyrocketed. The entire dynamics of medicine and health care have changed. The next frontier will be how to handle the rationing that will occur (it’s here already, in fact) as the population of baby boomers ages and resources are unable to keep up with the demand for healthcare services.

The question of what is a pharmaceutical company’s responsibility should be addressed. There are, broadly speaking, two schools of thought on corporate responsibility. The first is the one of “fiduciary responsibility,” which states roughly that a company’s role is to maximize profitability and shareholder/stockholder value while staying within the law. The second view holds that companies have additional moral obligations to their “stakeholders” above and beyond simply making as much money as possible for the stockholders (owners) of the company. The stakeholders include the patients and their families, healthcare personnel, employees, the communities where the company is located, the public at large, and vendors. America and other parts of the world have shifted from the first view toward the second one or some combination thereof. There is currently a major and ongoing debate on corporate ethics and responsibilities, with one side saying that “corporate ethics” is a contradiction in terms, or an oxymoron, and the other that we are moving to a new view of corporate behavior. This debate then tempers the view one takes regarding the behavior of companies and their individual employees, regulators, customers, bystanders, and others. The debate is not unique to the pharma world and has been seen with BP and the Gulf oil spill, Union Carbide and Bhopal, and many other tragedies. Business ethics is now a hot topic in business schools.

Accompanying the changes in the structure of medicine have been changes in the roles and obligations of physicians and other healthcare providers. For example, the physician’s role in clinical research is ambiguous. By doing clinical research, the physician is experimenting on patients (or even normal subjects) with new medications that may not help the individual patient but that may help humankind (if the new product represents a real breakthrough) and definitely will help the drug company involved. This is a concept not envisioned in Hippocrates’ time. An excellent review of the issues appears in the Stanford (University) Encyclopedia of Philosophy (Web Resource 50-2). The multiple views and conflicts are discussed relating to a basic philosophical question: “Clinical research poses a very practical and practically vital example of one of the most fundamental concerns in moral theory. When is it acceptable to expose some to risks of harm for the benefit of others?”

The specific ethical obligations and considerations in regard to the pharmaceutical industry is a topic of lively discussion, and many websites offer opinions. A Google search on “ethics” and “pharmaceuticals” produced more than 1.6 million hits, and a search on “ethics” and “drug safety” produced more than 100,000 hits.

For an excellent review of the ethical issues in the pharmaceutical world, see M. D. B. Stephens’s superb section entitled, “Ethical Issues In Drug Safety,” in Stephens’s Detection of New Adverse Drug Reactions, 5th ed. (Wiley, Hoboken, NJ, 2004, pp. 591–648). This article covers clinical trials, the use of placebo, ethics committees, conflicts of interest, informed consent, patient protection, publications, symposia, advertising and promotion, labeling, and relations with government.

Companies are set up, as noted above, to make money. They do so by selling various drug/device/biologic products that have known faults or defects listed in the labeling as adverse events (AEs), warnings, and precautions. For all new products, the complete risk profile is not completely known until well after marketing begins and exposure to much larger and heterogeneous populations than during clinical trials occurs.

For just about all drugs, the safety of use in pregnancy has not been studied. The company has invested enormous amounts of money in the development and then promotion of the products that have a finite (financial) life span due to patent expiration and new and better products coming along. When a drug is approved, it is judged by health authorities to have a benefit profile greater than its risk profile, translated by the public into the shorthand of “safe and effective,” although it really means “relatively safe and relatively effective and hopefully more of the latter than the former.”

Companies will do everything within their power to promote and protect their products. The drug safety group (along with the product quality department if separate) is the department that receives only bad news about product use. This department must determine, in very short time frames, whether the serious or fatal problems reported are due to the drug. Some of the cases must be reported to the government within a week or two and others tallied up in summary reports as signals for internal corporate review and, sometimes, submission to the health authorities. Real-time, online tracking of AEs and drug safety issues are coming but are not here yet.

The primary duty of the drug safety group is to protect the public health. A secondary duty is to protect the company’s products only insofar as this does not conflict with the primary protection of the public health. It is always interesting to read the introduction to the corporate standard operating procedure or mission statement for the drug safety group to see whether this distinction is respected. It usually is, at least on paper.

It is interesting to note that large universities in the United States, for the past 20-plus years, have had the right to patent and make profit from pharmaceutical discoveries from their labs. This has led to some phenomenal successes, with hundreds of millions of dollars of royalties from drug sales coming into the university treasuries. Not surprisingly, the universities are reacting just like for-profit pharmaceutical companies when their monetary stream is threatened or interrupted. They sue one another and drug companies to protect their interests.

The next sections address some of the areas of controversy that touch drug safety.

• Corporations are rarely run by physicians or clinicians and more often by non-medically trained marketers, sales personnel, lawyers, and accountants. Such managers, who work their way up the corporate ladder, usually do not do a stint in the drug safety department. It is thus understandable that the senior corporate view on drug safety is sometimes vague and often ill-defined.
  
• The rules governing drug safety are arcane, highly technical, and very difficult to understand (even for those in the business). Management rarely wants details but rather prefers “executive summaries” of data that may not capture the nuances of the clinical judgment involved in drug safety decisions. In addition, there is legal discouragement about writing down real or potential “bad things” about the drug products in e-mail or memos. Management may work on the MEGO (“my eyes glaze over”) or MITIN (“more information than I need”) principles regarding drug safety.
  
• The drug safety group is a “cost center” and not a profit center. Pharmacovigilance professionals often argue that their approach saves the company money and shame by preventing safety problems from becoming safety crises, resulting in crisis management procedures, patient harm, litigation, restrictions on use, or even withdrawal from the market. This argument, of theoretical future dollars saved by the safety department, usually carries little weight.
  
• The drug safety function is not glamorous and usually not well funded—at least not as well funded as the clinical research and sales organizations. The same holds true, by the way, in most drug regulatory authorities: there is more staff studying dossiers in view of approving new products than studying adverse drug reaction reports. And in medical schools, pharmacovigilance is not even part of the curriculum. As the saying goes, drug safety is the “poor stepchild.” This may be changing somewhat, as various “scandals” and the public awareness that drug safety really does matter may increase funding and resources available.
  
• In many companies, the drug safety group is scattered at several sites around the world and often away from the main campus or headquarters of the company (“out of sight, out of mind”).
  
• Delivering bad news up the corporate ladder is, in the best of times, accepted but not welcomed. In the worst of times, it is actively discouraged and punished. It is hard to “speak truth to power.” The messengers are indeed sometimes “killed.” The mechanism of reporting on signals that could drastically reduce sales, if confirmed or made known, is often convoluted, requiring the safety message to work its way up the corporate chain before it reaches someone with decision-making power.
  
• Delivering bad news is generally not as well paid as delivering good news (completing clinical trials, selling more drug, etc.) in companies. No one is compensated more for sending in additional 15-day alert reports.
  
• Rightly or wrongly, the reputation for honesty of drug companies (including their drug safety groups) is not high in the eyes of health authorities, regulators, consumer groups, and the public. This tends to produce a mentality within the companies of “circling the wagons.” Companies, again rightly or wrongly, put little trust or credence into AE reports from certain groups such as consumer groups, disease groups, and attorneys, and react defensively.
  
• The drug safety group (“the sales prevention department”) is usually grudgingly accepted as a “necessary evil” by other groups in the company.
  
• The group handling business negotiations for inlicensing new products often do not think of drug safety or bring it into play at the very last minute.
  
• It is often very difficult to convince sales and marketing departments of the need to train both new and current salespeople on AE reporting (“The job of the sales force is to sell.”). Training is often relegated to giving out reading material, or if an actual physical presentation is permitted, it is often done at 4:30 PM on a Friday afternoon.
  
• Drug safety often reports into the medical research department. Less commonly, it reports into the legal or regulatory departments. It should never report to a marketing or sales function. The drug safety organization may report to a nonempowered, low-level, relatively junior employee with little organizational voice or influence and no internal “champion.”
  
• There are few ways for management to measure drug safety performance. Clearly, measuring the on-time reporting performance for 15-day Periodic Safety Update Reports, New Drug Application periodic reports, and Investigational New Drug Application annual reports is the most common metric used, but this simply captures mechanical performance and not the medical protection and risk management aspects of pharmacovigilance. Softer measures such as “the health authority’s satisfaction with our performance” are nearly impossible to measure.
  
• Pharmaceutical companies are asked to present statistically significant efficacy data to prove that a drug should be approved by the health authorities to market a product. Thus, many in senior management assume that safety data work the same way. They do not.
  
• Management often takes the view that a serious safety issue must be proven with hard data. There must be clear causality associated with the drug and no alternate explanations for the safety problem. Thus, some managers will not accept drug safety physicians’ views that a particular serious and severe medical problem is probably or possibly due to the drug and that a change in the product labeling is warranted. Clear proof in several or many patients is demanded.
  
• Alternative explanations are often presumed to be the cause of the problem: “This patient smokes, drinks, is hypertensive and both parents have heart disease. How can you say our drug caused this patient’s heart attack?” Sometimes the drug truly is the cause of the problem even though there are other possible causes (see also the fialuridine story in Chapter 52).
  
• The problem may be reduced to a more simple question: is the drug innocent until proven guilty of a safety problem or is the drug guilty of a safety problem until proven innocent? In the past, the “innocent until proven guilty” view predominated. Now, the pendulum is swinging toward early notification of the public of potential safety issues even if events are not clearly due to the drug. Whether this will prove to be good for the public health (moving people off dangerous drugs) or bad for the public health (moving people to other more toxic or costly alternatives) remains to be seen. People feel better about warning the public and medical providers of possible issues. Whether this improves health outcomes has not been proven.
  
• The “level playing field” argument is often made by nonmedical personnel in regard to reporting and acting on safety issues. The argument for this runs roughly as follows: “If we as a company have to report that our drug X seems to be causing ventricular fibrillation, then our competitors’ products, which also cause ventricular fibrillation (as evidenced by Freedom of Information Act or medical literature reports), should also be obliged to change their labeling.” This then puts pressure on the drug safety department either to not report or to minimize such events until they are “proven.” Companies thus sometimes try to make deals with the agencies (“We’ll change our label if you make our competitors also change theirs,” or “This should be class labeling”). This rarely works.
  
• Interestingly, physicians are now found more and more commonly in marketing departments, where they tend to take on the coloration of marketers and lose the coloration of physicians. They then may take on an adversarial (“devil’s advocate”) role in relation to the drug safety physicians.
  
• In a similar vein, physicians working in the medical research department (phases II and III) often become quite “protective and possessive” about the drugs they are studying and may take a doubting view that “their” drug could produce such serious AEs and, thus, that these serious AEs are “unrelated” to the study drug. This is one reason the final determination of causality, labeling, and reportability should rest with the drug safety group.
  
• Physicians and, to a lesser degree, other healthcare professionals working in industry (including drug safety) are/were often looked down on by physicians and healthcare workers “out in the real world.” Some consider pharmaceutical professionals to have “sold out.”
  
• There are few formal training programs for drug safety personnel either in medical, nursing, or pharmacy schools. There are courses on drug safety lasting from a day to a week or two (usually by nonacademic institutions), and there is a scarcity of textbooks. Training tends to be similar to an apprenticeship. This is slowly changing, with universities in North America (University of Medicine and Dentistry of New Jersey, Eastern Michigan University, University of Montreal, McGill University) and others in Europe and elsewhere beginning to develop programs in “industrial pharmacology.” It is also hoped a better term will be found.
  
• Drug safety officers, unless they worked previously for health agencies, really do not have a good feel for how the drug safety agency works (and vice versa). Although there are contacts between industry and the agencies through the International Conference on Harmonization, Council for International Organizations of Medical Sciences, Drug Information Association, CIOMS, and other venues, such contact is usually at a distance and defensive because of perceived conflicts of interest and different “agendas.”
  
• Drug safety personnel, as with any other company personnel, receive performance bonuses and may own stock or stock options. Hence, pay is tied to company performance as well as to the individual’s work.
  
• Drug safety units are under continued scrutiny by the health agencies (particularly in the form of inspections) and internal auditors.
  
• There are significant pressures on drug safety personnel in regard to work volume and time allocated to complete tasks (especially those time frames regulated by law), difficulty in finding experienced safety officers, and difficulty in training safety officers.
  
• Outsourcing and off-shoring are moving many drug safety jobs out of Europe and North America, forcing a larger pool of workers in these venues to compete for fewer and fewer jobs. Drug Safety is now a “buyer’s market.”
  
• The upward corporate career mobility for personnel in drug safety groups is limited usually to that group or related (epidemiology, signaling) functions. Rarely do employees move high up in the corporate hierarchy unless they leave the drug safety unit.

There are clear and obvious potential conflicts evident in such a situation. Drug safety personnel are paid by the company and will, in general, receive better pay and more rewards if the company does well and sells more drugs. However, enlightened companies tend to realize increasingly that they cannot “play games” with the drug safety units. Drug safety personnel tend to be somewhat defensive and “paranoid,” lacing their worldview with dark humor. Whether the job produces such character traits or rather attracts people with such traits from the beginning is unclear.

Stay updated, free articles. Join our Telegram channel

Join