**Lasker Forum on Ethical Challenges in Biomedical Research and
Practice**

**[Off-Label Drug Prescribing]{.underline}**

**Case Study**

**For Discussion Only**

**May 2003**

***Background.*** MegaPharm Inc. has developed a drug that appears to be
very effective in treating a certain rare sub-set of adult-onset (type
2) diabetes, and it has been approved for that narrow indication by the
FDA following a large-scale Phase III trial in one thousand patients.
Previously, this form of type 2 diabetes was particularly resistant to
treatment and the new drug offered hope to the approximately 300,000
U.S. patients with this disease who usually developed serious
complications, including heart attack and stroke, kidney failure,
blindness, or vascular damage to the feet and legs that could require
amputation. The drug was rapidly approved under "fast track" and
priority review conditions since it was targeted for a serious unmet
medical need and since the study data indicated that the drug was both
safe and effective for lowering blood sugar in the study population.
Central to the FDA's marketing approval process is the approval of a
drug's labeling. The label information, whether on the container, in the
package insert, or in any advertising or promotion, is limited to
describing a drug's use [only]{.underline} for the approved doses and
routes of administration for the approved medical condition. The use of
a drug under circumstances not included in the labeling is considered to
be a non-approved or "off-label" use of the drug. Pharmaceutical
companies are forbidden by law to promote off-label drug use unless they
follow narrow "safe harbor" conditions.[^1] However, since the FDA does
not regulate the practice of medicine, physicians may prescribe a drug
for an off-label use if it seems reasonable or appropriate.

***The Professor and the Pharma***

Professor Leptinski is an endocrinologist at a leading medical college
and was the lead investigator on the diabetes drug trials. He and
MegaPharm have been lauded for their research work that led to the
marketing of a badly needed drug. This research was not the first time
that Dr. S had worked with MegaPharm. He had been a long-time consultant
and his drug studies on behalf of the company have always been first
rate and reliable. His drug research has been published in the more
prestigious medical journals. Theirs has been a successful collaboration
and, as a consequence, a significant portion of Dr. L.'s research
funding comes from MegaPharm. When Dr. L. was involved in the diabetes
drug trials, he noted that some of the subjects in the trial reported,
among other side effects of the drug, that they experienced weight loss
and "lost appetite." These problems were listed as side effects on the
drug's labeling but Dr. L. saw them as an opportunity since he guessed
that the drug might be effective for weight loss.

Dr. Leptinski knows that there is a strong need for an effective and
safe weight loss drug in the U.S. since in the last two decades, the
incidence of obesity among adults and children has risen nearly 50
percent. As defined by federal standards, approximately 30 percent of
adults and 25 percent of children are considered obese. The impact of
obesity in America is enormous. According to the Surgeon General, about
300,000 U.S. deaths each year are associated with obesity and overweight
(approaching the 400,000 deaths a year associated with cigarette
smoking). The total direct and indirect costs attributed to overweight
and obesity amounted to \$117 billion in the year 2000. If the new
diabetes drug could also be used to treat obesity, tremendous health and
health cost benefits could be achieved. Dr. L. pursued this possibility
in studies using an animal model, with very encouraging results. He then
began lobbying MegaPharm to undertake the necessary R&D program to gain
approval for this broader indication. He thought that MegaPharm would
leap at the chance to study the drug's weight loss potential since the
market for the relatively rare diabetic disease for which the drug was
approved was small.

However, because of the typical commitment of 6-8 years and hundreds of
millions of dollars to conduct clinical drug research and gain FDA
approval, the company is reluctant to commit. Too many of the promising
new molecules being developed for obesity treatment failed in clinical
trials, indicating to MegaPharm that not enough is known about the
underlying physiology and biochemical influences of weight control to
reliably develop a safe and effective drug. An additional deterrent is
that anti-obesity drugs, such as the notorious fen-phen combination, had
garnered a bad reputation since they seemed prone to causing severe side
effects that prompted litigation against the manufacturer. Despite the
fact that the anti-obesity drug market could be huge (a breakthrough
product in this market could net the company several billion dollars in
annual sales), MegaPharm decides that its interests would be better
served by staying out of the obesity and weight loss market. If the drug
is used by physicians to treat obesity, so be it. So long as the company
refrains from promoting the drug for this purpose, the added sales
attributable to the off-label use will benefit the company but the
responsibility for the drug's use in obesity will lay solely with the
prescribing physicians.

1.  Who has conflicts of interest in this scenario and how do these
    conflicts play out?

2.  Are there any ethical concerns about a pharmaceutical company that
    passively accepts the financial rewards of an off-label market?

3.  Is off-label drug prescribing the equivalent of experimental
    treatment and should it be treated as such? Would it be feasible to
    subject all new uses of approved drugs to clinical studies before
    prescribing is allowed? Or should the decisions about off-label drug
    prescription be left to the medical professionals?

***Dr. Leptinski Prescribes Off-Label***

Undeterred and convinced that it held promise, Dr. L. begins prescribing
the drug off-label for clinically obese non-diabetic patients. Although
he knows that the drug has the potential to cause significant side
effects, Dr. L. believes that the risks are reasonable given the serious
medical conditions and social problems attributable to obesity. This
treatment also seems medically justifiable, since Dr. L. suspects that
the drug's side effects are primarily linked to the diabetic condition.
In non-diabetics, Dr. L. expects the risks to be lower. In addition, Dr.
S's success with obese patients, he hopes, will prompt MegaPharm to
support official clinical trials and seek FDA approval for the
additional use. What he might have foreseen but did not was that his
clinic becomes known as a place to obtain diet pills and, increasingly,
patients who are not clinically obese but merely over-weight begin to
seek appointments and prescriptions from him. The demands increase after
Dr. S reports his initial patient results (which he calls "promising")
at a medical conference and some weight loss web sites begin extolling
the virtues of the drug.

Patient demand for the drug grows and soon many physicians are
prescribing the drug for weight loss, both in adults and in children. As
more medical journal articles (some of which are peer-reviewed and show
that the drug is safer than amphetamine-like drugs) describe the drug\'s
value for this unapproved use, the off-label prescriptions eventually
account for well over 60% of the sales of the drug, significantly
increasing MegaPharm's revenues. Some physicians, however, begin to
voice the opinion that the unknown risks of the drug do not justify
prescribing it to healthy over-weight people. These physicians begin to
refuse to prescribe the drug for any overweight patient except the
morbidly obese. However, patients who are denied prescriptions by one
physician always seem to find another who will prescribe. In addition,
some patients who are adept at obtaining prescriptions willingly share
them with friends.

1.  What does this case suggest about the consequences of Dr. S's taking
    the "individual innovator" route rather than the more formal
    research route?

2.  What disclosure obligations does Dr. L. have in prescribing the new
    drug for obesity?

3.  Should Dr. L. limit his off-label prescribing of the drug for
    patients with the most severe forms of weight problems? How should
    he decide what the reasonable cut-offs are? How does patient demand
    figure into his decision?

4.  Are additional professional practice laws needed to ensure
    responsible off-label prescribing?

5.  Should drug manufacturers take any responsibility for the off-label
    use and prescription of their drug products?

***MegaPharm Promotes***

MegaPharm is impressed with the success of the off-label prescribing of
this drug and becomes convinced of the benefits for obese patients. In
addition, company managers are concerned about the increasingly frequent
misconceptions about the drug found in both lay and professional
publications and on weight loss web sites and chat rooms. Some of this
information touts the benefits of the drug in overly optimistic terms
and, likewise, some of the purported harms are exaggerated. Based on
these responses, MegaPharm decides to launch an off-label promotion
campaign for the use of the drug in obesity. The purpose of the campaign
is to foster responsible prescribing and to provide physicians with
accurate information so that doctors can better inform obese patients of
the risks and benefits of the drug. MegaPharm also hopes that the
campaign will increase sales and prompt payors to cover the drug for
this use. Mindful of the "safe harbor" provisions of FDAMA, the company
is determined to stay within the bounds of the restrictions but knows
that these are relatively uncharted waters. It is therefore difficult to
know how the FDA, the medical professionals, and patients will respond
to this campaign.

1.  What are the distinctions between and the benefits and risks of
    off-label drug prescribing and promotion? Should physicians be
    entitled to obtain off-label information from the manufacturer? Are
    there controls that can be implemented (by the FDA or medical
    profession or the courts) that can maximize the benefit and minimize
    the harm of these activities?

***Is the drug too toxic?***

Inevitably, as the numbers of patients taking the drug grow and the
duration of use extends beyond the time studied in the Phase III trials,
reports of side effects in patients begin to appear. At first, it is
unclear whether the problems are caused by the underlying diseases of
the patients, or the other drugs they are taking, or by the drug. For
both the diabetic and the overweight patient populations, the side
effects are generally those that were reported during the clinical
trials of the drug. However, the company and the FDA begin to receive
reports that some of the side effects are more severe than expected,
specifically those related to the liver. These reports indicate a strong
suspicion of a causal link between drug use and liver problems. The FDA
asks and the company agrees to place a "black box" on the drug labeling
warning physicians to monitor for hepatic toxicity. But when the reports
of liver toxicity persist and when the number of deaths and liver
transplants reach 20 and 6, respectively, evenly divided between the
diabetics and the non-diabetic obese, some physicians and patient
advocacy groups begin lobbying to have the drug withdrawn from the
market.[^2] The spokesman for one patient advocacy group complains that
"Peer review simply isn't as rigorous as traditional FDA-mandated
clinical trials. Off label use puts increased numbers of Americans at
risk." On the other hand, the drug has its proponents, among them
physicians who believe that the adverse reaction rate is no higher than
a number of other highly useful drugs. What is needed, they say, is more
careful monitoring.

The most vociferous support comes from the patients who had lost
significant amounts of weight on the drug. One woman told a news
reporter, "I would half-kill to stay on it. When I was fat, I hated
myself, I knew my health was awful, I'm pretty sure it's why my husband
left me. But if something came along that would control my weight in the
same way, I\'d jump to it in a second because I don't want to risk liver
problems. But I also don't want to take any of those speed drugs either.
I got hooked on them, they made my heart race, and I ignored my kids
when I was on them. Then I lost fen-phen. So, as long as this new drug
is still available, I'm taking it."

1.  Current adverse drug reaction reporting is voluntary. Should more be
    done to report and monitor the off-label use of new drugs and report
    side effects?

2.  If the drug is recalled, whose responsibility should it be to
    address the complaints of patients (both diabetic and obese) who
    will be deprived of what they consider a vitally important drug?

[^1]: According to the Food and Drug Administration Modernization Act of
    1997 (FDAMA) section 401, drug manufactures can release qualified,
    objective, and balanced scientific information (mainly from
    unabridged peer reviewed journal articles) about off-label drug uses
    so long as manufacturers also provide data and/or conduct studies to
    support the submission of supplemental FDA applications to seek
    approval for the off-label uses. Exceptions include cases where it
    would be "economically prohibitive" to make the FDA submissions or
    when the off-label use is so well accepted that it would be
    unethical to conduct the studies and deprive the control subjects of
    an accepted therapy. The FDA has the authority to issue warning
    letters (but not fines), seek injunctions, or bring criminal charges
    against companies that violate the restrictions on off label
    promotion. In 1994, the FDAMA and regulatory restrictions on
    off-label promotion were challenged as an unconstitutional
    restriction on commercial free speech in *Washington Legal
    Foundation v. Jane Henney*. After years of appeals and rulings, the
    litigation was concluded without having settled a main question of
    whether FDA would violate the manufacturer's First Amendment rights
    with enforcement actions that prohibit or penalize certain off-label
    promotion.

[^2]: According to the FDA, 1-2% of new drugs are recalled from the
    market because of an unacceptable adverse reaction rate when used
    for an approved purpose. We know of no reliable data on adverse drug
    reaction rates for off-label uses.