Off-Label Reprints Still A Hot Issue In FDA Reform

A Senate bill dealing with dissemination by drug firms of articles describing alternative uses of approved medications could be reintroduced soon. Sidebar: Off-Labels Reprints -- For Further Information CURRENT THINKING: "These are guidelines for companies to follow, says FDA’s Ilisa Bernstein. "It’s not a regulation." As the 105th Congress gets down to business this month, reform of the Food and Drug Administration (FDA) is expected to be a lively topic of debate, especially in

Jan 20, 1997
Karen Young Kreeger


A Senate bill dealing with dissemination by drug firms of articles describing alternative uses of approved medications could be reintroduced soon.

Sidebar: Off-Labels Reprints -- For Further Information


CURRENT THINKING: "These are guidelines for companies to follow, says FDA’s Ilisa Bernstein. "It’s not a regulation."
As the 105th Congress gets down to business this month, reform of the Food and Drug Administration (FDA) is expected to be a lively topic of debate, especially in the early days of a post-Kessler era. One of the most contentious issues, according to observers, deals with agency regulations governing information dissemination by drug companies.

FDA issued guidelines last fall on pharmaceutical industry-sponsored distribution of journal reprints and textbooks. The agency prohibits the dissemination of articles describing "off-label" use of approved drugs-that is, a clinical application of a drug for a use that has not yet been approved by the agency. Controversy is swirling around the dissemination of such articles to physicians.

A bill sponsored during last year's FDA-reform deliberations by Sens. Connie Mack (R-Fla.) and Bill Frist (R-Tenn.) proposed to allow firms to distribute journal articles explaining off-label uses of already approved drugs to physicians and others. The so-called Mack-Frist bill never left the Senate committee in 1996, but a different incarnation is expected to be introduced to Congress later this year.

Supporters of disseminating off-label articles say companies should be allowed to hand out peer-reviewed information that is already in the public domain. "If there is an article published in a peer-reviewed journal-an article that is publicly available to anyone-it seems overly restrictive for the FDA to not allow the sponsor to disseminate an otherwise public document," states Edward L. Zimney, the director of medical regulatory affairs at Immunex Corp., a biotech firm in Seattle.


WATCHDOG: Public Citizen's Sidney Wolfe recommends that physicians rely on information from independent sources.
But critics like Sidney Wolfe, the director of Public Citizen's Health Research Group, a health-care watchdog organization in Washington, D.C., are concerned that physicians will receive misleading information and that an increased ability to promote unapproved uses would remove incentives for companies to undertake trials on off-label uses. "It is and should be illegal," contends Wolfe, who believes that pharmaceutical advertising and promotion unduly influence the way physicians prescribe drugs.

With the ever-increasing growth of the Internet, the development of policies for information dissemination in cyberspace is becoming a concern for government agencies, industry representatives, patient groups, and many others.

The following resources are available online:

October 1996 guidelines on the distribution of journal reprints and medical texts by drug companies issued by the U.S. Food and Drug Administration (FDA): http://www.fda.gov/cder/guidance/fr8oct96.htm

Transcripts of an FDA-sponsored public meeting held last October on the promotion of FDA-regulated medical products on the Internet: http://www.fda.gov/opacom/morechoices/transcript1096/fdainet.html

Full text of the Coalition for Healthcare Communication letter to FDA: http://205.186.39.3/assnnews/cfhc/Comments.html

U.S. Pharmacopeial Convention Inc.: http://www.usp.org

Last October, after almost a year of digesting comments, FDA issued guidelines in the Federal Register (see list of resources below) on the distribution of certain journal reprints and medical texts by drug companies. "These are guidelines for companies to follow," says Ilisa Bernstein, a senior science policy adviser at FDA. "This is basically the agency's current thinking on the issue. It's not a regulation."

The guidelines say it's okay for companies to distribute peer-reviewed drug-related articles whose principal subject is an FDA-approved use. But sometimes, explains Bernstein, these articles contain additional information such as regimens that are different from the FDA-approved labeling. "When data from a drug's clinical trial is submitted to the agency, not all of those indications may be approved," she says. "When researchers publish the data, oftentimes they include everything that they investigated, even for indications that weren't approved."

With these new guidelines, FDA has given its blessing for a company to distribute an article containing the extra information. However, FDA suggests that a permanent sticker stating the difference between what's in the article and what's on the approved labeling be prominently affixed to the reprint. This policy, however, clearly does not include articles on off-label uses.

"We very much endorse and applaud FDA's taking some positive steps in this area," says Zimney of Immunex. "However, regarding the reprint guidelines, the new policy is designed to cover an extremely small number of reprints. The FDA is not allowing anything new to be disseminated that they haven't already seen in some way."

Although no studies have been done to track how many journal articles actually describe off-label uses, Bernstein speculates that the number of off-label articles would be high, "because one of the only ways to find out whether or not a product is useful for a particular indication is to do a study."

It is not illegal for physicians to prescribe drugs for off-label uses, and roughly 50 percent of all drugs are prescribed for off-label purposes. Sixty percent to 70 percent of cancer drugs and 90 percent of pediatric drugs fall into this category. Information on the on-label and off-label indications for drugs is published every year-as well as in monthly updates-in a text entitled U.S PDI (an acronym for Pharmacopoeia Drug Information), issued by U.S. Pharmacopoeial Convention Inc. in Rockville, Md.

Legally, a drug manufacturer can make claims in advertising and promotion only for a drug's FDA-approved use. Physicians, however-based on knowledge from their colleagues and the biomedical literature-frequently prescribe medicine for an unapproved use. For example, the much-publicized drug taxol has been approved for treating ovarian cancer for many years. At the same time, oncologists know from published reports that taxol is effective for certain breast cancers.

With regard to textbooks, FDA has always permitted the distribution of texts and medical compendia under limited conditions. The new guidelines remove those limitations, allowing circulation of such information as long as it is "written, published, and disseminated independent of the commercial interest of a sponsoring company" and contain a "balanced presentation of the subject matter," according to the published guidelines. But who will judge whether a textbook or compendium is balanced or not? Bernstein says the agency will "rely on the editorial process."

For the most part, observers who submitted comments on the draft guidelines do not have any quibbles with the textbook portion of FDA's directive. However, it remains to be seen how the agency's thinking on drug-company-sponsored symposium proceedings will be greeted by onlookers. FDA policymakers are still finalizing a draft guidance on this type of publication.

Predictably, industry representatives, as well as some patient groups and professional organizations, view the guidelines as inordinately constraining. The New York-based Coalition for Healthcare Communication-a group of nine organizations that represents health-care communications professionals-contends that the FDA stance violates freedom-of-speech rights. In a Jan. 18, 1996, letter, submitted on behalf of the coalition by executive director Jack E. Angel, the group stated that "the FDA's continuing interference with the dissemination of independently prepared scientific information undermines its mission to protect the public health and violates the First Amendment rights of both recipients and the disseminators."

The Bethesda, Md.-based Endocrine Society, a group representing about 8,000 scientists and physicians, holds that members of the biomedical community are capable of making their own assessment of the peer-reviewed literature, regardless of who distributes it. "Physicians are highly educated and sophisticated readers who review most information with a healthy dose of skepticism-especially if it is sent to them by a pharmaceutical or device company," wrote past president D. Lynn Loriaux, an endocrinologist at the Oregon Health Sciences University, in a letter submitted to FDA last January on behalf of the society.


READY ACCESS: The free flow of peer-reviewed information on cancer is essential for physicians, remarks Ellen Stovall of the National Coalition for Cancer Survivorship.
Ellen Stovall, the executive director of the National Coalition for Cancer Survivorship, located in Silver Spring, Md., says that for her group the bottom line is "the free flow of validated scientific information on cancer," to allow physicians and patients ready access to up-to-date information on anticancer products and therapies.

"There's already legislative language about this that's working beautifully," she maintains, referring to the 1992 Medicare Cancer Coverage Improvement Act. It provides for Medicare reimbursement of the costs associated with off-label uses for treating cancer. The act also lists journals and medical compendia that are considered the best sources of information on off-label uses of drugs for treating cancer.

Industry representatives contend that the present policy impedes the flow of information to physicians. "Doctors only have so much time," says Jeff Trewhitt, a spokesman for the Pharmaceutical Research and Manufacturers of America (PhRMA). "This is vitally important information for them." Trewhitt states that if off-label reprints are ever endorsed, PhRMA would advocate a stamp that clearly states that FDA hasn't yet certified the reported data.

"FDA's unwillingness to allow physicians to have essential medical information is deplorable," declares Henry Miller, senior research fellow at the Hoover Institution at Stanford University. Miller calls the current FDA regulations "socially regressive." In his just-published book, Policy Controversy in Biotechnology: An Insider's View (Austin, Texas, R.G. Landes Co., 1997), he argues that health professionals working at teaching hospitals are better able to keep up with the specialized medical literature than are their colleagues at non-teaching institutions. Health professionals at these latter institutions depend more on informal channels for their information. Barriers to the flow of information erected by FDA's censorship, he contends, create an unfair impact on non-teaching hospitals, which disproportionately serve people in poorer economic classes than do teaching hospitals.


REMOVING INCENTIVES: Allowing companies to distribute off-label reprints takes away the carrot for supplemental research, maintains NORD’s Michael Langan.
Some patient and watchdog groups, as well as academicians, maintain that FDA's current policy on off-label reprints should remain intact. "We tend to oppose any loosening of that restriction," says Michael Langan, director of public policy for the National Organization for Rare Disorders (NORD), headquartered in New Fairfield, Conn. "In doing so, you're taking away the incentive for [drug companies] to conduct supplemental research on off-label uses. Our most serious concern is that the clinical tests are not being conducted to validate the safety and effectiveness [of off-label uses]." NORD is a patient-advocacy group representing people with rare disorders, many of whose therapies rely on off-label treatments.

Wolfe worries about misleading or incomplete information dissemination by drug companies. "If there are five articles on something, and four show harm and one shows benefit, the company will obviously hand out the one that shows benefit," he contends. "This can be misleading and lead the doctor to prescribe something for a purpose for Wolfe and others recommend that physicians get their information from independent sources like medical journals, or newsletters such as the Medical Letter or Worst Pills Best Pills News, which was started by Public Citizen last year. "It's just a matter of whether the control of the dissemination is in the hands of the industry or not," states Wolfe.

Immunex "only disseminates reprints that are in compliance" with FDA's guidelines, according to Zimney. But under the current rules, he says, the company is allowed to send a reprint describing off-label uses in response to an unsolicited request by an individual. "We do this quite frequently because so much of the use of our products is in off-label areas. There are a lot of questions about those [types of] uses."


GRAY AREAS: Lisa Bero of UC-San Francisco is concerned about industry-sponsored promotional materials on the Internet that resemble consumer educational pamphlets.
Last year, Lisa A. Bero, an assistant professor in the Institute for Health Policy Studies at the University of California, San Francisco, and Daniel Stryer, a physician with the Indian Health Service's Kayenta Health Center in Kayenta, Ariz., analyzed printed materials distributed to physicians by pharmaceutical companies to determine whether they comply with FDA regulations (D. Stryer, L.A. Bero, Journal of General Internal Medicine, 11:575-83, 1996). Forty-two percent of the 486 items collected failed to comply with at least one of three regulations. Seventeen of the items discussed unapproved uses for drugs.

"Most of the material that we collected that talked about unapproved uses [consisted of] reprints," reports Bero. "To me, the bottom line is that this probably actually happens a lot more than the FDA is aware of because there really is no mechanism to track down these recommendations of unapproved uses."

Bero says that the reprint guidelines are more important than those for textbooks. Based on her study, "the reprint articles are potentially more influential with physicians. I think it's a lot easier to talk specifically about drugs in reprints than in texts."

In one of four editorials accompanying the Stryer and Bero study (S. Wolfe, J. Gen. Int. Med., 11:637-9, 1996), Wolfe cites a recent example of the dangers in promoting unapproved uses of drugs. He quotes an Aug. 1, 1996, letter from Minnie Baylor-Henry, director of FDA's division of drug marketing, advertising, and communication, to William Steere, the CEO of New York-based Pfizer Inc., regarding the company's distribution of a reprint describing the unapproved use of Zoloft, a Pfizer drug, to treat depression after myocardial infarctions. The letter said that Pfizer's promotion raised "significant safety concerns. . . . According to its approved product labeling, Zoloft has been associated with cardiovascular adverse reactions." Wolfe points out that the senior author of the paper works for Pfizer (R.M. Lane et al., British Journal of Clinical Practice, 48:256-62, 1995).

Last September, FDA solicited statements from the public regarding promotion of FDA-regulated medical products on the Internet. In response, it received comments detailing a broad range of concerns, says Bernstein. "For example, on the issue of Web site links, the views ranged from 'FDA shouldn't be interested at all in links because companies can't control the information on the linked page' to 'Companies have a responsibility to determine whether that link is appropriate,'" she says.

The Washington, D.C.-based Biotechnology Industry Organization (BIO) weighed in on the subject in written testimony submitted to the agency last month. "FDA cannot realistically expect to tether the changes in information technology heralded by the Internet," wrote BIO president Carl Feldbaum. "FDA should recognize that most scientific and medical information disseminated to physicians and other medical professionals on the Internet is not promotional in nature."

Bero has growing concerns about data dissemination over the Internet and what policies FDA will develop. "This is an extremely hot issue," she says. "Many patient groups are starting to link to various sources in the Internet, without giving them any sort of quality rating. I could easily see a lot of industry-sponsored items on the Internet with a promotional spin that appear to look like an educational pamphlet for consumers. No one's really opposed to drug company advertising. It's the gray areas that bother me."