Off-label (unlabeled) Use of Drugs

ABSTRACT

Off-label use of drugs is widespread and unavoidable, especially when treating the young, the pregnant, the old and those with cancer. Some of the most striking advances in dermatology have followed the off-label use of drugs. This review examines some of the issues surrounding off-label use of drugs by dermatologists, illustrates the need for such use and looks at possible changes in the regulatory system.

Key Words:
minoxidil, methotrexate

Off-label use of drugs is widespread

Under the Federal Food, Drug, and Cosmetic (FD&C) Act, the labeling approved by FDA for a drug is limited to those uses for which the sponsor has submitted information regarding the safety and efficacy of that product and which information has been reviewed by the FDA; other uses for which the sponsor has chosen not to submit data to the FDA may be demonstrated in the clinical literature before and after the product is approved by the FDA. The FD&C Act does not, however, limit the manner in which a clinician may use an approved drug.¹

Dermatologists, like other physicians, face a dilemma when attempting to use only drugs with regulatory body approved indications. Neither industry or regulators want to be accused of experimenting on children, pregnant females or old people! In pediatrics, only about 20% of all drugs marketed in the US have been labeled for use by infants and children², such an exclusion results in widespread off-label use.^3,4 One study found that in 36% of 707 admissions, children received one or more courses of an unlicensed or off-label treatment.³ In 731 pregnant patients, 23% took more than one drug for off-label indications.⁵ Many drugs used in oncology⁶ and drugs prescribed for pain relief⁷ also have off-label uses.

Delays in obtaining supplementary indications cause problems

Delay, hesitancy or indecision by regulatory bodies in granting a drug supplementary approval, after it has been peer-reviewed and proven to be clinically effective and safe, results in widespread off-label prescribing and a very frustrated profession. Some examples illustrate this point:

• Several years delay in granting minoxidil approval for treating male-pattern baldness resulted in illicit importing, off-label prescribing and instances of faulty extemporaneous compounding.
• Methotrexate was found to be of benefit in the treatment of psoriasis, but approval was delayed and it was prescribed off-label for several years.

During the period that a new drug is passing through the bureaucratic maze, opinion provided by recognized authorities, and/or treatment protocols generated by expert panels, sometimes recommend the use of the drug for a new indication. Such direction provides support to the dermatologist or physician prescribing the drug for this new indication.

It is worthwhile understanding what happens next. This new, unapproved use, after discussion at clinical meetings, publication in journals and acceptance by a cross-section of authorities with a special interest in the field, is found to be of great benefit to patients, leading to widespread acceptance by the profession and listing in peer-reviewed publications such as the USPDI⁸ and the AHFS.¹

Practical implications

FDA approved drugs for off-label indications, and unlabeled drug uses, have played a significant role in the way in which we treat skin disease. A good example is the use of thalidomide to treat the cutaneous manifestations of erythema nodosum leprosum, first reported in 1965, recommended by the WHO in 1988 and finally approved by the FDA in September 1997.⁹

If the unlabelled use of a drug is for treatment rather than research, this constitutes innovative therapy and appears to be within the physician’s ethical and legal prerogative supported by FDA regulations, common law, and ethical cannons.¹⁰ Although the off-label use of a drug is not necessarily an improper use of the drug, there is no regulatory body approved information on risk/benefit available. In this situation, the prescriber has to utilize consultation with colleagues, plus information gained from the package insert and a review of the medical literature.¹¹ The ethical and legal implications of this situation are not always clear. Although no specific informed consent appears to be required, unlabelled drug use best serves the patient and protects the physician from liability when it is accompanied by informed consent that adequately informs the patient of the innovative nature of the therapy together with the greater uncertainty of risk.¹⁰ As recent well-known cases have shown, extra care must be taken to ensure that the physician and the patient are both well-informed of the risks and benefits, so their collaboration can result in the best possible clinical outcome.¹²

Ultimately, regardless of the legality of unlabelled drug use, if an approved drug is used for unlabeled purposes, a physician should carefully weigh the risk/benefit of the use of the drug before, during and after treatment.¹⁰

The position of the FDA is challenged

The FDA’s long-standing policy prohibiting drug companies from distributing information to physicians about off-label use of drugs or devices, or those applications outside the use specifically approved by the FDA, was recently overturned by a federal judge (July 30, 1998).^12,13 In the judges opinion, the FDA cannot prevent manufacturers from distributing articles or portions of studies on unapproved uses published in a bona fide, peer-reviewed professional journal; cannot block drug or device makers from distributing textbooks from independent publishers, and cannot prevent industry from suggesting content or speakers to independent program providers putting on continuing medical education symposiums.^13,14

The court rejected the idea that the FDA is the font of all medical knowledge in this country.
Richard Samp, Washington Legal Federation.¹⁴

Reasons for FDA policies on off-label use⁶

The current situation permits a company to promote the labeled use of a new drug. Permitting sponsors to promote off-label uses would diminish or eliminate the company’s incentive to carry out clinical trials and obtain definitive data. Such activity could result in harm to the patient, or fail to show that the drug is effective. If there is a deliberate attempt to diminish the use of evidence-based medicine in arriving at safety and efficacy decisions concerning a drug, the regulatory process will be eroded.⁶ Drug companies could get approval for a drug for some narrow use and then heavily promote it for much broader uses that had not been adequately tested.¹⁵ What if preliminary findings are not subsequently borne out by further study, or are refuted by other studies?

Decisions on efficacy should be based on significant results, obtained from well designed and administered clinical trials, published in peer-reviewed journals. Peer judgment and review is essential for balanced results.

The drug company position

There is an inherent conflict of interest because most studies involving drug safety and efficacy are funded by the manufacturers.⁶

However, in the real world who is going to carry the costs involved in bringing drugs to market if drug companies won’t! There are costs of millions of dollars involved in obtaining drug approval, and cost considerations influence the number of indications established, the number of indications applied for, and the priority given to each of these applications. The number of patients needed for trials and the time required to complete the trials both increase if indications are broadened. Furthermore, during the regulatory review the ‘patent time clock’ is ticking down.

A listing of some drugs and their unlabelled indications

These listings were compiled from the USPDI⁸, AHFS¹ Drug Information as well as suggestions from editorial advisors, other world experts and our peers.

Actions the FDA has taken

Many new treatment indications are granted each year—the FDA Center for Drug Evaluation and Research (CDER) approved 118 supplemental indications in the fiscal year 1996. In the future, when appropriate, clinical trials will enroll pediatric, female and geriatric patients. Other practical initiatives being discussed will affect the dissemination of information on off-label uses for approved drugs, as well as the information provided on labels and the granting of patent extensions. Future cooperation between the profession, government, industry and special interest groups will eventually help to remove some of the obstacles presently limiting our ability to prescribe drugs outside their approved indications.

Summary

Unlabelled drug use provides a realistic therapeutic option; patients demand the best and safest treatment and oftentimes there is no other treatment option available. With off-label uses, industry asks why they should be asked for more money, the regulators say that they weren’t asked for an additional indication, and the Doctor is left holding the bag!

What makes it so difficult to find a practical process to screen new uses of drugs?

• The FDA’s present mandate does not allow it to easily and quickly grant clearance for indications not backed by rigorous clinical studies.
• The pharmaceutical industry, already laboring under huge development costs (300–400 million dollars US over 10 years per drug) and erosion of their patent time, is reluctant to include extra indications that might further complicate their new drug submissions.
• In the past there was little incentive to encourage industry to apply for extra drug usage indications, either for new drugs under development, or for drugs already on the market. It has been suggested that if industry were granted extensions on their patent time, they might be more inclined to make such applications. A change in the law has recently been proposed which would extend the patent of a drug by six months if companies conduct pediatric studies.¹⁶

“Regulatory boards should acknowledge that many drugs work for unapproved uses. The unapproved use only means that it is too costly to get formal data for every last disease that a drug might work for.”

John Voorhees, University of Michigan, Medical School

Valid new uses for drugs are often first discovered via serendipitous observations and therapeutic innovations, and then subsequently may be confirmed by well-designed and controlled studies. Inclusion of such new uses in the FDAapproved labeling for a drug may take considerable time and, without the initiative of the manufacturer whose product is involved, may never occur. Therefore, accepted medical practice (state-of-the-art) often includes drug use that is not included in FDA-approved labeling.¹

References

1. AHFS 98 Drug Information: American Hospital Formulary Service. Bethseda, Md: American Society of Health-System Pharmacists; 1998.
2. Jaffe SY. Statement before the Subcommittee on Health and the Environment, House Committee on Energy and Commerce. February 8, 1994
3. Turner S, Longworth A, Nunn AJ et al. Unlicensed and off label drug use in paediatric wards: Prospective study. Brit Med J 1998; 316: 343–345.
4. Committee on Drugs. Unapproved uses of approved drugs: The physician, the package insert, and the Food and Drug Administration: Subject review. Pediatrics 1996; 98: 143–145.
5. Rayburn WF, Turnbull GL. Off-label prescribing on a State University Obstetric Service. J Reprod Med 1995; 40: 186–188.
6. Woodcock J. A shift in regulatory approach. Powerpoint presentation June 23, 1997.
7. Angarola RT, Joranson DE. Off-label uses of prescription drugs in pain management. APS Bulletin 1995; 5: 14–15.
8. Drug Information for the Health Care Professional. 18th ed. Rockville, Md: US Pharmacopeial Convention Inc; 1998.
9. Thalidomide. Skin Therapy Letter 1997; 3 Number 3: 1,2,5.
10. Torres A. The use of Food and Drug Administration approved medications for unlabelled (off-label) uses. The legal and ethical implications. Arch Dermatol 1994; 130: 32–36.
11. Shapiro SA. Limiting physician freedom to prescribe a drug for any purpose. Northwestern Law REV 1979; 83: 801–872.
12. Reardon F. Legal report: Off-label prescribing. Adapted from Harvard Risk Management Foundations Resource audiotape, November, 1997.
13. FDA off-label promotion rules overturned. Summary judgment July 30th, 1998, Judge Royce Lambert, US District Court for the District of Columbia. Scrip 2358, August 5, 1998.
14. FDA Off-label rules overturned. Reuters, August 6, 1998.
15. The dangers of off-label drug promotion. Public Citizen Internet URL http://www.citizen.org/congress/fda/S.%20830—FDA/offlabel.html.
16. Weschler J. Promoting pediatric and other new uses. Applied Clinical Trials 1998; 7:18–22.