OB-GYN-L Messages for June, 2005: The Case of Plan B (Long)

The Case of Plan B (Long)

From:

rmodugno@aol.com

Mon Jun 13 10:33:18 2005

Matthew Anderson, MD, MSc

My beeper goes off in the middle of a busy clinic session. The voice at the other end is that of a 16-year-old girl from my practice. She's calling from her high school. She doesn't stop to give me her name but immediately asks if I can call in a prescription for "those pills" to the pharmacy. I ask her when she had the accident ("last night"), whether she is taking any other medicines ("no"), and what the number of the pharmacy is. I ask her if I should also call in a prescription for oral contraceptives. She demurs and we agree she will come in to see me next week for these (she does). It is, of course, a bit inconvenient to manage such matters urgently when the waiting room is full, but I know time is of the essence. I get the prescription faxed off within the hour. When the session ends, I again wonder whether or not Plan B should be available without a prescription. The medical community has been pretty unanimous in arguing that Plan B should be made available over the counter (OTC). The American College of Obstetricians and Gynecologists (ACOG) called the United States Food and Drug Administration's (FDA's) decision not to approve OTC for Plan B "morally repugnant."[1] Yet, being a skeptical type, I was interested in reviewing the evidence myself. I was particularly curious because I had little idea about how and why drugs were classified as either prescription or OTC. The answer to this question begins with a little history. Our current regulation of drugs was established in 3 major pieces of legislation.[2,3] The Food, Drug & Cosmetic Act of 1938 required that the Food and Drug Administration approve all drugs used on humans. The legislation was concerned principally with making sure that drugs were safe and were accurately labeled. At the time, the distinction between OTC and prescription drugs was largely in the hands of the states. This changed in 1951 when the Durham-Humphrey amendments created federal criteria to distinguish OTC and prescription drugs. Prescription drugs were limited to those that were habit-forming and to those whose use required supervision by a licensed health practitioner. In 1962, the Kefauver-Harris amendments required that all drugs be not only safe, but also effective. Thus, an OTC drug must satisfy 3 criteria: (1) it must be safe, (2) it must be effective, and (3) it must be for a condition that the patient can manage without supervision by a licensed health professional. Although the federal law recognizes only 2 categories -- OTC and prescription -- there are other options for dispensing drugs. Many countries have "behind the counter" drugs that are available without a prescription but only after consultation with a pharmacist. In fact, 6 US states (Alaska, California, Hawaii, Maine, New Mexico, and Washington) allow for dispensing of Plan B [4] by certain pharmacists, sometimes acting under collaborative agreements with physicians. Plan B is the second, and the superior of 2 drug regimens approved by the FDA for emergency contraception (EC).[5,6] It consists of two 0.75-mg pills of the synthetic progestin levonorgestrol, which are taken 12 hours apart. It is clearly an effective drug in preventing pregnancy. If taken within 72 hours it is about 85% effective in preventing pregnancies, and there is some evidence that it may work up to 5 days after coitus. Yet time is of the essence. If taken within 12 hours of coitus, the pregnancy rate is 0.4%; at 60-plus hours the pregnancy rate rises to 4%. [ Preven , the other approved regimen, was purchased by Plan B 's manufacturer, Barr Pharmaceuticals, which wisely discontinued its production.[7]] By conventional criteria, Plan B is a very safe drug. It can cause nausea and vomiting, but these symptoms occur less commonly with Plan B than with postcoital regimens containing estrogens. It is not thought to be teratogenic. What about self-management? It would seem likely that women could self-diagnose unprotected intercourse and could "self manage" the taking of 2 pills. Indeed, with the clock ticking, women might be in a better position to self-manage than to do so under the direction of a physician. On the face of it, Plan B would seem an appropriate OTC drug. What then happened at the FDA? The regulations that govern making drugs OTC are rather complex and held some surprises for me. The first was that anyone can petition the FDA to make a drug OTC. In the case of nonsedating antihistamines, for instance, the FDA was petitioned by a health insurance company, WellPoint Health Networks of California, which wanted to see Allegra (fexofenadine), Zyrtec (cetirizine), and Claritin (loratidine) OTC. The insurance company, which does not pay for OTC drugs, was hopeful it could save money. The manufacturers were against the switch.[8] Something similar happened with EC. As early as 2001, 70 organizations, representing a broad spectrum of the health community (including the American Medical Association, ACOG, and the American Public Health Association), had petitioned the FDA to make EC available OTC.[9] Yet, it was not until 2003 when the manufacturer petitioned that FDA held hearings on the issue. Two FDA committees are charged with making a recommendation on OTC status for a drug. One committee is the Nonprescription Drugs Advisory Committee; the other is a committee with expertise in the particular field in which the drug is active. For Plan B this was the FDA's Reproductive Health Advisory Committee. We are fortunate in that the joint hearings of these committees on December 16, 2003 are available on the Web, along with all the supplemental materials presented to the committees.[10] The evidence is there for us skeptics. The FDA's Deputy Director of OTC Drug Products, Dr. Curtis Rosebraugh, outlined the criteria for OTC status: "When approaching a possible prescription to nonprescription switch candidate, there are several questions that the agency takes into consideration to assess whether the product is, indeed, a suitable switch candidate. Regarding the questions that we take into consideration, we wonder if the product has an acceptable safety margin, as demonstrated from prior prescription marketing experience; whether it has low misuse and abuse potential, a reasonable therapeutic index of safety; whether the condition that it is being used for can be adequately self-recognized and self-treated with minimal health care provider intervention; whether the benefits outweigh the risks; and when the product is used under nonprescription conditions, is it safe and effective? In favor of OTC were the facts that Plan B appeared safe. It needed to be used within 72 hours, and getting a prescription was clearly a barrier. It did not appear to substitute for traditional forms of contraception. It met a compelling health need. There are approximately 3 million unintended pregnancies in the United States annually. Half of these end in abortion. It is estimated that Plan B could cut the number of abortions in half. Dr. Carole Ben Maimon of Barr Pharmaceuticals summarized the specific argument for OTC status: Plan B clearly meets the requirements for OTC use. The post marketing and clinical safety trial data demonstrate an acceptable safety profile in a large number of women who have been exposed to the product. There is a low potential for abuse or misuse. There is no question that the benefits of over-the-counter availability strongly outweigh the risks, and finally, based on the label comprehension studies and the actual use studies, the product has been demonstrated to be or women have demonstrated that they can properly self-select, determine when they need it, how to use it, and they can use it correctly. There is really no medical reason why Plan B should not be sold over the counter. Against OTC status for Plan B were arguments that it would encourage sexual behavior (particularly among adolescents) leading to more sexually transmitted diseases and that it would substitute for other forms of contraception. Opponents saw it as an abortion pill. This position was most clearly enunciated during the public comment period by Dr. Hanna Klaus, an obstetrician-gynecologist who has done much to promote natural family planning.[11] The Chlamydia and gonorrhea rates have risen nearly 20 percent in this country in the last four years, concomitant to the high profile advertising of the morning after pill which, intended or not, promote the notion that taking Plan B will make up for the lack of sexual responsibility. Women also have a right to know that Plan B, if taken after conception, prevents implantation. If they have ethical objection to aborting an embryo at any stage, they have a right to the right information. The objections raised by Plan B 's opponents seemed to have more to do with the drug itself than with specific issues related to OTC availability. Evidence had been presented in the hearing that Plan B did not reduce rates of use of more traditional contraceptives. The FDA's own experts seemed to confirm that Plan B met the criteria for OTC status, and it is not surprising that the committee voted 23 to 4 in favor of Barr's request. Typically, the FDA commissioners accept the recommendations of the committees, but Plan B is not a typical drug. Five months after the hearings, on May 6, 2004, Steven Galson, the Acting Director of the Center for Drug Evaluation and Research, issued a "Not approvable letter" to Barr Pharmaceuticals. In his letter he cited concerns about adolescent women: "You propose OTC status for Plan B for both adults and children based primarily on an actual use study in 585 subjects. Only 29 of the 585 subjects enrolled in the study were 14-16 years of age, and none was under 14 years of age." Director Galson suggested that Barr Pharmaceutical conduct additional studies in adolescent women.[12] The unusual rejection of the committees' decision had dramatic consequences. In addition to ACOG's characterization of it as "morally repugnant," New York State Senator Hillary Clinton asked for an investigation by General Accounting Office as well as Senate Hearings.[13] The Washington Post leaked internal FDA documents showing that scientific reviewers within the FDA disagreed with Galston's decision.[14] John Jenkins, the Director of the FDA's Office of New Drugs wrote about Galston's reasoning: "The agency has not [previously] distinguished the safety and efficacy of Plan B and other forms of hormonal contraception among different ages of women of childbearing potential, and I am not aware of any compelling scientific reason for such a distinction in this case." It seemed to many that the FDA was bowing to pressure to postpone approval until after the election. Barr Pharmaceuticals responded to the Non-approvable letter on July 22, 2004. Rather than undertaking new studies, Barr suggested a dual approach for Plan B . It would be available OTC to women 16 and older and as a prescription for women under age 16.[15] As I prepared these Field Notes (May 2005), a Barr representative informed me that they were awaiting a response from the FDA. I always feel a keen sense of failure when one of my patients comes in with an undesired pregnancy. So while the FDA is deciding to decide, I will continue to give Plan B prescriptions to my patients. We are fortunate in the Bronx that Plan B is widely available in pharmacies, but I still tell my patients to get their prescriptions filled immediately so that they have the medicine "just in case." The time of the accident is not the time to be getting a new prescription and trying to find a pharmacy. I also tell them that an expired medication is better than none at all.[16] And I hope that one day the FDA will consider women responsible enough to take care of a situation calling for EC themselves. References Dickerson VM. Statement of The American College of Obstetricians and Gynecologists On the Failure of the FDA To Approve OTC Status for Plan B®. American College of Obstetricians and Gynecologists May 7, 2004. Available at http://http://www.acog.org/from_home/publications/press_releases/nr05-07-04.cfm Accessed May 11, 2005. Brass EP. Changing the status of drugs from prescription to over-the-counter availability. N Engl J Med. 2001;345:810-816. Jacobs LR. Prescription to over-the-counter drug reclassification. Am Fam Physician. 1998;57:2209-2214. Barr Pharmaceuticals. Barr's Proprietary Pharmaceutical Business. Barr Pharmaceuticals http://www.barrlabs.com/pages/corpprop.html . Accessed May 11, 2005. Emergency contraception OTC. Med Lett Drugs Ther. 2004;46:10-11. Westhoff C. Clinical practice. Emergency contraception. N Engl J Med. 2003;349:1830-1835. Barr Laboratories I. Preven Online Care Center. Barr Laboratories, Inc. Available at: http://www.preeven.com. Accessed May 11, 2005. 8. Reynolds T. Switching from prescription to over the counter. Ann Intern Med. 2002;136:177-180. Grimes DA. Emergency contraception: politics trumps science at the U.S. Food and Drug Administration. Obstet Gynecol. 2004;104:220-221. Nonprescription Drugs Advisory Committee. December 16, 2003. Joint meeting with Advisory Committee for Reproductive Health Drugs. United States Food and Drug Administration. Available at: http://www.fda.gov/ohrms/dockets/ac/cder03.html#NonprescriptionDrugs . Accessed May 11, 2005. Klaus H. Natural family planning: a review. Obstet Gynecol Surv. 1982;37:128-150. Galson S. Not approvable Letter. United States Food and Drug Administration. May 6, 2004. Available at: http://www.fda.gov/cder/drug/infopage/planB/planB_NALetter.pdf Accessed May 11, 2005. Clinton HR. Senator Clinton, Colleagues Call for "Plan B" Probe. Clinton, Hilary Rodman. June 16, 2004. Available at: http://clinton.senate.gov/~clinton/news/2004/2004618858.html . Accessed May 11, 2005. Kaufman M. FDA: Plan B sales rejected against advice; official denies that politics blocked contraceptive's over-the-counter status. Washington Post. 2004 May 8; A02. Barr submits response to FDA in support of over-the-counter status for plan B(R) emergency contraceptive company proposes dual marketing status. PR Newswire (US). 7-22-2004. Drugs past their expiration date. Med Lett Drugs Ther. 2002;44:93-94.

Matthew Anderson, MD, MSc , Assistant Professor, Albert Einstein College of Medicine, Bronx, New York; Staff Physician, Montefiore Medical Center, Bronx, New York. ************************************************* Robert Modugno MD MBA FACOG Marietta, GA

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