Emergency contraception historical perspective

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Overview

Interest in synthetic hormones as postcoital contraceptives originated several decades ago, with the first published study on the subject appearing in 1967. A few different drugs were studied, with a focus on high-dose estrogens, and it was originally hoped that postcoital contraception would prove viable as an ongoing contraceptive method.

Historical Perspective

• The first widely used methods were five-day treatments with high-dose estrogens, using diethylstilbestrol (DES) in the US and ethinyl estradiol in the Netherlands.

• In the early 1970s, the Yuzpe regimen was developed by AA Yuzpe (1974); progestin-only postcoital contraception was investigated (1975); and the copper IUD was first studied for use as emergency contraception (1975). Danazol was tested in the early 1980s in the hopes that it would have fewer side effects than Yuzpe, but was found to be ineffective.
• The Yuzpe regimen became the standard course of treatment for postcoital contraception in many countries in the 1980s.
• The first prescription-only combined estrogen-progestin dedicated product, Schering PC4 (ethinylestradiol and norgestrel), was approved in the UK in January 1984 and first marketed in October 1984. Schering introduced a second prescription-only combined product, Tetragynon (ethinylestradiol and levonorgestrel) in Germany in 1985.[3] By 1997, Schering AG dedicated prescription-only combined products had been approved in only 9 countries: the UK (Schering PC4), New Zealand (Schering PC4), South Africa (E-Gen-C), Germany (Tetragynon), Switzerland (Tetragynon), Denmark (Tetragynon), Norway (Tetragynon), Sweden (Tetragynon) and Finland (Neoprimavlar); and had been withdrawn from marketing in New Zealand in 1997 to prevent it being sold over-the-counter.[4][5][6]
• Regular combined oral contraceptive pills (which were less expensive and more widely available) were more commonly used for the Yuzpe regimen even in countries where dedicated products were available. Certain combined oral contraceptives for use as postcoital emergency contraception.
• Over time, interest in progestin-only treatments increased. The Special Program on Human Reproduction (HRP), an international organization whose members include the World Bank and World Health Organization, "played a pioneering role in emergency contraception" by "confirming the effectiveness of levonorgestrel."
• After the WHO conducted a large trial comparing Yuzpe and levonorgestrel in 1998, combined estrogen-progestin products were gradually withdrawn from some markets (Preven in the United States discontinued May 2004, Schering PC4 in the UK discontinued October 2001, and Tetragynon in France) in favor of progestin-only EC, although prescription-only dedicated Yuzpe regimen products are still available in some countries.
• In 2002, China became the first country in which mifepristone was registered for use as EC.

United States

DES

• In 1971, a New England Journal of Medicine editorial calling attention to previously published studies on the use of DES as a postcoital contraceptive at Yale University, and a large study published in JAMA on the use of DES as a postcoital contraceptive at the University of Michigan, led to off-label use of DES as a postcoital contraceptive becoming prevalent at many university health services.
• In May 1973, in an attempt to restrict off-label use of DES as a postcoital contraceptive to emergency situations such as rape, a FDA Drug Bulletin was sent to all U.S. physicians and pharmacists that said the FDA had approved, under restricted conditions, postcoital contraceptive use of DES. (In February 1975, the FDA Commissioner testified that the only error in the May 1973 FDA Drug Bulletin was that the FDA had not approved postcoital contraceptive use of DES.)
• In September 1973, the FDA published a proposed rule specifying patient labeling and special packaging requirements for any manufacturer seeking FDA approval to market DES as a postcoital contraceptive, inviting manufacturers to submit abbreviated new drug applications (ANDAs) for that indication, and notifying manufacturers that the FDA intended to order the withdrawal of DES 25 mg tablets (which were being used off-label as postcoital contraceptives).
• In late 1973, Eli Lilly, the largest U.S. manufacturer of DES, discontinued its DES 25 mg tablets and in March 1974 sent a letter to all U.S. physicians and pharmacists telling them it did not recommend use of DES as a postcoital contraceptive.
• Only one pharmaceutical company, Tablicaps, Inc., a small manufacturer of generic drugs, ever submitted (in January 1974) an ANDA for use of DES as an emergency postcoital contraceptive, and the FDA never approved it.
• In February 1975, the FDA said it had not yet approved DES as a postcoital contraceptive, but would after March 8, 1975 permit marketing of DES for that indication in emergency situations such as rape or incest if a manufacturer obtained an approved ANDA that provided patient labeling and special packaging as set out in a FDA final rule published in February 1975. To discourage off-label use of DES as a postcoital contraceptive, in February 1975 the FDA ordered DES 25 mg (and higher) tablets removed from the market and ordered the labeling of lower doses (5 mg and lower) of DES still approved for other indications be changed to state: "THIS DRUG PRODUCT SHOULD NOT BE USED AS A POSTCOITAL CONTRACEPTIVE" in block capital letters on the first line of the physician prescribing information package insert and in a prominent and conspicuous location of the container and carton label.
• In March 1978, a FDA Drug Bulletin was sent to all U.S. physicians and pharmacists which said: "FDA has not yet given approval for any manufacturer to market DES as a postcoital contraceptive. The Agency, however, will approve this indication for emergency situations such as rape or incest if a manufacturer provides patient labeling and special packaging. To discourage 'morning after' use of DES without patient labeling, FDA has removed from the market the 25 mg tablets of DES, formerly used for this purpose."
• In the 1980s, off-label use of the Yuzpe regimen superseded off-label use of DES for postcoital contraception.
• DES is no longer commercially available in the U.S.; Eli Lilly, the last U.S. manufacturer, ceased production in spring 1997.

Yuzpe Regimen & Preven

• On February 25, 1997, the FDA posted a notice in the Federal Register saying it had concluded that the Yuzpe regimen was safe and effective for off-label use as postcoital EC, was prepared to accept NDAs for COCPs labeled as ECPs, and listed 6 then available COCPs (there are now 22) that could be used as ECPs.
• On September 1, 1998, the FDA approved the prescription Yuzpe regimen Preven Emergency Contraception Kit (which contained a urine pregnancy test and 4 COCPs). Preven was discontinued in May 2004.

Plan B

• On July 28, 1999, the FDA approved the prescription progestin-only Plan B (two 750 µg levonorgestrel pills) emergency contraceptive.
• On August 24, 2006, the FDA approved nonprescription behind-the-counter access to Plan B from pharmacies staffed by a licensed pharmacist for women 18 or older; a prescription-only form of Plan B will remain available for young women aged 17 and younger.
• On November 6, 2006, Barr Pharmaceuticals announced that its subsidiary, Duramed Pharaceutials, had initiated shipment of dual-label Plan B OTC/Rx and it would be available in pharmacies across the U.S. by mid-November 2006.

Legal and Ethical Controversies

• A great deal of controversy accompanied the FDA approval of over-the-counter (OTC) access to Plan B. Supporters of over-the-counter access believe that easier access will reduce unintended pregnancy and abortion rates; some pro-life opponents believe that EC itself is a form of abortion. The American Medical Association, the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, and other leading U.S. medical organizations all supported OTC access. An advisory committee to the FDA recommended that Plan B be made available over the counter in 2003. In 2004, the FDA refused the advisory board's recommendation and prohibited over-the-counter sale, citing insufficient evidence that ECPs could be used safely by adolescents without medical supervision. Reproductive rights supporters accused the FDA of basing the decision on political pressure from the pro-life lobby. The Center for Reproductive Rights filed a lawsuit regarding the approval process, which has not been resolved as of December 2006. In the legal proceedings, two senior FDA officials have alleged in depositions that the decision to reject the OTC application was made on political, rather than scientific, grounds to "appease the administration's constituents". Depositions taken from other FDA officials do not indicate White House involvement. In 2006, the FDA approved over-the-counter access to Plan B for women 18 years of age and older.

• A Massachusetts law that went into effect on 14 December, 2005, requires all hospitals in the state to provide emergency contraception to any "female rape victim of childbearing age" including Catholic Hospitals who oppose the provision of emergency contraception. In a letter criticizing the joint UN/WHO Inter-agency Field Manual on Reproductive Health in Refugee Situations, the Catholic Church explains its belief that emergency contraception, along with IUDs and hormonal contraception, cannot be considered "solely contraceptive because in the case of effective fertilization a chemical abortion would be carried out during the first days of pregnancy. The Catholic position on family planning is explained further in Ethical and Religious Directives for Catholic Health Care Services.

• In isolated instances across the United States, pharmacists have refused to dispense emergency contraception even when presented with a legal prescription. In addition, Wal-Mart, the nation's fifth-largest distributor of pharmaceuticals, refused to stock EC, beginning with Preven in 1999. However, Wal-Mart reversed this position when it was announced that stores would sell Plan B in March of 2006.

International Consortium for Emergency Contraception

In 1995, the Rockefeller Foundation convened a meeting to discuss emergency contraception. After the meeting, a group of seven international organizations formed The International Consortium for Emergency Contraception (ICEC) to promote EC as a part of mainstream reproductive health care worldwide. Dedicated products for EC were "virtually unknown" in 1995, there was little awareness of EC as an option, and EC was not used as public health measure.

The seven founding member organizations were the Concept Foundation, the International Planned Parenthood Federation (IPPF), the Pacific Institute for Women's Health, the World Health Organization (WHO), the Population Council, Population Services International, and the Program for Appropriate Technology in Health (PATH).

The Concept Foundation is the distribution arm of ICEC; its funding for the development of Postinor-2 came from the Rockefeller Foundation and the David and Lucile Packard Foundation, as well as the other ICEC organizations.

The Consortium helped promote the availability of EC by:

• Manufacturing an EC product. The ICEC worked with the Hungarian pharmaceutical firm Gedeon Richter to repackage its contraceptive Postinor as an emergency contraceptive, called Postinor-2. Distributing Postinor-2, principally in developing countries, was the primary work of the ICEC.
• Facilitating product registration in two ways. First, the ICEC encouraged interest in EC products through meetings with public-sector agencies and non-governmental organizations (NGOs) who they perceived would benefit from adding EC to the products they distribute. Second, by helping organizations applying for EC registration through the country-specific approval process, including lobbying of local leaders who may be influential in the registration decision.
• Negtiotiating a public-sector price. The ICEC's agreement with Gedeon Richter provided a discount price at which EC could be obtained by public-sector agencies in developing countries.
• Marketing and social marketing.

An ICEC member organization, the International Planned Parenthood Federation (IPPF), has launched its own dedicated levonorgestrel EC product, Optinor.