FDA decision on Mifrepristone may bring back birth control pet food––but definitely not Alex Pacheco’s “Spay and neuter cookies”
WASHINGTON D.C.––The pharmacological race to be first to market a safe, affordable, easily administered contraceptive drug for dogs, cats, and nuisance wildlife, somewhat quiet of late, may soon heat up with December 16, 2021 U.S. Food & Drug Association (FDA) announcement that the progesterone-blocking chemical RU-486, marketed as Mifrepristone, is now permanently cleared for distribution by mail.
Summarized Associated Press health writer Matthew Perrone, without mentioning the implications for animal contraception, “Officials said a scientific review supported broadening access and allowing more pharmacies — including mail-order services — to distribute the medication.
“But prescribing will still be limited to doctors who complete special certification,” and are registered with the FDA,” Perrone said.
AMA & ACLU applied pressure
Responding to social distancing recommendations issued to fight the spread of the COVID-19 coronavirus, the Food & Drug Administration earlier in 2021 quit enforcing a requirement in effect since 2000 that Mifrepristone users had to pick the drug up in person.
That rule, Perrone wrote, “has long been opposed by medical societies, including the American Medical Association, who say the restrictions offer no clear benefit to patients.
“The FDA’s latest scientific review,” Perrone continued, “stems from a 2017 lawsuit by the American Civil Liberties Union, which argued that the agency’s restrictions block or delay medical care, especially for people in low-income and rural communities.”
No animal advocacy organization is known to have argued for easier access to drugs based on RU-486 in about 35 years. From 1975 to 1985, however, before the arrival of relatively easy access to high-low-cost spay/neuter surgery, the introduction of contraceptive pet foods containing an RU-486 version called Mibolerone was widely anticipated as the beginning of the end of dog and cat overpopulation.
Dog & cat contraception research turned away
The September 28, 2000 decision of the U.S. Food and Drug Administration to allow Danco Laboratories, of New York City, to market an RU-486 abortion pill called Mifeprex might have revived interest in Mibolerone use for animal birth control, but did not, possibly because dog and cat contraception research had by then turned mostly toward developing immunocontreptives and chemosterilants.
Immunocontraceptives, such as porcine zona pellucida and Gonacon, work by causing a female animal’s body to attack sperm as if it is an infectious agent.
Chemosterilants, such as Neutersol, Esterisol, Infertile, and calcium chloride, work by preventing the release of sperm from the testicles of a male animal.
Immunocontraceptives are now widely used in hoofed animals, but developing formulations suitable for use in dogs and cats has proved an elusive goal.
Many chemosterilants have appeared to be promising in preliminary trials, beginning with Talsur, developed by the Blue Cross of India in 1990, but all so far have produced severe testicular swelling as an unacceptably frequent side effect, causing the few products that have been introduced commercially to be taken off the market.
How RU-486 works in humans
The Danco formulation for “morning after” use, Mifeprex, requires ingestion of five separate tablets, to be taken in a two-step sequence.
The first three tablets, taken at once, contain Mifepristone.
Also known by the chemical index number RU-486, Mifepristone is an androgen steroid which blocks the production of progesterone, a hormone required to sustain pregnancy.
Two days after taking the mifepristone tablets, the user takes two more tablets containing misoprostol, another hormonal drug which causes her body to expell the aborted fetal tissue.
Mifepristone is a close chemical relative of Mibolerone, an androgen steroid developed and manufactured by the Upjohn Company.
Theory & practice
Mibolerone has been used by prescription for more than 40 years to suppress estrus in racing greyhounds, sled dogs, some show dogs, and many species of animals kept in zoos, but has not been marketed to the general public.
Mibolerone has never been available for use in controlling populations of street dogs, partly because of the difficulty involved in providing the necessary regular doses, but mostly because of political opposition.
In theory, Mibolerone could be mixed with food and fed as necessary to street dogs recognized by a neighborhood caretaker. Proper precautions, such as feeding only one dog at a time, could minimize the risk of overdose or underdose.
In present formulations, Mibolerone is not cost-competitive with surgical spaying. It also does not offer the advantages of surgical spaying in modifying animal behavior to increase compatibility in human households.
Mibolerone is not a sterilant
In addition, Mibolerone cannot be given in stronger dosage to induce permanent sterility.
Indeed, one advantage of Mibolerone for temporary use by zookeepers and owners of racing dog or show dog kennels is that the animals can readily breed if regular doses are discontinued.
If manufactured in sufficient volume and in appropriate formulations, however, Mlbolerone could become much less expensive, and could become an efficient humane means of controlling street dog or feral cat reproduction temporarily while rescuers catch female animals for conventional spay surgery.
The 70% solution
Stabilizing numbers of street dogs or cats, and beginning to achieve a population reduction, typically requires sterilizing approximately 70%.
Getting to 70% by catch-and-spay often seems painfully slow to communities eager to rid themselves of animals perceived as public health threats, even when the dogs or cats are also part of those communities’ first line of defense against vermin.
Meanwhile, until the rescuers reach 70%, sterilizing part of the population can actually increase the numbers of dogs or cats, because there is less competition for food among pregnant females, who then bear more live young, and nurse longer, and because more puppies or kittens from each litter survive.
The use of Mibolerone could accordingly save millions of animals per year from being poisoned, shot, drowned, electrocuted, or gassed with car exhaust, which are still frequent fates of street dogs, especially, and sometimes feral cats too, in parts of Asia, Africa, and Latin America.
In those places, rabies remains widely feared, with the majority of the victims young children who play with street dogs, while the barbiturates used to dispatch animals by needle in the developed world are either not affordable, not legally sold, or are simply not available.
Anti-rabies inoculation and surgical neutering have been introduced throughout the world in recent decades, but have just begun to become accessible in many underdeveloped nations, where the amount of sterilization surgery needed to reduce the numbers of street animals continues to far exceed the amount that veterinarians can quickly accomplish.
Mibolerone could slow breeding ahead of surgery
By preventing births in advance of surgery, Mibolerone could markedly reduce the numbers of dogs to be vaccinated and sterilized when possible. Seventy percent of the females could be taken out of the breeding population almost overnight, pending sterilization surgery.
A similar product for cats could prevent the growth of an immense feral cat population to take over the food sources and shelter vacated by falling numbers of dogs––a phenomenon retrospectively evident but not recognized in U.S. animal control pickup data from the 1970s and 1980s, before the advent of neuter/return in the early 1990s cut the U.S. free-roaming cat population by about 70%.
Despite the potential benefits to be had from introducing Mibolerone into the animal care-and-control chemical arsenal, the cultural obstacles to making it more widely available have proved immense.
Upjohn and the Carnation Company began developing a contraceptive dog food with Mibolerone as the active ingredient in 1975.
In August 1980, the same year that RU-486 was first synthesized by French chemical researcher Emile Baulieu, Carnation pet food division director L.G. Miller, Ph.D., wrote to Long Island animal rescuer Severa Aguero that the contraceptive dog food was almost ready to sell.
“We are currently involved with the FDA to get clearance on our birth control dog food,” Miller confirmed. “We may receive a marketing permit on our product this year,” Miller continued. “We would then be able to market the product through veterinarians. Hopefully in a couple of years we could market the product through retail stores.”
Approval for distribution of Mibolerone as an Upjohn product called Cheque Drops was obtained, after testing at racing greyhound kennels. Cheque Drops caught on with greyhound racers, and use soon spread to sled dogs. The Iditarod and other major dog sled races prohibit giving the dogs steroids or other drugs with similar effects, but Mibolerone is exempted.
But all did not go well for Carnation––not because of any problems associated with giving Mibolerone to dogs, but because of fallout from Mifepristone testing in France by the original manufacturer, Rousel Ucalf, a subsidiary of the German firm Hoescht A.G.
As well as having contraceptive properties, Mifepristone was in 1982 discovered to be an abortifacient. That projected the entire RU-486 chemical family into the middle of the ongoing international controversy over human abortion.
Reagan & Khomeini
Opposition to human abortion was just reaching peak momentum, worldwide. Then-U.S. President Ronald Reagan had been swept into office in 1980 partly for his opposition to the 1973 Roe-vs.-Wade U.S. Supreme Court decision legalizing abortion. Reagan received his strongest voting support from anti-abortion religious Catholics and Christian fundamentalists.
Also in 1980, Islamic fundamentalists overthrew the Shah of Iran, bringing the late Ayahtolah Khomeini to power. Khomeini’s anti-abortion views reinforced the position of most of Islam––although most branches of Islam do accept spay/neuter surgery.
In India, Hindu nationalism rose with opposition to abortion-as-birth-control promoted by then-prime minister Indira Gandhi as a rallying focus. Ironically, the Blue Cross of India and Beauty Without Cruelty-India were actively investigating chemosterilants for street dogs, leading toward the Talsur failure, and might have eagerly promoted Mibolerone had it become available to them.
Great Danes, the homeless, seniors, & low income families
Politically, it was a bad time to try to market anything with potential for causing human abortion even if a pregnant woman would have to eat enough hard-to-stomach dog food in one meal to feed a Great Dane for a week in order to achieve abortion.
Coincidentally, advocates for the poor were just then opposing federal budget cuts proposed by the Reagan administration by amplifying stories of homeless people, senior citizens, and large low-income families who were purportedly forced to eat dog food to make ends meet.
The RU-486 issue heated up in 1983, with fallout for Mibolerone, when the FDA authorized a nonprofit organization called the Population Council to begin sponsoring clinical trials of mifepristone on human volunteers at the University of Southern California.
Abortion opponents swiftly linked RU-486 and Mibolerone, using the images of humans eating dog food to squelch the Upjohn/Carnation contraceptive product.
China helped to make RU-486 a political target
Upjohn and Carnation did not give up easily. In early February 1985, Carnation pet food division new products manager Hugh Chamberlin released to media the then-current national animal shelter killing statistics and announced that Carnation would soon seek FDA approval to sell a contraceptive dog food called Extra Care in grocery stores.
“We have requested FDA clearance for over-the-counter sales of this birth control dog food. If we obtain this clearance, the product would be available in late 1985,” L.G. Miller confirmed to Severa Aguero on February 25, 1985.
By 1988, RU-486 was already in general use in France and China. China, in fact, reportedly made compulsory abortion by means of forced ingestion of RU-486 a central part of a one-child-per-family policy. The violations of human rights inherent in the policy––and that it was advanced by a Communist nation which was actively repressing religion, especially evangelical Christianity––made RU-486 an even larger target for the U.S. religious right.
Roussel Ucalf withdrew plans to sell RU-486 in the U.S.
The FDA then banned importation of RU-486 into the U.S.
Carnation quietly withdrew from the fight. The Extra Care brand name was trademarked but forgotten.
Upjohn equally quietly continued to sell Cheque Drops, in low-key competition with a canine formulation of the human birth control drug Ovaban.
Ovaban, available for dogs since circa 1983, also has some following among sled dog racers and show dog fanciers, but apparently has unpopular side effects in some dogs, and never been successfully incorporated into dog food.
Controversy raged on
The controversy over RU-486, and by extension Mibolerone, raged on.
Leading scientists told Congress in 1990 that RU-486 should be legalized for use in cancer treatment.
Austria, Belgium, Britain, Denmark, Finland, Germany, Greece, Israel, the Netherlands, Russia, Spain, Sweden, and Switzerland joined France and China in approving RU-486.
The U.S. Supreme Court in 1992 upheld the FDA ban on RU-486, but President Bill Clinton lifted the ban upon taking office in January 1993. Clinton directed the Department of Health and Human Services to investigate ways to test, license, and manufacture RU-486 for human use.
In May 1994 Roussel Ucalf donated its patent on RU-486 to the nonprofit Population Council.
Clinical trials on 2,100 women began in October 1994 at the University of California-San Francisco, similar to the trials begun more than a decade earlier at University of Southern California
Life term for selling
Private investors formed Danco Laboratories in 1995, specifically to market RU-486. The FDA conditionally approved RU-486 in September 1996, but required another three years of research before issuing the September 2000 notice of final approval.
Mibolerone meanwhile came into use for treating uterine cancer in dogs, and became the canine birth control method of choice throughout northern Europe, where many nations restrict use of surgical spaying.
Mibolerone became relatively familiar to athletic officials and law enforcement during the 1990s for wholly unrelated reasons, as result of largely illegal use by body-builders––almost all of them male.
Arizona eventually included Mibolerone by name on a list of drugs which if given or sold to juveniles can cost the source a life term in prison.
To date, formulations using Mibolerone seem to have been commercially manufactured only for use in canids. However, there seem to be no technical obstacles to making doses suitable for cats, deer, beavers, and other mammal species whose numbers may be considered problematic.
The major questions about whether Upjohn and Carnation or perhaps another pet food maker will try again to introduce a contraceptive pet food containing Mibolerone center on three other issues:
• Will the U.S. religious right reimpose a ban on RU-486 and related chemicals through an Act of Congress? Or might the U.S. Supreme Court, as part of an anticipated reconsideration of the 1973 Roe vs. Wade decision that established a constitutional right for a woman to obtain an abortion?
Africa, Asia, & Latin America
• Will the U.S. FDA action on Mifrepristone significantly influence acceptance of RU-486 and related drugs in Africa, Asia, and Latin America?
In general, once a drug is widely distributed in the U.S., it becomes available worldwide, including in unauthorized knock-offs, as with the penile stimulant Viagra, whether or not the regulatory bodies of other nations approve.
However, animal care-and-control is a sufficiently public function, even when done mostly by private charities, that animal rescuers are unlikely to be able to use Mibolerone or locally made knock-offs without at least tacit official approval.
Is there still market potential?
• Finally, will a market still exist for Mibolerone after the advent of other dog and cat contraceptive approaches now under investigation, encouraged by the Alliance for Cat & Dog Contraception and the $25 million Michelson Prize, offered since 2008 to anyone who succeeds in developing a single-dose, permanent, nonsurgical sterilant that is safe and effective in both male and female cats and dogs?
Thirteen years after the Michelson Prize was first announced, it appears relatively unlikely to be claimed; but it has produced a great deal of research, some of it funded by Michelson grants, which may yet produce safer, more easily used contraceptive methods than Mibolerone.
On the other hand, after 36 years in which little or no new Mibolerone product development has been done, the Mibolerone approach may have considerable unrealized potential.