JAPAN – On Approval of Mefeego Pack in Japan

On Approval of Mefeego Pack in Japan – What we can learn from the experience of preglandin (gemeprost) suppository, the only approved 2nd-trimester abortion drug in this nation

by Kumi Tsukahara, Hatena Blog, Abortion in Japan, 10 May 2023

The Mefeego Pack (Mife-Miso combi-pack), approved in Japan on 28 April, was designated as a “deleterious drug”. None of the documents or website information issued by the Japanese Ministry of Health, Labour and Welfare, which gave the approval, indicated that the pills were deleterious, it is only on the package insert that the words “Deleterious Drug” can be found. (See in Japanese: https://www.info.pmda.go.jp/go/pack/249910AX1028_1_01/)

Japan’s designation of these pills as deleterious can be traced back to the use of this same word to describe gemeprost, a prostaglandin and precursor of misoprostol, that was approved in Japan in the 1980s. Kumi Tsukahara, a Japanese feminist researching abortion issues in Japan, published her original note about Mefeego Pack and Preglandin (gemeprost) — both labelled as deleterious in Japan — in her blog, as follows:

In December 2021, Linepharma K.K., with a British parent company, filed for approval of the oral abortion drug Mefeego Pack, the first oral abortion pill in Japan, but it is not the first abortion drug. Preglandin Vaginal Suppository (chemical name: gemeprost) was the first modern abortion medication in Japan and abroad. Ono Pharmaceutical Co., Ltd. developed and got approval for manufacturing and marketing from the Japanese government in 1984. Since then, this drug has been the primary treatment for second-trimester abortion in Japan.

However, it has been kept as a secret that gemeprost had a high success rate in clinical trials for first-trimester abortion in Japan between 1977 and 1980. This report reveals the past of vigorous control over Preglandin (gemeprost) for the benefit of a few doctors to call attention to what the fate of the newly approved oral pills – Mefeego Pack – will be.

Gemeprost was developed under the name of ONO-802, which has several trade names in other countries, including Cervagem in Sweden and Singapore. When I searched for “ONO-802” up to 1980 in PubMed, I found 11 research articles from 1977 to 1980. Nine of these studies were conducted by Japanese, with two English reports and seven Japanese. Two other studies were conducted abroad and reported in English. Ten out of the eleven studies were related to first-trimester abortions.

For example, Karim et al. of the National University of Singapore, who reported the first clinical trial in 1977, found that 50 women 5 to 14 days over their expected menstrual period received one 1 mg tablet vaginally and were sent home with instructions to insert four suppositories, one every 4 hours and that 46 (98%) successful abortions were confirmed by a pregnancy test two weeks later [1]. The same year, Tominaga Yoshiyuki et al. of Tottori University in Japan reported for the first time as a Japanese that a 0.5 mg or 1 mg vaginal suppository was administered 3 to 5 times every 3 hours to 32 patients within four months of pregnancy, and 30 patients (93.8%) had successful abortions [2].

The women reported various side effects in the 10 studies, but they were considered only transient and treatable. Even in cases where abortions were unsuccessful, the cervical dilating effect of gemeprost was favorably reported as facilitating backup surgical procedures. In addition, there have been several successful cases in which women have self-administered the drug vaginally.

In the late 1970s, no medicines were available anywhere in the world for first-trimester abortion. It was 1982 when the clinical trials of RU-486 (Mifepristone) began in Switzerland, while ONO-802 had reported high success rates in 10 early pregnancy trials by 1980, and all the researchers involved saw it as a promising abortion drug for early pregnancy.

International attention
In July 1982, an international symposium on Cervagem (gemeprost) was held in Singapore, led by Karim, and scholars participated in the symposium from the United Kingdom, Singapore, Hong Kong, Norway, Sweden, and Japan. The next year, a book entitled “Cervagem” was published, containing a total of 10 presentations and 3 questions from the symposium. Chapter 7, jointly authored by K. Sato, K. Kinoshita, and S. Sakamoto of Japan, is entitled ‘Clinical Study of Cervagem (ONO-802) for Abortion in the First and Second Trimester in Japan.’ It reported the results of clinical trials conducted with ONO-802(gemeprost) at 12 Japanese universities from December 1977 to July 1978 in the first and second trimesters of pregnancy, respectively.

In “Cervagem”, researchers from May-Barker in the U.K. revealed the fact that in 1974 they began working with Japanese researchers at Ono Pharmaceutical Company “to find an effective drug for early miscarriage,” and believing that “this drug should also be a powerful cervical dilator.” ONO-802 is itself an ‘abortion drug’ that artificially causes miscarriage through uterine contractions, and at the same time, it has attracted attention as a ‘cervical dilator’ to ripen and open the cervix as a pre-treatment for surgical abortion.

On the other hand, the Japanese, who had been using laminaria tents mainly for cervical dilation since the 1950s, had no idea of using ONO-802 for cervical dilation, or rather, the method of opening the cervical canal with laminaria before intravaginal administration of this drug is still the current standard practice in Japan.

Lies told in Japan and abroad
However, in April 1981, the year before the international symposium on Cervagem, Ono had already applied for approval of Preglandin to the Ministry of Health and Welfare of Japan as a dedicated second-trimester abortion drug for use only after the 12th week of pregnancy. The only data submitted with the application were the results of a clinical trial on the second-trimester pregnancy. The results were published in Japanese in the 1981 issue of Obstetrics and Gynecology (No. 10) as “Therapeutic Miscarriage and Cervical Dilation of ONO-802 Vaginal Suppository in the Second Trimester of Pregnancy,” co-authored by 31 doctors from 12 universities in Japan. They entirely omitted the data for the first-trimester abortion which had been already published in the English book.

In August 1982, four months after the international symposium, the Central Pharmaceutical Affairs Council declared that approval was ‘appropriate’. In response, the Nihon Keizai Shimbun (Nikkei Asia) reported in its morning edition on September 28 that “The government will soon grant manufacturing approval, and that the MHW intends to approve it as an indication drug that only designated doctors under the Eugenic Protection Law can prescribe limited to the case of a therapeutic abortion in the second-trimester pregnancy,” and added, “Ono has been conducting clinical trials in more than ten foreign countries with the cooperation of WHO. However, since Ono has NO clinical trial data on abortions in the first-trimester pregnancy and on its effects on artificially delivered third-trimester fetuses.” As I mentioned earlier, this is contrary to the fact: clinical trials have been conducted abroad mainly on abortion in the first trimester of pregnancy. For some reason, data on the first trimester of pregnancy was concealed.

Mechanism to protect the rights and interests of the designated doctors
However, it took two more years after the news report until the government approved the drug due to lengthy procedures to impose even stricter restrictions. Besides the above requirements, the MHW also specified that the use of the drug must be limited to second-trimester therapeutic abortion to treat a maternal injury or illness, designated it as a deleterious drug, and established its management and handling guidelines, to supervise its quantity, lot numbers, and date of delivery in the aim to prevent illegal use or resale of the drug. After such exceptionally strict regulations, finally, Preglandin was approved as the first abortion drug in Japan on May 30, 1984.

The Nikkei Sangyo Shimbun (Nikkei Business Daily) explained the background of this “exceptional measure” as follows: “The simplicity of inducing miscarriage without general anesthesia by just inserting a suppository of Preglandin into the vagina every three hours stirred up anxiety in various quarters. Religious groups were concerned that the number of easy abortions would increase, and the designated doctors feared that laypersons and other non-designated doctors could perform abortions.”

What separates Preglandin from Mefeego Pack
Preglandin was filed for approval in 1981, and 40 years later the oral abortion drug of Linepharma was filed for approval in December 2021. During these 40 years, a vast amount of research has accumulated on abortion pills. However, the Japanese designated doctors are once again trying to protect their interests by insisting that only they can prescribe the drug, hospitalization is required, spousal consent is needed, and the fee would be about 100,000 yen (more than US$700).

However, there is a major difference between the two drugs: at the time of the application for Preglandin in the 1980s, only 125 people participated in the clinical trials, and the safety of this drug had not yet been established, and the problems of uterine rupture later arose. On the other hand, the combi pack that was approved in Japan has been used millions of times even in the U.S. alone. It has myriad evidence of safety and certainty so the WHO has selected abortion pills into the Essential Medicines List since 2005 and included them on its Core List in 2019.

In addition, the situation of women has changed dramatically over the past 40 years: in Japan in the 1980s, pseudo-religious aborted fetal offerings (mizuko kuyo) enjoyed extraordinary prosperity. The religious right made great use of the argument of mizuko kuyo, which considers abortion to be a “crime of women,” and denounced them verbally to impede abortion. For this reason, the view of abortion in public opinion at that time was far harsher than it is today.

The atmosphere of the era of abortion condemnation, in fact, even affected the psychology of some abortion pill developers. Yoshiyuki Tominaga of Tottori University, who is introduced as the “father” of Preglandin testified that he was horrified by the “frighteningly great” effects of this drug and anguished over whether such a medication was allowed to be introduced into the world. On the other hand, Tominaga also stated that “more women would be saved if it were allowed in the early stages of pregnancy as well”. Such views, centered on women’s health and well-being, did not catch Japanese people’s attention at the time and were forgotten.

Ten years later, ‘reproductive health and rights’ was proposed at the International Conference on Population and Development in Cairo, Egypt, in 1994, and at the World Conference on Women (Beijing Conference) the following year, “the freedom to decide whether or not to have children, when to have them, and how many to have,” was reaffirmed. In countries where abortion pills had been introduced earlier, the time to finish abortion is becoming shorter, and the stigma of “abortion” is diminishing as women who had used the pills began speaking out about their experiences. Then came the Covid-19 pandemic. The international specialists on reproductive healthcare reaffirmed abortion as essential medical care. Now the International Federation of Obstetrics and Gynecology has issued a statement calling for online prescription and home use of abortion pills to be made permanent. The United Nations has also made it clear that abortion restrictions are a violation of human rights.

In the 21st century, the world’s view of abortion has changed dramatically. Knowing this, we should keep a close eye on how Mefeego Pack will be used in Japan.

[1] Karim et al., ‘Menstrual induction with vaginal administration of 16, 16 dimethyl trans-delta2-PGE1 methyl ester(ONO 802),’ Prostaglandins Vol.14 No.3,1977.
[2] Tominaga et al., Abstract of ‘Basic and clinical study on medical abortion with vaginal administration of 16, 16 dimethyl trans-delta2-PGE1 methyl ester,’ in Japanese, Japan Society of Obstetrics and Gynecology, Vol.29 No.10, 1977.