The invention of the pill was probably the biggest earthquake undergone by feminism: a cheap and available means that allows billions of women worldwide to manage their future, their family and their livelihood. It was undoubtedly an event that makes it easy to see how life has changed before and since. The cultural-social transformation that the pill brought to the world was so dramatic and clear that the following statistic is hard to conceive: about 45% of the pregnancies in the world today are unwanted pregnancies (not including unplanned pregnancies in families and in cultures that do not encourage birth control) - according to the US National Center for Biotechnology Information (NCBI).
This is a statistic that has remained stable for the past 15 years and it demonstrates a problem: the pill that encompasses more than 40% of the contraceptives market isn't doing the job for everyone, and there are those who are forced not to use it and are not finding an alternative. At the same time men, except for using condoms that also have other health advantages in protected sex, are still essentially not part of the game.
The significance is that despite the availability of the pill and even that if used properly it has a 98%-99% efficacy against pregnancy many women choose to forgo it, among other things, because of the side effects that it causes, even at the cost of the risk of an unintended pregnancy.
And so women that want to plan their birthrate nevertheless consciously choose to forgo the pill: "Most of my life I used the pill," says Yael (45) from Givat Shmuel. "I began at a very young age, even before I had sexual relations, on the recommendation of doctors. I suffer from very difficult periods - a lot of bleeding, pains, depression - and they thought that this was the solution, and that the pill would sort out my body."
"For years I took them. Although the pain and the bleeding lessened, and there was something very convenient in knowing when I would have my period but beyond that the pills did not do impressive work with my body: I suffered from moodiness, my desire for sex was reduced and they caused me unpleasant side effects. Generally they made me feel that everything was monotonous and put me in very dull mood. I tried many types of pills. Every time my body did not feel good, I switched to a different type that the doctors decided to give me."
"At the age of 36, I decided to come off the pill. My body underwent an astonishing change. The exhilaration of my body was restored to me, it genuinely thanked me. I lost my excess weight, my sexual desire rose and I felt so much better."
Yael is not alone. For many women the pill to prevent pregnancy is far from a sufficient solution: they suffer side effects and a reduction in the quality of life. "For years I took the pill," recounts Hagit (37) from Tel Aviv. "I permanently had migraines during my period and as the years went by it got worse. At a certain stage it became intolerable. I already had small children and I felt that it was paralyzing me. For several days of the month I needed painkillers as frequently as possible and that did not always help. I felt so fragile that every little thing would set me off. I was scared do be outside in the heat or to drink alcohol on these days and I felt that any extra burden on my body would make me unable to function. In virtual despair, I arrived for treatment from an alternative medicine doctor and the first thing she recommended was to stop taking the pill - something that I had ever even thought of. A month later the headaches had stopped. Although I had been treated by acupuncture the change was so swift that it was clear to me that the pills were playing a major part in the matter. Since then I have hardly suffered from headaches during my period, and when I do get them they can go away by themselves."
Noga (42) from Yavne was really brought down by the pill. "I took the pill for the first time at the age of 17 when I had a boyfriend. I went to the gynecologist and he wrote me a prescription for the famous 'Diane.' After a short while, I flew with all the family on a trip and I completely freaked out there. Every time that it got dark I began to cry. I had a really queasy stomach and no appetite and I felt absolutely crazy, it really made me depressed and my parents didn't know what to do with me. I was crying all the time and I only wanted to go home. When we returned home, my mother believed that it as the pill that was throwing me out of balance. When I stopped taking it everything went away. Since then we have only used condoms."
Indeed, many women who take pills or other hormonal treatments report a decline in sexual desire, dryness in their vagina, moodiness and nausea (all the same because use is over the years, it is difficult to say if the side effects are definitely because of the pill).
On top of all this, in rare instances the pill can lead to much more severe side effects. The most prevalent of these are blood clots, which in the most serious cases can lead to irreversible disability and even death. Blood clots are caused by different reasons - flying, continued sitting without movement, pregnancy and also pills. Most of the risk in taking the pill is that it contains estrogen as well as progestin. The likelihood that women taking them will suffer from blood clots is between twice to six times higher than for women who take no hormonal treatments at all (this is still a very low risk compared with other factors causing clots). It is particularly more likely for women who smoke, older women who are overweight or with known clotting problems.
"Of course there are women for whom hormones are beneficial to, but you must understand the risk and that doesn't happen in the few minutes conversation that the gynecologist has with a young girl who is panicking because she fears that soon after leaving the clinic, she will be back with an unwanted pregnancy," says Dr. Anula Jayasuriya, Chairwoman of the Israeli innovative femtech company OCON Healthcare, which developed the IUB Intra Uterine Ball (see box). "It is an art to choose together with the patient the right contraceptive means for her. Sometimes when you give the wrong product to a woman, the risk of clotting can grow fifty times, and these are healthy women."
It is important to point out that for many women the pill for preventing pregnancy is an excellent solution. They do not suffer side effects or pain and this solution can serve them over the years. However, for those for whom this solution is not appropriate - there is virtually no other suitable solution, certainly not regarding the level of protection and effectiveness.
The market has been frozen for half a century
How is it possible then that a market worth billions of dollars annually has not renewed itself and improved these side effects and allow women who are their potential customers to simply forgo the convenience of the pill? It is likely that the answer is contained in the question: "The pill to prevent pregnancy was approved 60 years ago," says Stasia Obremskey, Managing Director of Rhia Ventures, which invests and specializes in reproductive technological developments for women - femtech. "Since then types and dosages of hormones have changed but the pharmaceutical companies have not invested in finding a different biological operating mechanism. They say: It's good enough. We can earn so many billions of dollars, so there is no point in investing in the next generation.
And so, even though it is already clear today that the pill is not a perfect solution, the field of contraception has not been developed for years, in contrast to other fields that are progressing at a meteoric pace. "The pharmaceutical companies have no interest in investing in this," explains Obreskey. "Although there is enormous competition in the field, and almost all the products are generic, they earn enough in relation to the cost of manufacturing them."
In 2019, for example, the global contraceptive pills market was worth $7 billion and according to the Grand View research, by 2027 it is expected to be worth about $10 billion.
Add to all this the dramatic change in the business model of pharmaceutical companies. "Until not so long ago the pharmaceutical companies loved huge markets. They had marketing systems that knew how to sell billions of dollars of treatments for common illnesses," says Dr. Jayasuriya. "But as there were more and more medicines in these markets, the regulators began to demand a much higher threshold of proof in order to bring in, for example, a new treatment for cholesterol or for diabetes. In order to bring a product like this to the market, the company has to today conduct huge trials with thousands and tens of thousands of patients and show beyond doubt that its product is better than the best that already exists."
"Therefore, we see today that the drug companies are turning more to niche markets, for rare diseases, for groups that can be segmented as sub-communities through genetic testing. For those niches that it is possible to say that these do not have good rival products - the regulator allows entry with a much lower hurdle and much smaller trials."
And there are other reasons. "One of them," according to Dr. Jayasuriya, "is that the regulators are very, very cautious about what they approve for women of childbearing age, who until recently didn't take part in clinical trials at all. This happens for more or less good reasons. There are considerations that new products might harm fertility, or if by mistake a woman anyway becomes pregnant during a trial, the product might harm the fetus. A woman of childbearing age is perceived as somebody who constantly has the potential to carry a sensitive embryo, and so it is always preferable for the medical world not to deal with it. But contraceptive means are a treatment that all the clinical trials must be conducted only with women of childbearing age. It very much complicates matters."
"Furthermore, we are talking about treatment for healthy people. The threshold of safety demanded by the regulators from a product like this is higher than a product designed to treat people who are suffering from an illness and have no other choice. Think about vaccinations, which were also only given to healthy people, and how cautious we have been about taking them. The pill is a product that healthy women take every day." Pharmaceutical companies distance themselves from this risk, also following lawsuits filed against pill manufacturers and the halting of marketing in the US of Essure for tying fallopian tubes due to safety problems.
Another thing that has put the contraceptives market behind is the widespread school of thought among gynecologists. "Veteran gynecologists operate through the approach of 'don't damage,'" says Jayasuriya. "It is exceptional for fertility doctors to respond to the request 'get me pregnant at any cost'. But for regular gynecologists it is not like that. It is an area rich in litigation, and one of the sectors in which doctors are sued most, and gynecologists have learned to be cautious, and not exceed even slightly the protocols, and that's what they have taught the next generations." "This has created a very pleasant and nice relationship between gynecologists who love protocols and the pharmaceutical industry, which tells them: don't deal with new things, simply sell what there is," explains OCON VP Marketing and Medical Affairs Daniela Schardinger. "And in this way women have remained almost without alternatives - and it is already half a century since the development of a major means that would provide an innovative solution to the issue - and that is exceptional compared with almost every other medical field. But then came women, who have circumvented the rules of the game through a completely new arena."
And then came the women
Yael, who hasn't taken the pill for ten years and reports an improvement in her quality of life, has discovered a new method of avoiding an unwanted pregnancy: "I rely on my safe days," she says, "I use an app that knows to forecast for me the date of my period, three months in advance - and adapts that to freedom in my sex life. It gives me a warning before ovulation and my period, averages and statistics. I leave a safety range, and in times when my period is less regular, I rely on it less. But when I am synchronized with the app, I know that everything is fine. It's enough for me."
And so while the conventional medical world has not supplied good solutions in recent years for women of childbearing age, salvation is at hand from digital health, and almost by accident, because technology designed to encourage fertility has revealed itself as also relevant for preventing pregnancy. Their aim was to find the window of fertility each month and this was achieved through a range of physical parameters that indicate ovulation. Having identifying this window, it is of course also possible to avoid it and so a new field of contraception was invented - apps.
Apps, in contrast to drugs, are not physically invasive, and do not have direct side effects. So it is also not subject to the same restrictions and the same obstacles. "These are products that are sold directly to the consumer. There is no doctor that needs to adopt them before offering it to a woman, and there is no real regulator, and there is a lot of innovation," says Jayasuriya.
A little like the monthly period sector, which seems to be exempt but nevertheless has brought us a range of new products like menstrual cups and absorbent knickers.
"Exactly as the tampon is also a product that enters into the body and is used by women of childbearing age regularly, but it is a consumer product, which is sold directly to women, so when breakthrough innovation reached this field, from the direction of unusual players, women adopted it. One of the reasons for innovation in the sector is that women have also recently entered these worlds more strongly - as engineers, investors and marketers.
When Dr. Jayasuriya speaks about 'these worlds' she is talking about the technological niche of women's health, femtech. The femtech world combines classic technological solutions in the field of health and the quality of life of women such as wearable monitoring devices, apps for managing medical situations, and digital diagnostic tools. Women use these tools for managing their health 75% more than men. Global expenditure by health systems and consumers on medical solutions for women is estimated at $500 billion, and according to research by Grand View, the women's health market is expected to be worth about $210 billion by 2025.
Dr. Benny Zeevi, a veteran venture capital investor in the field of life sciences and healthcare and one of the leaders of the femtech movement in Israel, says that in the past the investment world blocked solutions in the field of women's health, including contraception. Investors, he says, tend more to invest in problems closer to their heart. Although he adds, "In recent years there is a change because many more women have become partners in investment funds, including investment funds dedicated to the field of femtech."
In fact, the world of digital health has brought the subject of women's health to the fore. Because of the tendency of women to use more apps for managing their and their family's health, and because these problems did not have good enough solutions in traditional medicine, the femtech sector has become one of the hot sectors. Its very existence also reminds conventional medicine what it has missed.
Between 2015 and 2018, the global femtech sector raised about $1 billion in investments from leading funds like SOSV, Orbimed, and New Enterprise Associates. Research company Frost & Sullivan believes that the market's revenue will reach $50 billion in just a few years.
In Israel, there are 200 companies operating in the women's health sector with 21 in pregnancy and breastfeeding, 19 in fertility, and seven in the field of periods and the menopause.
The femtech sector alone in Israel has raised $314 million, 6% of all investments in healthcare.
The safe days according to high-tech
So what is an app that prevents pregnancy? The technology is in effect based on the most archaic approach, the safe days method - which relies on counting the days from the day that the period starts and which dictates the fertile days and the infertile days. This method alone does not reduce the risk of pregnancy sufficiently. But if the method is improved and combined with awareness of other signs warning that ovulation is approaching or receding, then the safe days can be better identified. It is so good that even the FDA has been persuaded to award two of these apps approval for preventing pregnancy at the same level granted to the pill and condoms.
One of these apps for example is Natural Cycle, which combines counting the days of the period with measuring the temperature of the body with the company's thermometer immediately after the user wakes up in the morning. The user must also add signs like discharges, typical pains for ovulation and the like. After taking the daily temperature and feeding in data, the user receives an answer to the question - is this a fertile day or not? The FDA approved the product in August 2018 and instructed the company to claim that it is 93% effective in preventing pregnancy. To date Natural Cycle has raised $37.5 million.
Another app is Clue, which broke through the barrier and received FDA approval in March 2021 after raising $29.7 million. Natural Cycle was not happy about the matter and claims that Clue received approval too quickly and that it is based solely on counting days. But that did not bother the FDA in approving it with an attachment of 92% effectiveness. The app does indeed not measure any biological signs but is based on reports about the user's moods, pains, sexual desire and the like. Over time, it is meant to learn all these signs and to understand, which off them bode the arrival of the period. As it learns more about the period, the risk window will become narrower.
Other apps for preventing pregnancy offer similar solutions. Kindara, whch has raised $8 million to date, measures the aforementioned changes and also instructs the user in measuring the position of the cervix. This change in position is another indicator that ovulation is approaching. This app is synchronized with Apple products like the watch, and claims it has effectiveness of more than 50%in identifying the window of fertility, so that users can abstain accordingly.
And there is of course an Israeli company that has developed a similar technology for preventing pregnancy. Tempdrop also counts the days and identifies physiological signs including automatically measuring the body temperature during the night and which according to the company founder and CEO Michael Vardi is much more precise in measuring the temperature as the user wakes up in the morning. The drawback is that the user must wear the watch all night. The app has 20,000 active users.
Vardi said, "We don't see ourselves only as a fertility company or as a company preventing pregnancy. Our product allows a woman to understand where she is in her cycle, and this cycle is of course for the entire month and not only during menstruation. Managing the monthly cycle allows her to plan her life and every woman learns for herself how each hormonal stage influences her mood, energy, sexual desire, anticipated pains, hunger, her weight and also fertility.
"This market today includes all the range - from simple apps which work only on the calendar and count days through to other linked to all sorts of sensors or ovulation trackers. The more you monitor the signs and update the app in an organized and consistent way, so the AI technologies can predict fertility days (vis-à-vis safe days G.W.) better. Many women feel that the period is back under their control after years in which it was owned by gynecologists."
They always said that the safe days approach was not effective enough
"If you track all the signs - temperature, discharges, vaginal changes and the date of the period - the efficacy is like real use of the pill."
Not the perfect solution
Apps designed to prevent pregnancy are certainly good technological news in the contemporary field of femtech. But despite the high efficacy of some of them and the sought after FDA approval, criticism is also heard about this method. First and foremost, as with the pill, women are dependent on the apps on a daily basis. In order to obtain reliability, the range of signs must be documented every day, and it can be tiresome. Exactly for this reason digital health apps, which require intensive documentation in order to achieve results, are for the most part less successful. It is considered a burden that most people aren't prepared to put up with.
Add to this that some women lead chaotic lives that the app finds it difficult to help with. Women who do shift work, who fly abroad a lot and move through different time zones and often don't sleep at home (and then need to carry the thermometer with them) - all these challenge the technology. Also if the period itself is not regular, the amount of time for which the app cannot provide an answer is lengthened until the entire effort becomes pointless.
One of the most severe critics of the apps is the writer Olivia Sudjic who published an article in "The Guardian" in 2018 in which she recounted that she became pregnant on a day that the Natural Cycle app told her she was not fertile. Later on in the day it told her that she was fertile but that was after she had already had sex. Sudjic felt betrayed: "I didn't ask myself how it works but I relied on what it was telling me. I was naïve." She explained how she was tempted, in her words, into buying the app, which emanated something natural for women who know their body and are not captive to the pharmaceutical industry. There was no need to book a doctor's appointment, to wait two weeks, and then wait in line - the app was within touching distance and the inventor was a former physicist with CERN and worked the Higgs boson particle accelerator. "They had succeeded in discovering the God particle but not mapping out my cycle," she wrote bitterly. In the same article, a woman called Marie said that she had undergone a similar experience. "I was angry that they related to me as a consumer and not as a patient."
The bottom line is that these apps succeed because they are designed for consumers and not for patients. Ultimately, the absence of interaction with the doctor and the professional disclaimer as well as the limitations of medical products marketing might be a disadvantage here. But it is difficult to compete with a contraceptive that is totally available and clearly non-invasive, when the other options can results in pains and other side effects.
However, it does seem that the market is waiting for a solution that is more 'use and not think about it' like the pill, but without the side effects. Pharmaceutical and medical device companies have a large opportunity to do something, if only they were given the appropriate incentive to go beyond what exists. Women in the femtech industry have already demonstrated that there is a hunger for these solutions and this can be translated into major money, because users are ready to be enthusiastic partners in managing their fertility, if they really get value with a solution that satisfies them. Now it is up to investors and senior biotech, pharmaceutical and medical device managers to continue pushing forward.
"Men must be part of the solution"
Why is almost all the responsibility for preventing pregnancy placed on women? It's possible to think that the result of unprotected sex is a joint child, which men would take seriously. "Women don't always trust men and the men are probably less sensitive to it being their responsibility because it is not they who will have to terminate the pregnancy," says Jayasuriya.
"The responsibility for preventing pregnancy must be shared," says Obremskey, "but women suffer more over an unwanted pregnancy, so if I had a dollar where would I put it? I do think that prevention from men is an opportunity for our generation. Men today are more aware of the needs of women. They want to be part of the solution."
Indeed it did actually both a group of American men and they founded the Male Contraceptive Initiative, an NGO to raise awareness on the issue of preventing pregnancy by men and also to raise capital to support research in the field. "We have only two options," they protest. "Condoms or vasectomy. Women have a range of options and we have only had two for the past 50 years."
MCI's members have also documented the history of male contraceptives in a podcast called "designed." According to the podcast, male contraception 2,000 years ago was done using a plant called Silphium, which was very popular in ancient Rome. But most of mankind was so enthusiastic about its various medical uses, that it succeeded in making it extinct.
In the 1950s, before the development of the female contraceptive pill, a drug named Win18446 was found to reduce sperm. But it proved to be fatal when combined with alcohol.
Back to today: Obremskey is actually optimistic. "Today the topic of contraceptives for men is more focused on than ever. The National Institute of Health in the US decided to allocate $15-30 million to support development of these products. It's not the $60 billion that has been invested in cancer research, but it's a start."
In another year, the trial of an innovative product will possibly herald good news. It is a type of cork for the sperm pipe, which can be removed after two years. The estimate is that urologists will like the solution because instead of one procedure for vasectomy for each man, they can perform procedures every few years for each patient and enjoy a similar payment that gynecologists receive for fitting intrauterine devices.
In addition, the company is financing research into drugs to reverse sperm production and drugs to prevent the sperm from penetrating eggs. "It's not that there isn't any research," says MCI research director Logan Nickels in the podcast supporting the company's activities. "But nobody is reaching the finishing line. To produce a new drug is very difficult."
Breakthrough in devices and other new developments in the market
From the point of view of many gynecologists, the clear solution for the day after the pill is an intrauterine device. This technology, which was invented even before the pill, and has remained virtually unchanged in its shape since then, is considered the holy grail in the contraceptive industry. What can be bad about a product that is fitted every five years in which you don't need to think about for the rest of the time?
But the device can cause excruciating pain to many women. True, it only happens once every five years but it can really be a traumatic experience. Very occasionally it can even cause damage to the uterus: if the device is hormonal, it can create clots like the pill; if it is not hormonal, it can cause massive bleeding or spotting during the month.
"The existing T-shaped IUDs are simply too big for the average uterus," says Keren Leshem, CEO of OCON Healthcare, which has developed the innovative IUB Ballerine intrauterine ball contraceptive, which is gaining popularity and recognition worldwide, already used by over 100,000 in 30 countries to date. "Until today, it has always been very difficult for gynecologists to find an alternative for the traditional T-shape devices. There were all sorts of attempts to change its shape a bit so that it’s more flexible or have smaller arms or to install it with different folding shapes, but it still remained the same T shape, with the same underlying problems.
OCON’s IUB Ballerine is designed to provide a solution precisely to this problem. "It has the friendly shape of a round and flexible sphere, which takes into account the fact that the uterus is 3D - a three-dimensional body cavity," says Leshem. "This allows its contact with the uterus walls to be soft and not pointed as with the T-shape IUD. It is made of nitinol alloy which has a memory shape, so during the placement in the uterus it regains its 3D round shape. OCON's IUB Ballerine utilizes copper for its contraceptive effect and therefore can cause excessive bleeding as with all copper contraceptives, but unlike the traditional T-shaped IUDs it substantially reduces the risk for bleeding from an IUD’s malpositioning, installation process or movement in the uterus, so it also prevents those pains for higher quality of life."
"Research shows that young women are also interested in long-term contraceptives that do not need maintenance, and with a very high percentage of pregnancy prevention," says Prof. Sergio Haimovich, Head of the Ambulatory Gynecology Department at Hillel Yaffe Hospital and Chief Medical Officer of OCON Healthcare. "Once IUDs are economically accessible so doctors can offer them and explain about them, the rate of women choosing them will rise substantially."
Another product, which has begun arousing interest in recent years, is the female condom. This is a very thin rubber sheet, just like a male condom, with two rings, internal and external, which prevent the condom from moving inside the body. The product was invented by Danish gynecologist, sexologist and nutritionist Dr. Lasse Hessel, who developed a food additive to improve female fertility and wrote a book about preferred positions for stimulating the woman, after researching couples having sex with ultrasound imaging. It is not an especially comfortable product and is marketed mainly for preventing sexually transmitted diseases. However, efforts are continually being made to improve it.
Female condoms are sold by many brands in the US and Europe, although their use is not very common. The reasons include the skills required to put them in, noises like a rustling bag that some of the first products made and which probably spoil the pleasure, and reduce sensation as well as the high price compared to male condoms. In addition, until 2018, the FDA demanded clinical trials for these products, which reduced the incentive for companies to develop them. Today these demands have changed and several improved products in the category are in development and trials.
Published by Globes, Israel business news - en.globes.co.il - on April 27, 2021
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