Playing Guinea Pig

“When I was seventeen, I developed a pronounced rash on my elbows and knees,” says Raizel, a 36-year-old mother of five from New York. “It was red with silvery, scaly flakes and very itchy. Even before I visited the doctor, I knew it was psoriasis because my father has suffered from it for decades.”

Psoriasis is an autoimmune disease where the body’s immune system mistakenly attacks healthy cells. Very often, it runs in families, and this was the case for Raizel. “One of my brothers has it, too. Sometimes people with psoriasis will get psoriatic arthritis, which causes swollen joints, pain, and fatigue — my father has that. At one point, it got so bad he couldn’t work and was on disability.”

Raizel’s doctor gave her a cream to put on her psoriasis, and that helped reduce the rash, but it got worse again in her twenties. “It spread to my scalp and caused pitting in my fingernails,” Raizel relates with a shudder. “I tried all sorts of medications, from creams to oral medications to light therapies. By that time, I was married and my husband and I were trying to start a family. It was frustrating because so many psoriasis treatments haven’t been tested on pregnant women, so I’d often have to stop my medication because I would get pregnant just when it was starting to work.”

By the time Raizel was in her thirties, she’d finally found medications that helped her manage her psoriasis. While she had never been diagnosed with psoriatic arthritis, her doctor believed that based on her symptoms and her family history, she was at high risk of developing it in the future. “My doctor told me about a study being done at NYU hospital that was testing a medication to prevent psoriatic arthritis,” Raizel says. “She asked me if I’d be interested in joining the clinical trial.”

Raizel spent weeks agonizing over the decision. “I was worried about how I would react to the medication, and if I would have side effects. But I was more concerned about the amount of time it would take up in my schedule. The treatment is only for six months, but you’re supposed to come in for follow-ups for two years. I have a job, a husband, five kids. Rearranging my schedule felt impossible.”

So many variables and viewpoints whirled through Raizel’s head. “What if I was only given the placebo? Maybe it sounds selfish, but I was going through this because I wanted to be helped, not to benefit a drug company,” she says. Raizel’s rabbi advised her to defer to whatever the doctors thought would be best for her. Her husband said he’d support her no matter what choice she made.

“What ultimately made me decide to do it,” Raizel remembers, “is something my father said. He told me, ‘If I had been given the chance to prevent this disease, I would have grabbed it with both hands.’”

Every clinical trial is a bit of a gamble, so patients can understandably feel nervous about joining them. That wasn’t the case with Yael Hacohen, however. “I wasn’t nervous, I wasn’t excited — really, I felt like I didn’t have a choice because I was wasting away,” she says.

Yael was 68 years old when she started to notice a dramatic change in her health. “I was working as a management consultant at the time and when I got home from work, I’d feel so weak that I just wanted to collapse on the couch. I couldn’t walk two minutes without huffing and puffing,” she remembers.

It wasn’t age that was slowing her down, though. It was hypertrophic cardiomyopathy, a condition that makes it hard for the heart to pump blood. Since there’s no cure for this genetic disease, doctors generally prescribe medicine that can ease symptoms and prevent sudden cardiac death.

“I saw several cardiologists, but the medications they gave me just weren’t working,” says Yael, who lives in Israel. “Eventually, one doctor said to me, ‘Look, I don’t know what to do for you anymore, but there’s a woman at the Hadassah Medical Organization who’s doing research on this, and you’d absolutely fit the bill.’”

Yael didn’t waste time: She spoke with the head researcher to learn more, weighed the pros and cons, and discussed it with her adult children. “They said that if it would help me feel better, they were all for it,” she says.

The doctors put her through a whole series of examinations and Yael had to, as she jokes, “Sign seven thousand pieces of paper.” But ultimately, she was accepted into the clinical trial.

To assess Yael’s heart health before giving her the new medication, named Mavacamten, she had to undergo a series of evaluations. Along with blood and liver tests, “I needed to ride a bike and be connected to all kinds of measurements,” Yael remembers. The “bike” was actually part of a cardiopulmonary exercise test, which can measure carbon dioxide and the amount of oxygen in your blood, as well as assess how well your heart is working.

“The goal of the trial was to try out a new medication that relaxes the heart and allows it to pump more efficiently. We checked out each patient’s exercise tolerance before the study, gave them the medication, and then after six months, rechecked their exercise tolerance,” says Dr. Donna Zwas, director of the Linda Joy Pollin Cardiovascular Wellness Center for Women at the Hadassah Medical Organization, the Jerusalem-based hospital system founded and owned by Hadassah, The Women’s Zionist Organization of America.

In the past, people like Yael would have been referred to surgery to remove areas of the heart that were too thick. “Or the doctors would have had to give them a tiny, medically induced heart attack to weaken the muscle,” Dr. Zwas says. “So we were really pleased to be part of the development of a new pharmaceutical alternative that may enable people to avoid invasive procedures.”

The study lasted eight months, followed by three years of follow-up. During this time, Yael typically had to go to the hospital every two weeks — sometimes for a quick check-in, other times for several hours. But she wasn’t frustrated by these interruptions to her daily life. “I liked that I was being carefully monitored.”

The clinical trial that Raizel joined for psoriatic arthritis was, relatively, a lot less demanding. “To make sure I was eligible to participate, I first had to undergo blood tests and an ultrasound of my joints. Then I was given a shot of the medication — every month at first, and then every eight weeks for twenty-four weeks. It really didn’t hurt much,” says Raizel. “The worst part is the traffic getting from Brooklyn to the city.”

Risk vs. Reward

Clinical trials are not a modern innovation; they can be traced back to ancient history. The first recorded clinical trial in recorded history is in Sefer Daniel. When Daniel was a slave to King Nevuchadnetzar, he refused to eat nonkosher meat and wine, opting for a vegetarian diet instead. The king’s chief officer was worried that Daniel wouldn’t be as healthy as the other men in the king’s service, and that he’d be held responsible and punished. So Daniel suggested putting it to the test — he, Chananiah, Mishael, and Azariah would all eat a vegetarian diet for ten days, and the rest of the servants would eat the king’s meat and wine, and they’d see who looked healthier. At the end of the ten-day experiment, Daniel looked healthier than the other servants, so he was allowed to continue his kosher diet.

In the 18th century, the first properly documented and controlled clinical trial was conducted by Scottish surgeon James Lind. Working in a hospital for men in the Royal Navy, Lind noticed that many patients had a disease called scurvy, which causes bleeding, swelling of the gums, anemia, and eventually death. Today, we know the disease is caused by a lack of Vitamin C, but in the 1700s, no one knew why sailors, who subsisted on biscuits and beef jerky, kept contracting this disease. Lind took 12 sailors suffering from scurvy and divided them into six groups of two. Each pair received a different treatment — cider, diluted sulfuric acid, vinegar, seawater, two oranges and one lemon, or a medicinal paste. He found that the pair given the citrus fruits showed the most improvement. Because of his experiment, the Royal Navy eventually started giving citrus fruits to all their sailors.

Since that time, clinical trials have helped scientists find cures and treatments for thousands of diseases: insulin for diabetics, a vaccine for polio, chemotherapy to fight cancer. But despite the many benefits, there are of course risks to the participants — the treatment might not work, it might not be better than the standard treatment, or you might get the placebo instead of the actual treatment.

Very rarely, there have been tragic outcomes for participants. In 2016, a study in France conducted with healthy participants to test a new drug called BIA 10-2474 killed one person and caused brain injuries in four others. A group of experts put together by France’s National Agency for Drug Safety believe it was the high dosage of the drug that killed and injured participants.

More recently, a 2024 New York Times investigation claimed that a drug trial run in 2021 by ESAI, a drug maker, to test a medication for Alzheimer’s disease, had caused participants serious brain swelling and bleeding. What’s shocking is that the New York Times obtained documents revealing that the drug maker had been aware that some of the participants’ gene markers showed that they were at higher risk for brain injuries and didn’t disclose that information to the participants.

Knowing that risk is an inherent part of clinical trials, how can a patient decide if participating in a clinical trial is worth it?

“That’s a very complex question and it depends on the situation,” says Dr. Tamir Ben-Hur, Chair of The Brain Division at the Hadassah Medical Organization, who has been conducting clinical trials for over 35 years. “The first reason might be because there is a need. With some diseases — like cancer, multiple sclerosis, or a brain disease — a patient reaches a dead end even with the best medical therapy we can offer, so they need to try something that isn’t approved yet. In that case, we’ll say, ‘Look, there is this clinical trial. We’re trying a new thing. We don’t know yet whether it will work for sure. But we think that there is a good chance.’ Then we’ll discuss the pros and cons of joining it.”

In terms of basic safety, clinical studies have gotten safer over time as scientists have learned from their mistakes. There’s also more oversight. Most studies in the United States are approved by an Institutional Review Board. The IRB is made up of doctors, scientists, and members of the public. They make sure that the study participants are not exposed to any unnecessary risks. The IRB regularly reviews the study and its results to makes sure the potential benefits of the study outweigh the risks.

How do you know if a study is legitimate? Dr. Ben-Hur suggests searching the clinicaltrials.gov website for registered trials. “I frequently send patients there if they have a rare disease and we have nothing else to offer them.”

Another tip: “Choose a clinical trial that will be performed in an academic medical center,” Dr. Ben-Hur advises. “That’s important because the reliability will be much higher. Also, if you do it in an academic center, they have an Institutional Review Board, and we, the researchers, have to convince them that what we’re doing agrees with the highest ethical standards.”

What if a patient joins a study, but then doesn’t feel safe, or changes their mind? “It’s built in that a participant has the right to withdraw whenever they want to,” Dr. Ben-Hur points out. “Also, by law and ethical standards, if you’re in a clinical trial, you never have to pay to take part in it.”

Once a person narrows down which trial they want to register for, next up is figuring out which “phase” of the trial to join. “There are three phases to every trial,” Dr. Ben-Hur explains. “In phase 1, we just have to see that it doesn’t cause harm. In phase 2, we test the efficiency of the new protocol, but on a very small scale. Phase 3 is a large-scale trial on many patients, and only after phase 3 will the drug be considered for approval by regulatory agencies like the FDA in America. It’s a very gradual process and the participant needs to consider what phase the trial is in when deciding whether to join.”

High Stakes

When Benny and Josh Landsman were first diagnosed with Canavan, their parents searched for anyone in the scientific and Canavan community who could help them. They eventually found Dr. Paola Leone, a professor of cell biology at Rowan University in New Jersey, who was doing cutting-edge work on Canavan disease. Her research showed that a benign virus could deliver the gene therapy to the brain and give patients the enzyme they were missing. Before the Landsmans reached out to her, she had gotten as far as she could in her work without patients to test it on. So the timing of the Landsmans’ call to create a clinical trial was perfect. But the risks were enormous.

“The treatment is delivered directly into the brain, so it’s a very serious brain surgery,” Jennie explains. “We needed a neurosurgeon who was comfortable doing this new technique. We worked with an amazing neurosurgeon, Dr. Robert Lober, at Dayton Children’s Hospital.”

Benny was up first. For his procedure, the Landsmans drove down to Dayton, Ohio from their home in New York. They rented an Airbnb, staying for a little over a month. “That first week, they did a ton of testing on Benny. He had to go under anesthesia to do these long, intricate MRIs where they measure the number of cells in the brain — they have to count them before and after the procedure to see if there’s growth or loss. He had gross motor function tests, IQ tests, bloodwork, EEGs, seizure activity, full neurological exams. It was pretty intense, and after the surgery, we had to come back to Dayton to repeat these tests at three months, six months, one year, and then every year,” says Jennie.

Until that fateful surgery, the Landsmans had battled fiercely to get their sons treatment. They had taken on the FDA and raised millions of dollars, but when it was time for Benny to be wheeled into the operating room, Jennie was terrified. “Just the medical waiver we had to sign was thirty pages long. He’s medically fragile so we were really worried about how he’d handle the surgery.”

The surgery lasted from 6 a.m. to 2 p.m. Alongside fear was hope; despite all the risks, this was their only chance of saving their son. After a month of recovery in the hospital, Benny was cleared to go home. But then a new problem developed: “He had a wound that opened to his brain that wasn’t closing or healing properly,” says Jennie. “We had it looked at by a neurosurgeon in New York, and she tried to close it up, but it opened again.”

At that point, the Landsmans wanted to go back to Dr. Lober. They were flown to Dayton Children’s Hospital by Hatzalah Air. With Josh’s surgery coming up, it didn’t make sense to travel back to New York and then back to Dayton again, so they ended up staying in Ohio for four months.

How are Benny and Josh doing in the aftermath of the surgery? “Much better than you would expect a Canavan kid to be,” Jennie says. “Before the treatment, they would regress all the time and lose skills and function. It’s halted the regression and they’ve actually been gaining very small skills. Even on their MRI, you can see that they’re growing new white matter, and white matter is what gets lost in Canavan. They’re gaining brain cells, and we weren’t even sure if that was possible before the surgery.”

Once a year, the Landsmans drive back to Dayton and stay for a week to repeat all the tests on their sons — MRIs, EEGs, IQ tests, gross motor function tests, full neurological workups. “We continue to see whether they’re still producing the enzyme they were missing, and we’ll just see how long they keep producing it, and how long it has an effect.

“In the meantime, we just learn to appreciate every single day and every single moment we have,” Jennie continues. “Some people get angry and wonder, why did this happen to me? Why do I have to go through this? But I feel like there’s a bigger picture that I can’t see. Before my pregnancies, I was actually tested for Canavan disease and was mistakenly told I was not a carrier, so it was very much against science what happened to us. So I know that Hashem really wanted these kids to be here, and they’re here to do a certain work that Hashem wants them to do. Because of them, and the work we’ve done over these four years, there are other children being treated. It means so much to me to know that everything has a bigger impact than just us.”

Jennie relates a moving story that happened to her just after Benny was rushed by Hatzalah to Dayton after his wound reopened: “We got to the hospital Shabbos morning, and Dr. Lober worked on Benny all day. When he was done, he asked me, ‘Where are you going to go now?’ By then it was 45 minutes until Shabbos ended, so I said, ‘We’re going to wait until Shabbos is over and then go to the Chabad Rebbetzin and stay with her.’

“Dr. Lober shook his head, and said, ‘I’m in the wrong religion. Your kids have an incurable disease. You and your community raise millions of dollars. You start a whole clinical trial for something that there was no treatment for before. When you have to travel, you’re airlifted on a Hatzalah flight, and now you have a place to stay?’ ”

A Small Contribution to Medicine

At 75, Barbara Sofer has a schedule that would tire out most people half her age. She works full-time as a public relations director, writes a column called “The Human Spirit” for the Jerusalem Post, is a motivational speaker, and has written multiple books to critical acclaim. She was born in America but made aliyah with her husband, the scientist-writer Gerald Schroeder.

Barbara Sofer is an interesting case, because while many people participate in trials because they’re unwell and conventional medicine isn’t working for them, Sofer chooses to join clinical trials for altruistic reasons. “I’ve participated in half a dozen clinical trials,” she tells me. “I feel this is a small contribution to medicine that will help others. I have friends who have donated their kidney, and my contribution is so much easier.”

In her column for the Jerusalem Post she writes, “We’re a country at war on seven fronts. So many wounded soldiers need medical evacuation and innovative treatment…. Here are our Israeli researchers still hard at work, juggling their day jobs with demanding medical and nonmedical roles in the IDF. Doing the test is personal, of course, but it’s also about being an Israeli and wanting to help fix the world.”

Recently, Sofer participated in a trial that Dr. Ben-Hur is conducting on Alzheimer’s disease. “The trial will test if a tuberculosis vaccine could reduce the chance of people developing Alzheimer’s disease,” explains Sofer. To receive the vaccine, participants first need to take a blood test to see if they have the markers that predict if someone is more likely to develop the disease (see sidebar for more). “I had known the blood test was available before. But since there was no known way to stop it, I was frightened to find out if I had the markers.”

As soon as Sofer discovered that this tuberculosis vaccine could hold out hope of slowing the disease, she signed up. “What I had to gain outweighed what I had to lose. Many billions have been spent unsuccessfully stopping brain deterioration, and if a simple and cheap vaccine might help, millions would benefit. I also like the idea that an Israeli hospital might come up with the solution,” Sofer shares.

“Unlike a previous clinical trial I had volunteered for, in which electrodes were put in my hair, this trial involved no mess. I took a cognitive test with pencil and paper, and a blood test. The whole process of passing the test, filling out forms, and having the blood test took under an hour.”

Sofer’s blood test showed no markers for Alzheimer’s, so her participation in the trial came to an end. If her markers had been positive, she would have received three shots of the tuberculosis vaccine and been carefully observed to see if she developed Alzheimer’s. “I found the good results of this clinical trial very empowering. They have also left me thinking about how I might assess the use of my time in the future. Had I, G-d forbid, learned that I was probably going to get Alzheimer’s, I would have made important and pleasurable activities a priority. Now that I hope to have the gift of time, why shouldn’t I make those a priority now?”

Placebo or the Real Deal?

Soon after Yael joined the clinical trial for her hypertrophic cardiomyopathy, she started to feel healthier. “They told us that some people are getting the placebo, and some are getting the real deal, and within weeks it was clear to me that I was getting the medication. I was distinctly feeling stronger, more capable and competent. It just gave me more energy and the feeling that I can do the things that I want to do. I didn’t have any side effects — I just felt better.”

Raizel is still waiting to find out how her story will unfold. “Now that I’ve received the shots, they’re going to monitor me for a few years to see if I develop psoriatic arthritis. I really hope that, after all this, I’m getting the real medication and not a placebo.”

It’s a legitimate concern. For instance, in the study that Yael joined, 130 people received the medication, and 130 got a placebo. While this structure is important — it allows the researchers to determine if the medication is really working or if it’s just a placebo effect (where patients feel improvement because they’re taking a pill, even if the pill contains zero medicine) — it means half the patients don’t get any drug benefits. Are the placebo patients just out of luck?

Not necessarily, according to Dr. Zwas. “In many studies, after you complete the randomized control trial, there’s a rollover where everyone receives the medication, so that everyone can benefit from the trial.”

Dr. Ben-Hur raises another point: “There’s a lot of medical literature that shows that just participating in a clinical trial improves the outcome of the patient, even if they got the placebo, because they do better than people not in a trial. They get better care. They come to follow-ups, they are evaluated repeatedly, and it improves the outcome.”

Today, Mavacamten is an FDA-approved drug that is used around the world and provides a better quality of living to tens of thousands of people like Yael. “I would participate in another trial if Dr. Zwas was running it. I’ve been in wonderful hands. I hear all kinds of criticism of the pharmacy and drug industry, but I wouldn’t be alive without them, so I’m so very grateful to researchers,” shares Yael. “I was helped more than I helped.”

*Please pray for Benny and Josh Landsman — Shalom Binyamin ben Shayna Toyba, and Yehoshua Natan ben Shayna Toyba.

HOPE ON THE HORIZON?

Three years ago, my grandmother died of Alzheimer’s disease. Before the disease ravaged her brain, my grandmother was a beloved teacher and a hands-on grandmother who taught us how to knit and play chess. Her signature mitzvah was hachnassas orchim and she was never happier than when her house was filled with guests. She ended up dying in a nursing home, unable to recognize her children and grandchildren.

Anyone who has witnessed this debilitating disease can understand how excited I was when I learned about the trial being done by Dr. Tamir Ben-Hur at the Hadassah Medical Organization to see if a tuberculosis vaccine can prevent Alzheimer’s. It’s an interesting medical leap, but researchers think the tuberculosis (BCG) vaccine might help slow Alzheimer’s by calming the body’s immune system and reducing brain inflammation, which plays a big role in the disease. People who receive the BCG vaccine — especially bladder cancer patients treated with it — seem to have lower rates of Alzheimer’s, possibly because it boosts helpful immune cells that protect the brain.

To qualify to receive the vaccine, participants first need to take a blood test, and only if it shows certain markers for Alzheimer’s are they eligible to continue in the study. It’s hard to find participants, though, because people are often reluctant to discover if they have markers.

“We are recruiting healthy, cognitively intact people, and in fact, many people don’t want to know if they have it,” Dr. Ben-Hur says. “When I sit around the table with friends, I sometimes ask, ‘If I have a test to tell you whether you will have Alzheimer’s in a few years, would you want to know?’ And around half of people say, ‘I wouldn’t take it. I wouldn’t want to know.’ ”

I’m well aware of this phenomenon. When my grandmother started forgetting things, family members wanted her to visit a neurologist. She was hurt and angry that we thought something was wrong with her. She refused to go. In fact, to get her to take the Alzheimer’s medication that her doctor prescribed, my grandfather would say it was just a memory vitamin. He went so far as to take the pill along with her, even though his memory was just fine. That’s how real the fear of an Alzheimer’s diagnosis is.

“Even those who say, ‘I would want to know if I have markers for Alzheimer’s,’ half of them won’t have the courage to actually come in and do the test because it’s frightening,” says Dr. Ben-Hur. “But if we know, maybe we can do something with the test result to prevent it. Alzheimer’s disease is around half our genetic makeup, but half the risk factors are things we can change to reduce our risk.

“In fact, some of the participants in the trial got an answer that they’re high-risk, and they changed their lifestyle. We saw one of our participants at his one-year follow-up, and he was a different person. His cholesterol was good, as was his blood pressure and blood sugar. He was exercising and taking care of his gums. The results gave him the motivation to take better care of himself. And the trial will show whether the vaccine will prevent the disease or not — so now we have something to offer.”

Will the shot work? Dr. Ben-Hur says it will take a year and a half to get preliminary results, but at least now there’s a ray of hope on the horizon.

(Originally featured in Family First, Issue 956)