SICKENING: FDA BUREAUCRACY BLOCKS COMMON “MIRACLE DRUG”

By Mark Flatten National Investigative Journalist for the Goldwater Institute ow do you tell a 7-year-old child she are facing the inevitable reality that we will not must go back on a feeding tube? be able to get it soon. C assie Le is facing that terrible “I fear she will need to get a feeding tube question. placed back in,” Le wrote. “How do I tell her H Her daughter spent the first that? How would you as a parent tell your child seven months of her life unable to eat without ... ‘sorry the medicine that has helped you to eat vomiting. The doctors ran the usual tests and and enjoy eating is no longer available so now tried the usual medications. you can’t eat ... you will get fed to your intestine Nothing worked. by a feeding tube.’ She is a little girl who has The girl was put on a feeding tube when worked extremely hard to overcome her fears she was 7 months old. It helped some, but she of eating and now her joy of being a normal continued vomiting regularly. little girl will be taken away.” “Feeding became something she feared,” Le Le said she is comfortable with the of Texas said in a May 2016 email describing her Goldwater Institute quoting from her email. daughter’s condition. However, she did not want to be interviewed Finally, doctors tried domperidone, a because of concerns for her daughter’s privacy. medication widely used throughout the world The child’s name is not being used. to treat gastric conditions like those afflicting “She has been able Le’s daughter. It worked. The feeding tube was removed about four years ago, and since then ‘SERIOUS OR LIFE to eat because of the girl has been able to eat normally. That is coming to an end because of new THREATENING’ Domperidone. Now we rules restricting the availability of domperidone imposed by the U.S. Food and Drug illions of people worldwide have are facing the inevitable Administration. regularly taken domperidone since it Domperidone is not approved to treat any M was firstdeveloped and marketed in reality that we will not condition in the United States. Despite that, 1978. It is a common treatment for a variety of it was relatively easy to obtain until recently gastric disorders, nausea and vomiting. through compounding pharmacies, which were The most serious condition treated with be able to get it soon.” able to legally get it from international suppliers domperidone is gastroparesis, a potentially and blend it into compounds to fill prescriptions deadly condition in which food basically sits – Cassie Le – from a doctor. in the stomach rather than being digested and But in the past couple of years, the FDA passed normally. Patients with gastroparesis has clamped down, restricting access and suffer from a variety of conditions, including importation of the drug. Doctors and pharmacies severe and uncontrolled vomiting, bloating and risk punishment from the FDA if they prescribe abdominal pain. It can lead to other conditions or provide it to patients. such as malnutrition and dehydration. So people like Le’s daughter can no longer The FDA classifies gastroparesis as a legally get it, except through an FDA program “serious or life-threatening” condition. It is the known as an Expanded Access Investigational condition Le’s daughter suffers from. New Drug (IND) protocol. The agency refuses to The agency’s concern about domperidone say how many people are receiving treatment is that it may cause a condition called QT through that program. No one younger than 12 prolongation. This is a pause in the electrical years old can qualify, so Le’s daughter would not buildup in the heart between beats. be eligible. There are conflicting studies about how “She has been able to eat because of much, if any, risk of QT prolongation can be Domperidone,” Le wrote in an email to the FDA linked to domperidone in patients who are as part of a public comment process. “Now we properly screened and monitored for heart

2 • DOMPERIDONE • RIGHT TO TRY ACT RIGHT TO TRY ACT • DOMPERIDONE • 3 complications. Even the FDA acknowledges the process by which a pharmacist mixes drugs, get out of bed. I’m so sick I can’t do anything. connection between domperidone use and heart chemicals or other products to tailor a medica- But when I take it, I have days that I can go complications is “not well characterized.” tion to an individual patient. watch my grandkids swim or play soccer or There are about 150 FDA-approved drugs Since only small quantities of compounded whatever. As far as I am concerned, that’s the on the market that have been linked to QT medicines are produced, they were treated risk-reward balance that I have to take.” prolongation, including cardiac drugs. differently than new drugs because it would Beener was a software consultant living in Only one drug is FDA-approved for treatment be unfeasible to go through the rigorous FDA Florida when the symptoms of gastroparesis of gastroparesis — metoclopramide, which is testing regimen for each unique compound. first surfaced about 2001. Her job required sold under the brand name Reglan. However, The FDA left the regulation of compounding extensive travel. One day she started to Reglan is only effective in about 40 percent of pharmacies to the states. experience uncontrolled vomiting. It got so the patients with gastroparesis, and it can cause For domperidone users, that meant bad that she routinely carried plastic bags and a serious and permanent disorder characterized compounding pharmacies still were able to paper towels on business flights, knowing she by uncontrollable muscle movement in the lips, obtain the drug through international sources would likely vomit while in the air. tongue, eyes, face, arms and legs. and compound it to fill prescriptions for “I threw up all across this country,” Beener Domperidone is available in more than 100 individual patients. said. “I was in hospitals all over the country.” countries, including those in the European Union, But Congress changed the law in 2013, Doctors tried Reglan, which worked for a Canada and Mexico. In many of those countries, clarifying the FDA’s power to fully regulate all while. But within about five months she suffered it is available over the counter. The prescription products made through compounding. The severe depression and was suicidal. It got so requirement was imposed only recently in the FDA responded by aggressively enforcing bad that her husband hid her pills. United Kingdom and some other European its import ban on domperidone, effectively When Beener stopped taking Reglan, the nations. In Canada, about 2 million prescriptions closing down the domestic market. The agency severe vomiting returned. for domperidone are written annually. initially attempted to halt importation of the A doctor in Georgia told her that he might In the United States, domperidone has drug in 2004, citing concerns it might be linked be able to get access to domperidone and never been approved by the FDA to treat any to heart problems and was being improperly warned her of possible heart problems. condition. prescribed to increase milk production in “I said I will take anything. I don’t care. I Before any new drug can be prescribed or lactating women. However, that ban was largely can’t live like this,” Beener said. sold in the U.S., it must be approved by the FDA unenforced until Congress clarified the FDA’s At first, domperidone was easy to get. after a series of clinical trials and agency reviews regulatory power over drug compounding in Doctors were willing to prescribe it and to determine whether it is safe for use in humans the 2013 law. compounding pharmacies would dispense it, and effective at treating the targeted condition. despite the FDA’s 2004 import alert. That process of getting FDA approval to market But by 2014, the FDA was warning a single new drug normally takes more than 10 WHATEVER IT TAKES pharmacies they could be shut down for years and costs drug companies in excess of $1 dispensing domperidone and doctors could billion. olleen Beener knows about the safety face sanctions if they prescribed it, said Beener, “I am choosing quality of life Janssen Pharmaceutical conducted clinical concerns associated with domperidone. who helped form a gastroparesis patient over quantity of life. I don’t trials and in 1985 submitted its new drug applica- C It is a risk she is willing to take because support group soon after she was diagnosed. tion to the FDA for approval. Those tests showed she cannot lead anything resembling a normal Beener still gets domperidone through want to spend my days in bed. domperidone was both safe and effective. How- life without it. other sources, but doesn’t want to say what ever, an FDA review panel had concerns the clini- Beener, 62, of Florida, said she has taken they are out of fear the FDA will close that And if I get 10 years less because cal testing was not robust enough and repeated- domperidone for 15 years, and she has never had supplier down. She has effectively been forced ly asked for additional studies. any heart problems associated with the drug. onto the black market because of the FDA’s of that, so be it. I want to enjoy Janssen withdrew its application instead. The “I am choosing quality of life over quantity actions, she said. exact date and reasons for the withdrawal are of life,” Beener said. “I don’t want to spend my “I am going to get this drug, whatever I have my grandkids. I want to enjoy confidential. days in bed. And if I get 10 years less because to do to get it,” Beener said. “When I’m not on my life, and domperidone helps Despite its failure to receive FDA approval, of that, so be it. I want to enjoy my grandkids. I domperidone, I am so sick that I literally stay in domperidone still was readily available in the want to enjoy my life, and domperidone helps bed all day. With domperidone, I can get up. me do that.” United States through compounding pharmacies me do that. “As long as I can get it, I don’t care. I will because of the exception they historically oper- “It certainly doesn’t make me well. But it sacrifice and do whatever I have to do.” – Colleen Beener ated under in federal law. Compounding is the makes me better. When I’m not taking it, I don’t

4 • DOMPERIDONE • RIGHT TO TRY ACT RIGHT TO TRY ACT • DOMPERIDONE • 5 ‘MIRACLE DRUG’ problems. More controlled studies in Canada events, including deaths or other serious from El Paso,” Sarosiek said. “So some of those and other places showed little or no risks in reactions to medication, must be reported to the doctors, they take the risk of suggesting the or 20 years, Drs. Richard McCallum and properly screened and monitored patients. agency. If there was any evidence of widespread drug to their patients.” Irene Sarosiek have worked together to Patients in the Texas Tech expanded access complications from domperidone, it’s something That carries risks as well — for doctors and F treat patients with severe gastrointestinal program are treated with much higher doses the FDA would be aware of through those for patients. disorders with domperidone. They say the of domperidone than what are typically recom- reports. Someone who buys domperidone over drug is for many patients the last hope for a mended for patients in Europe, McCallum said. “That’s something that if the FDA had the counter in Mexico or another country may normal life. Even at that, he said he has not seen evidence concerns, it would already be known to not be told of the potential risks and safe “We are very worried about the fact that of any significant increase in risk, certainly not all of us and it would be discussed at the dosage, or be sure of its quality. They might many patients cannot get easy access to it and enough to outweigh the benefits to patients. gastroenterology meetings, and we would all not be monitored with regular heart testing to benefit from the medication, which we believe is “This is a risk-benefit ratio on a population know the drug is dangerous,” Sarosiek said. “This ensure there is no QT prolongation or other like a miracle drug,” Sarosiek said. “This agent is with no options,” McCallum said. “After Reglan, is not the case.” complication. one of the best, if not the only, drug which could there is no option. So when you boil it down Domperidone continues to be cited as Also, the fact that they are taking help patients with gastric emptying conditions.” to that, the benefit is great and the risk is an effective treatment for patients who domperidone will not show up in their medical McCallum is a professor and founding chair- miniscule.” cannot tolerate Reglan by the American charts, and so their doctors will not be aware of man of the department of internal medicine At Texas Tech, patients treated with Gastroenterological Association and the potential interactions with other drugs. at the Paul L. Foster School of Medicine at the domperidone are carefully monitored with American College of Gastroenterology, though Texas Tech University Health Sciences Center in regular electrocardiograms and other tests both note it is not available in the United States El Paso, and director of its Center for Neurogas- to ensure they are not experiencing QT outside of the FDA’s expanded access program. HORRIBLE TIMES troenterology and GI Motility. Sarosiek is a pro- prolongation or other serious complications, McCallum does not fault the FDA for fessor and director of gastrointestinal motility McCallum said. No deaths of any of his patients restricting availability of domperidone or exie Cox knows there are risks that come neurostimulation research at Texas Tech. have been linked to domperidone use, he said. requiring it to be obtained only through the from getting domperidone outside of the Since 2009, McCallum and Sarosiek have “We are living this whole thing every expanded access program. The agency is in an L FDA-approved process. But the 24-year- run the FDA-approved expanded access day,” McCallum said. “We don’t just refer to it unusual position. Since Janssen did not complete old woman who lives near Seattle is willing to program at the health center to treat patients once a year as a news release. We’re actually its new drug application, domperidone was never take those risks. with domperidone. They also have co-authored generating the data. We’re living it. And we approved by the FDA to treat gastric disorders “Domperidone is one of the only things numerous reports advocating domperidone as just don’t see it. We don’t see it, and we have or any other condition in the United States. The that has helped my gastroparesis and helped the only viable treatment for many patients and to be convinced a lot more that we’re missing expanded access program is a means to allow improve my quality of life,” Cox said. “I’ve told a much safer alternative to other FDA-approved something because we’re doing everything we patients to be treated despite that, he said. many people many times I truly don’t know therapies in patients who are properly screened can not to miss it.” However, McCallum said risk aversion at the what I would do if I didn’t have it. The times and monitored. Sarosiek notes that every patient treated FDA does seem to be a factor in the way dom- I have had to go without, they’re miserable. Fears about heart risks are overblown through the FDA’s expanded access program peridone is treated. While there is scant evidence It’s horrible. There’s times when I’ve wound and based on academic research outside the must be closely monitored and any adverse of harm, any possible link to heart problems is up in the hospital because I haven’t had my real-world clinical setting where something the FDA is not likely to ignore. domperidone and I’ve gotten so sick and I can’t patients are treated on a daily “It’s really all that theoretical risk,” McCallum maintain it on my own.” basis, McCallum said. The academic said. “It’s not so much a headache or tremor. The signs of gastroparesis started with studies cited by the FDA and other “That’s something that if the FDA had It’s a cardiac event and that makes people very stomach spasms when Cox was in high school. critics of domperidone tend to nervous, and that’s why there’s this paranoiac Within six months, she became extremely be “very, very, very poor quality concerns, it would already be known approach.” ill with nausea, vomiting, bloating, diarrhea studies,” he said. Further complicating the FDA’s attempts to and constipation. She was unable to keep Many studies were done in to all of us and it would be discussed regulate domperidone is that it is readily avail- any food down. Her deteriorating condition countries where domperidone was at the gastroenterology meetings, able in other countries, Sarosiek said. So rather required multiple hospitalizations because of sold over the counter and failed to than go through the FDA-approved process, dehydration and other health concerns. account for other factors such as and we would all know the drug is some doctors might simply tell their patients “I would throw up for days on end, complicating medical conditions about the benefits and risks of domperidone and anywhere from three hours to three days,” Cox and other drugs the patients were dangerous. This is not the case.” inform them that it can be obtained without a said. “I would vomit continuously. I could not taking that also have been linked prescription at a pharmacy in Mexico. keep food down. I could not keep water down. I to QT prolongation and other heart – Dr. Irene Sarosiek “They learn very quickly that patients can get could not keep anything down.” this drug from another country across the bridge About seven years ago, doctors identified

6 • DOMPERIDONE • RIGHT TO TRY ACT RIGHT TO TRY ACT • DOMPERIDONE • 7 Cox’s condition as gastroparesis and put her Dr. Irene Sarosiek and “It’s really all that on domperidone. She regularly undergoes Dr. Richard McCallum theoretical risk. It’s not electrocardiograms and other monitoring. Those tests have not shown any problems with her so much a headache or heart. The only side effect from domperidone tremor. It’s a cardiac has been lactation. To control that, Cox takes periodic “medication vacations” in which she event and that makes stops taking it until the milk production ceases. people very nervous, and Those are difficult times, she said. During one of those breaks, doctors tried that’s why there’s this Reglan and she did not respond well, she said. When Cox was first put on domperidone, it paranoiac approach.” was easy to obtain from a local compounding pharmacy, she said. About two years ago, when – Dr. Richard McCallum the FDA began enforcing its ban aggressively, Cox was notified domperidone was only ap- proved as a veterinary medicine, and therefore her local pharmacy could no longer supply it. She was forced to temporarily go without and the severe symptoms returned. Eventually she found a mail-order pharmacy in Canada to fill the prescription from her doctor. But she knows her supply could be cut off at any time. “I would be forced to be trying other medications which I’ve already tried, which didn’t work,” she said. “I would be basically back to ground zero. Without domperidone, they don’t really know how else to get my stomach to function properly.”

DOSING DISPUTE

here is not much dispute that domperidone is effective in treating T patients with gastroparesis, nausea and vomiting. Even the FDA grudgingly acknowledges that. There also is general acknowledgment that, like any drug, domperidone can be dangerous in very high doses for some patients. That was largely established in the 1980s when at least seven cancer patients developed serious cardiac conditions, including QT prolongation, when they were given rapid infusions of domperidone intravenously during chemotherapy. The intravenous formula was pulled from the market in 1985.

8 • DOMPERIDONE • RIGHT TO TRY ACT RIGHT TO TRY ACT • DOMPERIDONE • 9 What is in dispute is whether the pill form taking domperidone. Among past users, there arrhythmias, but studies do not substantiate Because Janssen withdrew its application, of domperidone is dangerous at doses used was no statistically significant risk. cardiac adverse events in patients receiving oral domperidone never was approved for sale in to treat patients with gastroparesis, and if it For comparison, that is the same risk of administration of domperidone, even at very the United States by the FDA. is, whether those risks can be minimized with sudden cardiac death that is associated with high doses,” the study concluded. Officials at Janssen Pharmaceutical refused proper screening and monitoring. erythromycin, a commonly prescribed antibiotic Both advocates and critics of domperidone’s to comment. Many commonly used drugs have been that is FDA approved, has been widely used safety cited other research during an October Domperidone remained readily accessible linked to QT prolongation, which in itself is since the 1950s, and has also been linked to 2015 hearing by an FDA committee weighing in the United States because of the way not fatal. What is of concern is whether the QT prolongation. Studies have found the risk whether access to the drug outside the compounding pharmacies were historically connection is strong enough to prove causation, of sudden cardiac death among people taking expanded access program should be allowed. treated in the law. They were free to fill and whether the prolongation is severe enough erythromycin is about double those not taking The FDA acknowledged an assessment prescriptions from doctors, obtaining that it could trigger serious events including it. There was no significant increase in risk done for the European Medicines Agency in domperidone from foreign suppliers and ventricular arrhythmia — an uncontrolled among past users. 2014 that found “no clinically relevant effect blending it into doses for individual patients. irregular heartbeat — or sudden cardiac death. Erythromycin is sometimes prescribed by of domperidone” on QT intervals when given In 2004, the FDA imposed its first import The FDA’s conclusion that domperidone doctors to treat gastroparesis, though it is not at normal doses to healthy patients. However, restriction, citing concerns that domperidone is too dangerous to be used outside its FDA-approved for that condition. FDA officialsdismissed those results because was improperly being used to enhance lactation limited access program is based largely on Critics in the medical and academic doses far higher than those that would normally in nursing mothers. two separate studies done in Canada and the communities dismissed the Johannes and van be used for treatment were not studied. Those The import alert notes that the intravenous Netherlands in 2010. Noord studies as flawed. One common criticism “supratherapeutic” doses would better reflect form of domperidone had been linked to The Canadian study, authored by Catherine is they examined elderly patients. The mean age “the real-world worst-case scenarios” that can cardiac arrhythmias and sudden deaths. It Johannes and four other researchers, was of those in the Johannes study was 79.4 years occur with domperidone use, according to the warned women not to take domperidone to based on electronic medical records of people old. In the van Noord study, the mean age was FDA. They were not studied because of ethical enhance milk production, but did not offer receiving government-paid health care in 72.5 years. concerns about exposing patients to very high a specific warning against taking it to treat Saskatchewan between 1990 and 2005. It The Johannes study also lacked doses of a drug with known potential dangers. gastric conditions, other than to note it is not identified patients who experienced sudden transparency, failing to mention the number Committee member Dr. Lin Chang, professor approved for any medical condition in the U.S. ventricular arrhythmias and sudden cardiac of cases and controls in subgroups based on of medicine at the University of California, Los The alert notified agency field personnel to death while using domperidone or another variables such as age, according to a separate Angeles, summed up the conflicting data during watch for attempts to import domperidone so it type of treatment, proton pump inhibitors, and study published in 2014 in the Canadian Journal the hearing by saying, “I do think that these are could be “detained and refused admission into compared the outcomes to those who were not of Hospital Pharmacy. Even at that, the data in low-quality studies, unfortunately.” the U.S. if appropriate.” taking either medication. the Johannes study indicated the number of Despite the alert, the FDA was unable to The Johannes study concluded that the risk cases in subgroups was small. enforce the ban effectively because the law that of a sudden ventricular arrhythmia or cardiac And while the Johannes study essentially COMPOUNDING gave it authority over compounding pharmacies death among those taking domperidone was merged its overall findings to show a 59 was essentially in legal limbo. about 59 percent greater than those who were percent increase in risk, it also showed that COMPLICATIONS Compounding pharmacies were historically not taking the drug at the time of the event. the correlation was higher among patients regulated by states with little oversight from the The Netherlands study, done by Charlotte more than 60 years old. However, there was egulation of domperidone in the United FDA, even though the agency had at least some van Noord and her colleagues, used a no statistically significant increase in risk for States has followed a twisted path regulatory authority since passage of the Food, health database to track domperidone use patients 60 years old or younger. R since Janssen withdrew its application Drug and Cosmetic Act in 1938, according among people who had non-fatal ventricular The van Noord study faced similar criticism, for new drug approval. After its introduction to a series of reports from the Congressional arrhythmias and sudden cardiac deaths. A total including its reliance on elderly patients. in 1978, domperidone was used extensively in Research Service. of 1,366 cases were identified, 1,304 of which McCallum of Texas Tech co-authored a study Europe, Canada and other countries to treat a By the mid-1990s, there were mounting were fatalities. Of those, the study found 10 published in 2015 that noted only 10 of 1,304 variety of gastrointestinal conditions, including concerns that some pharmacies were abusing patients who died while taking domperidone at patients in the van Noord study were using gastroparesis, nausea and vomiting. It also that exception to essentially manufacture and the time of a sudden cardiac death, and none domperidone at the time they experienced was used to treat less-serious ailments such as sell drugs on a large scale under the guise who were taking it at the time they experienced sudden cardiac death, “which translates to a heartburn, upset stomach and constipation. of compounding. In 1997, Congress gave the non-fatal ventricular arrhythmias. statistically non-significant increased risk.’’ Some nursing women also took it, sometimes FDA broader powers to define and regulate The van Noord study concluded the risk for “Domperidone has the potential for on the advice of their doctors, to enhance milk compounding pharmacies. either ventricular arrhythmia or sudden cardiac cardiac side effects based on concerns for QT production, one of its side effects. The revised law also specified compounded death was double among patients currently prolongation and increased risk of ventricular In many countries, it was available over the drugs could not use as ingredients any drugs counter. that had been withdrawn or removed from the

10 • DOMPERIDONE • RIGHT TO TRY ACT RIGHT TO TRY ACT • DOMPERIDONE • 11 market because they were found to be unsafe ‘BENEFITS OUTWEIGH Canada also issued guidance on or ineffective. growing concerns about domperidone Since domperidone was never approved for THE RISKS’ use in 2015, recommending a maximum use in the United States, it was never removed dose of 30 milligrams per day and re- or withdrawn from the market. bout that same time, European officials stricting use on patients with heart con- The 1997 law also included a provision were scrutinizing the links between ditions or taking other drugs. that barred compounding pharmacies from A domperidone and QT prolongation, About 2 million prescriptions for advertising. That provision was challenged as largely because of the Johannes and van domperidone were written in Canada a violation of free speech on First Amendment Noord studies. In 2013, the European Medicines in 2013, according to the government’s grounds. A federal judge in Nevada agreed and Agency re-evaluated the risks and benefits of safety review. At the time of its 2015 voided the advertising restriction, but said the domperidone and recommended changes in the review, Health Canada had received 18 balance of the law could remain intact. way it is used. reports of serious adverse heart events in The 9th U.S. Circuit Court of Appeals agreed The FDA, in a report to the review commit- people who took domperidone, none of the advertising prohibition violated the First tee that met in October 2015, characterized the which were deaths. Twelve of those cases Amendment, but said it could not be severed EMA’s actions by saying the use of domperi- were evaluated to determine whether from the other provisions of the law. That meant done “has recently been significantly restricted domperidone was the cause of the heart the entire statute was void. because of cardiac safety concerns.” But what event. The agency concluded that while it But when the government appealed to the the EMA recommended was that domperidone was a possible cause for heart problems, U.S. Supreme Court, it challenged only the find- be retained as a treatment for symptoms of “it is difficult to determine to what extent ing dealing with the speech issue, not the law’s nausea and vomiting, but not for other less-se- domperidone contributes to heart events severability. When the high court ruled against rious conditions like heartburn and bloating. It because other conditions known to the agency on the free speech argument, it did advised the recommended dose be reduced cause electrical heart problems were also not resolve the issue of severability, creating a from 20 milligrams to 10 milligrams, three times present in many cases.” legal mess when it came to the enforceability of per day. Health Canada also did not express a nationwide import ban. In the United Kingdom, Belgium and the confidence in the Johannes and van In 2012, the FDA issued another import alert, Netherlands, the non-prescription status of Noord studies or other research sug- this one much more ominous than its warning domperidone was revoked and it was made gesting domperidone was the cause of eight years earlier. It declared importation prescription only. About 2 million people took serious cardiac events. of domperidone “presents a public health domperidone in the United Kingdom annually. “Studies in patients have shown risk” and is against the law except in certain While the FDA characterized the European that domperidone may increase the circumstances, including approved research or reaction to safety concerns as significant, the risk of sudden death and serious abnormal symptoms for several years prior to that. She through the expanded access program. Even warnings themselves were less ominous. A heart rhythms,” the Health Canada report and her husband, Army Sgt. Patrick Stewart, then, domperidone was still readily available, safety alert issued by the British Medicines says. “However, these studies had limitations, led active lifestyles that included kayaking and either through mail-order pharmacies outside and Healthcare Products Regulatory Agency including small numbers of patients, and the skydiving. the United States or as a veterinary medicine. (MHRA) in May, 2014, characterized it as a possibility that factors other than domperidone Roberta Stewart worked as a paralegal and Then, in 2012, a meningitis outbreak linked “small increased risk of serious cardiac side could have led to the heart events.” business consultant. Her husband, a Desert to more than 50 deaths was traced to unsani- effects.” Storm veteran, completed his active duty and tary conditions at a compounding pharmacy in The advisory recommended people with enlisted in the Nevada Army National Guard. In Massachusetts. The outbreak had nothing to do heart trouble or taking other drugs linked to ‘ANGRY WITH 2005, he was deployed to Afghanistan. with domperidone, but it prompted Congress QT prolongation not take domperidone. It also At first, Roberta Stewart was not too to renew the FDA’s authority over compound- indicated domperidone was appropriate for MY COUNTRY’ concerned about the queasiness she felt in her ing pharmacies by passing a new law in 2013. children less than 12 years old at reduced doses. stomach, dismissing it as nerves associated with The new law was virtually identical to the 1997 The review demonstrated “the benefits oberta Stewart of Cottonwood, Ariz., is her husband’s deployment. law, but without the advertising restriction. outweigh the risks of using domperidone not worried about a sudden death from Her fears were realized in September 2005. Since then, the FDA has enforced its import ban when used to treat nausea and vomiting, but R domperidone. She is worried she will die Patrick was killed when the helicopter he was on domperidone more aggressively, and has that there should be restrictions on its use,” a slow and miserable death because she cannot flying in was shot down. warned compounding pharmacies of potential Dr. Sarah Branch, the deputy director of the get it. Stewart became embroiled in a fight legal action if they continued filling prescrip- MHRA’s vigilance and risk management of Stewart, 47, was diagnosed with gastropare- with the Department of Veterans Affairs over tions for the drug. medicines division said at the time. sis in 2010, although she had suffered from the the placement of a religious symbol on her

12 • DOMPERIDONE • RIGHT TO TRY ACT RIGHT TO TRY ACT • DOMPERIDONE • 13 husband’s tombstone. The Stewarts practiced As the FDA tightened its importation ban, Unable to keep down food or even water, of domperidone dried up and got more Wicca, a religion based on the belief in the it became ever more difficult to obtain dom- she lost 80 pounds in four months. expensive, Sherman said. The added restrictions magical powers in nature. peridone through Canada, Stewart said. With Even after the gastroparesis was diag- and rising cost forced her to stop taking The VA refused to recognize the Wiccan supplies dried up, and with Reglan not a viable nosed, doctors were reluctant to try domperi- domperidone about six months ago, after eight symbol of a five-pointed star in a circle. The fight option, the only treatments left were pain pills done, Sherman said. They put her on a variety years of using it successfully. gained national media attention and several and a feeding tube. She wound up with renal of gastric medications, none of which worked. The old symptoms quickly recurred, and elected officials intervened on Stewart’s behalf. failure and was placed in hospice care to die. When they tried Reglan, she almost immediately have left her nearly bedridden. But the controversy brought added stress, and the Somehow, she didn’t. developed the muscle twitching that is a known Now, she is trying to qualify for an FDA- queasiness turned to nausea and severe vomiting. Stewart said her weight dropped below side effect of the drug in some patients. It also approved expanded access program in the “It just gradually got worse to the point that 100 pounds, far less than her normal weight triggered severe anxiety that required hospital- Philadelphia area, so far without success. I was vomiting all the time and the abdominal of about 140 when she was healthy. After ization. As her condition deteriorates, she worries pain was just so painful that I was calling 911 at nearly dying five times, she’d had enough. The first gastroenterologist she saw refused she is running out of time. all times and going into dehydration seizures,” She stopped taking the pain pills and refused to prescribe domperidone. That was about the “I see my life going in a downward spiral,” Stewart said. “I’ve always been a person that further invasive treatments. time the FDA issued its first alert. He said he Sherman said. “Since I have not been able to can’t sit still for more than an hour. And all that “I just left it to a higher power,” she said. was concerned he might face sanctions if he get it, it’s been a lot worse and I’ve gotten a lot changed. It took my entire life away. I can’t even Stewart survives now largely on nutritional sent a patient to Canada to obtain the drug. more depressed. Just waiting is very difficult. go check the mail any longer.” drinks and homeopathic treatments that involve The second doctor agreed to write a single Not knowing is very difficult.” Stewart’s doctors spent three years trying about 100 injections per week of a mix of prescription, but said he could not continue to figure out what was wrong with her. She vitamins and amino acids that seem to help. treating her. underwent intensive surgeries that left her It’s expensive and not covered by insurance, so Finally, Sherman found a third esophagus and colon paralyzed. They tried she’s not sure she will be able to continue when gastroenterologist who was willing to “I see my life going in a downward Reglan, but that caused severe seizures and had the money runs out. prescribe domperidone for longer-term to be discontinued. Her weight has stabilized at about 115 treatment, which she obtained through a spiral. Since I have not been able Finally, in 2010, after she was diagnosed pounds, but she has difficulty maintaining it. pharmacy in Canada. with gastroparesis, Stewart’s doctors tried “I was very disappointed when I could no “It was excellent,” she said. “I could to get it, it’s been a lot worse and domperidone. longer get (domperidone) and very angry that get out of the house. I could start doing It was not a cure-all. But at least with they had taken away the one and only drug that things again. I could eat. I ended up I’ve gotten a lot more depressed. domperidone, Stewart was able to start living gave me any kind of assistance at all,” she said. gaining weight back.” Just waiting is very difficult. Not something akin to a normal life. She could eat “It gives us a lifestyle where we can maybe get She has been taking domperidone for small bites of food without triggering excruciating out to lunch with our mother once a week. They about eight years. Her doctor discussed knowing is very difficult.” pain and vomiting. are taking something away that at least allows the risks before starting it, and runs tests “Domperidone was the best thing for me,” us to get some nutrition into our body. on her heart at every visit. – Yvanna Sherman she said. “I wouldn’t have to run to the bathroom “I was so angry with my country, the “I’ve never had a problem, but I’m and vomit after eating. So it controlled that and government, the FDA that they did this to us.” also willing to take that as a risk because allowed me to live a more functional life. I did start I’m of the opinion that if I go too long seeing some hope.” without domperidone, I’m going to be at risk of WORKAROUND Stewart had to go through a pharmacy in ‘RISK OF DEATH’ death,” Sherman said. Canada to fill the prescription. At first it was not The doctor who prescribed the he FDA’s expanded access program is difficult. But the FDA’s restrictions created other or Yvanna Sherman, 42, of Philadelphia, domperidone also put Sherman on a gastric supposed to be a workaround for people complications, she said. the FDA’s rigorous enforcement of its pacemaker, an implanted device which T with gastroparesis who cannot get Even with the domperidone, Stewart could not F ban on domperidone leaves her little electrically stimulates the stomach muscle to domperidone because of the agency’s efforts eat normally and she periodically was hospitalized hope of leading a somewhat normal life. With control nausea and vomiting. to shut down importation and compounding. with complications or for hydration therapy, supplies dwindling and the cost shooting up, At one time, Sherman and her husband There is not much evidence it is working. The which was needed because her body was unable getting into the agency’s expanded access considered moving outside of the United States FDA refuses to say how many people are being to properly absorb even water. But because program may be her last chance to get the drug to obtain domperidone, but that would mean treated through the program. domperidone was not approved by the FDA to that helped save her life, she said. she could no longer qualify for the pacemaker, Beener, the Florida woman who uses treat her condition, she was not allowed to take it Gastroparesis came on suddenly about she said. domperidone, says she has known thousands in the hospital, so that led to a cycle of stopping 2004 for Sherman. She lost her appetite, was About 2014, as the FDA was more of people with gastroparesis through her work and starting the treatment. vomiting frequently and in extreme pain. aggressively enforcing its import ban, supplies with the Gastroparesis Patient Association for

14 • DOMPERIDONE • RIGHT TO TRY ACT RIGHT TO TRY ACT • DOMPERIDONE • 15 Cures and Treatments (G-PACT), a volunteer serious incidents and patient deaths, and get ‘UNWORKABLE’ (PCAC). The committee was established to organization where she serves as operations approval from the drug manufacturer. determine whether certain drugs should remain director and a member of its board of directors. Any treatment plans also must be approved COMPASSION available for compounding. She knows only one person who is treated by institutional review boards (IRBs), internal The 2013 changes in federal law prohibited through the FDA’s expanded access program. panels that weigh the ethics and risks of he domperidone program is somewhat compounding of any drugs unless they met at McCallum, the Texas Tech doctor, said about treating an otherwise terminal patient with a unique, in that it treats patients with a least one of three conditions. Compounding 100 to 120 patients are getting domperidone drug that has not received final approval from T drug that is not in clinical trials or under is permitted if the new medication uses only treatment through the expanded access program the FDA. Doctors cannot charge for the cost of review for marketing approval by the FDA. drugs already approved by the FDA. It also is al- in El Paso. preparing the application, developing treatment The agency has streamlined the process lowed for drugs that have a “monograph” from The FDA did say that its review of data protocols or securing IRB approval. somewhat for the domperidone protocol by the U.S. Pharmacopeia or National Formulary, from all retail, mail-order and long-term care Normally, expanded access programs developing the model treatment plan. But which set standards for the strength, quality pharmacies in the United States shows between are available only to patients with serious its instructions for doctors seeking to treat and purity of medicines. 7,500 and 11,600 prescriptions for domperidone or life-threatening ailments to obtain drugs patients through the expanded access program Domperidone does not qualify. were dispensed annually between June 2009 undergoing clinical trials. Those are the years- still list a litany of requirements, including The third category allows a drug to be and May 2015. Only one pharmacy is authorized long studies conducted by the drug makers IRB approval, extensive patient monitoring, compounded if it is placed on a list developed to distribute domperidone through the expanded to develop data they will use to show their reporting adverse events and submitting an by the secretary of the Department of Health access program, and must report the information products are safe and effective when they annual report for each patient. and Human Services. The secretary also was to the FDA. submit their new drug application to the FDA “It’s completely unworkable for any health required to create an advisory committee to Those numbers compare to the 2 million for authority to sell it. care practitioner in a community setting,” said develop the list of products that would be prescriptions filled annually Dr. A.J. Day, a pharmacist and director of phar- available for compounding until final rules are in Canada and an estimated macy consulting at PCCA, a drug wholesaler published by the agency. 2 million domperidone users that supplies local pharmacies. That committee is the PCAC, which weighed in the United Kingdom as of Day’s company nominated domperidone domperidone at the October, 2015, meeting. 2013. for inclusion on the list of drugs that could be FDA officials recommended domperidone FDA officials compounded. not be allowed for compounding, citing fears acknowledged many people Day tried to navigate the process to qualify that it had been linked to QT prolongation and are getting domperidone under the expanded access program to see how that some doctors could prescribe it to enhance from sources other than difficult it would be. He couldn’t get past the lactation. domestic pharmacies and first step, approval from an IRB. Those with gastric conditions who need outside the expanded access Day said he contacted more than 30 domperidone could obtain it through the program. leading research hospitals and clinics around expanded access protocol, which ensured they The FDA’s expanded the country. None would agree to provide IRB are properly screened and monitored, said Dr. access system is so layered reviews for doctors who are not on staff or have Catherine Sewell, who presented the FDA’s case with paperwork, bureaucracy admitting privileges. and recommendation. and financial disincentives Day did find one independent IRB, which “Given the safety concerns, there is that it is bound to fail in most charged in excess of $3,000 to review the appli- potential for significantharm to the public if cases, the Goldwater Institute cation for a single patient. When he contacted domperidone is prescribed and used without found in an investigative the FDA for assistance, he was told all anyone important safeguards to ensure patient report published in February there could do was read the directions posted protection,” Sewell said. 2016. Doctors seeking to on the website. They could not help him find an Dr. Anil Rajpal, another FDA presenter, said treat patients through IRB or explain anything on their website. doctors who want to treat patients through the expanded access, also known “So this idea that the (expanded access) expanded access protocol have to go through a as “compassionate use,” had IND is a solution creates more problems than it simple process that involves filling out atwo- to commit to an estimated actually solves,” Day said. page form. 100 hours just to fill out Whether the expanded access program is “It’s a standardized form. So there’s just the agency forms. They a realistic alternative for gastroparesis patients portions to complete,” Rajpal said when asked must develop and submit who need domperidone was a key issue whether it is practical to expect a front-line treatment and monitoring discussed at the October 2015 meeting of the doctor to qualify under the program. “It’s a two- plans to the FDA, report all Pharmacy Compounding Advisory Committee page IND.”

16 • DOMPERIDONE • RIGHT TO TRY ACT RIGHT TO TRY ACT • DOMPERIDONE • 17 When asked directly how many patients are me that that’s coming from someone who hasn’t the review process, FDA officials consistently safe and effective drugs, such as those in the being treated under the protocol, Jane Axelrad, tried to get an expanded IND.” discounted studies that show domperidone can European Union, Canada and Australia. This associate director of regulatory policy at the Dr. Gigi Davidson, a committee member be safely used in properly screened patients while would allow drugs approved in those countries FDA, refused to answer, saying that information representing the U.S. Pharmacopeial Convention, overhyping those that suggest some risk, he said. to be accepted for use in the United States, even was confidential. Agency officials also would not said access to the drug through Canada or “This is beyond risk aversion,” Day said. “That if they have not completed the FDA’s testing provide a figure to the Goldwater Institute. Mexico makes it unlikely most front-line doctors lack of impartiality is just blatant. There’s not even and approval process. would go through the FDA’s paperwork to an attempt to hide it. There is an absolute lack Aside from making certain life-saving drugs qualify for the expanded access program. of impartiality when it comes to assessing the available more quickly in the U.S., reciprocity ‘HEADS IN THE SAND’ Davidson, a veterinary pharmacist, also risk versus benefit equation which goes into all would create an incentive for FDA regulators to noted domperidone is available in the United medications.” approve new medications that are proven safe ront-line gastroenterologists and States as a veterinary medicine used to FDA officials would not agree to an interview. and effective rather than continually subject pharmacists rebutted the notion that treat horses. Every week, she gets calls from them to new rounds of testing long after they F qualifying for the FDA protocol is simple. people asking about the veterinary form of have gone into widespread use around the “The IND process is cumbersome, time- domperidone, she said. OUT OF OPTIONS world, Olsen said in her book, The Right to Try. consuming,” said Dr. Alan Diamond, a Davidson said she struggled with the “If domperidone is available in Canada, for gastroenterologist in Montgomery County, Md. question of whether patients are best served by eener said she has hope that Congress will heaven’s sake, it should be available here. That’s “It takes hours to fill out your papers. Trust me expecting them to get domperidone through intervene at some point, especially in light simple,” Olsen said. that nobody is going to fill out those papers to the heavily regulated expanded access program B of the Right to Try movement spearheaded “Countless Americans with terminal illnesses get domperidone for their patients. It just isn’t “which appears to be inaccessible,” or through by the Goldwater Institute. More than 30 states and conditions like gastroparesis face the going to happen. So you’re actually depriving other sources that are less controlled. have passed Right to Try laws, which would allow terrible choice of spending their final days them of that drug.” “I’m really struggling with the gap between patients with serious or life-threatening conditions traveling abroad in search of medical care, Dr. Richard Moon, a compounding patient access and total, uncontrolled availability to access drugs that have not completed clinical facing prison for illegally accessing medicine pharmacist, testified the ability of patients to of it by going to the equine product and going trials or been approved for use by the FDA. through the U.S. underground, or dying. The get domperidone in other countries coupled across the border,” Davidson said. Domperidone would not FDA insists that all treatments with the difficulty of qualifying for the expanded At an earlier public hearing in May 2015, qualify under Right to Try. While must be approved firsthand access program forces many patients to get the the FDA took testimony from numerous gastroparesis is classified as by them, but why not consider drug outside of FDA-approved channels. The patients with gastroparesis who described how a serious or life-threatening “If domperidone alternative approval? Letting result is they face greater risks because there is domperidone had worked for them and asked condition by the FDA, Right to Americans access treatments no guarantee they will be properly screened or that they be allowed to continue accessing it. Try laws specify a drug must is available in available in Canada simply gives monitored, or that their domperidone use will One described domperidone as “my magic have completed the first phase of Canada, for Americans the same opportunities show up in their medical charts. bullet” and a “godsend.” Another said she felt testing to establish its safety, and as Canadians.” “We are not protecting the public” by “blessed” when she started taking it. must continue to be under review heaven’s sake, Beener of G-PACT said people prohibiting the compounding of domperidone, “It saved my life, literally,” she said. in clinical trials. like her with gastroparesis fear Moon said. “We’re just poking our heads in the Despite pleas from patients and their Because domperidone is not in it should be the day when the FDA is able to sand and letting the world go on around us. own concerns about the viability of the FDA’s clinical trials in the United States, fully enforce its import ban on “The vast majority of clinicians simply will not expanded access program, committee members patients could not be treated available here. domperidone. She also resents follow the IND process when they can get the voted 8-3 to ban compounding of domperidone. under the law. That’s simple.” the federal government telling her medicine elsewhere without the extra headache.” It was the first drug added to the list of products There have been bills in she can no longer have access to a Even committee members were skeptical that cannot be compounded. Congress that would allow – Darcy Olsen drug that she has taken safely for of the effectiveness of the expanded access What happens next is unclear, said Day, the patients with serious or terminal 15 years and has changed her life, program. pharmacist. The 2013 law requires the Health illnesses to access drugs that all in the name of protecting her. “The expanded IND process is too difficult and Human Services secretary to develop a are approved for sale in the European Union or “The FDA has become my parent and I don’t for everyone to be able to use, and probably for permanent list of permitted compounds. Unless Canada without interference from the FDA. None like that,” Beener said. “I should have the right most people to be able to use,” said Dr. John the FDA changes its view of domperidone, its has passed. to determine whether or not I should be able to DiGiovanna, a staff clinician at the National status is not likely to change, he said. Darcy Olsen, chief executive officer of the take something that helps me. I understand that Cancer Institute and a member of the committee. There’s not much chance of a change in Goldwater Institute, says the United States should they are trying to be protective. But tell me the “To use in the equation that the expanded IND attitude about domperidone given the agency’s have a policy of regulatory reciprocity with other risks and then let me make my own decision. I is an acceptable alternative really suggests to history of risk aversion, he said. Throughout countries that have a proven record of approving don’t need a nanny.” J

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