3

Patients’ Experiences

Individual speakers at the workshop focused specifically on the experiences of patients who seek out stem cell therapies. Many of these patients suffer from life-threatening conditions and cannot wait for therapies to be developed in clinical trials. Yet some are spending their life savings on treatments that are very unlikely to be effective. Patients who engage in what has become known as stem cell tourism consult with their own physicians before going to a stem cell clinic in their home countries or abroad. Yet some also feel abandoned by the medical system, especially when they cannot gain access to clinical trials or to the therapies being tested in those trials (for a summary of highlighted points, see Box 3-1).

BOX 3-1
Summary from Individual Speakers About Discussions
on Regulation and Patients’ Expectations

  • Patients can be motivated to seek treatments outside of their home countries for reasons such as cost, quality, and circumventing domestic laws or regulations. (Cohen)
  • Regulation could encourage the responsible development of stem cell therapies while allowing greater access to experimental treatment. (Cohen)
  • Government encouragement of accreditation and experimentation would generate a more positive response from patients than simply prohibiting access to clinics. (Cohen)
  • Providing more accurate information about treatments to patients does not necessarily mean that the information will affect their decision to take risks on unproven therapies because other factors, such as hope, can play powerful roles in medical decision making. (Charo, Petersen)


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3 Patients’ Experiences Individual speakers at the workshop focused specifically on the ex- periences of patients who seek out stem cell therapies. Many of these patients suffer from life-threatening conditions and cannot wait for ther- apies to be developed in clinical trials. Yet some are spending their life savings on treatments that are very unlikely to be effective. Patients who engage in what has become known as stem cell tourism consult with their own physicians before going to a stem cell clinic in their home countries or abroad. Yet some also feel abandoned by the medical system, especially when they cannot gain access to clinical trials or to the therapies being tested in those trials (for a summary of highlighted points, see Box 3-1). BOX 3-1 Summary from Individual Speakers About Discussions on Regulation and Patients’ Expectations • Patients can be motivated to seek treatments outside of their home countries for reasons such as cost, quality, and circumventing domes- tic laws or regulations. (Cohen) • Regulation could encourage the responsible development of stem cell therapies while allowing greater access to experimental treatment. (Cohen) • Government encouragement of accreditation and experimentation would generate a more positive response from patients than simply prohibiting access to clinics. (Cohen) • Providing more accurate information about treatments to patients does not necessarily mean that the information will affect their deci- sion to take risks on unproven therapies because other factors, such as hope, can play powerful roles in medical decision making. (Charo, Petersen) 17

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18 STEM CELL THERAPIES MEDICAL TOURISM: PATIENTS SEEKING STEM CELL TREATMENTS The medical tourism industry can be subdivided in three different ways, Cohen said. The first is by the legal status of the treatment. Some treatments are legal both in the patient’s own country and in the destina- tion country, such as hip replacements, cardiac bypass, and cosmetic sur- gery, while others are illegal both in the patient’s home and in the destination country, such as the sale of organs for transplantation. Final- ly, some are illegal in a patient’s home country but legal in the destina- tion country—a situation that Cohen termed circumvention tourism. Examples of treatments that attract circumvention tourism include abor- tion, assisted suicide, and stem cell therapies. In the case of stem cell tourism, a treatment may not be illegal in a patient’s home country, but rather it simply may not be approved. The second division is based on who is paying for the treatment, Cohen said. In some cases, patients pay out of pocket; in other cases, insurers are willing to pay. For example, some large insurers in the United States now offer incentives to private employers to send their patients abroad. In places that have universal health care coverage, the government may pay for individuals to be treated in other countries. The final division is according to where patients are traveling to re- ceive treatment. Patients may go from a developed country to another developed country; they may travel from less developed countries to more developed countries; or they may go from a developed country to a less developed country, which is common with stem cell tourism, Cohen said. Motivations for Stem Cell Tourism Patients have a variety of motivations for pursuing treatments abroad, Cohen said. These include cost, quality, circumventing domestic prohibition, inability to participate in clinical trials, and lack of access to unapproved treatments. For example, in the United States the FDA regu- lates such items as drugs, medical devices, and blood and biological products. Though the FDA does not regulate surgical interventions, legal barriers for patients getting experimental surgeries also exist. Insurers in the United States typically do not reimburse for experimental or investi- gational surgeries unless clinical effectiveness has been proven. Medical malpractice liability may also limit a surgeon’s willingness to provide

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PATIENTS’ EXPERIENCES 19 therapies. Finally, innovative surgery that is considered research is gov- erned by the Common Rule,1 which ensures proper protection of human subjects in research and essentially imposes an ethical and regulatory review restriction similar to that of clinical trials. Medical tourism to countries with more permissive drug approval or access regimes can be an enticing alternative for patients who want the drug or treatment in question, Cohen said. By traveling abroad, patients can engage in a form of “regulatory arbitrage” in order to get experi- mental therapy. While stem cell therapy and liberation therapy for MS are prominent current examples, medical tourism for experimental thera- pies has occurred for decades. Many U.S. patients used to travel to Mex- ico and elsewhere for treatment with laetrile and other experimental cancer therapies. However, laetrile was later shown to be ineffective and unsafe (Moertel et al., 1982). “One of the big questions is whether stem cell therapy is the laetrile of our generation,” Cohen said. Potential for Regulatory Involvement From a regulatory perspective, prohibiting stem cell tourism is diffi- cult, Cohen said. Stem cell therapies do not fit well into the current FDA model. Stem cells are living biological products susceptible to genetic instability and do not have the predictability of the small molecules that are used in pills. While some stem cell–based interventions may prove amenable to multistage clinical trial approaches, a surgical or transplan- tation approach may be more appropriate for others (Hyun, 2010). With those interventions, clinical trials are the exceptions rather than the norm because they are so hard to do properly. Cohen suggested that stem cell treatments may be better suited to the same regulatory constraints as transplantation and surgery instead of drugs, small molecules, or biologics. ISSCR—discussed in greater detail in Chapter 5—posed two ques- tions on its website for clinicians or patients considering stem cell thera- pies. The first asked about the protocol of a clinical trial and the head of the institutional review board (IRB) overseeing that trial, which was de- signed to indicate whether the trial was independent. The second asked which regulatory body had shown a treatment to be safe and efficacious. The website was viewed by a large number of people, but it also generat- ed a letter from a lawyer asking on whose authority these questions were 1 45 CFR part 46.

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20 STEM CELL THERAPIES being asked. In response, ISSCR shut down the website to avoid legal proceedings, Weissman said. The government needs to encourage accreditation and experimenta- tion that falls into the category of research rather than charlatanism, Cohen said. He suggested that a consortium of private and public actors, includ- ing the FDA and the EMA, could produce a quasi-governmental version of the ISSCR’s approach. By calling attention to such factors as IRB ap- proval, whether data from treatments are being published, and the inten- tion to pursue treatments in more widespread clinical trials, such an approach could provide a seal of approval. Eventually, accreditation may be the best option, with standards increasing over time. Cohen pointed to concerns about the lack of information about both safety and efficacy from treatments that are being performed in these clinics because they are not required to report this information. Treat- ments done outside the United States raise difficult issues in such areas as fraud, monitoring pediatric patients, and incentives to institute best practices. In particular, Cohen pointed to the involvement of children in stem cell therapies. “It is a very difficult situation for everybody in- volved,” he said. Physicians may try to educate parents about the risks or dissuade them from a particular decision. One question, Cohen said, is whether physicians also have an obligation to report cases to authorities in situations where treatment is considered not only ineffective but actu- ally dangerous. In such cases, it may be appropriate for the states to step in and exert medical guardianship, he suggested. PATIENTS SEEKING UNPROVEN OR UNREGULATED TREATMENTS Many factors drive patients to seek out unproven or unregulated stem cell therapies, said Petersen, who has been leading a sociological investi- gation into the phenomenon since 2009 (Seear et al., 2010). The reasons are underpinned by hope and the desire to exhaust all available options, particularly with parents who are seeking treatment for children, but also with adult patients. Many patients are disillusioned with the available medical care and see limited treatment options. They could be called desperate, but the language of desperation often simplifies the situation because it implies a lack of understanding and a lack of due considera- tion of all the risks. Internationally, many clinical trials involving stem cells are currently

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PATIENTS’ EXPERIENCES 21 recruiting subjects. However, the majority of these trials are in early stages and are only enrolling small numbers of patients (Trounson et al., 2011). As a result, patients are turning to overseas clinics as a way of receiving treatments that they cannot access in their home countries, Petersen said. Patients often learn about these clinics through word of mouth, such as from work colleagues or patient groups. Newspaper coverage spurs online investigations, especially with stories that frame stem cell research in a positive light, Petersen said (Petersen and Seear, 2011). Support from families, patient groups, and communities is often quite strong. Many of these groups even participate in fundraising efforts that make the trip possible. Patients generally do not receive strong attempts at dissuasion from clinicians or others when discussing these treatments, which is taken al- most as an endorsement, Caulfield said. The clinicians tend to believe that the therapies do not work and that a lot of the treatments are danger- ous, but they also want to keep their patient’s hopes alive, Petersen said. “They are, in a sense, managing patients’ hopes.” As Charo noted, there is an argument that patients should be able to seek out and receive treat- ments even if they are unproven or unregulated, especially when dealing with degenerative or terminal diseases. Ultimately, patients are more willing to tolerate uncertainty, and they have different conceptions of risk. An impression gained through early contact with a provider may be enough for a patient to decide that a treatment is worth the risk, Petersen said. Cohen added that countervailing testimony on clinic websites and in patient blogs can also be convincing enough to outweigh warnings about the potential health risks from the treatments. Individual decisions to seek stem cell treatments also occur in a larg- er political and economic context, Petersen noted. Stem cell treatments are just a subset of a range of different treatments that people can seek wherever they are available and must be seen within the context of the entire health and medical tourism industry (Connell, 2011; Kangas, 2010). For example, the World Health Organization has published re- ports on health and medical tourism and sees it as a potential contributor to the economies of developing countries (NaRanong and NaRanong, 2011). In Australia, in a case similar to the U.S. situation that Cohen de- scribed earlier, the insurer NIB Health Fund announced a plan to sell medical tourism packages to Australians who are looking for lower cost options in Asian clinics but with safety and quality guaranteed (Parnell, 2013).

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22 STEM CELL THERAPIES Patient Experiences In a study focused specifically on patients who sought treatment in China (Chen and Gottweis, 2013), patient testimonies were found to gen- erally include three themes, Cohen said. The first was suspicion about the motives of home country physicians who do not offer these treat- ments. The second was the fact that some consultation did take place with home country physicians about using Chinese stem cell treatments. The third was the idea that parents need to try everything for their chil- dren. As one study participant noted, “It is good to know you have done everything and you have tried everything for your child even if that means going offshore and trying something experimental.” Most of the parents did not get exactly what they want from these treatments, but they remained hopeful. They were often offered booster therapies as an incentive to return for more treatments, Cohen noted. Experiences during treatment were positive for many of the inter- viewees in Petersen’s project (Petersen et al., 2013). Respondents gener- ally had little knowledge about the source, storage, or handling of the stem cells used, but all respondents reported benefits from an initial treatment, such as stabilization of a patient’s condition or a minor im- provement in physical function. Sometimes they reported more substan- tial improvements. For example, one commented that while he was in India he began to breathe independently of his ventilator for the first time in many years. After the initial treatment, though, some people said they did not have any further benefit. But the initial positive experience led some patients to take multiple trips. None of the patients expected a “miraculous” recovery after receiv- ing their stem cell treatment, Petersen said. Rather they looked for small improvements and used subjective forms of assessment, such as being able to wiggle their toes. The improvements were not things that, in clin- ical terms, would be seen as restoration of function, and some Australi- ans did not experience the improvements they sought. Improvements could not be clinically verified and could not be linked to the stem cell treatment, as these patients are often exploring complementary and alter- native treatments in addition. In most cases, however, patients were pleased that they had at least tried it. The organizations offering these therapies are marketing hope, Petersen said.

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PATIENTS’ EXPERIENCES 23 How Patients Use Information More needs to be done than simply providing information to patients who are considering stem cell therapies, Petersen concluded. The idea of providing a package of information is based on assumptions about how patients understand information. It assumes that if people are given the requisite information they will act in a certain predefined way. But this is a limited way of thinking about how people make decisions. It does not take account of all of the other factors that shape decisions, such as ex- pectations developed by various constituencies or hope. For example, patients and clinicians each have their own set of hopes which often do not correspond. A full understanding of the issue will require a multifac- eted approach rather than just thinking about more information as the answer. ONE PATIENT’S EXPERIENCES Michael Phelan co-founded a successful software company and served as its chief executive officer (CEO) until he recently had to step down due to health issues related to MS. He has gone to top neurologists in the United States and has been on standard FDA-approved treatments for more than 6 years, but the treatments have not been effective for him. Not being satisfied with his existing options, he began to research promising clinical trials and found the results with autologous stem cell treatments impressive. But the only way to get this type of treatment in the United States is to be in an approved trial. Phelan tried to qualify for two separate trials that he identified, even paying $10,000 out of pocket for the testing involved for one trial, but he was told that he did not meet the requirements for either. He corresponded with physicians and re- searchers at the Stem Cell Institute in Panama, and after noting that they had published some of their research, he pursued therapy there, receiving an autologous stem cell treatment using cells that were derived from his adipose tissue. After his treatment in May 2012, the double vision prob- lems he had been having for the previous year resolved, and he was able to continue driving. His mental and physical energy also improved dramat- ically, as did other problems such as incontinence. “I was very pleased with the outcome,” he said. “I do not know the science behind it. I do not know if the trophic factors or the immunomodulation helped, but the bot-

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24 STEM CELL THERAPIES tom line was it helped.” Some people may think of stem cell therapy as a disservice, Phelan said, but “it helped me, so I consider it a service.” Extracting a patient’s cells and preparing them for reinjection carries risk, but so does banking blood or freezing cells for later use. Of more than 2,000 patients in 66 different completed trials that Phelan identified as using expanded mesenchymal stem cells, not a single adverse condi- tion had been reported. “To me that was easy to demonstrate safety. In fact, [this is] probably safer than some of the approved treatments.” Transplants and in vitro fertilization are regulated as medical proce- dures, but the FDA wants to regulate cells taken from a person’s body that are manipulated and injected back into that person’s body as a drug. “From my viewpoint, it looks like the FDA is more interested in protect- ing markets over patients,” Phelan said. If these types of treatments were available in the United States, they could be regulated in such a way that data could be collected on safety and efficacy. Phelan suggested that there may also be financial motives involved with trying to limit access to treatments. Many of those voicing safety concerns hold patents on potential stem cell therapies. While patents and financial incentives are not a bad thing, he said, it could indicate a con- flict of interest. If research on embryonic stem cells or induced pluripotent stem cells results in new, cell-based, mass-produced products, those products will require regulatory attention, Phelan noted. But autologous stem cell treatment is not something new. The use of one’s own cells for treatment is a one-on-one decision, Phelan said, and should be treated as the prac- tice of medicine for which multiple layers of regulation already exist. Accreditation could ensure that laboratories follow proper procedures, which is difficult to determine as an outsider and a nonprofessional (Trounson et al., 2012). More regulation will not stop charlatans or in- competent physicians from committing malpractice or malfeasance. That is why the civil tort system exists. But, he said, “if the safety has been proven, I do not understand why this has not become a standard treat- ment in this country.” Patients have to wait for legal decisions and clinical trial results. Un- fortunately, disease does not wait, Phelan said. “I consider this a crime against patients. For me, it is robbery. It robs my time and my money. But I am fortunate to have the resources to travel overseas for treatment. Not everyone does. This crime could cost them much more.”