Beating the evidence and regulatory game: Medical tourism and the direct-to-consumer marketing of stem cell therapies

Ubaka Ogbogu, LLB, BL, LLMAdjunct Associate Professor of LawAssociate Director of Research and EducationConsortium on Law and Values in Health, Environment and the Life Sciences & Joint Degree Program in Law, Health and the Life SciencesUniversity of MinnesotaBeyond evidence and regulation: Medical tourism and the direct-to-consumer marketing of stem cell therapiesOutlineMedia reports and examples of stem cell offeringsResearch objectives/questionsResearch methodologyResultsConclusionCurrent policy landscapeSomatic stem cell research has reached the clinical trial phase for diabetes mellitus, MS, stroke, myocardial infarction, among others.Therapies remain unapproved and unavailable outside of experimental trials due to knowledge gaps, technical challenges, and regulatory hurdles.*Only one approved hESC therapy clinical trial, currently on hold due to safety concerns. Stem cell cures: Ready for prime time?

Scientists do not recommend general access: (Braude et al., 2005; Coutts and Keirstead, 2008; Daley et al., 2003; Lassmann, 2005)3Putative Stem Cell Therapies and Offerings

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Research Objectives/QuestionsReview of media reports indicated that DTCA via the Internet plays an important rolePrimary objective was to document and characterize a novel occurrence of DTCAWhat sorts of therapies are offered?How are they portrayed?Is there clinical/scientific evidence to support the use of these therapies? Are they regulated and in what way?One cannot deprive the patient of the right to decide for himself/herself to die from the disease, incurable by conventional methods, or to risk and try a new method though not fully tested - NeuroVita Clinic in Russia

6Study methodsTwo prongs:Content analysis of websites offering stem cell therapies EBM-based analysis of peer-reviewed clinical evidence for primary human studies reporting clinical effects of any stem cell therapies*Websites identified through media reports and Google searches (final sample:19) and coded for therapeutic offerings, indications, claims, benefits, risks, cost of therapy, evidence, location of clinic, etc.Clinical evidence identified through comprehensive PUBMED search. 45 records met relevance criteriaInter-coder reliability testing completed on random sample

Content analysis - quantitative method widely used to characterize and evaluate Internet dataInter-coder reliability testing/Cohens Kappa measurements not completed*For indications associated with top 2 disease conditions: neurologic & cardiovascular7Content analysis results: Stem cell types offeredStem cell typeFrequencyAdult, autologous9Fetal6Cord Blood4Embryonic2Adult, allogeneic2Stem cell sourcesStem cell sourceFrequencyBone marrow7Blood or marrow donors5Peripheral blood5Fetuses4Fat2Unspecified2Other (animal sources (shark, sheep) and skin stem cells)3Transplantation procedureProcedureFrequencyIntrathecal, into CSF6Intravenous6Subcutaneous or intramuscular4Surgical transplantation4Catheterization of deep body vessels (injection deep into the brain via craniotomy or by injection into the spinal cord parenchyma via laminectomy)3By mouth1Topical1Treatment indicationsDisease conditionFrequencyNeurologic (MS, Stroke, Parkinsons, SCI, Alzheimers, etc)16Cardiovascular12Diabetes11Musculoskeletal11Cancer7Autoimmune (systemic), Blood (non-cancer), Gastrointestinal, Ophthalmic, Sex-related 5, respectivelyBlood, cancer4HIV/AIDS, Infectious (non-HIV), Dermatological, Respiratory3Allergies, Endocrine (non-diabetes), Nephrologic2PSYCHIATRIC111Benefits vs. Risks MentionedAll websites surveyed mentioned improvement of disease state as main benefit of treatment14 (74%) of the websites did not mention any risksFew websites mentioned procedural risks, and nonspecific fever and tingling as only risks of procedureExample statementsOf over 1800 patients we have treated, we estimate that 85% have gotten some kind of improvement and 80% have been satisfied with the improvements that they have gotten. We by no means guarantee improvement, but ... we are extremely surprised when patients do not get improvementTransplantation is a safe, painless procedure. It is conducted in a sterile environment by professional medical personnelList of contraindications against cell therapy is rather limited. No negative side effects were observedTreatment portrayalsIndications scored very or somewhat unclear or indeterminate in 68% of sites (websites use catch-all categories like aging, increased feelings of energy)12 of 19 websites has indications which spanned 4 or more broad disease categoriesBenefits portrayed as somewhat or very relevant in 79% of websitesRisks portrayed as very irrelevant in 74% of websites17 of 19 websites portrayed treatments as routine or somewhat routineCredibility established through numerous patient endorsements, patent claims, media reports, and publications

EmcellPublications either unavailable, do not exist, or are safety studies without randomization or double-blind controls14We have proved that the efficacy of autologous stem cell therapy in minor spinal cord injury ranges from 45 to 70%. Here everything depends on the size of the lesion, the level of injury, and the years post injury. The best results were obtained in the patients with thoracic level of injury; 2-5 years post injury and incompleteness of SCI Neurovita.ruLocationLocationNumber of clinicsMexico4China3India, Philippines, Russia, Thailand2Puerto Rico, Holland, Ukraine, Costa Rica, Barbados, Dominican Republic, Turkey, Germany1The average cost of a course of therapy among the four web- sites that mentioned costs was $21,500, excluding travel and accommodation for patients and care givers.16Clinical evidence study: Inclusion/exclusion criteriaTargeted indications mentioned 10 or more times in top 2 disease categories: neurologic & cardiovascularMS, Parkinsons disease, Stroke, Alzheimers disease, SCI, and autologous hematopoietic stem cell transplantation (AHSCT) for acute myocardial infarction (AMI)89 total records, of which 45 included. Excluded records were unavailable (1), duplicative, non-stem cell interventions, reviews, or non-English (2), or referenced no clinical outcomesStudy not focused on describing current state of stem cell medicineResultsEvidence for stem cell therapies for SCI and stroke is generally underdeveloped: small size, low methodological quality (e.g., no control group), and uncertain, negative, or contradictory findingsNo studies of stem cell therapy for Alzheimers or ParkinsonsSome history of stem cell therapy for MS, but clinical outcomes are variable and not obviously better than the natural history of patients with multiple sclerosisTreatment recommendations made on the basis of the reviewed evidence likely to be low gradeTreatments offered by websites generally unsupported by clinical evidence

Study LimitationsPublicly available information is not indicative of information actually shared with patients during clinical encountersWe did not analyze actual outcome data for particular clinics. Instead we showed that high quality supporting evidence is lackingBias from exclusion of non-English studies. However only 2 such studies were excluded 19ConclusionsDTC portrayal of current stem cell medicine appears optimistic and unsupported by clinical evidencePatients may not be receiving proper or accurate information, and are subject to inordinate risk and financial burdenClinics may be contributing to stem cell hypeTourism aspect complicates post-treatment monitoring, protection of patient rights and regulatory scrutiny

Tourism is necessitated by unavailability of treatment, not affordability20Current policy landscapeSupranational soft regulation and advocacy (ISSCR, JDRF Intl, ALS Worldwide)Statutory intervention through physician standard of care rules?Physicians duty to report abuse, neglect, or situations of risk under minor and incompetent adult welfare legislation Truth in advertising rules (FTC) Local regulation stem cell clinics have been shut down by regulators in the Netherlands, Ireland, USLobbying by research community for stricter national regulation

But cf. Laetrile controversy21AcknowledgmentsCo-authors: Darren Lau, Timothy Caulfield, Tania Stafinski, Devidas Menon, Benjamin TaylorCanadian Stem Cell NetworkREMEDiELinda Hogle