Placebo Surgery for Parkinson's Disease: Do the Benefits Outweigh the Risks?

The significance of this first government-financed study using fetal tissue is that President Reagan had banned the use of taxpayer support for this type of experimentation in 1988. President Clinton lifted the ban in 1993, and President George W. Bush reinstated it in January 2001.

Stolberg S. , “Sham Surgery Returns as a Research Tool,” New York Times, April 25, 1999.

Stolberg S. , “Hints of Success in Fetal Cell Transplants,” New York Times, April 22, 1999.

Freeman T. , “Use of Placebo Surgery in Controlled Trials of a Cellular-Based Therapy for Parkinson's Disease,” N. Engl. J. Med., 341 (1999): 988–91.

See also Clark P.I. Leaverton P.E. , “Scientific and Ethical Issues in the Use of Placebo Controls in Clinical Trials,” Annual Review of Public Health, 15 (1994): 19–38;.

Hauser R.A. Olanow C.W. , “Designing Clinical Trials in Parkinson's Disease,” in Olanow C.W. Lieberman A.N. , eds., The Scientific Basis for the Treatment of Parkinson's Disease (Park Ridge, New Jersey: Parthenon, 1992): 275–93.

Freeman , supra note 4, at 988.

Id

See also Boncheck L.I. , “Are Randomized Trials Appropriate for Evaluating New Operations,” N. Engl. J. Med., 301 (1979): 44–45;.

Love J.W. , “Drugs and Operations: Some Important Differences,” JAMA, 232 (1975): 37–38;.

Pocock S.J. , Clinical Trials: A Practical Approach (New York: John Wiley Publisher, 1983).

See Freeman , supra note 4, at 988.

The pertinent ethical regulations and guidelines can be found in the following: The Nuremberg Code, reprinted in Trials of War Criminals Before the Nuremberg Military Tribunals Under Control No. 102 (Washington, D.C.: U.S. Gov't Printing Office, 1949): At 181–82.

Declaration of Helsinki, adopted by the 18th World Medical Assembly, 1964 and revised in 1975 and 1983; National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, DHEW Pub. No. (OS) 78–0012 (Washington, D.C.: U.S. Gov't Printing Office, 1978) [hereinafter cited as The Belmont Report].

World Health Organization, Proposed International Guidelines for Biomedical Research Involving Human Subjects (Geneva: CIOMS, 1982).

Medical Research Council of Canada, Guidelines on Research Involving Human Subjects (Ottawa, Canada: Minister of Supply and Services, 1978).

Phillips P. , “New Surgical Approaches to Parkinson Disease,” JAMA, 282 (1999): 1117–18.

The Belmont Report, supra note 8, at 5.

Olanow C.W. , “A 61-Year-Old Man with Parkinson's Disease,” JAMA, 275 (1996): 716–22.

Stage I involves only one side of the body. Stage II involves both sides of the body, but does not impair walking. Stage III impairs both balance and walking. Stage IV markedly impairs balance or walking. Stage V results in complete immobility. For a more detailed analysis, see Family Caregiver Alliance, Fact Sheet: Parkinson's Disease (San Francisco: Family Caregiver Alliance, 2000), available at <http://www.caregiver.org/factsheets/parkinsons.html> (last revised August 2000).

Dopamine is a neurotransmitter of some peripheral nerve fibers and many central neurons (e.g., in the substantia nigra, midbrain, ventral tegmental area, and hypothalamus). The amino acid tyrosine is taken up by dopaminergic neurons and converted by tyrosine hydroxylase to 3,4-dihydroxyphenylalanine (dopa), which is decarboxylated by aromatic-L-amino-acid decarboxylase to dopamine. After release, dopamine interacts with dopaminergic receptors, and its residue is actively pumped back (reuptake) into prejunctional neurons. Tyrosine hydroxylase and monoamine oxidase regulate dopamine levels in nerve terminals. Beers M.H. Berkow R. , eds., The Merck Manual of Diagnosis and Therapy, 17th ed. (Whitehouse Station, New Jersey: Merck Research Laboratories, 1999): at 1360.

See Freeman , supra note 4, at 989.

See Family Caregiver Alliance, supra note 12, at 2–3.

For a more detailed analysis, See Prasad K.N. ., “Efficacy of Grafted Immortalized Dopamine Neurons in an Animal Model of Parkinsonism: A Review,” Molecular Genetic Metabolism, 65 (1998): 1–9. In these experiments, researchers established immortalized dopamine neurons from fetal rat mesencephalon by inserting the large T-antigen (LTa) gene of the SV40 virus into the cells. A clone of the dopamine neuron (1RB3AN27) was isolated, characterized, and tested in 6-hydroxydopamine (6-OHDA)-lesioned rats (a model of Parkinson's disease). These cells divided with a doubling time of about twenty-six hours, expressed the LTa gene, and contained the tyrosine hydroxylase and dopamine transporter proteins and their receptive mRNAs, which became elevated upon differentiation. These cells were nontumorigenic and nonimmunogenic and improved the symptoms of neurological deficits (methamphetamine-induced rotation) in 6-OHDA-lesioned rats. The differentiated dopamine neurons were more effective than undifferentiated ones. These studies suggest that immortalized dopamine neurons generated in vitro by LTa gene insertion may be used in transplant therapy without the fear of tumor formation or rejection.

See also Hauser R.A. , “Long-Term Evaluation of Bilateral Fetal Nigral Transplantation in Parkinson's Disease,” Archives of Neurology, 56 (1999): 179–87. Hauser and colleagues concluded that fetal nigral tissue can be transplanted bilaterally into postcommissural putamen in patients with advanced Parkinson's disease safely and with little morbidity. Clinical improvement appears to be related to the survival and function of the transplanted fetal tissue.

See also Piccini P. , “Dopamine Release from Nigral Transplants Visualized In Vivo in a Parkinson's Patient,” Natural Neuroscience, 12 (1999): 1137–40. In a patient who had received a transplant in the right putamen ten years earlier, grafts restored both basal and drug-induced dopamine release to normal levels. This release was associated with sustained, marked clinical benefit and normalized levels of dopamine storage in the grafted putamen. Thus, despite an ongoing disease process, evidence indicates that grafted neurons can continue for a decade to store and release dopamine and give rise to substantial symptomatic relief.

See also Honey C. Gross R.E. Lozano A.M. , “New Developments in the Surgery for Parkinson's Disease,” Canadian Journal of Neurological Science, 26, no. 2 (Supp. 1999): S45–S52.

For a more detailed analysis, See Kordower J. , “Neuropathological Evidence of Graft Survival and Striatal Reinnervation After the Transplantation of Fetal Mesencephalic Tissue in a Patient with Parkinson's Disease,” N. Engl. J. Med., 332 (1995): 1118–24.

Mahowald M. , “Philosophical and Ethical Issues,” in Reich W. , ed., Encyclopedia of Bioethics, rev. ed. (New York: Simon & Schuster, 1995): 851–56.

Id. at 856. In addition, some researchers question whether transplantation of human fetal tissue is necessary for effective treatment of Parkinson's disease, or whether similar results could be produced with different types of cells. In fact, researchers are currently experimenting with as many as eighteen different ways of transplanting cells other than fetal cells. Two such methods involve cells derived from stem cells. Another involves retinal cells, which secrete dopamine and neurotropic factors. Recent evidence indicates that one or more of these new strategies may be useful clinically

For an example, see Phillips , supra note 9, at 1118.

The stereotactic needle has a maximal outer diameter of 1.5 millimeters, which tapers to 0.9 millimeters at the tip. Multiple needle trajectories (six to eight per side) are used, and four tissue deposits are injected into each burr hole so that the deposits are separated by no more than 5 millimeters throughout the three-dimensional configuration of the target region. For a more detailed analysis of this procedure, see Kordower , supra note 17, at 1118–24.

See Phillips , supra note 9, at 1118. Of the 360 patients who have received fetal cell transplants for Parkinson's disease, approximately 150 were in the United States. Since 1988, sixty procedures have been done at the University of Colorado, fifty in Los Angeles, thirty at the University of South Florida, and four at Yale University. Outside the United States, transplants occurred in England, Mexico, Canada, and Sweden. Sweden has had the largest experience with fetal cell transplantation, where patients have received transplants (although on only one side of the brain rather than both) since 1989 and showed improvements lasting about five years before deterioration began.

For other studies supporting Freeman's claims, See Kopyov O.V. , “Clinical Study of Fetal Mesencephalic Intracerebral Transplants for the Treatment of Parkinson's Disease,” Cell Transplantation, 327 (1996): 327–37;.

Ugriumov M.V. , “Use of Neurotransplantation in the Treatment of Parkinson's Disease,” Vestn Ross Akad Med Nauk, 8 (1996): 40–51.

See Family Caregiver Alliance, supra note 12, at 3–4.

For a more detailed analysis, See Freed C.R. , “Survival of Implanted Fetal Dopamine Cells and Neurologic Improvement 12 to 46 Months After Transplantation for Parkinson's Disease,” N. Engl. J. Med., 327 (1992): 1549–55;.

Freed C.R. , “Transplantation of Fetal Mesencephalic Tissue in Parkinson's Disease,” N. Engl. J. Med., 333 (1995): 730–31.

In one large double-blind pharmacological study, patients assigned to the placebo group had 20 to 30 percent improvement in motor scores, and this improvement persisted throughout the six months of the trial. See Freeman , supra note 4, at 989.

See also Clark P.I. Leaverton P.E. , “Scientific and Ethical Issues in the Use of Placebo Controls in Clinical Trials,” Annual Review of Public Health, 15 (1994): 19–38;.

Olanow C.W. , “The Effect of Deprenyl and Levodopa on the Progression of Parkinson's Disease,” Annals of Neurology, 38 (1995): 771–77.

The Parkinson Study Group “Effects of Tocopherol and Deprenyl on the Progression of Disability in Early Parkinson's Disease,” N. Engl. J. Med., 328 (1993): 176–83. In both of these studies, significant improvement and deterioration were observed after the introduction and discontinuation, respectively, of placebos in patients with Parkinson's disease.

Wolf S. , “Pharmacology of Placebos,” Pharmacological Review, 11 (1959): 689–704.

Johnson A.G. , “Surgery as Placebo,” Lancet, 344 (1994): 1140–42.

Beecher H.K. , “Surgery as Placebo,” JAMA, 176 (1961): 1102–07.

Id. at 1106. To examine the placebo effect and researcher bias, Freeman et al. have documented a trial design consisting of thirty-six adults with advanced Parkinson's disease whose symptoms could not be adequately controlled using medical therapy. These patients voluntarily consented to undergo one of three study procedures: bilateral fetal nigral transplantation with tissue from one donor per side, bilateral transplantation with tissue from four donors per side, or bilateral placebo surgery. According to the trial protocol, patients in the control group undergo two placebo surgical procedures designed to provide an equivalent experience for the patients and their family members. Each placebo procedure includes the placement of a stereotactic frame, target localization on magnetic resonance imaging, the administration of general anesthesia with laryngeal-mask airway, and a skin incision with a particular burr hole that does not penetrate the inner cortex of the skull. There are no needle penetrations into the brain, and no fetal tissue is implanted. The duration of the surgical procedures and the perioperative care are identical in all groups. All patients receive low-dose cyclosporine for six months and continue to receive medical therapy. Patients are evaluated in an identical manner at three-month intervals. To maintain the blinding of investigators, the surgical and evaluation sites are at separate locations. The surgeon is the only member of the research team who is aware of an individual patient's group assignment

See Freeman , supra note 4, at 988–91.

For a more detailed analysis, See Freeman T.B. , “Bilateral Fetal Nigral Transplantation into the Postcommissural Putamen in Parkinson's Disease,” Annals of Neurology, 38 (1995): 379–88. It should be noted that at the conclusion of the study, if fetal tissue transplantation is found to be safe and effective, subjects in the placebo group will be offered the better of the two transplantation procedures (with tissue from one donor per side or four donors per side).

See Freeman , supra note 4, at 989–90.

See Freeman , supra note 4, at 989.

See also Nutt J.G. Holford N.H.G. , “The Response to Levodopa in Parkinson's Disease: Imposing Pharmacological Law and Order,” Annals of Neurology, 39 (1996): 561–73.

See Freeman , supra note 4, at 989.

See Beecher , supra note 28, at 1102–07.

Id.

See also Johnson , supra note 27, at 1140–42.

Ross S. Buckalew L.W. , “Placebo Agentry: Assessment of Drug and Placebo Effects,” in White L. Tursky B. Schwartz G.E. , eds., Placebo: Theory, Research, and Mechanisms (New York: Guilford Press, 1985): 67–82.

See also Freedman B. Weijer C. Glass K.C. , “Placebo Orthodoxy in Clinical Research I: Empirical and Methodological Myths,” Journal of Law, Medicine & Ethics, 24 (1996): 243–51.

Freeman , supra note 4, at 991.

Macklin R. , “The Ethical Problems with Sham Surgery in Clinical Research,” N. Engl. J. Med., 341 (1999): 992–96.

See Stolberg , supra note 2, at 3.

See Macklin , supra note 36, at 993.

Id.

See Freeman , supra note 4, at 990.

For a more detailed analysis of informed consent, see Appelbaum P.S. Litz C.W. Meisel A. , Informed Consent: Legal Theory and Clinical Practice (New York: Oxford University Press, 1987): at 6–62;.

Faden R. Beauchamp T. , A History and Theory of Informed Consent (New York: Oxford University Press, 1986): at 287–94.

See Macklin , supra note 36, at 994.

See also Johannes L. , “Sham Surgery Is Used to Test Effectiveness of Novel Operations,” Wall Street Journal, December 11, 1998, at A1, A8.

Kopelman L. , “Controlled Clinical Trials,” in Reich W. , ed., Encyclopedia of Bioethics, Revised ed. (New York: Simon & Schuster, 1995): 2278–85.

Under the circumstances, it is not uncommon for subjects to engage in “selective hearing,” that is, taking in all information about potential benefits and filtering out all information about potential risks.

Levine R.J. , “The Use of Placebos in Randomized Clinical Trials,” IRB: A Review of Human Subjects Research, 7 (1985): 1–4.

Schafer A. , “The Randomized Clinical Trial: For Whose Benefit?” IRB: A Review of Human Subjects Research, 7 (1985): 4–6.

Those researchers whose treatments fall below the professional standard and cause harm to subjects may be held civilly liable for that failure. Freedman B. Glass K.C. Weijer C. , “Placebo Orthodoxy in Clinical Research II: Ethical, Legal and Regulatory Myth,” Journal of Law, Medicine & Ethics, 24 (1996): 252–59.

See Johannes , supra note 42, at A1, A8;.

Stolberg S. , “Decisive Moment on Parkinson's Fetal-Cell Transplants,” New York Times, April 20, 1999, at F2.

For a more detailed analysis of clinical equipoise, see Freedman B. , “Equipoise and the Ethics of Clinical Research,” N. Engl. J. Med., 317 (1987): 141–45.

Id. at 144.

Weijer C. , “Thinking Clearly About Research Risk: Implications of the Work of Benjamin Freedman,” IRB: A Review of Human Subjects Research, 21 (1999): 2.

Id.

At least eighteen centers around the world have introduced clinical transplantation programs for the treatment of Parkinson's disease. The results have been variable, but several centers have observed consistent and clinically meaningful benefits.

See Freeman , supra note 29, at 379–88;.

Lindvall O. , “Evidence for Long-Term Survival and Function of Dopaminergic Grafts in Progressive Parkinson's Disease,” Annals of Neurology, 35 (1995): 172–80;.

Wenning G.K. , “Short and Long-Term Survival and Function of Unilateral Intrastriatal Dopaminergic Grafts in Parkinson's Disease,” Annals of Neurology, 42 (1997): 95–107;.

Defer G.L. , “Long-Term Outcome of Unilaterally Transplanted Parkinsonian Patients,” Brain, 119 (1996): 41–50.

Department of Health and Human Services, National Institutes of Health, Office for Protection from Research Risks, “Protection of Human Subjects,” 45 C.F.R. § 46.111 (a)(1)—(a)(2) (1991).

See Freeman , supra note 4, at 990.

Hróbjartsson A. Gøtzsche P. , “Is the Placebo Powerless? An Analysis of Clinical Trials Comparing Placebo with No Treatment,” N. Engl. J. Med., 344 (2001): 1594–602.

Proponents could also argue that Hróbjartsson and Gøtzsche's conclusions were too sweeping because, despite the large sample size, the statistical power to examine many subgroups of interest was low. Second, they found statistical evidence of heterogeneity of results in studies with binary outcomes. Third, they studied patients in randomized clinical trials, many of which focused on serious conditions whose clinical consequences may have overshadowed small but useful effects of placebo. Fourth, Hróbjartsson and Gøtzsche noted that the low methodological quality of some trials might explain a lack of effect, though they found no association between dimensions of trial quality and significant effects of placebo. Bailar J. , “The Powerful Placebo and the Wizard of Oz,” N. Engl. J. Med., 344 (2001): 1630–32.

See Schafer , supra note 46, at 6.

See Freeman , supra note 4, at 990.

For a more detailed analysis, See Kordower J.H. , “Fetal Nigral Grafts Survive and Mediate Clinical Benefit in a Patient with Parkinson's Disease,” Movement Disorders, 13 (1998): 383–93.

Freed , supra note 24, at 730–31.

See Freeman , supra note 4, at 988.

Williams P.C. , “Why IRBs Falter in Reviewing Risks and Benefits,” IRB: A Review of Human Subjects Research, 6 (1984): 1–4.

See Macklin , supra note 36, at 993.

See Family Caregiver Alliance, supra note 12, at 4–5.

For a more detailed analysis, see Phillips , supra note 9, at 1117–18.

Editor, “Cell Discovery May Bring Therapies for Parkinson's,” Washington Post, December 1, 2000, at A15.

Wakayama T. , “Differentiation of Embryonic Stem Cell Lines Generated from Adult Somatic Cells by Nuclear Transfer,” Science, 292 (2001): 740–42.

See Johnson , supra note 27, at 1141.

Pollack A. , “Companies Announce Setback in Treatment for Parkinson's,” New York Times, March 19, 2001, at C2. “These two Bostonian companies used cells from pig fetuses. Pig cells are easier to obtain in large quantities and their use avoids the controversy attached to abortion.” Id. This clinical trial involved eighteen patients, ten of whom had fetal pig cells implanted into their brains, and eight of whom had sham surgery. After eighteen months, the two groups showed no difference on a standard rating scale used for Parkinson's disease. Dr. Thomas Fraser, chief executive of Diacrin, stated that both the treated and the control group seemed to improve, indicating a strong placebo effect. The treated patients did experience some side-effects, however.

Id.

Freed C.R. , “Transplantation of Embryonic Dopamine Neurons for Severe Parkinson's Disease,” N. Engl. J. Med., 344 (2001): 710–19.