in High Risk Research

I am Adil E. Shamoo from Columbia, Maryland (see Appendix for brief biography). I am here today to speak on behalf of thousands of vulnerable patients and their families not able or not willing to speak for themselves. I am here to speak on behalf of Citizens for Responsible Care and Research.

I would like to thank you Mr. Chairman and members of your Subcommittee for giving me this opportunity to inform you of my personal and my organization’s grave concerns regarding the current ongoing research practices. Vulnerable human beings such as veterans with medical illnesses are being used as human subjects in high risk experiments with no medical benefits which cause them harm.

Mr. Chairman, a man serves his country; he comes back with a disability--post-traumatic stress disorder, or with depression or even schizophrenia. He turns to his VA hospital expecting the care and compassion. His doctor is the one who can help him the most. His doctor is his psychiatrist. He treats him and he becomes stable and functional. His doctor, however is also the researcher who conducts experiments on patients. His doctor asks him to sign informed consent. The doctor then proceeds to take him off medication abruptly. This causes him to become psychotic. In some instances he is left, in the community with psychosis, delusion, depression or post-traumatic stress disorder for weeks and months. Or, the researcher may administer chemicals such as cocaine or amphetamine or yohimbine (an African drug) to induce psychosis or delusion or post-traumatic stress disorder because he wants to study the illness. Is this fair?

Let me state at the outset that we support ethical research with human subjects where basic human rights are fully respected. But we do strongly oppose unethical research.

In March, 1996 (Shamoo, 1996) in a written testimony to the Committee on Governmental Affairs of the U.S. Senate, I stated: "This type of research is on-going nationwide in medical centers and VA hospitals supported by tens of millions of dollars of taxpayers money. These experiments are high risk and are abusive, causing not only physical and psychic harm to the most vulnerable groups but also degrading our society’s system of basic human values. Probably tens of thousands of patients are being subjected to such experiments."

In 1994, we wrote to OPRR about unethical experiments at Bronx VA. It took OPRR five years to issue their report this January. In June, 1997 we wrote to NIH Director, Dr. Varmas, and in April, 1998 we also wrote to Secretary Donna Shalala about these unethical research experiments. Secretary Shalala did not reply and Dr. Varmas did nothing about it.

The recent revelations in The Boston Globe (Whitaker and Kong,1998) and the LA Times (Monmaney, 1999) are only the tip of the iceberg about which the public learned. Evidence demonstrates the risk to patients who are veterans, or poor, or uneducated or elderly and seeking care in hospitals across the country. This is especially true if your illness is of a psychiatric nature such as depression, schizophrenia, and post-traumatic stress disorder to name a few. The recent suspension of VA hospital in Los Angeles by the Federal Office of Protection from Research Risk (OPRR) was in large part dealing with psychiatric patients (OPRR, 1999).

Decisionally impaired individuals should only be used as research subjects when it is in their best medical interest. Only under extreme, unique and rare circumstances should this population be ever used for research without direct medical benefit to them. And only when there is minimal risk involved.

The scope of the problem before us is truly unknown. There are 173 Veterans Hospitals across the country. All of these hospitals, their researchers, and their patients are intermingled with University’s Medical Centers. There are probably hundreds of thousands of human subjects enrolled in research protocols across the country. I do not know nor I think it is possible to accurately know the exact number of veteran patients among them. My own survey of studies clearly indicates that veteran patients play a prominent role as human subject in the open literature.

The problems before us falls in one or more of the following categories:

1. Non-Compliance with the existing federal regulation.
2. Non-Enforcement of the existing federal regulation and
3. No independent oversight and no accountability
4. The need for legislative reforms of the federal regulation.

Allegations of abuse of patients with questionable decisional capacity include exposure to needless risks including, in some cases, suicides. These allegations have come to light from families, patients, patient advocates, researchers surveying the published literature, conferences, media, hearings of the National Bioethics Commission and congressional hearings (NBAC, 1997). The recent decision by Dr. Steven Hyman, Director of the National Institute of Mental Health (NIMH), acting on the advise of a review panel, was to suspend 29 intramural clinical trials while requiring more than 50 additional studies --out of 108—to give adequate scientific justification for conducting them (Marshal, 1999).

The following are the four categories of problems with research that have come under scrutiny and criticism: (1) sudden medication washout studies. In these experiments, researchers take stable patients (many of whom are outpatients living at home), off medication and as a consequence, most relapse into psychotic states; (2) chemical provocation experiments ("challenge studies") in which patients are injected with chemicals of no therapeutic benefit --such as cocaine, amphetamine, and ketamine (Special K), an animal tranquilizer in order to provoke severe psychotic episodes for the study of the "mechanism of psychosis." (3) the fundamentals of informed consent are blatantly violated: patients incapable of comprehending the purpose of the research or the risks involved are asked to sign informed consent; insufficient information to make an informed decision; and duress and coercion are commonplace; and (4) hiding data on the number of suicides or attempted suicides of patients enrolled in psychiatric research, although, the incidence of suicide is very high in this population ( for details on this topic see Shamoo and Irving, 1993, Shamoo and Keay, 1996, Shamoo et. al., 1997, Shamoo, 1997, Shamoo and O’sullivan, 1997, Lehrman and Sharav, 1997) .

Examples of Unethical Research on Veterans

1. Behavioral vs. Biochemical Prediction of Clinical Stability Following Haloperidol Withdrawal in Schizophrenia," (van Kammen, 1995), a relapse experiment involved 88 veterans who had been stable and living in the community, when they were recruited and hospitalized for eight to ten weeks. Their medications were abruptly withdrawn and replaced by a standard dose of Haldol for 2 to 4 weeks, they were then "washed-out," subjected to lumbar puncture, and observed for at least 6 weeks without medication to see who would relapse. According to the investigators, 50 of these patients had been subjects in their earlier studies – 30 had been used repeatedly in three separate experiments: (van Kammen, 1989; 1994; 1995) each involved lumbar punctures and abrupt withdrawal from all medications for six weeks to see who would relapse. In each experiment about 50% relapsed: it is not indicated how many times these 30 experimental repeaters relapsed.
2. Induction of Post-Traumatic Stress Disorder (PTSD) (Sowthick et al., 1997). 26 veterans were given a chemical called Yohimbine to induced PTSD.
3. Induction of Post-Traumatic Stress Disorder (Brenner et al., 1997) on ten Vietnam Veterans with a chemical.
4. In 1993, an experiment conducted at West Haven VA, on 12 inpatient and 15 healthy volunteers, a chemical called MCPP "significantly increased" the patients’ psychotic symptoms, and they "exhibited prolonged anxiogenic responses to MCPP." The authors indicate that: "Schizophrenic are the only psychotic patient group studied to date."
5. Between 1994-1997, we found four federally funded amphetamine experiments at New York VA Medical Center, (Wolkin, 1994; Sanfilipo, 1996); West Haven VA; (Laruelle, 1996); and NIMH (Breier, 1997). The investigators cite numerous previous studies in which stimulants were used in schizophrenia research, indicating that: "Psychotic symptoms are exacerbated in approximately 40% of schizophrenic patients after doses of [central nervous system] stimulants….Moreover, a rather consistent body of data suggests that patients who show such symptom exacerbation are at increased risk for acute relapse if not taking neuroleptics." (Wolkin, 1994)
6. In 1994, a double-blind experiment at NY VA Medical Center and Brookhaven National Laboratories, where two PET scans were conducted. Twenty-three schizophrenia inpatients were taken off their medications for a median period of 30 days; 17 were subjected to 0.5 mg/kg oral amphetamine challenge, and six served as placebo-controls. The investigators stated that the purpose of the study was "to specifically evaluate metabolic effects in subjects with varying degrees of amphetamine-induced psychotic exacerbation." (Wolkin et al., 1994)

(7) "Single Photon Emission Computerized Tomography Imaging of Amphetamine-Induced Dopamine Release in Drug-Free Schizophrenic Subjects," 1996. "The study was performed according to protocols approved by Yale School of Medicine and West Haven Veterans Affairs Internal Review Boards." The stated risks: "Acute exposure to amphetamine induces emergence or worsening of positive symptoms in schizophrenic patients at doses that do not produce psychotic symptoms in healthy subjects." (Laruelle, p. 9236) Fifteen stable schizophrenia patients who were living in the community with "no current suicidal or homicidal ideation" (Lieberman et al., 1987) (emphasis added) were withdrawn from their medications (for at least 21 days), then injected intravenously with amphetamine. They were then infused for over six hours with radioactive substance before having their brains scanned at West Haven VA Medical Center. The experiment induced the "emergence or worsening of positive psychotic symptoms" using "a newly developed noninvasive method to measure amphetamine-induced dopamine release." The report indicates, "we could not assess the respective contribution of amphetamine and of the stress associated with the experimental setting to the indication of psychotic reactions." (Laruelle et al., 1996)

The article claims patients included in this experiment "were able to provide informed consent and to comply with this demanding protocol." However, since the consent form signed by patient-subjects does not inform them about any risks associated with amphetamine, we wonder how they could do so. We also question how this consent form complies with federal requirements of full disclosure of the risks?

8. Repeated Amphetamine challenge to 13 patients (we are not certain they were veterans) (Strakowski et al., 1997). The patients were experiencing psychosis, delusion, hallucinations, or through disorder. However, the paper claims all provided "informed consent."
9. In 1994, we complained to the OPRR about an L-dopa experiment conducted on 28 veterans at Bronx VA medical center. These recovered veterans while living in the community were recruited into an experiment that was deliberately designed to induce psychotic relapse. All 28 veterans suffered the agony of psychotic relapse in order for the investigator to record how long it will take to relapse.

On September 18, 1997, patients and families testified before the National Bioethics Advisory Commission (NBAC, 1997) that they are victims of therapeutic neglect, betrayal of trust and institutional deception. The patients endured horrendous treatment in ill conceived, highly speculative, dangerous experiments which clearly undermined the best medical interest of the subjects, often causing them profound harm. These living witnesses represent countless others who have also been harmed and abused in experimental research but who remain silent. The families and patients testified that drug "washout" and placebo experiments were conducted without disclosure of known risks, in other words without informed consent: (1) Consent forms were often presented to subjects who could not understand them, and often presented after the experiments were already under way. (2) Patient records were deliberately changed to fit the experimental protocol (3) Patients’ medical and psychiatric conditions were allowed to deteriorate severely. (4) Patients were subjected to illegal use of restraints. (5) Patients were assaulted and injured by staff. (6) Experimental drug withdrawal procedures led to a suicide attempt. (7) One patient on a locked research ward was impregnated and then driven quickly to a clinic outside the institution to obtain an abortion.

High Risk and Unethical Research with Placebo Protocol

When medications are abruptly withdrawn in a research protocol, the relapse rate is as high as 80%. When is the risk to patients considered a sufficient deterrent to the researcher or to the Institutional Review Boards, which routinely approve such protocols? A schizophrenia relapse has serious, lasting, harmful consequences for the patient, it can even be life-threatening (Shamoo and Keay, 1996, Shamoo et al, 1997).

Mr. Chairman, scientists know that in any study there are dropouts, people who suffer consequences of the study and quit. Thus, it is particularly disturbing that in 88% of the studies we looked at, the researcher failed to report any dropouts during research, and those that mention dropouts do not indicate the outcome or whereabouts of these human subjects.

Three arguments have been used justify this type of research in the past: (1) subjects signed informed consent, (2) studies are not of high risk and thus reasonable, and (3) this was good for society, advancement of knowledge, and benefit for future generations. Most observers due to testimonies of patients and their families have discredited the first two arguments. Surveys of past research practices and experiments of high risk have been shown to be harmful. The most cited argument that such research is good for society; is the utilitarian calculus that a few should suffer for the benefit of the majority. The proponent’s claim that this research is acceptable if society’s benefit exceeds the risk to the patients, (thus equating the interest of society with the interest of patient), and the claim that psychiatric patients have moral obligations to volunteer for research as subjects violate the Nuremberg Code and the Helsinki Declaration. Serving public good at the sacrifice of individual liberties, freedom, and autonomy Cannot be condoned except in the rarest circumstances such as the prevention of an epidemic by using quarantine, limiting individual liberties of citizens during their service in the army, conviction of crimes and other national emergencies. The advancement of drug development certainly does not fit one of these national emergencies. The fact is, the majority of mentally disabled individuals are not capable of giving truly informed consent.

We call for the following national reforms:

I. A moratorium on non-therapeutic, high risk experimentation such as abrupt drug "washouts" and "chemical provocation" experiments that are likely to exacerbate severe, incapacitating illness, and expose vulnerable persons to addictive drugs which may, with repeated exposure, lead to addiction and/or cause neurotoxic brain damage.

Brenner, J.D. et al (1997). "Positron Emission Tomography Measurement of Cerebral Metabolic Correlates of Yohimbine Administration in Combat-Related Post-traumatic Stress Disorder," Arch. Gen. Psychiatry 54:246-254.

Davidson et al (1987), "L-dopa challenge and relapse in Schizophrenia", Am. J. Psychiatry 144:934-938.

Kratofil, P.H., Baberg, H.T., Dimsdale, J.E. (1996). "Self-mutilation and severe self-injurious behavior associated with amphetamine psychosis," General Hospital Psychiatry 18:117-120.

Krystal, J.H., Seibyl, J.P., Price, L.H., Woods, S.W., Heninger, G.R., Aghajanian, G.K., Charney, D.S. (1993). "m-Chlorophenylpiperazine effects in neuroleptic-free schizophrenic patients. Evidence implicating serotonergic systems in the positive symptoms of schizophrenia," Archives of General Psychiatry 50:624-35.

Laruelle, M., Abi-Dargham, A, van Dyck, C.H., Gil, R., D’Souza, C.D., Erdos, J., McCance, E., Rosenblatt, W., Fingado, C., Zoghbi, S.S., Baldwin, R.M., Seibyl, J.P., Krystal, J.H., Charney, D.S. (1996). "Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects," Proceedings National Academy of Science, Aug.,. pp. 9235-9240.

Lehrman, N. S., and Sharav, V. H. ( 1997 ). " Ethical Problems in Psychiatric Research ", J. of Mental Health Administration 24:227-250.

Lieberman, J.A., Kane, J.M., Alvir, J. (1987). "Provocative tests with psychostimulant drugs in schizophrenia," Psychopharmacology 91:415-433.

Marshal, E.(1999)."NIMH to Screen Studies for Science and Human Risks,"Science 283:464-465.

Mathew, R.J., Wilson, W.H. (1989). "Changes in cerebral blood flow and mental state after amphetamine challenge in schizophrenic patients," Neuropsychobiology 21:117-123.

Monmaney, T. (1999). "VA Hospital’s Ethical Nightmare," Los Angeles Times, March 25, A01.

National Bioethics Advisory Commission (NBAC), hearings of Sept. 18, 1997.

Office of Protection from Research Risk (OPRR) (1999). "Letter of March 22, 1999, from OPRR to VA Greater Los Angeles Healthcare System.

Sanfilipo, M.,Wolkin, A.,Angrist, B.,van Kammen, D.P., Duncan, E., Wieland, S., Cooper, T.B. (1996)."Amphetamine and negative symptoms of schizophrenia,"Psychopharmacology (Berl) 123:211-214.

Schulz, S.C., Cornelius, J., Schulz, P.M., Soloff, Ph.D. (1988). "The amphetamine challenge test in patients with borderline disorder," American Journal of Psychiatry 145:809-814.

Shamoo, A.E. (Editor). "Ethics in Neurobiological Research with Human Subjects," pp. 1-335, Gordon and Breach Publisher OPA, Amsterdam, B.V., The Netherlands.

Shamoo, A.E. and Irving, D.N. (1993). Accountability in Research Using Persons with Mental Illness, Accountability in Research 3:1-17.

Shamoo, A.E. (1994). "Our Responsibilities toward Persons with Mental Illness as a Human Subjects in Research," The Journal 5:14-6.

Shamoo, A.E. (1996). "The Inhumane Use of Persons with Mental Illness in Biomedical Experimental Research," In proceedings of Human Radiation Experiments, S. Hrg. 104-108. Hearing before the Committee on Governmental Affairs, United States Senate, March 12, 1996, pp. 63-73, Superintendent of Documents, Congressional Sales Office, Washington, D.C.

Shamoo, A.E. and Keay, T. (1996). "Ethical Concerns about Relapse Studies" – Cambridge Quarterly of Health Care Ethics, 5:373-386.

Shamoo, A.E., Irving, D.N., and Langenberg, P. (1997). "A Review of Patient Outcomes in Pharmacological Studies from the Psychiatric Literature, 1966-1993," Science and Engineering Ethics, 3:395-406.

Shamoo, A.E., and O’Sullivan, J. O. (1997). "The Ethics of Research on the Mentally Disabled " In Health Care Ethics : Critical Issues for the 21st Century, Edited by Thomasma, D. C. and Monagle, J. In Press.

Southwick, S.M. et al. (1997). "Noradrenergic and Serotonergic Function in Post-traumatic Stress Disorder," Arch. Gen. Psychiatry 54:749-758.

Strakowski, S.M., Sax, K.W., Setters, M.J., Stanton, S.P. and Keck, P.E. (1997). "Lack of Enhanced Responses to Repeated d-Amphetamine Challenge in First – Episode Psychosis: Implications for a Sensitization Model of Psychosis in Humans.

van Kammen, D.P., Docherty, J.P., Marder, S.R., Bunney, W.E. Jr. (1981). "Acute amphetamine response predicts antidepressant and antipsychotic responses to lithium carbonate in schizophrenic patients," Psychiatry Research 4(3): 313-325.

van Kammen, D.P., Docherty, J.P., Marder, S.R.,Schulz, S.C., Dalton, L., Bunney, W.E. Jr. (1982a). "Antipsychotic effects of pimozide in schizophrenia. Treatment response prediction with acute dextroamphetamine response," Archives of General Psychiatry 39(3):261-266.

van Kammen, D.P., Bunney, W.E., Jr., Docherty, J.P., Marder, S.R., Ebert, M.H., Rosenblatt, J.E., Rayner, J.N. (1982b). "d-Amphetamine-induced heterogeneous changes in psychotic behavior in schizophrenia," American Journal of Psychiatry 139(8):991-997.

van Kammen, D.P., Docherty, J.P., Bunney, W.E. (1982). "Prediction of early relapse after pimozide discontinuation by response to d-amphetamine during pimozide treatment," Biological Psychiatry 17:233-342.

van Kammen, D.P., Docherty, J.P., Marder, S.R., Rosenblatt, J.E., Bunney, W.E. (1985a). "Lithium attenuates the activation-euphoria but not the psychosis induced by d-amphetamine in schizophrenia," Psychopharmacology, (Berl) 87:111-115.

van Kammen, D.P., Schulz, S.C. (1985b). "d-Amphetamine raises cortisol levels in schizophrenic patients with and without chronic naltrexone pretreatment," Journal of Neural Transm, 64:35-43.

van Kammen, D.P., Peters, J., Yao, J., van Kammen, W.B., Neylan, T., Shaw, D., Linnoila, M. (1990a). "Norepinephrine in acute exacerbations of chronic schizophrenia. Negative symptoms revisited," Archives of General Psychiatry 47:161-8.

van Kammen et al., (1995). "Behaviorial vs. biochemical prediction of clinical stability following haloperidol withdrawal in schizophrenia," Archives of General Psychiatry, 52:673-678.

van Kammen, D.P., Kelley, M.E., Gurklis, J.A., Gibertson, M.W., Yao, J.K., Condray, R., Peters, J.L. (1996). "Predicting duration of clinical stability following haloperidol withdrawal in schizophrenic patients," Neuropsychopharmacology 14:275-283.

Whitaker, R. and Kong, D., (Nov.14-18, 1998), The Boston Globe.

Wolkin, A., Sanfilipo, M., Angrist, B., Duncan, E., Wieland, S., Wolf, A.P., Rodie, J.D., Cooper, T.B., Laska, E., Rotrosen, J.P. (1994). "Acute d-amphetamine challenge in schizophrenia: effects on cerebral glucose utilization and clinical symptomatology," Biological Psychiatry 36:317-325.

APPENDIX

04/09/99

BIOGRAPHY OF ADIL E. SHAMOO, Ph.D.