Center for Bioethics N504 Boynton 410 Church Street Minneapolis MN 55455 612-624-9440 Fax: 612-624-9108 www.bioethics.umn.edu Dr. Susan Berry Chair, IRB Executive Committee University of Minnesota D528 Mayo Memorial Building 420 Delaware St. SE Minneapolis, MN 55455-0392

January 20, 2015

Dear Dr. Berry:

We are writing with an urgent request. According to the attached brochure, as well as the Experts@Minnesota website maintained by the University of Minnesota, it appears that Dr. Stephen Olson in the Department of Psychiatry is conducting two new clinical trials that pose serious risks to vulnerable subjects.1 We would like to ask that the Institutional Review Board put a temporary halt to recruitment. The studies in question are:

A Randomized, Double-Blind, Placebo-Controlled Study of SD-809 for the Treatment of Moderate to Severe Tardive Dyskinesia, Protocol SD-809-C-18 (NCT02195700)

An Open-Label, Long-Term Safety Study of SD-809 for the Treatment of Moderate to Severe Tardive Dyskinesia (NCT02198794)

We should note that we have not yet been given access to the study materials reviewed by the IRB. All of the information included in this letter comes from public sources. If there is information provided to the IRB that has persuaded the review panel that these studies pose little risk to subjects, we would be grateful if you could provide that material to us.

Background

According to Auspex Pharmaceuticals, SD-809 is a modified version of tetrabenazine, a drug used to treat the chorea that results from Huntington's Disease.2 Auspex has hypothesized that a modified version of tetrabenazine will have a longer half-life than the original drug and will thus require less frequent dosing and cause fewer side-effects. Company press releases suggest that Auspex plans an NDA submission for SD-809 by mid-2015.3 The company has also begun trials in patients with other

1 http://experts.umn.edu/expertGrants.asp?n=Stephen+C+Olson&u_id=2089 2 http://www.auspexpharma.com/wp-content/uploads/2013/12/D-Stamler-Auspex-HDSA-2013-0621-FINAL.pdf;

movement disorders, such as Tourette Syndrome and tardive dyskinesia, an extrapyramidal side-effect of antipsychotic drugs.

Tetrabenazine, however, is not a benign drug. It carries a black box warning for depression and risk of suicide. According to a briefing document submitted by Prestwick Pharmaceuticals for the FDA Peripheral and Central Nervous System Advisory Committee on December 6, 2007, 32% of subjects taking tetrabenazine in one study experienced depression. Among the Serious Adverse Events for tetrabenazine in another study was a death attributed to suicide in a 40-year-old male with no known history of depression but a past history of suicidal ideation, and no evidence of depression observed by the investigator and family just 2 weeks prior to the event.4

The boxed warning for tetrabenazine for Prestwick Pharmaceuticals under the trade name Xenazine states:

Anyone considering the use of Xenazine must balance the risks of depression and suicidality with the clinical need for control of choreiform movements. Close observation of patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior should accompany therapy.5

The manufacturers warning from Roche, which produces tetrabenazine under the trade name Nitoman, states:

Tetrabenazine may cause depression. Recognition of depression may be difficult because this condition may often be disguised by somatic complaints. The drug should be stopped immediately at the first signs or symptoms of depression. The depression can be profound, and the possibility of suicide should be kept in mind until the depression clears. There is no information on the safety or efficacy of antidepressant drug treatment in tetrabenazine-induced depression.6

Concerns

We have two serious concerns about the risks posed to subjects recruited into these studies of SD-809 at the University of Minnesota.

First, most subjects with tardive dyskinesia will have a history of serious mental illness such as schizophrenia. Such illnesses may interfere with the ability of these subjects to give proper informed consent. Many subjects may also have a history of depression and suicide attempts. At such an early stage of testing, it appears extraordinarily risky to expose this patient population to a modified version of a drug that carries a boxed warning for risk of suicide.

3 http://investor.auspexpharma.com/releasedetail.cfm?ReleaseID=887958 4 http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4328b1-02-Prestwick.pdf 5 http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021894lbl.pdf 6 http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20(General%20Monographs-%20N)/NITOMAN.html

Second, Dr. Olson was the principal investigator for two previous studies of vulnerable subjects that have prompted external reviews of potential misconduct in the Department of Psychiatry. Both of those studies involved subjects with schizophrenia. The CAF study, or Comparison of Atypicals in First-Episode Psychosis, sponsored by AstraZeneca, resulted in the suicide of Dan Markingson. The second study, An Open Label, Flexible Dose, Long term Safety and Efficacy Study of Bifeprunox in the Study of Schizophrenia, was the topic of an investigative report on KMSP News last May. According to that report, a research subject with psychotic illness on a locked ward at Fairview was pressured into the bifeprunox study and suffered injuries so severe he considered suicide.

In both of these cases, serious questions have been raised about the ability of subjects to give proper informed consent, as well as whether Dr. Olson paid sufficient attention to evidence that subjects were in danger of committing suicide. Among the many alarming errors and lapses documented by the Minnesota Board of Social Work in the corrective action issued to the study coordinator of the CAF study in 2012 was a failure to document issues relevant to suicide prevention.7

Given the potential risk of irreversible harm to subjects in these studies, we request that the IRB put an immediate stop to recruitment until the Office of the Legislative Auditor completes its review of psychiatric research at the university. If there are reasons why you or the members of the IRB believe that our concerns about the safety of subjects in the SD-809 studies are unwarranted, we would be grateful if you could provide us with those reasons and the relevant documentation as soon as possible.

Yours sincerely,

Carl Elliott MD PhD Professor, Center for Bioethics

Leigh Turner, PhD Associate Professor, Center for Bioethics cc Arne Carlson, James Nobles, Teri Bonoff, Brian Herman, Michael Oakes, Carolyn Wilson, Eva von Dassow, Rebecca Ropers-Huilman

7 http://www.circare.org/dw/ACA_Kenney-13622-11082012.pdf