Yale Complaint

ALLIANCE FOR HUMAN RESEARCH PROTECTION*

(AHRP)

April 10, 2000

Gary Ellis, Ph.D, Director
Michael A. Carome, M.D.
Chief Compliance Oversight Branch
Division of Human Subject Protections
Office of Protection from Research Risks
Rockville, MD 20892-7507

Re: High Risk Experiment With Children Who Have No Medical Diagnosis

Dear Dr. Ellis & Dr. Carome:

We have serious cause for concern about recent reports in the national press describing a highly unethical, so-called "schizophrenia prevention" experiment at Yale University that is putting children as young as 12 years
of age at high risks of harm.  The children in the experiment have no medical diagnosis, and are, therefore, not ill.

Yet, researchers, who are under contract with the sponsoring drug company, (Eli Lilly) hypothesize that the children may be "at risk" for schizophrenia.

They hypothesize without solid evidence, merely on the basis of conjecture – as there are as yet no objective tests or biological markers for the illness. The shaky basis for their conjecture is the assumption that the children may develop schizophrenia because one of their siblings has the disorder.

The risk of schizophrenia for the general population is 1%, for siblings the risk increases to 8% to 15% – in other words there is a 90% likelihood that these children will not develop schizophrenia.  Even for those who already exhibit early signs ("prodromal symptoms"), the estimated risk for developing schizophrenia is highly variable (25% to 50%), given the absence of scientifically accurate tools for interpreting psychiatric "symptoms."

Psychiatrists cannot as yet accurately diagnose schizophrenia; much less predict who will get it. In this experiment, healthy children-who are not capable of giving voluntary, informed consent – are being put at high risks of harm for experimental purposes. The children are being given powerful anti-psychotic drugs that – in a significant number of patients – have high risks and serious side-effects.

"No one knows the long-term dangers of putting such patients on antipsychotic drugs," acknowledged Dr. Rex Cowdry (formerly with NIMH). Doctors in clinical practice and research must have solid medical evidence to justify prescribing medications – particularly powerful psychiatric drugs that cause severe, disabling side-effects.  The Physician Desk Reference (PDR) states that it is unknown how Zyprexa or any other neuroleptic works. The PDR includes a warning about possible serious adverse side effects, including:

sedation, cardiovascular and liver enzyme abnormalities, anticholinergic effects, extreme weight gain (50lbs is not unusual) – thereby significantly increasing the risk for diabetes, sexual dysfunction, seizures, induced mania, potentially-fatal neuroleptic malignant syndrome (NMS) and tardive dyskinesia.

Additionally, mounting clinical evidence and findings-from non-industry sponsored research-point to other, severe, adverse neurological changes in response to long-term exposure to neuroleptics.  These drugs’ actions suppress certain brain receptors (e.g., dopamine, glutamate), and when such drugs are withdrawn (or a patient stops taking them) the drug-induced receptor changes are unmasked, causing an acute "discontinuation syndrome" (i.e., "rebound psychosis" ) that is often more severe than the original symptoms of the illness.

FDA DATA: In pre-marketing clinical trials lasting on average, 6-weeks, olanzapine (Zyprexa) caused serious adverse drug side effects in 22% of patients – only 26% responded favorably. The severe side effects included:

Cardiac & Hypotension – 10% to 15%; Serious weight gain – 50% had gained 7% of their body weight; Parkinson-like motor dysfunction – 11.7%; Akathesia – 7.3% ; FDA data reveals that the drop-out rate during clinical trials was 65%.

In an extended (one year) trial, the drop out rate was 83%. There were 22 deaths during clinical trials of Zyprexa, of which 12 were suicides.

In a 1998 prize winning investigative series, "Doing Harm: Research on the Mentally Ill," the Boston Globe reported that the suicide rate during clinical trials of the atypical neuroleptics – Zyprexa, Risperdal and Seroquel – was "two to five times higher than the norm."

The Globe reported that "in the medical literature, annual suicide rates for schizophrenia patients range from two to five deaths per 1,000 people. The annual suicide rate in the trials, on a time-adjusted basis, was close to 10 per 1,000."

Was this risk disclosed to the parents and subjects on the informed consent documents?

In addition to documented serious adverse drug reactions after short-term exposure in clinical trials, a growing body of evidence – some obtained by photo imaging techniques – demonstrates abnormal, permanent brain receptor alterations and changes in volume of several regions of the brain in schizophrenia patients – after exposure to psychotropic drugs. For example, in 1994, Dr. Jeffrey Lieberman reported that brain scans of young schizophrenia patients before and after 18 months of exposure to neuroleptic drugs showed abnormal enlargement of brain caudate after drug treatment. Drug induced changes have been linked to cognitive deterioration, tremors, jerky impaired motor movements, and TD – an irreversible, disfiguring, involuntary facial movement disorder that develops in 40% to 60% of patients treated with neuroleptics.

The specific serious Federal regulatory violations that have raised our concerns are as follows:

The Code of Federal Regulations prohibits the use of children in research presenting "greater than minimal risk" if the children have no diagnosed disorder or condition. Children can be included in research only if:

(a)"the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches" 45CFR46.405; 

(b) "the risk represents a minor increase over minimal risk" and

(c) the research "is likely to yield generalizable knowledge about the subject’s disorder or condition." 45CFR46.406. 

If the research presents more than minor increase over minimal risk and no prospect of direct benefit, the approval by "the Secretary, after consultation with a panel of experts in pertinent disciplines [ ] and following opportunity for public review and comment" is required. 45CFR46.407.

Since this study presents more than minimal risk, and no potential direct to more than 85% of the minors recruited, it would fall under section 407.

Was this study submitted to the Secretary of HHS for review? Did the Secretary conduct a review with expert consultants and the public? Was this experiment approved after such a review and consultation?

We therefore, ask for an investigation and determination.

Sincerely,

Vera Hassner Sharav, President

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

(*The complaint was filed at that time under the corporate name, CIRCARE)

The letter of findings following an investigation by the federal Office of Human Research Protections (OHRP) indicates there were violations of informed consent, including failure to disclose risks. The agency did not address the issue of ethical and medical justification.

http://ohrp.osophs.dhhs.gov/detrm_letrs/feb01g.pdf

Note: This page has been updated as of July 15, 2002, to correct typographical errors. Please replace any copies of the prior version with this updated copy.