* The views expressed in the 'Research Compliance Note' below are the personal opinions of the author, do not reflect any official position of the University of Washington, and were circulated at the University for information only, not in response to any request for information or advice or particular factual situation. The author is now the Director of the Office of Research Integrity at the University of Louisville.
Research Compliance Note
Subject: Human Subjects Compliance Re: OHRP "Compliance Determination Letters" Respond to Allegations From Any Source; Some Provide Basis for Civil Litigation
From: Thomas K. Dalglish, J.D., Ph.D.
Sr. Asst. to the Vice Provost, Research
University of Washington
Date: February 19, 2001
Since last July, the OHRP (Office for Human Research Protections) in DHHS, under the direction of Greg Koski, M.D., has issued, and published on its web site, what it calls "Compliance Determination Letters." These letters are the result of compliance oversight evaluations conducted by OHRP in response to complaints, and are directed to institutions about whose research activities the complaints have been concerned.
OHRP has posted ninety-four (94) such "Compliance Determination Letters" between July 1, 2000 and January 31, 2001, including a small number of follow-up letters. The letters are case-specific, and describe the complaints, state findings resulting from the evaluations, are addressed to the institutions involved, and typically make recommendations (some quite serious) concerning the activities in question and the overall human subjects protection programs at the institutions.
While the letters are intended for the institutions to which they are directed, they make interesting reading, as almost a kind of "common law" of compliance oversight decision-making. Additional documents, presumably including institutional/OHRP correspondence, from the closed cases are available under the Freedom of Information Act.
As discussed further below, six (6) such Compliance Determination Letters could be viewed as instigating, or at least furthering, civil litigation brought by subjects wronged in the research activities complained about. Whether or not so intended by OHRP, that is most assuredly one result. It is fair to note, however, that from the perspective of the offended subjects, or in some cases of their surviving family members, there are probably legitimate and common sense reasons in any event to consider filing legal claims for damages. The OHRP letters are not themselves the cause of litigation. The facts in each of the six cases are compelling. Given the unacceptability of the research conduct and the scope of the noncompliance in question, and the nature of the harms experienced by the subjects, it should not be surprising at all to hear the word "lawsuit" mentioned.
As noted, the compliance oversight evaluations represent OHRP's response to specific complaints made to it about alleged research improprieties or inadequate protections afforded human subjects at the institutions in question. According to Dr. Koski, OHRP "evaluates all written allegations or indications of noncompliance with HHS Regulations derived from any source [emphasis supplied]." See Memorandum from Dr. Koski to OHRP Staff dated December 4, 2000, found at the following website:
The Compliance Determination Letters contain the results of the evaluations.
Apart from the litigation-promoting nature of some of these letters, there are four conclusions of note that emerge from a review of the 94 such letters issued through January 31, 2001 and from the OHRP policy Memorandum quoted from above.
First, all it would take to precipitate a "compliance oversight evaluation" of any institution's human subjects program or of a particular research project is a credible telephone call, or written complaint, "from any source."
Second, in responding to a complaint, OHRP doesn't appear to limit itself to an investigation of the specific conduct upon which the complaint is based. Rather, the compliance oversight evaluations often enlarge the frame of reference and assess the complete human subjects protection programs and procedures at the institutions in question.
Third, it is apparent that OHRP conducts strategic literature searches to determine whether published results of research by investigators under scrutiny gives evidence of their having obtained prior IRB review of research before enrolling subjects and actually conducting the research.
Fourth, OHRP appears quite willing independently to obtain expert assessment of various kinds of risks to which subjects in the research in question are exposed. Armed with such assessments, OHRP then evaluates representations (if any) investigators made about risks in particular projects to the relevant IRBs, and the degree to which IRBs themselves demand further information from investigators or otherwise hold investigators accountable for disclosing risks to the IRBs and thereafter to subjects as part of informed consent.
Following its complaint-based oversight evaluations, and in the resulting Compliance Determination Letters, OHRP typically communicates to the institutional recipients a range of "recommended" actions. To the undoubted relief of many of its critics, OHRP clearly has, and uses, sanctions that are other than draconian. These can include suggestions for improvement in human subjects protection procedures, recommendations for "corrective action," restriction or even withdrawal of an institution's assurance of compliance, restriction or suspension of an institution's or an investigator's research activities, debarment, and other appropriate sanctions or reporting requirements. However characterized, comments contained in the OHRP Compliance Determination Letters seem to evoke nearly universal remediation on the part of the recipient institution. Deficient responses result in follow-up letters from OHRP.
A summary of all findings (entitled "Common Findings and Guidance") made by OHRP as a result of its evaluations and that are contained in the 94 Compliance Determination Letters issued in the seven months between July 1, 2000 and January 31, 2001, can be found at the following website:
The letters themselves can be found at:
In six (6) Compliance Determination Letters, and as part of mandated "corrective action" following compliance oversight evaluations in the six cases, OHRP has required the institutions under scrutiny to provide subjects with documentation and written statements describing how subjects were wronged in the offending research activity.
This form of "corrective action" is variously expressed. Institutions are asked to develop a "plan" for informing the wronged subjects, and to submit the "plan" to OHRP for review and approval. The plan typically includes notifying allegedly wronged human subjects of the full nature of their involvement in the research (not always clear to those imperfectly consented). It also includes, as appropriate, a mandate that the subjects be given an accurate account of the risks associated with the research they were involved in. Institutions are further required to detail in writing for the subjects the precise nature of the noncompliance engaged in by the investigator or institution. This detail presumably includes answers to the where, when, how, and by whom questions.
Intentionally or not, these OHRP-mandated disclosures by miscreant institutions to subjects - "debriefings," OHRP calls them - set the stage for, or actively facilitate, civil litigation. Armed with newly disclosed details about the offending research they participated in, subjects are better prepared as a result to file claims for damages for harms caused by the activity. Their trip to a lawyer's office, debriefing documents in hand, is even more predictable if their participation in the research was unwitting and without their informed consent. In effect, OHRP's "sanction" for serious noncompliance, however indirect in its application, takes the form of money damages available through the civil justice system. The disclosures, or "debriefings" in OHRP parlance, accomplish one of the early goals sought by plaintiffs' counsel in the first stages of discovery in civil litigation, namely establishing - and documenting in writing - the basics about who did what to whom, when, where, why, and how. Not so incidentally, the formal disclosures to subjects are also likely to start the clock running on whatever statute of limitations applies, an advantage to an institution seeking loss containment and control.
Whatever one's views about sanctions for non-compliance imposed in recent years upon Duke University, the University of Colorado, and others, it is apparent that facilitating civil litigation, and the imposition of money damages for harm caused, introduces a new dimension into compliance enforcement. Litigation brought by human subjects claiming injuries in research is now underway involving the University of Oklahoma and, it appears, the University of South Florida. It is not just the federal regulators, and regulations, that institutions must now be concerned with when configuring human subjects protections systems. They must now keep an eye on evolving judicial precedent and the availability to wronged subjects of legal remedies.
The six (6) institutions required by OHRP to "debrief" subjects - to disclose to them specific details about alleged institutional wrongdoing - are identified below. The dates of the initial Compliance Determination Letters, and follow-up correspondence, are as noted. A brief description of the reasons given by OHRP for the mandated disclosures is provided.
1. University of Oklahoma (6/29/00, 7/7/00, 7/13/00).
Melanoma vaccine. Multiple violations involving nearly every aspect of human research activities (e.g. design, safety, risks, recruitment, consent, etc.). Nine allegedly injured subjects. Major litigation filed about February 5, 2001 in federal district court in Oklahoma. See "Research Compliance Note" February 14, 2000.
2. University at Buffalo, SUNY (7/12/00).
Spinal internal fixation trial. Modification of protocol and enrollment of human subjects without IRB approval. Research conducted after expiration of approval. Failure to obtain informed consent of some subjects. Actual physical injuries or nature of harm unknown. Not known either whether litigation is being considered or has been filed. Due to the need for pre-filing investigation, it is probably too soon after the disclosures to know.
3. University of Pennsylvania (8/23/00, 1/22/01).
Perception of acetone study. Subjects asked to sniff various concentrations of acetone to measure irritation thresholds and perceptual responses. Project not minimal risk as investigators had claimed, and should have been reviewed by IRB. IRB failed to receive, and failed to request from investigators, sufficient information about acetone exposure to determine levels of risk involved. Consent documents did not adequately explain purpose of research, procedures to be used, reasonably foreseeable risks, benefits, whom to contact for questions about subjects' rights. Also, statement contained in informed consent form that "odors you will be smelling are regarded as harmless" was misleading and not consistent with known potential acute toxicity for acetone.
By follow-up letter 1/22/01, OHRP advised the University of Pennsylvania, and the research center it was collaborating with, that their debriefing plan was inadequate, in three particulars. One, documentation that the plan had been reviewed and approved by the University IRB, as the OHRP had required, was lacking. Two, there was no description proposed to be given the subjects of the concentration of the chemical they had been exposed to, and there should have been. Three, the language used in the proposed debriefing statement was highly complex and technical, and unlikely to be understood by the subjects. OHRP in its 1/22/01 letter told the University and the research center that it "anticipates that any proposed debriefing text would summarize (i) the names and concentrations of the chemicals to which the subjects were exposed; (ii) the exposure safety limits for each chemical; and (iii) the known side effects of each chemical for the range of concentrations at which subjects were exposed."
At this time the exact nature and extent of physical harm to subjects is unknown. Not known either is whether litigation is being considered or has been filed, although due to the need for pre-filing investigation, it is probably too soon to know.
4. University of South Florida (9/28/00, 11/17/00. 12/4/00, 1/25/00).
Use of Tampa Trephine in corneal transplant surgery (a penetrating keratoplasty procedure) under direction of Dr. J. James Rowsey. Sixty (60) subjects underwent procedure. OHRP made the following formal findings. Procedure was research despite protestations by investigator to contrary. Procedure used only in limited pre-clinical testing in animals, results from which had not been completed prior to use in humans. Dr. Rowsey systematically and prospectively gathered data regarding the procedure using an open-label, non-randomized, single-treatment-arm pilot study. Dr. Rowsey never sought or obtained IRB review or approval for the procedure used on the 60 subjects, some of whom were children. No legally effective informed consent was obtained from the subjects. Children involved in the research were not given the special protections, reviews, and consent procedures provided for children in the federal regulations. Plan for disclosure of details about research to subjects approved with revisions by OHRP on 11/17/00, 12/4/00, and 1/25/00. Litigation is believed to be underway, but this cannot be presently confirmed.
5. National Institutes of Health (11/3/00).
Obesity study begun in 1996 of population differences in insulin sensitivity, resting energy expenditure, and body composition. Subjects were 100 overweight children and 93 normal weight children of overweight parents. Children were ages 6 to 10 years old. Duration of study was to be from date of enrollment to adulthood. Investigators were able successfully to claim (in error), and the IRB at the National Institute of Child Health and Human Development (erroneously, as it later turned out) agreed, that the following procedures, performed at time of enrollment and at five year intervals until adulthood, were no greater than "minimal risk," no more hazardous, they said, than playing for several hours in the streets or sidewalks: standardized psychological testing designed to uncover significant psychiatric illness; fasting blood tests; bone age x-rays; screening two hour glucose tolerance test; a two-day, one-night admission to the hospital for additional testing; 2 IV lines in place for 18 hours; abdominal MRI; two hour hyperglycemic clamp study; three hour euglycemic, hyperinsulinemic clamp study; another separate daytime hospital admission for testing; a pelvic ultrasound for girls; heart rate monitoring involving the wearing of a wrist band and chest belt monitor system. Some of these procedures involved pain, some could cause anxiety. There were informed consent deficiencies. No benefits directly accrued to any of the children subjects, and the research was therefore impermissible under 45 CFR 46.405. OHRP ordered the research immediately suspended. Not known whether litigation is being considered or has been filed, although it is probably too soon to know at this time.
6. University of Missouri - Columbia (11/22/00).
78 patients, who between June 1991 and March 1992 underwent isolated coronary artery bypass grafting by a single surgeon (Dr. Jack Curtis), were randomized to receive one of two myocardial preservation techniques. Controls (n=38) received cold intermittent cardioplegia, while the experimental group (n=40) received continuous (warm) cardioplegia. The two methods were compared. The activity did not receive prior review by an IRB. Responding in April 1992 to a subsequently submitted protocol by the investigator who wished to perform the same procedure prospectively on (presumably) a new group of subjects, the University IRB determined that the project presented "significant risk" to the subjects, and required that the investigator obtain informed consent from the subjects. While this April 1992 protocol was never carried out, the IRB's findings at that time evidence generically the level of risk determined to exist in the particular procedure, and the necessity for obtaining the informed consent of the patients involved.
After the results of the 1991-1992 research were published in two separate journals (in 1993 and 1996), and became known to the University IRB, the IRB not once, but twice, met and required that the principal investigator and the university notify the subjects or the families of deceased subjects by letter that the subjects had been involved in research in those years without their informed consent. The dates of these IRB determinations were 12/16/98 and 1/27/99. Though notified of the two IRB determinations, the Provost, Dr. Brady Deaton, decided not to notify the subjects of their involvement in the research without their consent.
Thereafter, OHRP, following a compliance oversight evaluation, made findings that the 1991-1992 activity in question was research, was greater than minimal risk, was not exempt from IRB review, should have been reviewed but was not, and required the informed consent of subjects, which was not obtained. As a result, in its 11/22/00 Compliance Determination Letter, OHRP required the University to develop a "plan" for notifying all surviving subjects or their surviving relatives that the subjects had unwittingly participated in research. The University was also required to disclosing the risks of the research to the subjects or their families, and the nature of the investigator's non-compliance, with appropriate documentation including the relevant IRB minutes.
The outcome of these required disclosures is not known at this time. Not known either is whether litigation is being considered or has been filed, although it is perhaps too soon after the disclosures to know.
Compliance Determination Letters, and the compliance oversight evaluations upon which they are based, are a unique, quite powerful, but thus far unappreciated resource in the effort to cultivate compliance and protect human subjects in research.
They are instructional, providing factual context for those interested in learning how requirements for protecting subjects are applied in actual cases, and what happens when they are not. This is particularly helpful for those who find interpreting black letter rules a dry and unilluminating exercise. The letters also give insight into how OHRP approaches compliance education and enforcement, discrediting some of the phobias - the monsters in the closet - that have crept into discussions about compliance post-Duke. For those interested in crafting arguments against the perceived excesses of OHRP, the letters provide a foil for testing the merit of their arguments.
The letters, especially the six that require debriefings, help to understand why subjects who have experienced harm might turn to the civil justice system for a remedy, even while the letters somewhat facilitate that avenue of recourse. The letters also give evidence of the utility, as practiced by OHRP, of independent assessments of risk and of the transparent ease of demonstrating non-compliance through literature searches.
Finally, the letters help us appreciate the fragility of a research system, where so much can go wrong with so little justification, where due care could avoid so much grief, where so little separates enforcing basic principles from bureaucratic hassle. They illustrate how little it takes to have great effect - a simple failure to gain informed consent can corrode an entire research project, just one credible telephone call or written complaint can launch a compliance oversight investigation, and one short letter from OHRP requiring that subjects be "debriefed" can inspire litigation and result in a judicial precedent with broad effect.
There is more to be found in OHRP's attic, for those interested in filing freedom of information act requests. This Research Compliance Note barely skims the surface. What kinds of complaints, written or otherwise, go uninvestigated? What alleged deficiencies in protection procedures lack merit? What are the criteria for triaging really bad cases from those that merely warrant suggestions for improvement? At what point does a wrong require what OHRP calls a "debriefing?" What offenses committed against subjects, or the system set up to protect them, are the most common, and why do they keep recurring? How can they best be prevented? Answers to these and numerous other questions might be found in the as-yet unpublished exchanges of correspondence between OHRP and the many institutions identified in the 94 Compliance Determination Letters issued between July 1, 2000 and January 31, 2001.