Termination of Baclofen Study at UofL Discloses Influence of Catholic Health Initiatives on University Research.

Informed consent forms reflect Ethical and Religious Directives of the Catholic Church.

A recent report by Kate Howard of the Kentucky Center for Investigative Reporting on the withdrawal of federal funding for a University of Louisville research study conducted at Frazier Rehabilitation Hospital shines a bright light on how research –specifically research involving human subjects – is performed at the University of Louisville and in its partner institutions. The specific research protocol in question, directed by UofL faculty member, Dr. Susan Harkema, was intended to examine if adding the muscle relaxer Baclofen to a regimen of physical therapy on a treadmill improves or worsens function in patients who are partially paralyzed as a result of spinal cord injury.  The study holds out what is in my opinion an insufficiently proven hope of a possible increase in ability to stand or ambulate. Many aspects of the study were criticized by both federal authorities and by the university’s own investigation. I believe those criticisms to be valid but will not address them in this article.  In my own professional opinion, the study as designed and conducted had very little chance of producing meaningful data in any event.

Informed consent – The ethical core of human subject research.
Human subject research must be reviewed and approved by the University of Louisville’s research Institutional Review Board (IRB) using a rigorous national set of requirements and guidelines designed to put the interests of the research subject first. These rules comprise a ‘Federal Policy for the Protection of Human Subjects’ and collectively are called the ‘Common Rule‘.   Violation of the Common Rule can result not only in grant support being withdrawn as it was here in Louisville, but in prohibition of future human subject research.  To put things in perspective, this would be the equivalent of a death-sentence penalty from the NCAA.  By contract, KentuckyOne has agreed to use the UofL IRB to supervise research performed in its facilities, including in University of Louisville Hospital.

Problems with informed consent.
The IRB’s own recent internal investigation revealed that that some Baclofen study participants signed the wrong consent forms.  Specifically, this had to do with whether or not the research subject was aware that they would be personally responsible to pay for the (expensive) experimental physical therapy that is at the center of the research protocol.  Initially some subjects were surprised to get very large bills for their participation on top of the unreimbursed travel and housing expenses required for the several-month study. The consent form had been changed by the IRB to make it clear that there were financial implications to participation.

I too was concerned about the informed consent forms used, but for a very different and profoundly more significant reason.  In my opinion, full informed consent was not being given.  Additionally, the template consent form required by the University of Louisville’s IRB had been altered to conform to the religious tenants of the Roman Catholic Church – changes which I and others had been promised would not occur.  If these alterations to the standard informed consent form template were made without the documented express permission of the IRB, this would constitute a major violation of research protocol and ethics.  If my University’s IRB did in fact approve the changes, my earlier concerns have been realized and I am ashamed for it.  Let me explain.

A proposed change in traditional research ethics.
Three years ago, I wrote a pair of articles (An initial article and follow-up) describing how KentuckyOne Health, an arm of Catholic Health Initiatives, made a low profile effort to get the UofL IRB to change its standard template language to conform to the Ethical and Religious Directives of the Catholic Church. Specifically, KentuckyOne wanted changes in the language informing women of child-bearing potential of real and potential risks to themselves and their developing fetuses that might arise as a result of participating in the research.  Mandatory language had always included a pregnancy test before entering the study, and a requirement for the use of effective contraception for its duration.  In the event of an unplanned pregnancy, the subject was advised to consult with their physician to include the possibility that a decision might have to be made about “whether or not to end the pregnancy.”  Of course both contraception and abortion are never on the table for the Catholic Church and it was predictable that KentuckyOne would attempt to change what is representative language throughout the national research community.  Indeed, large multi-center studies can and do require all research centers to use their unaltered consent forms without exception as a condition of participation.  I am unaware that exceptions are allowed for religious purposes.

UofL almost caved.
Initially, the University IRB appeared to be willing to make the requested changes so as not to increase barriers to participation in research by its faculty.  However, largely as a result of push-back by the separate Ethics Committee of University of Louisville Hospital, all the changes requested by KentuckyOne were not made.  I do not have a copy of the template consent form earlier than 2013 before the management agreement with KentuckyOne was finalized, but it is my understanding that some changes in the language were made including substitution of “birth control” for contraception – presumably to allow notoriously unreliable abstinence or withdrawal to count as alternatives to effective contraception.  It is also my understanding that language was altered making full disclosure of the possible risks to the “unborn child” (as opposed to the fetus) dependent on the research subject actually taking the initiative of “asking” for the information.  This latter approach is not how the process of informed consent is supposed to work!

Required vs. actual language used.
Attached is the relevant text from the current template that the UofL IRB requires, and the relevant portion of what the research subjects at Frazier Rehabilitation Center (a CHI/KentuckyOne Health facility) were asked to sign. Links to full copies of the respective consent forms are present at the end of this article.

To summarize the discrepancies between the required and the actual consent forms with regard to pregnancy risks, the requirement for a pregnancy test before the study is curiously delayed until 2 months after participation when a positive test would be too late to make any difference.  There is no mention of a requirement for any kind of birth control, or family planning, let alone contraception.  There is no language referring to termination of pregnancy.  Even the language offering the opportunity to discuss potential risks to the ‘unborn baby’ “on request” is deleted.  By omission, the potential research subject is not told that his or her participation is subject to the religious directives of a church that might not be their own.   I and members of the Hospital Ethics Committee were assured that this would not happen. Troublingly, I was told by a member of the IRB at the time of my initial investigation that once a research project had been approved, that follow-up was not very consistent. The current Baclofen study appears to lend validity to that comment in multiple dimensions.

University comment – declined.
I offered the University an opportunity to comment on the discrepancy between the required template and the language of Baclofen study including a specific question of whether the University IRB approved the alteration of its template consent language related to risk of pregnancy.  The University declined comment at this time and advised me that I would have to make my request using the open record mechanism.  Since the UofL IRB had at least two opportunities to review the consent form in question, I must tentatively assume its members approved the forms they read. Whether or not this approval is specifically recorded in the minutes of the IRB as required is not known at this time.

It is very true, as the University reminds me, that “informed consent forms can be modified to meet study-specific needs.” Baclofen is often used to treat the muscle spasms of individuals with neurological disorders including spinal cord damage. It is however, not approved for use in pregnancy – few drugs are. In rats it cases fetal defects. It is not known to cause defects in humans but a study proving it does not is nearly impossible to do. The effects of the aggressive assisted treadmill ambulation on pregnancy in partially paralyzed people are unknown.  The forces involved are enough to break bones. If the risks of drug or therapy are minimal, this could have been disclosed.  Nonetheless, there is nothing about this research study that requires a departure from the University’s Common Rule language, and everything about the vulnerability of its subjects that demands its full and rigorous application.

Is this a big deal or not?
Human subject research is one of the most important responsibilities a school of medicine or university undertakes.  In a setting of medical education where future health professionals are watching, how such research is conducted reveals the ethical heart of the institution and its members. Strictly speaking, research subjects are not patients, but how they are treated sheds light on how patients seeking medical care are treated. As I discuss in my earlier articles on this subject linked in the first paragraph above, fully informed consent consists of telling the subject-patient the truth, nothing but the truth, and critically – the whole truth.  Anything less robs the subject-patient of the opportunity of self-determination or full expression of free will. Anything less opens a door to a perception –true or false – that priorities other than those of the research subject are more important to the institution or the investigator.  Therefore, how the University of Louisville and its partners handle this matter is of critical importance.  Their work is not yet done. There are no doubt other investigations that will follow from this event – on this specific proposal and on others.

What happens now?
I for one will ask to see contemporary informed consent forms used for clinical research in the James Graham Brown Cancer Center or on the wards of our teaching hospitals where drugs with demonstrable undesirable effects on mothers and fetuses are used.  I will want to see the minutes of the University IRB for meetings during which any informed consent form differing in its pregnancy-risk language deviates from that in the approved template. Deviations are permissible in our public University only for scientific and medical reasons, not religious ones. I will be watching closely, as will others, about if and how the University changes its internal procedures, or if there are any consequences for anyone for the breakdown in research practice and protections. I hope to find a template consent form used before the management agreement with KentuckyOne to determine if the template language vocabulary was changed from one of science and medicine into the one used by the pro-life side of the abortion debate.

I have argued that in exchange for merely a promise of research money, that UofL gave away too much of its ethical, clinical, academic, financial, and yes, even its research independence.  I will ask what the role of CHI or KentuckyOne is in determining UofL research practices.  What veto powers might these religious institutions have over research activity in University facilities?  I will ask how the CHI Center for Clinical Research interfaces with the University of Louisville. Documents disclosed in the unfortunate Baclofen affair tell of clinical samples sent to the CHI Center.  Data collected in the Baclofen study were transferred and stored in a CHI facility but were not even readily available to the IRB for its investigation.  I will ask what CHI does with all the clinical data that it is collecting.  If research subjects were required to pay for the research themselves, I will want to know what happened to any money that might have been budgeted for the clinical expenses of the Baclofen study but not spent. Such monies can get investigators and their institutions in trouble. Others will have additional questions that will have to be answered.

In the end.
I cannot disguise that I am profoundly disturbed by the revelations of the Baclofen debacle.  A rock has been turned over and I do not like what I see.  Coming on a multiple-year string of frank scandals and illegal events in recent University of Louisville history, with its Senior Vice President for Medical Affairs under FBI investigation, and after today’s dismissal of its President; this is the worst possible time for these matters to boil to the surface. On the other hand, perhaps this provides an opportunity – a mandate to make the major changes at the University of Louisville and its medical center that so many of the public have been asking for.

Peter Hasselbacher, MD
President, KHPI
Emeritus Professor of Medicine, UofL
27 July, 2016

Full Text of IRB Consent Template of July 2016.
Full Text of Original Baclofen Consent Form.