VA Testimony of Kenneth W. Kizer, MD, MPH before Congress on April 21, 1999

STATEMENT OF
KENNETH W. KIZER, M.D., M.P.H.
UNDER SECRETARY FOR HEALTH
DEPARTMENT OF VETERANS AFFAIRS
ON
OVERSIGHT OF RESEARCH IN THE
VETERANS HEALTH ADMINISTRATION
BEFORE THE
SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS
AND THE
SUBCOMMITTEE ON HEALTH
OF THE
COMMITTEE ON VETERANS' AFFAIRS
U.S. HOUSE OF REPRESENTATIVES

Mr. Chairmen and Members of the Subcommittees, thank you for the opportunity to appear before you to discuss issues related to the recent suspension of research at the Greater Los Angeles Health Care System (GLAHS), specifically, and oversight of VA's research program, generally.

I want to unequivocally state at the outset that the standards for research conduct within VA are among the highest in the country. VA regulations, as applicable, are as comprehensive as the other 16 federal agencies and are more comprehensive than most agencies that are also bound by regulations governing the conduct of research involving humans.

Research is a very important part of VA healthcare, and while VA's medical scientists are devoted to seeking new knowledge, they are, above all else, committed to patient and research subject safety. VA scientists are expected to abide by stringent ethical principles and rigorous regulatory requirements to ensure the protection of their subjects. Respect for the rights, dignity, and safety of research subjects must be, and is, paramount, and there should be no question that all VA research – human, animal or laboratory – shall be performed in accordance with the highest standards and shall be overseen by vigorous, independent processes.

I have previously conveyed to you the specific problems with human, animal and basic research that led to my March 22, 1999, decision to suspend all research activities at GLAHS. In the interest of brevity, I will not repeat all of that here, but I have provided a reasonably detailed recitation of the facts in attachment 1. In addition, I will summarize some of the key points here.

The problems with the human research program at GLAHS involved violations of VA's regulations and policies, which are designed to protect the welfare of human volunteers. Although VA currently has no evidence that anyone was physically harmed by these transgressions, I expect VA investigators to adhere to high ethical standards, federal regulations and VA policy. Clearly, that did not occur at GLAHS for at least one research protocol.

Because the VA Headquarters Office of Research and Development (ORD) had identified various concerns about the fiscal, personnel and animal aspects of the GLAHS research program during the past two years, when the most recent problems were identified it was decided that an all encompassing suspension of research activities was in order (attachment 2). VA Headquarters viewed the action at GLAHS as a pre-emptive measure that was designed to prevent untoward events from occurring at GLAHS. At the time the order was issued, the concerns related to the Cardiology Department were unknown to me. While this suspension has caused significant disruption, I am fully confident that the research program at GLAHS will resolve its problems and emerge stronger and, more importantly, that all parties will have confidence in the conduct of research at its facilities.

Since the March 22nd suspension order, a new Acting Associate Chief of Staff for Research (ACOS-R) and an Acting Administrative Officer (AO) have been detailed to GLAHS; both are from facilities outside of VISN 22. They, along with VISN management and the VHA Headquarters ORD, are addressing many of the immediate issues that led to the suspension or issues that have been identified since the initial action.

Individual research projects requiring reassessment for human, animal or biohazards concerns are being reviewed by appropriately and legally constituted review panels that have replaced the previous GLAHS groups. I am pleased to report that virtually all animal and non-human/non-animal projects with biosafety concerns have now been appropriately re-reviewed and are once again operational and enrolling new subjects.

With respect to research involving human subjects, a number of important administrative actions must occur before these projects can resume or new projects be initiated. Because of the deactivation by the Office for Protection from Research Risks (OPRR), Department of Health and Human Services (HHS), of the GLAHS Multiple Project Assurance (MPA-1087), GLAHS has had to establish administrative and review mechanisms that provide HHS, VA and other funding sources with the assurance that its human subjects research is conducted in accordance with applicable regulations and policy.

Specifically, GLAHS is negotiating an Inter-Institutional Agreement with its affiliate, the University of California, Los Angeles (UCLA), which holds its own MPA with OPRR. This agreement will allow HHS grants that are funded to UCLA, but performed at GLAHS, to be reviewed by UCLA’s Institutional Review Boards (IRBs). Additionally, GLAHS has had to negotiate a multiple project assurance with VA Headquarters to provide VA with binding assurance for all non-HHS funded human research at GLAHS. IRBs constituted under the MPA with VA are re-reviewing all non-HHS funded human research protocols. For HHS-funded human studies at GLAHS, each investigator for each study will submit a Single Project Assurance to OPRR in accord with the terms of the MPA deactivation. These actions are ongoing, and it is VA's hope that the GLAHS research program will be fully stable by the end of April.

Numerous regulations and policies govern the conduct of VA research involving human volunteers. In fact, VA policies and regulations exceed those required by other government agencies, including HHS.

This past weekend, a distinguished gathering of scholars paid tribute in Charlottesville, Virginia, to the 20th anniversary of the Belmont Report, the genesis for federal requirements to ensure the ethical conduct of research involving humans. These federal regulations, and by extension VA's, derive from the Federal Policy for the Protection of Human Subjects (often referred to as the "Common Rule," 56 FR 28003). Seventeen federal agencies, including VA, are co-signatories to the Common Rule.

VA has incorporated the Common Rule into its own regulations at 38 CFR 16. VA is legally bound to adhere to the regulations articulated within 38 CFR 16, which includes detailed descriptions of informed consent and the structure and responsibilities of Institutional Review Boards (IRBs). (Some VA facilities have adopted the terminology Human Subjects Subcommittees [HSSs] for this entity.)

I note that it is important to recognize that VA considers all research at a VA facility as VA research, even if the funding is from non-federal sources. Thus, any research, at VA, regardless of the funding source, is subject to the regulatory requirements of the Common Rule and VA's additional protections. VA's blanket pledge of full and equal protection for all human subjects exceeds that of even some institutions who hold MPAs with OPRR. Of note, OPRR has identified unchecked human experimentation at a broad range of venues, including some colleges and universities not receiving federal research funds and some physician, dental and psychotherapist practices. None of this involves VA facilities.

For human studies conducted at a VA facility in support of a new drug or device application to the Food and Drug Administration, the human studies component also comes under the authority of FDA regulations for the protection of human subjects in research (21 CFR 50 and 21 CFR 56). Because 38 CFR 16 regulates all federally sponsored research at VA – and because 21 CFR 50 and 21 CFR 56 cover all VA research in support of a new drug or device application – when VA researchers are engaged in research that supports a new drug or new device application, the researchers must comply with both sets of regulations.

VA and FDA are partners in a memorandum of understanding that enhances the communications between FDA and VA with respect to a number of FDA requirements. In particular, FDA has agreed to notify VA medical center directors of investigative findings relating to a particular study, and advise VA of any violations resulting from investigations into the performance of clinical investigators or Human Studies Subcommittees (HSSs/IRBs) associated with VA.

Finally, VA has gone further in protecting human research subjects than is provided by either the Common Rule or FDA regulations. Despite repeated calls that the federal government address the issue of compensating research injuries, VA is the only agency that has extended its regulations (38 CFR 17.85) to provide for compensation to persons injured as a result of participation in VA research.

In 1992, shortly after the establishment of the federal Common Rule, VA issued a revised policy and incorporated it into our policy manual, M3, Pt.1, Ch.9, "Requirements for the Protection of Human Subjects".

Chapter 9 incorporates the provisions of the Common Rule (38 CFR 16), and FDA regulations (21 CFR 50 and 56). In addition, Chapter 9 explains how the provisions of these regulations are to be implemented in the specific context of research at VA medical centers.

Just as VA's regulatory requirements exceed those under the Common Rule, VA policy (M3, Pt. 1, Ch.9) exceeds the policy and regulatory requirements of other entities. For example, the Common Rule is relatively silent on the issue of informed consent in persons with impaired decisionmaking capacity, only pointing out the possiblity of consent by a legally authorized representative. In contrast, M3, Pt.1, Ch.9, sec.12 is devoted entirely to "Research on Human Subjects with Surrogate Consent". It describes in explicit detail the specific conditions under which an investigator may seek surrogate consent for an individual with impaired decisionmaking capacity.

Finally, because VA has a large program in cooperative trials for the study of new drugs, therapies and devices, the VA Cooperative Studies Program developed detailed guidelines, "Cooperative Studies Program: Guidelines for the Planning and Conduct of Cooperative Studies," in 1997. A major part of these guidelines is devoted to describing the requirements for protocol review and informed consent. These guidelines derive from 56 FR 280003 (the Common Rule), 38 CFR 16, and the VA policy manual M3, Pt.1, Ch.9.

VA oversight of its human subjects research is equal, or in many ways better, than oversight by non-VA research institutions. Indeed, a broad series of initiatives to assess the systemic nature of any deficiencies, or lack thereof, have been underway for some time. I am also initiating two new, broad-based initiatives that will position VA as the clear leader in ensuring that its research is of the highest ethical and legal caliber.

Before describing the two new initiatives, I would like to briefly highlight six programs that demonstrate that VA has been cognizant of the need to exercise due diligence in monitoring the conduct of VA research that involves human subjects.

In 1995, the VHA Office of Standards in Human Research (part of ORD) was formed and located at the Portland VAMC. Since its inception, the office has conducted 12 random site visits to medical centers across the country. Site visit teams reviewed: IRB records, informed consent documents, all local policies and procedures in place to implement national requirements under the Common Rule, FDA regulations, and VA manual M3, Pt.1, Ch.9. In addition, medical center directors, chiefs of staff, associate chiefs of staff for research, and researchers were interviewed. At the sites visited, the site visit teams found failures in documentation, but no instance of violation of any patient’s rights or health and well-being. Likewise, they found no instance of either willful or intentional misconduct.
Since 1975, the VHA Cooperative Studies Program Human Studies Committees have conducted performance site visits and they currently assess 12 sites per year. Along with audit activities, the Committees also interview research volunteers regarding their experience as a research participant, including an assessment of the subjects' informed consent.
The VA Cooperative Studies Program conducts 45 audits per year, on average, of its drug studies at selected performance sites. These audits began in 1997.
The VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center is FDA-approved for packaging, dispensing, and monitoring pharmaceuticals and devices for drug trials. The Coordinating Center audits each drug trial at each study site at least once during the life of the trial; these audits began in 1975.
ORD conducts approximately six site visits per year of its research centers for evaluation of performance and determination of continued funding. It also investigates allegations of variations from prescribed research policies.
The Nuclear Regulatory Commission conducts site visits of its low-level radiation licensees (including VA medical centers and research facilities) every three years. When human studies are conducted under the license, NRC site visitors review human ethical standards and compliance.

Clearly, the most important question facing the VA research program is whether the problems at GLAHS are an isolated occurrence, or do they represent a more serious endemic problem within the VA research system?

I have no evidence that the latter is the case. Moreover, I am pleased at the level of Headquarters oversight that ORD has to date initiated or has underway. Nevertheless, I believe the time has come for more comprehensive and systematic efforts at overseeing research programs. Veterans, the Congress, and VA need independent and routine assurance that VA research is conducted ethically, legally, safely and with integrity. I have, therefore, directed the implementation of two major new initiatives:

First, I am establishing a new office, the Office of Research Compliance and Assurance (ORCA), which shall report directly to the Office of the Under Secretary for Health. This office will be in several ways similar to the Office of the Medical Inspector (OMI). ORCA's mission will be to provide VHA with the assurance that research conducted by our scientists is done with maximal regard for issues of: 1) human and animal subject protection; 2) safety of laboratory personnel (chiefly chemical and biological, and in consultation with the National Health Physics Program, radiological); and 3) research integrity (e.g., conflict of interest, scientific misconduct, research ethics).

ORCA will operationalize its functions in a manner similar to that of OMI, but, in contrast, a majority of ORCA's compliance officers will be based in field offices located across the country (up to six) to: 1) enhance the ability of ORCA to rapidly respond to or consult on emergent incidents, and 2) facilitate a reduction in the costs of routine inspections.

I want to particularly emphasize that ORCA will be an independent, objective and unbiased entity in its compliance and oversight activities.

Today, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) provides the public assurance that JCAHO-accredited healthcare organizations meet or exceed minimum quality standards. All VA medical treatement facilities participate in JCAHO inspections. Similarly, the Association for the Assessment and Accreditation of Laboratory Animal Care, International (AAALAC) inspects and accredits research animal facilities in the United States and abroad. VA animal laboratory facilities, along with scores of private-sector sites, are inspected every three years by AAALAC. No comparable mechanism exists for institutions conducting research involving human research. VHA intends to address this vacuum.

In the very near future, VHA will publish a notice that seeks to identify an external entity to serve as an accrediting body for its research programs. The highest priority will be for the selection of an accrediting body to perform routine site visits (e.g., every three years) for the purpose of reviewing the performance of the IRB/HSS systems and other such processes at VA medical centers and research institutions. Through this notice, VA will become the driving force to establish both an accreditation entity and an accreditation process for research involving human subjects similar to that performed by AAALAC for animal research. No such entity currently exists, and thus, VA will clearly be traversing new ground with this effort.

That such an entity is overdue is now without question in my mind. In March 1999, the HHS Regional Inspector General who was responsible for a 1998 HHS Office of Inspector General review of IRBs stated, "…as a matter of public policy, the time is right to foster a system of accrediting IRBs. I believe that FDA and NIH should collaborate in determining what they can do to stimulate this development, and I think they should do it with some sense of urgency." Moreover, accreditation was recommended in 1983 by the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. I am particularly pleased that VHA will provide the leadership whereby, at last, nationwide accreditation in this area could be achievable. I hope other federal agencies will join with VA in this effort.

Today, as in the past, the research enterprise of the United States is the envy of the world. It has produced extraordinary advances in medical care and many other areas. There is no dispute that such advances depend on the participation in research of our relatives, neighbors, friends and fellow citizens – including men and women who have served in the Nation's armed forces.

I am proud that VA scientists have made more than their fair share of contributions to medical research. But I am more proud of, and grateful for, the willingness of veterans to afford VA the privilege of participating in the U.S. research enterprise. Having served this country once in the military, veterans' participation in biomedical research again serves the interests of the Nation because research is the cornerstone for increasing knowledge that helps us all. We owe them assurances that their interests will be protected by standards second to none.

While the increasing reports of investigations into VA research at multiple facilities may cast a temporary shadow over our program, I am confident it will do so only briefly. The existing measures and policies in place, combined with our new initiatives, will place VA at the forefront of protecting human research subjects. To maintain the public trust we must all share a vigorous commitment to protect the rights and welfare of those who participate in research protocols. I hope those outside of VA will quickly join our efforts to ensure there are effective checks and balances in place to protect human research subjects.

Again, I appreciate the invitation to discuss these important issues with you, and I will be pleased to try and answer any questions you might have.

VHA considers the protection of human and animal subjects and our laboratory employees to be among our highest priorities. Dating to a site visit in September 1996, VHA Headquarters has had concerns about the administration of the Research Service at the West Los Angeles campus (then West Los Angeles VAMC), in particular. This attachment summarizes the concerns identified at GLAHS to date and the current plan to address them.

In spring 1997, the National Institute on Drug Abuse (NIDA) raised concerns about the financial management of a VA-NIDA collaborative agreement for medication development by the Research Service at the West Los Angeles facility. In May 1997, the Chief Research and Development Officer (CRADO) placed the West Los Angeles Research Service on administrative probation. This history of financial management concerns, coupled with new and historical concerns about administration of human, animal, and bio-safety research (described below), led VHA to suspend all research conducted at GLAHS as of March 26, 1999.

On March 22, 1999, OPRR deactivated its Multiple Project Assurance (MPA-1087) for GLAHS, which encompasses the former VA medical centers at West Los Angeles and Sepulveda, and affiliated clinics. MPA-1087 is the mechanism by which GLAHS assures OPRR that GLAHS conducts its research involving human subjects in conformance with 45 CFR 46. This HHS regulation incorporates 52 FR 28003, also referred to as the "Common Rule" for the protection of human subjects in research and which is subscribed to by 17 federal agencies that fund research involving human subjects.

As permitted under the Common Rule, VA accepted MPA-1087 as its own assurance that VA research at GLAHS was conducted in accordance with federal regulations. Moreover, since VA considers all research, regardless of sponsor, conducted at VA medical centers to be VA research, MPA-1087 covered all human research conducted at GLAHS whether HHS, VA, or any other source funded it. Consequently, OPRR's actions effectively removed all assurance that research involving humans being conducted at GLAHS was in legal and ethical compliance.

OPRR's deactivation of MPA-1087 resulted from the failure of GLAHS to adequately respond since April 1993 to requests by OPRR to change and/or document procedural and administrative matters related to the way GLAHS conducted initial and ongoing reviews of protocols involving humans. Specific problems cited by OPRR included:

Most of these infractions occurred at the West Los Angeles campus of GLAHS. Since the merger of West Los Angeles and Sepulveda, both campuses have operated under the same MPA. Thus, the deactivation of the MPA-1087 affected both campuses equally.

Both the West Los Angeles and Sepulveda campuses have problems with their animal programs, but those at Sepulveda are more serious.

A report of the Institutional Animal Care and Use Committee (IACUC) of the GLAHS Research and Development (R&D) Committee found that the laboratory animal care facilities at the West Los Angeles campus were acceptable. A site visit by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC) to the West Los Angeles animal care facility found that the occupational risk of animal handlers had not been assessed properly and is requiring changes in policies and procedures. AAALAC’s final report on West Los Angeles is pending. It is likely AAALAC will recommend additional minor policy and procedures changes and place the West Los Angeles campus under restriction until it is satisfied that the problems have been rectified. Additionally, in April 1998, the Medical Research Service, Office of Research and Development (ORD), VHA Headquarters, expressed its concern to the Associate Chief of Staff for Research (ACOS-R) at the West Los Angeles facility about the lack of progress to correct infrastructure and leasing deficiencies related to building 337 and about attempts to pressure members of the Institutional Animal Care and Use Committee (IACUC) inspection report. Although requesting a response within seven working days, none has been received.

At the Sepulveda campus it is anticipated that AAALAC will place the animal facility on probation for multiple program deficiencies related to the occupational risks of animal handlers and specific problems with animal housing, such as temperature, humidity and crowding.

This classification covers virtually all basic research. The VHA Headquarters Emergency Management Site Visit Team that visited GLAHS on March 25-26, 1999, found serious deficiencies in the bio-safety program at GLAHS, in particular at the West Los Angeles campus:

The Emergency Management Site Visit Team found no significant problems at the Sepulveda campus with respect to bio-safety issues.

A full Recovery Plan for research at GLAHS has been developed by VHA Headquarters, Office of Research and Development and Veterans Integrated Service Network 22.