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**

**APRIL 21, 1999**

**\*\*\***

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.

**Research Suspension at Greater Los Angeles Healthcare System**

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.

**Existing VA Protections for Human Research Subjects**

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.

[Federal Regulations]{.underline}

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]{.underline} 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.

[VA Policies]{.underline}

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.

**Enhancing Oversight of VA Research**

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.

[Existing Efforts]{.underline}

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.

[New Initiatives]{.underline}

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:

-   establishment of an independent Office of Research Compliance and
    Assurance, and

-   publication of a request for proposals to establish an external
    accreditation program for VA research, in general, and VA research
    involving human subjects, in particular.

*Office of Research Compliance and Assurance (ORCA)*

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.

*External Accreditation*

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.

**Conclusion**

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]{.underline} 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.

[Attachment 1]{.underline}

**GREATER LOS ANGELES HEALTHCARE SYSTEM:**

**SUMMARY OF RESEARCH ISSUES**

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.

# Financial Issues

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.

# Human Studies

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:

-   meetings of Institutional Review Boards (IRBs) (committees that are
    responsible for the review and monitoring of human studies
    protocols) that did not meet with a quorum of voting members as
    required by 45 CFR 46;

-   the absence from IRB membership roles of appropriate
    community/patient representatives;

-   Data Safety Monitoring Boards had not been established by GLAHS as
    requested by OPRR in 1994;

-   inadequate procedures for continuing review of ongoing projects;

-   failure to implement policy changes recommended by OPRR; and

-   the use of "expedited review" procedures by IRBs to approve research
    studies with greater than minimal risk in contradiction to the
    requirements of 45 CFR 46.

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.

**Animal Studies**

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.

# Non-Human/Non-Animal Studies

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:

-   Required reviews of research protocols for bio-safety issues were
    done by a junior investigator without appropriate expertise for all
    hazards being reviewed;

-   No minutes of the Bio-Safety Subcommittee (a subcommittee of the R&D
    Committee) documented any kind of bio-safety review. The reviews
    existed only in draft form in the reviewer's laptop computer;

-   The Bio-Safety Subcommittee accepted verbal reports from the
    reviewer without written documentation of review;

-   Bio-Safety Subcommittee minutes are more than six months in
    arrears---i.e., over six months of minutes are missing. R&D
    Committee minutes repeatedly note that Bio-Safety Subcommittee
    minutes are missing, but no action had been taken to correct this
    problem. Since the R&D Committee is supposed to accept committee
    reports as final approval, [none]{.underline} of the bio-safety
    studies has had proper approval for months.

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

**Reinstatement of Research at GLAHS**

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.

Phase 1

-   The GLAHS is notified on March 22, 1999 that all research activities
    will be suspended on March 26, 1999.

-   Research suspended encompasses all human, animal,
    non-human/non-animal research at the West Los Angeles, LA Outpatient
    Clinics, and Sepulveda campuses of GLAHS. Exceptions are made for
    human and animal studies whose suspension could place research
    subjects at risk if respective studies were stopped abruptly.

Phase 2

-   Total research suspension in effect and all VA research funds are
    withdrawn on March 26, 1999.

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-   On-site Emergency Management Team from VA Headquarters is on-site at
    West Los Angeles and Sepulveda on March 25-26, 1999.

Phase 3

-   Full-scale site visit team at GLAHS to assess status of entire
    research program April 5-9, 1999.

Phase 4

-   Partial research suspension in place (expected April 1999 after
    review of site visit report); external management team in place
    (ACOS-R and Administrative Officer detailed from other facilities).
    If the site visit team identifies specific components of the
    research program that are functioning properly, legally, and
    ethically, it may recommend to the Under Secretary for Health that
    discrete components of the research program should be re-instituted.

Phase 5

-   Research suspension removed partially, but probation in place
    (expected action of April-May 1999); interim management team (i.e.,
    temporary ACOS-R and Administrative Officer) identified.

-   Re-constitution of the research administrative and oversight
    functions completed;

-   Probationary period and HQ monitoring instituted.

Phase 6

-   Suspension removed, probationary period in place (1999); expected
    minimum duration May 1999-May 2000;

-   National search for new, permanent ACOS-R.

Phase 7

-   Probationary period in place to extend one year after appointment of
    the new, permanent ACOS-R (likely May 2000-May 2001).