oversight

NIH Clinical Trials: Various Factors Affect Patient Participation

Published by the Government Accountability Office on 1999-10-30.

Below is a raw (and likely hideous) rendition of the original report. (PDF)

                  United States General Accounting Office

GAO               Report to Congressional Requesters




September 1999
                  NIH CLINICAL TRIALS
                  Various Factors Affect
                  Patient Participation




GAO/HEHS-99-182
      United States
GAO   General Accounting Office
      Washington, D.C. 20548

      Health, Education, and
      Human Services Division

      B-281108

      September 30, 1999

      The Honorable James M. Jeffords
      Chairman, Committee on Health, Education,
        Labor, and Pensions
      United States Senate

      The Honorable Joseph I. Lieberman
      United States Senate

      Clinical trials generate the evidence base for decision-making in all areas
      of medicine, and they can be especially important for patients with serious
      or life-threatening health conditions that have limited treatment options.
      For those patients, participation in a clinical trial—a formal investigation
      of the effects of an experimental intervention on people—may offer the
      best chance of finding an effective treatment. Concerns have been raised
      that patient access to trials has become increasingly constrained as the
      financing of health care has changed. These concerns stem, in part, from
      researchers’ reliance on insurance payments for the standard,
      nonexperimental patient care1 provided in clinical trials as well as health
      plans’ efforts to minimize their financial exposure. In response, the
      Congress is considering legislation that would require health plans to pay
      for the nonexperimental care provided to patients in federally approved
      clinical trials.

      At your request, we conducted a review of patient access to clinical trials
      sponsored by the National Institutes of Health (NIH). Specifically, you
      asked us to examine (1) how health insurers’ coverage policies and
      practices affect patient participation in clinical trials, (2) researchers’
      experience in enrolling patients for trials sponsored by the National
      Cancer Institute (NCI) and factors that may explain this experience, and
      (3) whether NIH has evidence of recent difficulties in enrolling patients in
      clinical trials.

      To address these issues, we obtained information from health insurers,
      researchers, and NIH officials. We interviewed medical directors at 26
      private health insurers that together reflect the distribution of enrollment
      nationally in preferred provider organizations, health maintenance

      1
       Standard, nonexperimental patient care includes those medical services that patients would receive
      for their condition regardless of whether they received the experimental treatment. Such services
      include physician visits and prescription drugs, for example. While there is not complete agreement on
      which particular services constitute standard, nonexperimental care for any particular condition, there
      is agreement that such care should be provided to patients. In this report we refer to this care as
      “standard care.”



      Page 1                                                       GAO/HEHS-99-182 NIH Clinical Trials
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                   organizations (HMO), and point-of-service plans. In addition to discussing
                   the indemnity products offered by some of these plans, we also contacted
                   a large indemnity plan. HMOs were further distributed to reflect three size
                   categories (plans with under 100,000 enrollees, those with 100,000 to
                   250,000 enrollees, and larger plans) and various model types. Also, plans
                   were selected to provide distribution across geographic areas to include
                   different levels of managed care activity. We also interviewed directors or
                   their designees at 11 of the 48 NCI-designated clinical and comprehensive
                   cancer centers that were chosen to represent different types of institutions
                   as well as geographic diversity, concerning their trial recruitment
                   experience. (App. I contains a list of health plans and cancer centers that
                   participated in our review.) Although neither the insurers nor the cancer
                   centers were statistically representative groups, and thus the findings from
                   our interviews cannot be generalized, the findings from these two groups
                   of interviews were consistent. In addition, we obtained information from
                   NIH officials and officials at several NIH institutes on the recruitment and
                   enrollment of trial participants. We also reviewed clinical trial monitoring
                   reports. Finally, we conducted a review of the health care literature on
                   barriers to patient participation in clinical trials and spoke with
                   representatives of patient advocacy organizations. We performed our work
                   from September 1998 to August 1999 in accordance with generally
                   accepted government auditing standards.


                   While policies generally exclude coverage for clinical trials, nearly all the
Results in Brief   insurers we interviewed allow for exceptions following case-by-case
                   reviews by the insurers’ medical personnel. If coverage is approved,
                   insurers generally agree to pay the standard, nonexperimental care costs
                   associated with a trial; but because there is little agreement on which trial
                   services constitute standard care, payments can vary from insurer to
                   insurer. Given the uncertainty about approval and payment levels, patients
                   and physicians can be discouraged from seeking prior approval from
                   insurers. Insurers report that they receive few requests for clinical trial
                   coverage and that they do not maintain data to separately track such
                   requests. Yet, insurers may pay for medical care in trials because they are
                   unaware it is provided in a research context.

                   Most cancer research centers we contacted said they did not experience
                   what they considered to be serious difficulties enrolling adequate numbers
                   of patients for NCI-sponsored clinical trials. But all the centers described
                   clinical trial enrollment as challenging, in part because of the significant
                   administrative burden incurred in dealing with health insurers about trial



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             coverage and payment issues. Paperwork requirements can be
             labor-intensive and time-consuming when staff physicians and nurses must
             document the necessity of enrolling each patient and negotiate the specific
             services and amounts to be paid as standard care. Center representatives
             also cited an array of physician- and patient-related factors that affect the
             availability of patients for NIH-sponsored clinical trials. For example,
             community physicians may be unaware that clinical trial opportunities
             exist or lack the time and resources to evaluate candidates for trials. Some
             patients want the promise afforded by new or untested treatments but may
             be unable to participate because of a trial’s eligibility criteria or
             constraints on patients’ time and resources. For many other patients,
             uncertainty about the benefits and risks of experimental treatments can
             make clinical trials unattractive.

             NIH has expressed concern that trial enrollment is declining, but the data
             provided to us by several of the largest institutes did not document the
             basis for NIH’s concerns. Patient enrollment in the NIH-sponsored clinical
             trials for which we could obtain data appeared to be meeting the goals of
             those trials. In 1998, NIH officials reported to the Office of Management and
             Budget that patient participation in trials was a substantial problem,
             particularly for cancer trials. They cited 1996 testimony from clinical
             investigators that managed care seemed to have affected patient
             participation in cancer clinical trials. Beyond such anecdotal information,
             however, NIH does not have quantitative data that indicate that patient
             enrollment has slowed or that trials have been delayed or prematurely
             closed because of patient enrollment problems. Information on heart
             disease and diabetes trials at two other NIH institutes shows that most
             trials were close to meeting their recruiting targets as of the fall of 1998.


             A clinical trial is a method for testing new approaches to disease
Background   prevention, diagnosis, or treatment. The number of clinical trials has
             increased dramatically over the years.2 NIH and pharmaceutical companies
             are the major sponsors of clinical trials that focus on assessments of new
             drugs, devices, and vaccines. NIH-supported trials also may address
             prevention strategies and surgical procedures and may target special
             populations, such as patients with rare diseases. Research groups at
             academic and other medical centers typically organize NIH clinical trials,
             but patients may enter into trials in a range of settings, including
             community hospitals and physicians’ offices. The pharmaceutical industry

             2
              For example, between 1975 and 1980, the results of six randomized controlled trials a year were
             published in the area of heart disease. In contrast, between 1993 and 1997, the results of 149
             randomized controlled trials in the area of heart disease were published each year.



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supports the majority of large clinical trials that determine therapeutic
efficacy of new drug products. These trials generally focus on conditions
that affect large numbers of people. An official of the Pharmaceutical
Research and Manufacturers Association has estimated that drug trials
represent about 75 to 80 percent of all approved trials in the United States
and that pharmaceutical companies sponsor about 80 percent of all drug
trials. The association also has estimated that trials of medical devices
represent less than 5 percent of all approved trials and that nondrug
therapies, such as new surgical or radiation treatments, represent about
10 percent.

Many clinical trials provide standard, nonexperimental treatment along
with an investigational drug or procedure. In cancer care, for example,
trials typically consist of modifications to standard care, such as an added
drug or adjustments to the combination, dosage, and timing of drugs. In
other trials, there can be significant variations from standard care, or
alternative treatments, such as surgical lung volume reduction for
emphysema or bone marrow and stem cell transplants for leukemia and
other conditions, may be evaluated. The cost of care in a trial, relative to
the cost of standard care, depends on the nature of the trial. A recent study
of cancer chemotherapy trials at the Mayo Clinic found that the additional
costs of clinical trial protocols may not be great: at 1 year after trial
enrollment, average costs per patient were $24,645 for trial enrollees
compared with $23,964 for comparable patients receiving standard care.3
Trials involving treatments such as bone marrow transplants, however,
can be very costly.

The sponsors of a clinical trial, whether NIH or private industry, pay for
research costs, such as for data collection and management, research
physician and nurse time, tests performed purely for research purposes,
and often the experimental therapy as well.4 Trial sponsors typically rely
on insurers to pay for usual patient care costs, such as for doctor visits,
hospital stays, laboratory tests, and X rays—costs that are incurred
whether a patient is participating in a trial or receiving standard treatment.
There may be uncertainty, however, about coverage of extra care costs
associated with clinical trial participation, such as for additional tests.

3
 See Judith L. Wagner, Steven R. Alberts, Jeff A. Sloan, and others, “Incremental Costs of Enrolling
Cancer Patients in Clinical Trials: A Population-Based Study,” Journal of the National Cancer Institute,
Vol. 91, No. 10 (May 19, 1999), pp. 847-53.
4
 A 1999 survey conducted by the American Society of Clinical Oncology, a professional society
representing cancer physicians and researchers, showed that research costs per patient ranged from
$581 to $5,028 for government trials and from $569 to $6,567 for industry trials. NCI paid an average of
$750 per patient, while pharmaceutical companies paid an average of $2,500 per patient.



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                       Insurers’ willingness to pay for medical services associated with trials may
                       affect patients’ ability to participate. (For a discussion of clinical trial
                       coverage policies in Medicare, the Department of Defense, and the
                       Department of Veterans Affairs, see app. II.)

                       In order to increase patients’ access to clinical trials, efforts are under way
                       to strengthen links between research entities and insurers. In December
                       1998, NIH and the American Association of Health Plans finalized an
                       agreement that encourages member plans, on a voluntary basis, to refer
                       patients to trials and cover the costs of standard patient care in
                       NIH-sponsored clinical trials. Members of the Congress and the
                       administration have shown interest in requiring public and private payers
                       to cover standard care costs for insured individuals enrolled in clinical
                       trials, particularly cancer trials. Bills have been introduced in the House
                       and Senate to this end,5 and a number of states also have taken action. In
                       July 1999, the Senate approved a bill that would require self-funded health
                       plans to cover standard patient care costs in cancer clinical trials. The
                       Balanced Budget Act of 1997 required the Health Care Financing
                       Administration (HCFA) to contract with the National Academy of Sciences
                       for studies of extending Medicare benefits in five areas, including standard
                       patient care in clinical trials. Under that contract, the National Academy’s
                       Institute of Medicine is examining the current status of clinical trial
                       reimbursement and may recommend changes in Medicare policy in a
                       report to be released in November 1999.


                       As a general rule, health insurance policies exclude coverage of clinical
Insurers Report        trials. However, most insurers we interviewed indicated that they allow for
Coverage of Clinical   exceptions to be made selectively following a case-by-case review.6 None
Trials on a            of the plans we contacted provided us with data on the numbers of
                       requests considered or cases approved, saying they do not track requests
Case-by-Case Basis     for trial coverage or their disposition separately from other benefit
                       coverage disputes.

                       Once coverage is approved, insurers told us they often negotiate payment
                       amounts for the standard, nonexperimental care given to trial participants,

                       5
                         Bills on this issue introduced in the 106th Congress include the Medicare Clinical Trial Coverage Act of
                       1999 (H.R. 61) and the Improved Patient Access to Clinical Studies Act of 1999 (S. 117).
                       6
                        Our findings are similar to those reported in a 1995 NIH study, prepared at the request of the
                       Congress. That study was based on a survey of high-level executives (including vice presidents and
                       medical directors) of nine major third-party payers representing indemnity insurers and managed care
                       plans. See NIH, “Third-Party Reimbursement Policies for Clinical Trials: Survey Report” (Bethesda,
                       Md.: Jan. 1995).



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                           but insurers vary in how they define “standard care.” Although the
                           uncertainty of insurer approval and payment decisions may discourage
                           participation in clinical trials, insurers may unknowingly pay for
                           trial-related care for patients who enroll without their insurers’ explicit
                           approval.


While Policies Generally   Patient participation in NIH clinical trials often depends on prior approval
Exclude Coverage,          by insurance plans of the proposed treatment. Typically, the request for
Insurers Claim to Review   approval initially is submitted to the insurer’s benefits manager,
                           accompanied by information on estimated charges, the clinical assessment
and Approve Some Trial     of the patient, data from the literature on outcomes, a description of the
Services                   protocol, and the consent form. Denials are routinely appealed by the
                           attending physician to the medical director of the insurance plan.

                           Denials are generally based on the grounds that health insurers consider
                           clinical trials to be “investigational and experimental” care and, as such,
                           are excluded from coverage.7 In addition, insurers sometimes deny
                           coverage because they consider standard treatment in clinical trials to be
                           ineligible for payment, despite the fact that most insured patients would be
                           receiving some form of treatment if they were not in the trial. According to
                           a leading expert on patient recruitment for clinical trials, insurers might
                           deny all coverage for patients participating in a trial of combination drug
                           therapy for cancer treatment if, for example, one of the four drugs in a trial
                           was not approved by the Food and Drug Administration.

                           Medical directors for most of the 26 insurance plans in our interview
                           group reported policies that exclude clinical trials from benefit coverage,
                           but these medical directors also reported willingness in some cases to
                           consider coverage for plan members participating in trials. Some managed
                           care plans, in addition, have special programs that support limited patient
                           participation in clinical trials. One large national plan, for example, has a
                           terminal illness program that allows a plan member with a life-threatening
                           illness to be approved to participate in a clinical trial.8 Another large plan
                           has established a nationwide program that refers members needing organ
                           and bone marrow transplants to selected clinical trials.

                           7
                            Coverage policies, including those dealing with investigational and experimental treatments, are
                           specified in the contracts between the insurer and the purchaser of the insurance, which is usually an
                           employer.
                           8
                            In December 1998, this plan also agreed to participate in an NIH-supported cancer coalition
                           demonstration project to study the costs for members enrolled in cancer prevention and treatment
                           trials. During the first 6 months, only one patient participated in this program; a second patient is
                           undergoing eligibility review.



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All but one of the plans we contacted reported having a mechanism for
reviewing and approving participation in trials on a case-by-case basis. An
insurer that covered over 6 million people in managed care and indemnity
plans reported making no exceptions to its exclusionary policy. In general,
insurers that do make case-by-case decisions prefer to review requests for
clinical trial coverage individually because they perceive a great deal of
variability in trial costs and quality. Several medical directors said they are
wary of small, poorly designed clinical trials that may not have been
subjected to rigorous peer review.

In considering individual patient requests, the plans we interviewed
typically follow decision-making procedures established for determining
coverage of experimental treatments. At most plans, the medical directors,
an internal committee of physicians, or an independent panel of medical
experts evaluates patient requests for trial services. Three plans told us
that such coverage decisions are made by the medical provider groups that
make up their networks when the financial risk has been transferred to
those groups under capitation arrangements, but that patients have the
option to appeal to the plan level. Insurers we spoke with reported that
certain plan members have access to various types of external review. The
Medicare program and some states, for example, require that managed
care enrollees have access to an external appeals process if they are
denied care. In the case of self-insured health plans, the employer, rather
than the plan administrator, may be the final decisionmaker on requests
for clinical trial coverage.

In conducting their case-by-case reviews, the medical directors reported
considering a range of factors. The most common considerations were the
scientific merit of the trial and the anticipated costs. Although none of the
insurers had data on the cost of covering clinical trials, most perceived
trials to be somewhat more costly than standard treatment. Medical
directors for 19 plans said they would be inclined to approve coverage if a
patient had a life-threatening disease and the experimental treatment
offered some chance of clinical benefit. About one-third of the insurers
would consider approving a prevention trial for a high-risk patient,
one-third would likely deny such coverage, and the remainder would
decide depending on the circumstances. Sixteen insurers mentioned their
preference for NIH-sponsored phase III trials,9 and six indicated that they
would not approve requests to participate in commercial drug company
trials. Given concerns about the cost of trials, some insurers said trials

9
 Phase III trials involve relatively large patient populations (perhaps hundreds or thousands) and are
designed to confirm benefits and risks and to compare the efficacy of new therapies with that of
standard treatments.



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                             conducted by providers in their networks receive preference.10 Twenty
                             insurers reported that whether the trial treatment was provided in an
                             inpatient or an outpatient setting was unimportant. Public pressure—as in
                             the case of bone marrow transplantation for treatment of breast
                             cancer—also has influenced coverage decisions.

                             Medical directors reported that, among the benefit disputes brought to
                             them for reconsideration, coverage requests for clinical trials are not
                             common. Cancer treatment is the most frequently requested type of
                             clinical trial. Although plans generally do not track the number of clinical
                             trial requests or their disposition, estimates ranged from as few as two
                             cases per year at one plan with 180,000 members to several hundred
                             requests per year at another with an enrollment of 10 million.


Insurers Report Variations   Once insurers decide to cover services provided in clinical trials, they
in How They Decide Which     decide which services should be covered and at what payment amounts.
Trial Services to Cover as   Nearly all of the insurers we spoke with said that they pay standard care
                             costs for approved trial participants. However, there is little agreement on
Standard Care                which trial services constitute standard care, and, therefore, payment for
                             services provided in a trial can vary widely. Moreover, insurers may not
                             always be aware when services are provided in the context of a trial.

                             Insurers we interviewed stated that it is often difficult to distinguish
                             expenses that constitute standard care—those services that otherwise
                             would have been provided to the patient, absent the trial—from strictly
                             research-related services. For example, physician visits and laboratory
                             tests are components of standard care that would be covered by the
                             insurer outside a trial. While the frequency of these services may increase
                             in a trial to more closely monitor the patient, separately identifying claims
                             for these additional services may be difficult. Similarly, disputes may arise
                             if a patient has an adverse reaction to an investigational drug and requires
                             an emergency room visit or additional treatment. While 14 insurers in our
                             group said they would cover the cost of treating medical complications, 7
                             said it would depend on the situation, and 4 said they would not pay for
                             services needed to treat research-related complications.

                             Several insurers said they found it too burdensome to try to separate trial
                             costs from standard care costs in the relatively few cases at issue.
                             Therefore, once they have approved participation in a clinical trial, they

                             10
                               All 11 of the cancer centers we contacted participate in managed care networks in their areas. Only
                             three reported that one or more of the networks in their areas currently refuse to refer patients to their
                             centers.



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generally pay all patient care costs. More commonly, however, insurers
negotiate what services they will cover in clinical trials and how much
they will pay for them. Many insurers we talked with said they negotiate
with trial researchers regarding payments for each individual case and,
therefore, payments can vary considerably. In some cases, insurers
negotiate an overall fee, or case rate, while in other cases they use
network fee schedules, such as discounted fee-for-service rates. Typically,
patients are responsible for any deductibles and copayments required
under their benefit contracts.

Trials conducted by providers outside of plans’ networks complicate these
payment issues. Managed care plans may negotiate or even contract for
coverage of an individual patient or ask the out-of-network trial provider
to accept in-network provider rates. Many insurers we contacted
encourage the use of their own network of health care facilities and trial
providers to hold down costs. The cost of obtaining a magnetic resonance
image in a research setting, for example, may be considerably higher than
the cost of performing the procedure in a facility under contract with the
managed care plan.

Some of the medical directors we spoke with believe that, in many cases,
patients enroll in trials without prior authorization by their plans.
Moreover, these medical directors acknowledged that the plans may make
payments without knowing that the care was provided in the context of a
clinical trial.11 The directors could not estimate the extent to which this
happens but suggested that it could happen frequently. Similarly, officials
of the NCI cancer centers we interviewed reported that all types of
insurers, including public payers, pay some claims for patients who are
treated in clinical trials at their centers. In 1997, we surveyed physicians
and found that Medicare reimbursed certain trial costs despite a general
policy not to cover patient care associated with clinical trials. Of 186
physicians responding, all but one received Medicare reimbursement for
patients in cancer trials.12




11
 This observation was previously reported in Robert Mechanic and Allen Dobson, “The Impact of
Managed Care on Clinical Research: A Preliminary Investigation,” Health Affairs, Vol. 15, No. 3 (fall
1996), pp. 72-89. Another way that plans may cover care in trials without specifically authorizing it is
by including academic health centers, which are known to enroll patients in trials, in their provider
networks.
12
  Cancer Clinical Trials: Medicare Reimbursement Denials (GAO/HEHS-98-15R, Oct. 14, 1997).



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                            A shortage of patients for NCI-sponsored clinical trials does not appear to
Researchers Meet            be a significant problem at most of the cancer research centers we
Trial Enrollment            contacted. Nonetheless, all of the centers reported incurring a significant
Needs Despite Many          administrative burden when dealing with health insurers over trial
                            coverage issues for patients on a case-by-case basis. In addition, center
Challenges That Can         officials cited a number of physician- and patient-related factors that can
Discourage Patient          influence clinical trial participation.
Participation
Cancer Centers Report       Most of the NCI-designated cancer centers we contacted report they are
Adequate NCI Trial          able to enroll adequate numbers of patients to conduct NCI-sponsored
Enrollment Along With       trials, but recruitment is not without its challenges.13 Cancer center
                            representatives reported a range of experiences in obtaining health plan
Some Payment Difficulties   coverage for patients enrolled in trials and said that the process is
                            time-consuming and labor-intensive. According to most centers,
                            third-party payments generally cover the standard care provided to trial
                            participants but are less consistent in covering extra care costs associated
                            with trials.

                            Officials at 8 of the 11 NCI-designated cancer centers we contacted around
                            the country reported that they were not having serious difficulties
                            enrolling an adequate number of patients in NCI-sponsored clinical trials.14
                            Many centers estimated that 10 to 30 percent of their patients were
                            participating in trials. Three centers reported experiencing what they
                            considered to be serious difficulties enrolling patients, including a variety
                            of marketplace and clinical factors; but generally the centers were
                            working to overcome those difficulties. Center officials cited only two
                            examples of trials that were closed prematurely because of enrollment
                            problems: a costly liver infusion trial and a trial of bone marrow
                            transplantation for a serious connective tissue disease.

                            Nearly all the cancer center officials we interviewed reported some degree
                            of difficulty in dealing with insurers over clinical trial coverage, but they
                            generally characterized these difficulties as “business as usual.” These
                            officials said their experiences varied with the individual insurers in their
                            areas: some rejected requests for coverage, some paid fully for standard
                            care in trials, and others frequently denied coverage for specific services.

                            13
                             All of the centers conducted a mix of NCI- and pharmaceutical industry-sponsored trials, with
                            NCI-sponsored trials predominating.
                            14
                              Individual cancer centers in our contact group reported total numbers of open clinical trials ranging
                            from roughly 60 to more than 400. Numbers of patients enrolled in these trials ranged from about 350
                            to 450 at some centers to 1,000 to 2,000 at others.



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                          Center physicians and staff reportedly spend considerable time and effort
                          dealing with insurance issues for patients in trials. Research physicians are
                          required to document that the trial is medically necessary and to provide
                          other information to justify enrollment in a trial. Officials at two centers
                          explained that efforts to obtain coverage were enhanced when they could
                          provide data showing that the cost of patient care in certain cancer trials
                          was the same as or less than that of care provided outside of trials. Other
                          officials noted that some patients at NCI-designated centers get insurance
                          approval for trials because they know how to appeal an initial denial. It is
                          rare, another official said, for a persistent patient to be denied coverage,
                          because some accommodation usually is made to pay for services. As a
                          result of these efforts, officials reported that insurers usually agreed to
                          cover patients in trials at their centers.

                          Center officials stated that insurers that approve coverage generally pay
                          for the standard care provided to trial participants. Most of the centers in
                          our group are able to separately identify and exclude research costs (such
                          as trial organization, administration, and data collection) and bill insurers
                          for standard care. Insurers typically pay the centers under the same
                          arrangements that apply to patients at the centers who are not in
                          trials—for example, discounted fee-for-service charges or limited case rate
                          payments. Representatives of two centers specifically stated that the
                          payments they received from insurers were insufficient to cover the costs
                          of standard care involved in trials. In addition to payments from private
                          health plans, the cancer centers reported that Medicare and Medicaid also
                          paid claims for patients in their clinical trials.

                          It is not uncommon for managed care plans to require that laboratory and
                          other testing services related to trials be performed at facilities in the
                          plans’ networks. Some cancer center researchers we interviewed contend
                          that the inconvenience of having to visit several sites of care discourages
                          patient participation.


Many Factors Other Than   Our cancer center interviews and the research literature indicate that
Insurance Coverage        many factors, in addition to insurance coverage practices, can influence
Influence Patient         patient participation in clinical trials. For example, physicians are often
                          unaware of relevant trials or unable to meet the time and resource
Participation in Trials   demands associated with enrollment activities. In addition, many patients
                          are not interested in enrolling in trials. Other patients face eligibility
                          limitations or logistical barriers, or are reluctant to participate in a
                          randomized experiment. The influence of these various factors depends on



                          Page 11                                      GAO/HEHS-99-182 NIH Clinical Trials
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                                  the type of disease, type of trial, phase of trial, and other unique
                                  circumstances.

Physician Awareness and           Because patients rely heavily on their physicians to inform and advise
Resources                         them about treatment options, physicians are often the most influential
                                  factor in a patient’s decision to participate in a clinical trial. However,
                                  physicians and other health care providers can be unaware of the
                                  opportunities for participation in clinical trials. Decisions regarding
                                  enrollment in trials are made locally by physicians, hospitals, and health
                                  plans and, as a result, promotion of trials within the medical community is
                                  considered key.15 Some cancer center officials we interviewed contend
                                  that managed care patients may not be referred to specialist physicians,
                                  who are most likely to be aware of clinical trial opportunities in their area.
                                  These officials reported more intensive efforts to make patients aware of
                                  trials directly, through Internet Web sites, media advertising, and other
                                  strategies.

                                  Officials we interviewed from 8 of the 11 cancer centers, as well as
                                  oncologists recently surveyed by the American Society of Clinical
                                  Oncology, indicated that constraints on physicians’ time, available
                                  research resources, and administrative support are significant factors
                                  affecting participation. The burden on physicians often includes the need
                                  to devote additional time to identifying and enrolling suitable individuals
                                  as well as the extra paperwork involved in recording baseline data and
                                  screening candidates. In a study conducted by NCI to explore reasons for
                                  low enrollment in certain breast cancer trials, community-based
                                  oncologists cited the following issues: the time it takes to obtain consent
                                  and to attend to ongoing paperwork, to explain trial criteria to the patient,
                                  and to learn the protocol; the lack of uniform standards; and the burden
                                  and expense of performing numerous tests and following up with the
                                  patient.16

Patient Eligibility, Logistics,   Patients who are motivated to participate in clinical trials often perceive
and Attitudes                     them as an opportunity to receive superior care and make a contribution
                                  to medical knowledge. However, these patients can be held back by the
                                  narrow eligibility criteria used to select study subjects, or discouraged by

                                  15
                                    According to the mandate of the Food and Drug Administration Modernization Act of 1997, NIH is
                                  responsible for developing a “one-stop shopping” clinical trials database that eventually will include
                                  information on publicly and privately funded clinical trials for drugs for life-threatening diseases and
                                  conditions.
                                  16
                                   NCI, Office of Cancer Communication, “Patient Referral to the National Cancer Institute’s
                                  Autologous Bone Marrow Transplantation Clinical Trials: The Physician’s Perspective” (Bethesda,
                                  Md.: Aug. 1995).



                                  Page 12                                                        GAO/HEHS-99-182 NIH Clinical Trials
B-281108




logistical considerations or their own apprehensions about medical
experimentation.

According to the 1999 American Society of Clinical Oncology’s survey of
oncologist opinion, strict trial eligibility criteria are the “single greatest
barrier” to enrolling patients in trials. Patient eligibility criteria (such as
the type and stage of disease under investigation and absence of other
medical conditions) are necessary to define study populations and support
reliable conclusions. However, when these criteria are very restrictive,
they act as barriers to patient access. In 1997, the NCI Clinical Trials
Program Review Group reported that there were too many exclusion
criteria in the cancer clinical trials system, with the result that potential
enrollees were being disqualified for seemingly arbitrary reasons from
trials for which they would otherwise qualify.17 A related concern is that
researchers may be inclined to select subjects who are likely to provide
the best trial outcomes. A recent study of high-dose chemotherapy for
breast cancer showed that, in identifying candidates for a trial, clinicians
limited referrals mostly to patients who had the best chance of survival.18

Logistical concerns can also influence patients’ decisions about whether to
enter trials. In some cases, participation in a trial may require traveling to
a distant trial site and, possibly, staying overnight or longer. Such
requirements can be time-consuming and impose financial and child care
burdens on individuals who may be seriously ill. Moreover, such demands
can add to stress by separating patients from family support and making it
difficult to meet work obligations. As one cancer center official told us,
many of life’s practical concerns are magnified in a clinical trial, because
trials place more requirements on and offer less flexibility to the patients.

In addition, eligible patients may choose not to enroll in clinical trials
because of their personal preferences for certain types of care or their
limited understanding of the clinical trials system. Sound research design
requires that clinical studies minimize bias by random assignment of
patients to treatment and control groups. But patients who view the
experimental intervention as their best hope for treatment may be
reluctant to participate if they cannot be assured they will receive what

17
 NCI, “Report of the National Cancer Institute Clinical Trials Program Review Group” (Bethesda,
Md.: Aug. 26, 1997). This study is often referred to as the Armitage report, after the panel’s chairman,
James O. Armitage, M.D.
18
 Z.U. Rahman, D.K. Frye, A.U. Buzdar, and others, “Impact of Selection Process on Response Rate
and Long-Term Survival of Potential High-Dose Chemotherapy Candidates Treated With
Standard-Dose Doxorubicin-Containing Chemotherapy in Patients With Metastatic Breast Cancer,”
Journal of Clinical Oncology, Vol. 15, No. 10 (Oct. 1997), pp. 3171-7.



Page 13                                                        GAO/HEHS-99-182 NIH Clinical Trials
                            B-281108




                            they believe to be superior care. Further, difficulty with the informed
                            consent process can be a factor; even patients who want to participate in
                            clinical trials may feel overwhelmed by the treatment decision-making
                            process involved in informed consent. According to the NCI Clinical Trials
                            Program Review Group report, this process has become “a disclaimer for
                            institutions rather than information for the participant” and “may be
                            inappropriately deterring individuals from participating in clinical trials.”
                            Finally, a lack of trust in medical research can make patients unwilling to
                            participate. Several of our cancer center officials said that, combined with
                            language and cultural barriers, this lack of trust can make it especially
                            difficult to recruit minority populations.


                            Citing anecdotal reports, NIH contends that insurer resistance to covering
NIH Has Little              services has contributed to a significant decline in clinical trial enrollment.
Evidence of Problems        Yet we received little quantitative data from NIH to indicate that fewer
With Patient                patients are entering NIH-sponsored trials or that more trials are being
                            delayed or cancelled. NIH does not maintain a centralized tracking system
Enrollment in Trials        on the number of people who enroll in clinical trials each year, overall, or
                            by institute. Therefore, we contacted some of the institutes with the most
                            clinical trial activity for information about patient enrollment. The
                            institute sponsoring the most clinical trial activity, NCI, could not provide
                            reliable data to demonstrate growing difficulties in enrolling patients in
                            cancer trials. Officials of another large institute we contacted, the National
                            Heart, Lung, and Blood Institute (NHLBI), reported no major new difficulties
                            in meeting patient enrollment needs; in fact, NHLBI’s monitoring data on
                            heart disease trials showed that most were enrolling patients at or above
                            80 percent of target levels. In its data system for monitoring trial
                            enrollment, NHLBI considers meeting 80 percent of target levels good
                            progress in recruiting. Moreover, data from the National Institute of
                            Diabetes and Digestive and Kidney Diseases (NIDDK) showed diabetes trials
                            enrolling at or above target levels in 1998.


NCI Is Concerned About      In a 1998 paper prepared for its fiscal year 2000 budget submission to the
Difficulties in Enrolling   Office of Management and Budget, NIH stated that increased resistance by
Patients in Cancer Trials   insurers to covering standard care costs for trial participants had slowed
                            patient enrollment and led to longer studies.19 Among the NIH officials we
                            contacted, NCI officials expressed the greatest concerns about increased
                            difficulties enrolling patients in clinical trials. Citing testimony before the

                            19
                             NIH, “Current Structure of NIH Support for Clinical Trials: Responses to Questions for the Fiscal
                            Year 2000 OMB Budget Submission” (Bethesda, Md.: Aug. 1998).



                            Page 14                                                      GAO/HEHS-99-182 NIH Clinical Trials
                          B-281108




                          President’s Cancer Panel at four regional hearings in 1996, NCI officials
                          indicated that insurers do not want to pay for standard care associated
                          with clinical trials, and, as a result, “the type and number of patients that
                          get into a trial are changed; the type of clinical trial that is conducted is
                          changed; and the speed of the trial is changed.”20

                          Although NIH has asserted that there is a crisis in patient participation in
                          clinical trials, NCI officials could not provide reliable patient enrollment
                          data that would enable us to determine whether enrollment in trials was
                          declining or whether actual enrollment lagged significantly from planned
                          enrollment levels.21 NCI is currently developing a standardized electronic
                          monitoring system to track an array of clinical trial data, including planned
                          and actual patient enrollment. However, NCI officials told us that the new
                          reporting system, known as the Clinical Data Update System (CDUS), did
                          not capture information on all cancer trials. For example, it included
                          studies by cooperative groups and some individual investigators but not
                          those conducted at NCI-funded cancer centers. CDUS developers reported
                          that, in converting historical data from an earlier monitoring system, they
                          had experienced difficulties with the reporting of enrollment information.
                          In addition, only a few data submissions had been audited since the
                          system was implemented. Because these data were not complete or
                          adequately verified, we could not determine whether patient enrollment
                          had slowed or trials have been delayed.


Evidence From Other       The NHLBI at NIH also has a high level of clinical trial activity. NHLBI officials
Institutes Shows Little   told us that, while recruitment challenges are always present, in general
Problem With Enrollment   the Institute has not experienced major new difficulties in meeting patient
                          enrollment needs. Specifically, officials noted that in the few cases in
                          which they found enrollment lagging behind schedule, they were able to
                          provide researchers with additional funds to help them meet recruitment
                          targets. Factors influencing patient recruitment have not changed
                          substantially over the past 20 years, officials told us, although NHLBI does
                          now compete more actively for patients with trials sponsored by the
                          pharmaceutical industry.

                          NHLBI monitoring data support these assertions. When NHLBI’s Division of
                          Heart and Vascular Diseases reported third-quarter 1998 monitoring data

                          20
                           President’s Cancer Panel, “Fighting the War on Cancer in an Evolving Health Care System”
                          (Bethesda, Md.: NCI, 1997).
                          21
                           To examine trends in overall enrollment, we requested data on all cancer trials from 1994 to 1998. To
                          examine delays in meeting enrollment targets, we requested planned and actual enrollment data on
                          breast and prostate cancer trials recruiting patients during 1997 and 1998.



                          Page 15                                                      GAO/HEHS-99-182 NIH Clinical Trials
              B-281108




              on 19 heart trials, of 13 trials that had been recruiting for at least a year, 6
              were at or above 100 percent of their patient recruiting targets; 4 were at
              80 to 99 percent of their targets; and 3 were below 80 percent of their
              goals.22 From the Division of Epidemiology and Clinical Applications we
              received mid-1998 recruitment data on six heart trials that had been
              recruiting for at least a year. The data showed that two trials were at or
              above 100 percent of their targets, three were at 80 to 99 percent of their
              targets, and one was slightly below 80 percent. Recruitment report notes
              stated that this last trial is expected to finish within budget and on time.

              We also contacted NIDDK. In 1997-98, two large phase III trials were
              recruiting patients with diabetes, the leading area of NIDDK research. The
              Diabetes Prevention Program—Type II (seeking 3,000 individuals at high
              risk for developing non-insulin-dependent diabetes) reported that, as of
              December 1998, the total number of participants exceeded the target
              recruitment level. Specific data on 21 participating clinical centers showed
              that 10 clinics had recruited over 100 percent of their goals, 9 had achieved
              between 80 and 99 percent of targets, and 2 were at 70 to 79 percent of
              their goals.

              NIDDK officials told us that the Diabetes Prevention Trial—Type I (enrolling
              individuals at high risk for developing insulin-dependent diabetes) was
              having difficulty with recruitment. A progress report from the trial
              coordinating center noted that, because only a small percentage of people
              are eligible to participate, the trial needs to screen an estimated 80,000 to
              100,000 individuals to identify 830 participants. As of November 1998, 441
              were enrolled in the study—mostly people under age 20. Officials also
              noted that low payments to physicians—$10 for each screened
              patient—may be discouraging physician referrals to this trial.


              We did not find evidence of widespread limitations on patient access to
Conclusions   clinical trials. Most health insurers we interviewed said they allow for
              coverage of trials in some circumstances, most cancer centers we
              interviewed reported no shortage of patients for trials, and NIH did not
              document significant trial enrollment problems. Nevertheless, information
              on the extent to which insurers cover clinical trials is not clear-cut. On the
              one hand, having to seek approval through a plan’s review and appeals
              process and negotiating payment for standard care in a trial may dissuade
              some patients and physicians from pursuing clinical trial opportunities. On

              22
               Reports on new patient enrollment in 1997 and 1998 included recruitment start and stop dates, target
              enrollment and actual enrollment (cumulative to date and tracked against quarterly targets on a
              graph), and actual minority and female enrollment compared with targets.



              Page 16                                                     GAO/HEHS-99-182 NIH Clinical Trials
                   B-281108




                   the other hand, because of the perceived obstacles associated with
                   obtaining insurance coverage, some patients and physicians may submit
                   claims without identifying the services as trial-related. Consequently,
                   insurers may be covering more trial services than they officially approve.
                   Moreover, in addition to insurance coverage, there are many patient- and
                   physician-related factors that affect patient participation in clinical trials.


                   We provided a draft of this report for comment to the Institute of Medicine
Agency and Other   (IOM), the American Association of Health Plans (AAHP), and NIH. The IOM
Comments           and AAHP generally concurred with the information presented and offered
                   technical suggestions that we have incorporated as appropriate. The IOM
                   reviewer, for example, stated that our findings are consistent with
                   information gathered over the past year for an IOM report looking at
                   overlapping issues (related specifically to Medicare).

                   NIH disagreed with our conclusion that evidence of widespread limitations
                   on patient access to NIH-supported clinical trials is lacking, stating that our
                   study design was flawed and our results are not generalizable. In general,
                   NIH officials argued that we should have broadened the scope of the study
                   to include a greater number and wider range of insurers, research
                   institutions, and investigators, as well as physicians and patients. We
                   recognize that NIH clinical trials involve a prescribed patient population,
                   physicians, investigators, and academic and other medical centers, and
                   that patients may be entered into trials in a range of settings, including
                   community hospitals. However, we focused our work on three key
                   participants—health insurers, cancer centers, and several of the largest
                   trial-sponsoring institutes at NIH—because they are in a strong position to
                   illuminate the range of factors that influence patient participation in
                   clinical trials, and to provide evidence of recent difficulties, if any, in
                   enrolling patients for NIH-sponsored clinical trials.

                   Specifically, NIH argued that our data collection efforts were insufficient on
                   several counts: (1) the 26 managed care and indemnity insurance plans we
                   interviewed represent a small, nonrepresentative sample; (2) in addition to
                   interviewing officials at NIH-designated cancer centers, we should have
                   included community physicians who participate in cooperative groups,
                   generalist and specialist physicians who do not regularly refer patients to
                   trials, and researchers who did not receive NIH funding; (3) we should have
                   surveyed patients to determine factors that influence their decisions to
                   enroll in clinical trials; (4) in addition to gathering data about insurance
                   policies, we should have documented health plans’ policies on physician



                   Page 17                                         GAO/HEHS-99-182 NIH Clinical Trials
B-281108




referral patterns and productivity; (5) we should have used additional data
from NCI on actual and projected enrollment for clinical trials; and (6) we
should have documented the need for additional resources to recruit
patients into trials.

As we noted in the report, the results of our insurer and cancer center
interviews should not be generalized because these groups were not
statistically representative. Nonetheless, the information reported to us by
health plan medical directors and cancer center directors was consistent.
Insurers were selected to represent a variety of plan types, sizes, and
geographic areas, and they included many large, nationwide plans. The
cancer centers likewise reflected geographic diversity and different levels
of managed care activity.

We did not seek out researchers and physicians who were not successful
in obtaining NIH funding for proposed clinical trials. There are many
reasons that researchers’ proposals do not receive support from NIH, and a
perceived inability to recruit a sufficient number of research subjects may
play a role in the funding decision. However, our focus was on factors that
affect the ability of patients to participate in trials that do receive funding
from NIH institutes, and by and large, the cancer centers we contacted
reported no major difficulties enrolling patients into trials.

A survey of patients with cancer or other serious diseases would have
been especially problematic, given concerns about confidentiality of
medical information. Instead, we discussed with cancer center directors
the patient-related barriers to participation, reviewed the literature on
factors that affect patient enrollment in clinical trials, and interviewed
patient advocacy groups. From these sources, we learned that trial
eligibility criteria can limit patient access, and practical matters such as
additional demands on patients’ time and resources, as well as uncertainty
about the benefits and risks of experimental treatments, sometimes
discourage patients from participating in trials.

A review of health plans’ policies on physician referral rates and
productivity was beyond the scope of our study. The results of a recently
completed survey by the American Society of Clinical Oncology may shed
light on these issues when published later this year. Other research is
under way to develop data on several other aspects of the clinical trials
issue, including the impact of managed care on academic health centers’
ability to do clinical research.




Page 18                                        GAO/HEHS-99-182 NIH Clinical Trials
B-281108




We asked NCI for data that would enable us to determine whether
(1) overall enrollment in cancer trials declined over the past 5 years and
(2) recent breast and prostate cancer trials were meeting patient
enrollment targets or were requiring more time than planned to do so.
Although NCI provided partial data to us, we decided that the data were not
usable for assessing patient enrollment patterns. In discussions between
our statisticians and the head of the Drug Management and Authorization
Section of the Cancer Therapy Evaluation Program and other NCI officials,
our data experts determined that the NCI data system is in transition and
the trial-specific database was incomplete, inconsistent, and had not been
adequately verified. We therefore concluded that NCI did not have reliable,
quantitative information documenting problems on patient enrollment.

In discussions with NCI, NHLBI, and NIDDK, none of these institutes cited an
increasing use of administrative supplements as an indicator of enrollment
problems. Officials at one of the smaller institutes, the National Institute
on Aging, reported that it had been forced to add additional funds to
clinical trial grants to support more extensive minority patient recruitment
efforts than anticipated. However, they said that, in general, investigators
were not experiencing major patient enrollment problems.

Appendix III contains the general comments received from NIH. In
addition, the agency provided a number of specific suggestions, many of
which are reflected in the final report.


As agreed with your offices, unless you publicly announce its contents
earlier, we plan no further distribution of this report until 30 days after the
date of the report. At that time, we will send copies to interested parties
and make copies available to others upon request.




Page 19                                        GAO/HEHS-99-182 NIH Clinical Trials
B-281108




Please call me at (202) 512-7119 if you or members of your staff have any
questions about the information in this report. Other contributors to this
study include Rosamond Katz, Ellen M. Smith, Margaret Buddeke, and
Jennifer Grover.




Janet Heinrich
Associate Director, Health Financing
  and Public Health Issues




Page 20                                      GAO/HEHS-99-182 NIH Clinical Trials
Page 21   GAO/HEHS-99-182 NIH Clinical Trials
Contents



Letter                                                                                              1


Appendix I                                                                                         24

Health Plans and
Cancer Centers
Interviewed
Appendix II                                                                                        28

Clinical Trial
Coverage in Federal
Health Programs
Appendix III                                                                                       31

Comments From the
National Institutes of
Health




                         Abbreviations

                         AAHP      American Association of Health Plans
                         CDUS      Clinical Data Update System
                         DOD       Department of Defense
                         FDA       Food and Drug Administration
                         HCFA      Health Care Financing Administration
                         HMO       health maintenance organization
                         IOM       Institute of Medicine
                         NCI       National Cancer Institute
                         NHLBI     National Heart, Lung, and Blood Institute
                         NIDDK     National Institute of Diabetes and Digestive and Kidney
                                         Diseases
                         NIH       National Institutes of Health
                         STAR      Study of Tamoxifen and Raloxifene
                         VA        Department of Veterans Affairs


                         Page 22                                   GAO/HEHS-99-182 NIH Clinical Trials
Page 23   GAO/HEHS-99-182 NIH Clinical Trials
Appendix I

Health Plans and Cancer Centers
Interviewed

                    We selected individual health plans to represent a variety of plan
Individual Health   types—HMO, preferred provider organization, or point-of-service
Plans               option—and we asked plan medical directors to focus on that selected
                    type of plan in our interviews. However, most of the respondents reported
                    that the same policies regarding patient participation in clinical trials
                    generally apply to all of the plan types they offer, including indemnity
                    plans.

                    Advantage Care, Inc.
                    Lexington, KY

                    Alliance Health Network
                    Erie, PA

                    Allina/Medica Health Plans
                    Minneapolis, MN

                    Blue Cross of Idaho
                    Boise, ID

                    CAPP-Care, Inc.
                    Newport Beach, CA

                    Empire Blue Cross Blue Shield
                    New York, NY

                    First Health Group, Inc.
                    Downers Grove, IL

                    George Washington University Health Plan
                    Washington, DC

                    Group Health Cooperative of Puget Sound
                    Seattle, WA

                    Group Health Northwest
                    Spokane, WA

                    Harvard Pilgrim Health Care
                    West Brookline, MA




                    Page 24                                    GAO/HEHS-99-182 NIH Clinical Trials
               Appendix I
               Health Plans and Cancer Centers
               Interviewed




               Highmark Blue Cross Blue Shield
               Pittsburgh, PA

               M Plan
               Indianapolis, IN

               Pacificare of Oklahoma
               Tulsa, OK

               Pacificare of Washington
               Seattle, WA

               Penn State Geisinger
               Danville, PA

               PHP Companies, Inc.
               Knoxville, TN

               PHP of Northern Indiana
               Fort Wayne, IN

               Presbyterian Health Plan
               Albuquerque, NM

               QualChoice Health Plan, Inc.
               Cleveland, OH

               ViaHealth
               Rochester, NY


               Aetna US Healthcare
Corporate      Blue Bell, PA
Headquarters
               CIGNA HealthCare
               Bloomfield, CT

               Kaiser Permanente Regional Office
               Oakland, CA

               Pacificare Health Systems
               Santa Ana, CA



               Page 25                             GAO/HEHS-99-182 NIH Clinical Trials
                 Appendix I
                 Health Plans and Cancer Centers
                 Interviewed




                 United Healthcare, Inc.
                 Minneapolis, MN


                 Barbara Ann Karmanos Cancer Institute
Cancer Centers   Wayne State University
                 Detroit, MI

                 The Cancer Institute of New Jersey
                 Robert Wood Johnson Medical School
                 New Brunswick, NJ

                 Cancer Research Center
                 Albert Einstein College of Medicine
                 Bronx, NY

                 Cancer Research Center
                 University of Chicago
                 Chicago, IL

                 Chao Family Comprehensive Cancer Center
                 University of California at Irvine
                 Orange, CA

                 Comprehensive Cancer Center
                 Bowman Gray School of Medicine
                 Wake Forest University
                 Winston-Salem, NC

                 Comprehensive Cancer Center
                 Yale University School of Medicine
                 New Haven, CT

                 Fred Hutchinson Cancer Research Center
                 Seattle, WA

                 H. Lee Moffitt Cancer Center and Research Institute
                 University of South Florida
                 Tampa, FL

                 Johns Hopkins Oncology Center
                 Baltimore, MD



                 Page 26                                    GAO/HEHS-99-182 NIH Clinical Trials
Appendix I
Health Plans and Cancer Centers
Interviewed




Lombardi Cancer Research Center
Georgetown University Medical Center
Washington, DC

USC/Norris Comprehensive Cancer Center
University of Southern California
Los Angeles, CA




Page 27                                  GAO/HEHS-99-182 NIH Clinical Trials
Appendix II

Clinical Trial Coverage in Federal Health
Programs

               Federal health programs vary in how they cover services provided in
               clinical trials sponsored by the National Institutes of Health (NIH). The
               Medicare program and the Department of Defense’s (DOD) TRICARE
               program—both large payers—generally exclude coverage for unproven
               therapies, including clinical trials. The Department of Veterans Affairs (VA)
               and DOD’s direct care system have actively promoted biomedical research
               for decades. VA and DOD have expanded their NIH research affiliations by
               developing agreements with the National Cancer Institute (NCI) to increase
               beneficiary access to NCI clinical trials.


               Administered by the Health Care Financing Administration (HCFA),
Medicare       Medicare insures 38.6 million elderly and disabled beneficiaries.
               Medicare’s policy is that, to be covered, services must be reasonable and
               necessary for diagnosis and treatment of disease or injury, and they may
               not be experimental or investigational. Medicare does make some
               exceptions to its general policy not to cover patient care costs in clinical
               trials, particularly in the area of medical devices.23 On the basis of a 1995
               agreement between HCFA and the Food and Drug Administration (FDA),
               patients participating in trials of most devices that have FDA-approved
               Investigations Device Exemptions are eligible for Medicare payment. For
               example, patients receiving investigational pacemakers or defibrillators
               that are refinements of approved devices may be covered under the
               standard Medicare diagnosis-related group system that pays for both the
               device and the implantation procedure.

               In practice, it appears that Medicare pays for a considerable amount of
               care provided in clinical trials. Since Medicare billing practices do not
               distinguish clinical trial services from standard care services, HCFA does
               not know how much investigational care is being reimbursed. If a patient
               receives chemotherapy for cancer, for example, the Medicare contractor
               may not know if it is provided in the context of a clinical trial. Similarly,
               the diagnosis-related group system for reimbursing hospital care prevents
               Medicare from knowing if a patient is participating in a clinical trial. HCFA
               would only know a clinical trial was under way if the provider
               purposefully notified HCFA or if an exceptional claim for reimbursement
               for experimental care drew attention during claims processing.

               For the first time, HCFA has recently decided to provide conditional
               coverage of an emphysema clinical trial that examines the effectiveness of

               23
                Medicare also explicitly does pay for treating medical complications that may result from patient
               participation in clinical trials.



               Page 28                                                      GAO/HEHS-99-182 NIH Clinical Trials
      Appendix II
      Clinical Trial Coverage in Federal Health
      Programs




      lung reduction surgery as a treatment. This National Heart, Lung, and
      Blood Institute multicenter trial has screened about 1,600 patients, and
      nearly 400 have enrolled so far. An NIH official, estimating that the surgery
      will cost approximately $30,000 per case, told us that this demonstration
      project provides a good research model for third-party payers participating
      in clinical trials.

      Under a HCFA contract, the Institute of Medicine (IOM) is conducting a
      study of routine patient care costs that could be incurred in clinical trials
      involving Medicare beneficiaries. The IOM report, which is expected to be
      released in November 1999, will recommend criteria that HCFA can use to
      determine both which services associated with clinical trials to cover as
      well as what Medicare payment levels should be.


      The DOD health care system, administered by the TRICARE Management
DOD   Activity and the Army, Navy, and Air Force, provides both direct care and
      contracted care for 8.2 million individuals. DOD policy excludes coverage
      of services considered to be unproven and restricts coverage to safe and
      effective treatments, but DOD does conduct medical research in its network
      of military treatment facilities and, since 1996, has participated in NCI
      clinical trials.

      DOD officials relaxed the clinical trial coverage limitation in 1996 to permit
      access to NCI-sponsored clinical trials during a 3-year demonstration
      project, which was extended in June 1999. The purpose of the NCI-DOD
      Clinical Trials Demonstration Project is to support and expand the clinical
      trials conducted at the military treatment facilities and to provide
      beneficiaries with access to NCI clinical trials at civilian institutions.

      During the first 3 years of the project, 206 patients participated in
      NCI-sponsored clinical trials. Over half of these patients received care for
      breast cancer, which, according to DOD officials, indicates that the
      agreement has so far been a vehicle for providing access to high
      technology, such as bone marrow transplantation. For instance, all
      patients who meet the eligibility requirements are automatically accepted
      into a clinical trial, and they receive the transplant without risk of being
      assigned to a control group. However, overall participation has been lower
      than expected, which has created a delay in evaluating the project: DOD
      officials told us that they plan to increase participation by raising
      awareness through education efforts. DOD officials also reported that NCI
      will be conducting a demonstration project evaluation that will examine



      Page 29                                       GAO/HEHS-99-182 NIH Clinical Trials
     Appendix II
     Clinical Trial Coverage in Federal Health
     Programs




     access and cost issues. Meanwhile, the new 1999 DOD agreement with NCI
     extends coverage to prevention clinical trials, such as the nationwide
     breast cancer prevention trial known as STAR (Study of Tamoxifen and
     Raloxifene), as well as to cancer early detection trials.


     A direct care provider for nearly 3 million veterans, VA actively promotes
VA   intramural and extramural medical research. Fifty-two VA medical centers
     maintain research affiliations with NCI, and VA collaborates on clinical
     research with several other NIH institutes, pharmaceutical companies, DOD,
     and the Department of Health and Human Services. Supported by a
     research budget of over $1 billion, VA announced a major expansion of its
     clinical trial program in 1999.

     In 1997, VA reported that cancer was the second leading cause of death
     among veterans. At that time, about 170,000 veterans were affected, and
     approximately 50,000 new cases of cancer were being reported each year.
     VA has responded by developing a National Cancer Strategy that expands
     on the already-existing relationship between VA and NCI. A key component
     of the strategy is an NCI-VA agreement, similar to DOD’s agreement with NCI,
     intended not only to increase veteran access to cancer clinical trials, but
     also to expand opportunities for clinician participation in trials. The NCI-VA
     agreement allows veterans to participate in a broad range of cancer
     prevention, diagnosis, and treatment clinical trials.




     Page 30                                       GAO/HEHS-99-182 NIH Clinical Trials
Appendix III

Comments From the National Institutes of
Health




               Page 31          GAO/HEHS-99-182 NIH Clinical Trials
Appendix III
Comments From the National Institutes of
Health




Page 32                                    GAO/HEHS-99-182 NIH Clinical Trials
Appendix III
Comments From the National Institutes of
Health




Page 33                                    GAO/HEHS-99-182 NIH Clinical Trials
           Appendix III
           Comments From the National Institutes of
           Health




(101808)   Page 34                                    GAO/HEHS-99-182 NIH Clinical Trials
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