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Minutes of the Seventh Meeting - May 31, 2001

National Advisory Council for Complementary and Alternative Medicine (NACCAM)

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General Statement
NACCAM Members Present
NACCAM Ad Hoc Members
NACCAM Members Absent
NIH Staff Members Present
Public Present
  I. Call to Order
  II. Future Meeting Dates
  III. Review of Confidentiality and Conflict of Interest
  IV. NCCAM Director's Remarks
  V. NCCAM Intramural Program
  VI. NCCAM Health Disparities Plan
  VII. Overview of Sister Agencies in DHHS
  VIII. Concept Clearance
  IX. Public Comment
  X. IRB Discussion
  XI. CAPCAM/Best Case Series Update
  XII. Closed Session
  XIII.

Adjournment

General Statement

The National Advisory Council for Complementary and Alternative Medicine (NACCAM) convened at 8:15 a.m. on May 31, 2001, at the NIH Natcher Conference Center in Bethesda, Maryland. Dr. Richard Nahin, Executive Secretary, called the meeting to order. The meeting was closed to the public on May 31, 2001, from 3:00 p.m. until adjournment as provided in Sections 552b(c)(4) and 552b(c)(6), Title 5 U.S. Code, and section 10(d) of Public law 92-463, for the review, discussion, and evaluation of grant applications and related information.

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NACCAM Members Present (1)

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NACCAM Ad Hoc Members

NACCAM Members Absent

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NIH Staff Members Present

Public Present

Dr. Ian Coulter, RAND

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I. Call to Order

Dr. Nahin opened the meeting by reviewing the agenda. In addition to presentations by Dr. Marc Blackman and Dr. Morgan Jackson of the National Center for Complementary and Alternative Medicine (NCCAM), NIH, and Dr. Ruth Kirchstein, Acting Director, NIH, there would be time for public comment and a presentation of two concepts for initiatives. Additional presentations would address Institutional Review Board (IRB) issues as they relate to NCCAM, and the Cancer Advisory Panel on Complementary and Alternative Medicine (CAPCAM) best case series. The closed session would be held at the end of the day. Dr. Nahin noted that because the Council had a substantial number of conflicts of interest with applications under review, NCCAM had brought in four ad hoc Council members: Drs. Berman, Cho, Goldstein, and Timmermann.

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II. Future Meeting Dates

Dr. Nahin reviewed the scheduled meeting dates. The next meeting will be August 27-28. A meeting scheduled for October 2 will focus on R01s and R21s. These meetings will take place in the Neuroscience Office Building. [Note: Since the May meeting, the October 2 meeting has been canceled. A September conference call is planned.]

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III. Review of Confidentiality and Conflict of Interest

Dr. Nahin reviewed the rules under which the Council operates. The meeting is open to the public as required by Public Law 92-409, the Federal Advisory Committee Act, and the Government in the Sunshine Act. The open portion of the meeting consists of reports to the public, Council, and staff, including concept clearances. The closed portion allows the review, discussion, and evaluation of grant applications in accordance with Title 5, U.S. Code 552 (b)(c)(4) and 552 (b)(c)(6), and Section 10 (d) of Public Law 92-463. Attendance at the closed session is limited to Council and appropriate NIH and DHHS staff.

Dr. Nahin reviewed conflict of interest and confidentiality requirements. A conflict of interest may occur when any of the following exist: (1) the member has a designated role in the research; (2) the member has a self-interest-- professional or financial --in the research results; (3) there is even an appearance of conflict stemming from participation of a family member or associate. Committee members should not be present for reviews in which they, a spouse, minor child, or partner (including close professional associates) or organization with which the Council member is connected has a financial interest. In addition, when an institution with which the reviewer is affiliated has an application under review, there is the appearance of conflict of interest even if the reviewer will not benefit financially and knows none of those involved in the proposed project. Council members are responsible for ensuring that they meet these conditions. Council members must sign a form indicating that they did not have a conflict of interest, and this written certification becomes part of the public record. All Council members may participate in general discussions. Members must refrain from discussing review topics outside the forum of NACCAM meetings. The content of review documents may be disclosed only by staff under the appropriate circumstances and all questions must be handled by NCCAM staff. All closed session review materials must be left in the room.

Dr. Kail noted that he was a consultant on one grant this time, but received a notice disqualifying him from the review of 11 applications. He asked about the rules governing this situation. He saw possible difficulties in this. Dr. Nahin explained that Council members will be in conflict with every application in response to the same RFA for which they or their affiliation applied. At this meeting, seven members were in conflict with one or more P20 applications, which was the reason for having the ad hoc members. Ms. Holloran asked if this meant that the underlying principle had to do with the mechanism. Dr. Nahin explained that applications in response to the RFA are competing for the same limited pool of money. If a Council member recused themselves only for the specific application on which they were named (i.e., in conflict), they could still influence whether this application is funded by voting to lower the priority for all other applications in response to the RFA.

Ms. Holloran had a question about the confidentiality issue. She thought her own application list and assignment sheet were her own. Dr. Nahin explained that the assignment sheet lists which Council member did which review. That key information that would allow an applicant to link the grant application with an individual Council member. It is inappropriate to keep these items because if the list became public knowledge, it would break the confidentiality of peer review.

Dr. Nahin told Council that three late summary statements and other materials (a special action memo from staff and copies of letters of appeal) were provided in their folders. He asked them to read the letters of appeal before the closed session. Dr. Nahin noted that NCCAM takes all letters of appeal to the Council.

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IV. NCCAM Director's Remarks

Dr. Stephen Straus introduced Dr. Jane Kinsel. She has years of experience in medicinal chemistry and pharmacology and served in several senior roles at the National Institute of Allergy and Infectious Diseases (NIAID) including that of Chief of the Office of Science Policy before recently joining NCCAM as the Associate Director for Science Policy and Operations. She will also become the executive secretary of the Council at the next meeting. NCCAM has designated Dr. Martin Goldrosen as the new Chief of Review. Dr. Goldrosen, a cancer immunologist and former Professor at the State University of New York at Buffalo, comes to NCCAM from the National Cancer Institute where he directed major scientific review activities.

Dr. Straus noted that recently elected President Bush supports NIH and requested the largest NIH budget increase ever. This request would increase the NCCAM budget to about $100 million in FY 2002 from $89 million this year. Congress seems equally committed.

Regarding funding projections, Dr. Straus reminded the Council that in 1999, when NCCAM was created, NCCAM received 23 research applications, and funded 13. In 2000, there were 177 submissions, 44 of which received funding. In February, Dr. Straus projected that NCCAM would receive 212 submissions in FY2001, with funding projected for 37 of those. However, NCCAM has received approximately 400 applications. Depending on the average costs of the grants awarded and other factors, the Center will be able to fund 10 to 18 percent of all applications. The Center and Council must make strategic decisions about what kinds of applications to fund. NCCAM is likely to receive even more applications in FY2002, which may result in a lower percentage funding. Dr. Straus added that NIH as a whole finds about 40 percent of applications to be unscorable, but NCCAM finds 60 percent unscorable. Dr. Kail suggested that as funding percentages decrease, it will be more difficult for complementary and alternative medicine (CAM) institutions to compete. He asked if co-funding with other NIH institutes might help. Dr. Straus explained that some CAM institutions have been competing successfully and should continue to do so. To increase co-funding, Dr. Straus is building relationships with other Institutes. He has commitments for several million dollars in FY 2002.

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V. NCCAM Intramural Program

Dr. Straus introduced Dr. Marc Blackman, the clinical director of the NCCAM intramural program, and reviewed his background. Dr. Blackman outlined his goals. The mission of the intramural program is to explore CAM practices in the context of rigorous science, train CAM researchers, and disseminate information to the public and professionals. Among the guiding principles are an unwavering commitment to excellence; absolute integrity of purpose and actions; and uncompromising respect for all stakeholders. Dr. Blackman's objective for FY 2001-2002 is to establish administrative, scientific, clinical, and training priorities and infrastructure, while developing a web of intramural and extramural collaborative relationships. He also intends to establish an extramural board of scientific counselors to advise and monitor the program, as is done elsewhere in NIH.

Dr. Blackman explained that he has a special interest in gerontology. The population of individuals 85 and over is the most rapidly growing segment worldwide. The next 50 years will see a four- to five-fold growth in this group. In that context, his investigational theme for the NCCAM intramural program will be stressors and aging: depression/dysphoria; cognitive decline; chronic pain; sleep disorders; and frailty. Each of these conditions is more problematic in older people, and each accounts for disproportionate use of CAM modalities, usually in addition to standard medicine. In addition, these conditions coexist together.

With this as background, Dr. Blackman proposed an intramural program with a lab of clinical investigation (LCI) having six sections: endocrinology, metabolism and nutrition; neurobiology; clinical immunology and rheumatology; cardiology; oncology; and pharmacology. Through these sections, he hopes to approach CAM modalities in groupings of biologically based therapies (such as DHEA and other androgenic dietary supplements, phytoestrogens, soy, melatonin), mind-body medicine (placebo effect, meditation, laughter), and alternative medicine systems (acupuncture). Manipulative and energy systems will be studied later.

Dr. Blackman explained that there is a drop in DHEA in the human body as a person ages which may contribute to age-related changes in the body that affect immunological, psychological, and cardiovascular and body composition aspects of health. DHEA administration to old rats reverses or attenuates many of these components of aging. DHEA is now in wide use as a dietary supplement for anti-aging purposes, although its efficacy and safety in humans are not established. Purity is uncertain from lot to lot, and it is regulated as a supplement, not a medicine, by the FDA. Dr. Blackman proposes studies that will: assess DHEA's possible clinical utility as a neurosteroid, immunomodulator, and cardiovascular enhancer in healthy and frail elderly individuals; and assess the effects of DHEA on gene transcription and the resultant biological effects in neural, immune, and vascular human cell lines.

To train CAM researchers, Dr. Blackman plans to stimulate collaborations between CAM practitioners and conventional investigators; train individuals and practitioners to conduct broad-based CAM research; increase the number of minority trainees; and initiate research training programs. In the month he has been with NCCAM, he accomplished the following: drafted an initial strategic vision; established the LCI and endocrinology section; and recruited key personnel. He has also initiated research collaborations with other NIH Institutes and a number of universities. Finally, he has initiated clinical/educational collaborations through the NIH inter-institute endocrine fellowship program, the NIH clinical center pain and palliative care service, and NCI's Office of Cancer and CAM.

Among Dr. Blackman's goals are to facilitate the coupling of effective CAM and allopathic practices in the interdisciplinary healthcare system of the NIH clinical center and to facilitate development of research and clinical training curricula that include information about safe and effective CAM practices. The longer term scenario is to establish a clinical program in CAM, form an inter-institute CAM training program, expand research activities, begin studies in children and neonates, and establish a lab of cellular and molecular biology to complement the LCI. Ultimately, he hopes to help establish a scientific basis for integrative medicine, and to have NCCAM become the leading source on this kind of information.

Ms. Holloran said that she was extremely encouraged by this presentation. She has used the modalities he mentioned, and has used DHEA since 1994. As a patient, she could not find much information on DHEA, which led to her interest in CAM. Dr. Blackman noted that there has not been an economic incentive to study DHEA. Dr. Goldstein asked if the intramural program had assigned clinical space at NIH. Dr. Blackman replied that NCCAM is negotiating with NIH leadership to secure lab space. Clinical investigations will take place within the clinical center. Dr. Kahn noted that she does not consider acupuncture a system, but rather part of a system. Dr. Blackman said that a growing body of data indicates that acupuncture has utility, and he wants to start investigating those CAM modalities with the highest body of evidence. It is not well-understood how acupuncture achieves its effects; he would like to examine this.

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VI. NCCAM Health Disparities Plan

Dr. Jackson, Director, NCCAM Office of Special Populations, presented the draft NCCAM Health Disparities Plan for Council review and comment. He explained that the DHHS established an initiative to eliminate racial and ethnic health disparities that focuses on six priority health areas: cardiovascular disease, cancer, diabetes, HIV/AIDS, immunization, and infant mortality. As part of the DHHS initiative, NIH is developing a consolidated plan with the goal of reducing and ultimately eliminating health disparities (REHD) among racial and ethnic minorities. Within this goal are three objectives that NIH will address: research, research infrastructure, and public information and community outreach.

Dr. Jackson outlined the process for drafting the plan, which involved multiple reviews by NIH staff and select Council members. A revised plan will be posted on the NCCAM web site for public comment, updated based on public comment, and presented to the Council once more. The NCCAM REHD plan reflects the NCCAM mission to explore CAM healing practices with rigorous science, train CAM researchers, and disseminate authoritative information.

To address the first NIH priority for dealing with health disparities, research, the NCCAM plan will advance our understanding of, and develop new or improved approaches for, treating diseases and disabilities. These approaches will incorporate research on CAM systems and interventions for specific diagnoses of concern, while expanding minority participation in CAM research. To address the second NIH priority, that of research infrastructure, the NCCAM plan will support research training and career development and provide support for institutional resources. The plan will also address the NIH priority of communications and outreach.

Research initiatives will include epidemiological studies of CAM in minority populations. There is also a proposed initiative for outcomes research on CAM in minority populations and for testing several CAM interventions used to treat or prevent several of the the six disease areas prioritized by NIH. Coordinated efforts will be made to increase minority participation, both investigators and patients, in NCCAM research.

To increase research infrastructure, NCCAM is supporting research training and career development of minority scientists. The Center recently received applications for T32 research training grants at minority serving institutions. The Center will also support summer internship programs at NIH and will participate in NIH-wide minority research supplements and DHHS minority youth initiatives targeting high school students.

NCCAM will collaborate with other NIH institutes and centers on communication and outreach initiatives, which will disseminate CAM information to professional organizations and the general public, and collaborate on a community consultation workshop.

In closing, Dr. Jackson noted that the NCCAM REHD plan is a dynamic document, and hopes that through execution of the plan, NCCAM can enhance the cultural competence of the conventional care system and advance the development of interdisciplinary health care.

Col. Williams and Drs. Rhoades and Lawrence led the discussion. Dr. Rhoades cautioned that to eliminate disparities, socioeconomic disparities and stress health education must be addressed. The clinical conditions discussed in REHD, though identified by DHHS and NIH, don't address violent death and intentional and unintentional injuries, which are epidemic among Native Americans. Dr. Rhoades noted that these problems do not necessarily fall within NIH's purview. Dr. Rhoades added that Native Americans have a different list of conditions from other minority groups. Alcoholism and lung cancer are third and fourth on their list. Nonetheless, he liked the draft plan. He thought a workshop would be a good idea, observing that Native Americans will want their own breakout sessions. He felt that getting public comment will be critical.

Col. Williams observed that true integration of CAM will involve elimination of health disparities. Societal integration is a work in progress, and CAM is facing a parallel path of integrating into the mainstream. Much of the challenge will be driven by politics. Many CAM practices attempt to bring balance to our lives. Col. Williams said that he likes the work NCCAM is doing to collaborate among agencies. Building research infrastructure in minority institutions is very important, and release of faculty time is important as well. He added that NCCAM should not forget the potential of minority investigators at majority institutions.

Dr. Lawrence said that he was struck by the fact that it will require economic and educational work to address health disparities. When he looked at the document, he looked at it from global and specific perspectives. From the global perspective, he thought it was very good, dovetailing nicely with the NCCAM strategic plan. In terms of specifics, a couple of things caught his eye. He is having more trouble with CAM being discussed in terms of what it is not. He wants to give greater attention to integrated medicine. In addition, he thought that in-depth surveys of specific subpopulations are important. Regarding research training and career development, he wondered about the level of faculty staffing at CAM institutions in terms of minorities. Otherwise, he thought the document was very well done.

Dr. Straus asked if there were other comments. Dr. Debas said that he also liked the plan, but felt it tried to address too many issues. There should be more focus and some milestones. Dr. Standish asked about the T32 program. Dr. Jackson said that applications for T32 programs were due to NCCAM on May 14. Dr. Kaptchuk said that they should investigate some of the ethnomedical practices in minority communities. He would like to make sure that minority medicines and practices are addressed. Dr. Jackson said that this has been discussed in the plan, including the incomplete picture of minority CAM usage.

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VII. Overview of Sister Agencies in DHHS

Dr. Straus invited Dr. Ruth Kirchstein, Acting Director of NIH, to address how NCCAM relates to its sister federal agencies. After a general overview of DHHS, Dr. Kirchstein discussed some of the DHHS agencies that share areas of concern with NIH. The Agency for Healthcare Research and Quality (AHRQ) supports research on crosscutting health care issues (health care systems, effectiveness of medical treatments, health care quality, medical errors, health care cost) that are often in the news. The Center for Disease Control and Prevention (CDC) provides a system of health surveillance to monitor and prevent the outbreak of disease. CDC helps to guard against international disease transmission, maintains national health statistics, provides for immunization services, and supports research into disease and injury prevention. The Food and Drug Administration (FDA) regulates and ensures the safety of food and cosmetics, and ensures the safety and effectiveness of pharmaceuticals, biological produce, and medical devices. The Health Resources and Services Administration (HRSA) provides health resources for medically underserved populations through the National Health Services Corps, and oversees the organ transplant system, the Ryan White Services for People with AIDS, and various local and regional centers. The Indian Health Service (IHS) provides health care services to 1.5 million Native Americans. This system encompasses 37 hospitals, 60 health centers, school health centers, health stations, and urban Indian health centers. Much of what they do is through contracts with tribes, some of which run their own systems. The Substance Abuse and Mental Health Services Administration (SAMHSA) works to improve the quality and availability of substance abuse prevention, addiction treatment, and mental health services. The Administration for Children and Families (ACF) provides services and assistance to needy children and families, usually through block grants. The Administration on Aging (AOA) works closely with the National Institute on Aging, and administers block grants to provide for the aging population. Health Care Finance Agency (HCFA), through Medicare and Medicaid, provides programs that support health care for the aged and poor. This is not a discretionary budget. HCFA has recently put together regulations of interest to NIH, allowing HCFA to provide care for patients who are being studied under research protocols. This will now allow elderly and needy people to be part of studies, since they will no longer have to pay for their routine care while participating.

Ms. Holloran asked if there were collaborations among these agencies to focus on disparities issues. Dr. Kirchstein said that there is a great deal of collaboration. There are transagency programs on health disparities. There is a close collaboration between IHS and NIH. In addition, all agencies are developing strategic plans. One thing to note about the health disparities issue is that these are not all in the traditional NIH area. Some issues are about access, for example. As such, NIH Institutes have increased outreach and education programs. Dr. Debas asked about the selection of the director of NIH. Dr. Kirchstein explained that this is a presidential appointment. Various factors go into the selection. In the past, there have been search committees. Dr. Schlitz asked if the role of prevention is increasing in significance. Dr. Kirchstein said that it is increasing within all parts of DHS. There will be an initiative involving all agencies.

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VIII. Concept Clearance

Dr. Nahin introduced Dr. Nancy Pearson of NCCAM, who presented initiative concepts for clearance. Dr. Pearson provided some general background on two conferences that directly led to the two concepts for initiatives on placebo: the November 2000 placebo workshop and a conference on mind-body interactions held in March 2001.

The first proposed initiative, The Placebo Effect in Clinical Practice, is expected to stimulate investigator-initiated research investigations on how placebos and placebo effects affect clinical practice, with the goal of understanding which factors are necessary to elicit a placebo effect in clinical practice. This will allow practitioners to enhance the benefits of therapeutic intervention to improve health and promote wellness. The objectives are to solicit studies: 1) that determine the psychosocial factors in the patient/caregiver relationship that elicit the placebo effect; 2) on tools that might elicit the placebo effect; 3) into the role of belief systems and social systems in eliciting the placebo effect; 4) of ethical questions related to placebo; and 5) on how different types of caregivers can maximize the placebo effect.

The goal of the second proposed initiative, An Integrative Approach to Elucidation of the Underlying Mechanisms of Placebo Effect, is to stimulate research on the underlying biological mechanisms of placebo that lead to its ultimate physiological and psychological effects. An integrative research approach is encouraged, defined as combined use of approaches with several different scientific disciplines. The idea is that understanding of the underlying mechanism of placebo effects will elucidate and enhance both conventional and CAM medical therapies in clinical practice. Expanded placebo research incorporating the fulle palette of contemporary biomedical techniques as well as development of better animal models is encouraged.

Dr. Schlitz asked about the impact on these proposed initiative of the recent meta-analysis published in JAMA, which suggested that there is no placebo effect. Dr. Pearson said that the analysis was very provocative, but actually creates a need for more research. Dr. Schlitz ask what NCCAM would do if the data do not look compelling. Dr. Berman said that the article questions whether there is an effect, rather than saying that there is none. Dr. Kaptchuk added that the meta-analysis was well done, but that the question should be raised to a higher level. However, one meta-analysis does not negate numerous research in the area. The controversy makes it that much more timely for NCCAM to initiate this project. There is much evidence both ways, which is a reason to do more research.

Dr. Meeker thought the meta-analysis demonstrated a significant pain effect, which is especially significant for CAM treatments and modalities. He said that the development of placebos for testing nonpharmacological treatments is a large issue. Dr. Straus replied that these types of studies are in the NCCAM portfolio, such as with acupuncture. Dr. Goldstein added that in the same issue of JAMA, there was an informative editorial comment that took issue with the conclusions of the meta-analysis. The commenter noted that questions have now been raised that demand answers. There was also a recent study on brain injury in which the placebo group had a substantial long-term benefit.

Dr. Kail said that looking at the biological reasons for the placebo effect could be complex, and the proposed funding seemed small in that light. Dr. Straus replied that NCCAM was seeking additional funds from other NIH Institutes and Centers. Dr. Cantwell said that regardless of the article, this is the first time NCCAM has looked at intentionality. This a new direction, and brave. Dr. Cho said he was glad to see the concepts. He just completed an acupuncture study in which he saw some of the placebo effect; a sham intervention found an effect similar to true acupuncture. Dr. Debas noted that even if there is no placebo effect, there should still be a placebo in trials to control for investigator bias and the like. Dr. Pearson said that she would meet soon with interested institutes.

The concepts were approved unanimously.

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IX. Public Comment

Dr. Nahin announced the time for public comment. No members of the public signed up to speak, and no one came forward when he asked if anyone would like to speak.

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X. IRB Discussion

Dr. Christine Grady of the NIH Department of Clinical Bioethics, spoke about institutional review boards (IRBs). Dr. Straus explained that the Council had previously raised issues regarding IRBs and ethical review. There has been concern within the Council that it might be inappropriately difficult to get a CAM proposal through an IRB.

Dr. Grady explained that IRBs are formed to review and monitor research involving human subjects. The official guidance is under 45CFR46, which applies to all federal agencies and which protects human subjects. Regulations also address informed consent, which is the responsibility of the IRB. Non-government-funded research still must follow FDA regulations (21CFR56) if the researchers want to take research results to market. FDA regulations for IRBs are different on very minor points. Most institutions try to comply with both sets of regulations. The purpose of an IRB is to assure that human subjects are protected in terms of their rights and welfare. IRBs have authority to approve, require changes to, and disapprove studies and protocols. Specific language in 45CFR46 requires that IRBs have at least five members with varying backgrounds in order to adequately review research activities commonly conducted by the institution. If an institution has a higher volume of protocols in alternative medicine, they might want to have CAM people on the IRB. There are also membership considerations regarding sex, experience, and diversity, along with considering community sensitivities, including a nonaffiliated member who is from outside the institution. IRB membership cannot be concentrated in one profession and must have at least one scientist and one nonscientist. Membership requirements include competence in reviewing the specific research activities, and members must be able to determine that the proposal is appropriate for the institution. IRBs pay special attention to proposals involving "vulnerable" subjects. Finally, IRBs may invite ad hoc members with competence in special areas to assist in the review of issues that require expertise beyond or in addition to that available on the IRB.

Many IRBs have only one nonscientific member, but that person must be present in order to proceed. IRBs must assess whether risks to subjects are minimized by using procedures that are sound and that do not expose subjects to unnecessary risk. This generates some disagreement among IRBs with respect to the review of proposed science. Many institutions have a scientific review that precedes IRB review. Others argue that IRBs should ensure science of high quality, so that a separate review process is unnecessary. Another requirement of IRBs is to determine that risks to subject are reasonable in relation to the benefits. IRBs judge the balance of risks and benefits, and the value of the knowledge gained from the proposed study. They must determine that the selection of subjects is equitable and appropriate, and ensure appropriate consent and documentation of consent. IRBs have come under much scrutiny in the last few years. A few studies have looked at their function. Two studies in 1998, one by NIH and one by the Inspector General, were released in the same month. They used very different methods of evaluation and came to contradictory conclusions. One said the IRB system was in jeopardy; the other said they were doing a good job with minimal resources. The reality is that there are about 3,000 IRBs. They are variable in how they operate.

Ms. Holloran explained that some members of Council were concerned with the composition of IRBs and the familiarity (or lack thereof) that IRBs, especially small ones, might have with CAM modalities. She asked if it were possible for an IRB to specialize in CAM, or if it would be better to educate existing IRBs about CAM. Dr. Grady suggested that efforts should go into providing IRBs the information they need to evaluate CAM and urging them to use ad hoc consultants. She has found that IRBs with few qualms about Phase I drug studies have problems approving surveys, because they do not understand this type of research as well. As a result, there is disproportionate scrutiny of survey studies, a situation that might apply to CAM as well. There is an increasing effort to provide educational materials to IRBs. There are many web sites that provide IRB members with information. Issues important to NCCAM could be introduced.

Dr. Meeker asked for a distinction between local and single project assurances. CAM seems to be in the single project category, resulting in serious delays. Dr. Grady said that there is a new mechanism, a federal-wide assurance, that replaces the other assurances and simplifies the process. There is a grace period in which institutions can apply for those. NCI has started a pilot project of a central IRB for its oncology groups. This IRB will review multicenter protocols in order to circumvent problems inherent when multiple IRB's review the same project. This is a pilot and there will be an evaluation down the road.

Dr. Debas noted that the costs of running an IRB are large and increasing. Dr. Grady said that there are almost no data on the costs of IRBs. The business IRBs have their own data, but institution-level data have not been disaggregated. Members are usually volunteers. Dr. Debas observed that while this is true, it is no longer as easy to get volunteer time from faculty. Some are asking to be paid. Dr. Straus noted that NIH views its indirect payments as covering IRB costs. NIH no longer requires IRB approval before review, and since 70 percent of proposals do not get funded by NIH, this should decrease the number of proposals that IRBs review. Dr. Straus added that no NCCAM proposal approved by Council has failed IRB review. Dr. Straus explained that research is becoming more administratively burdensome, not just for CAM.

Dr. Pardes observed that mental health investigators whose proposals were reviewed by non-mental health people often feel there work is not understood. He believed that investigators think they are being reviewed by a homogenous group, but this is rarely the case. He was also concerned that the research oversight structure is growing cumbersome and may prevent good research. Dr. Grady agreed with his point, giving an example relating to gene therapy. Dr. Straus said that he senses a tension in CAM research. The fact that something has been used by many people for many years seems to provide an inherent reason to explore. However, unlike work in other areas, there is not much preclinical work before preceding to clinical trials in CAM, which could put NCCAM funded projects at a disadvantage.

Dr. Olness presented two examples where IRB members did not understand what they were reviewing. In one case, the IRB felt CAM interventions were not legitimate and therefore dismissed them. In another case, the IRB passed protocols that were done in error. Dr. Debas asked about the personal liability of IRB members. Dr. Grady replied that few IRBs have been sued as a body. Individuals are not usually held accountable, as they make group decisions.

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XI. CAPCAM/Best Case Series Update

Dr. Straus introduced Drs. Jeff White and Ian Coulter, who gave an update on the Cancer Advisory Panel for Complementary and Alternative Medicine (CAPCAM) and the best case series (BCS). Dr. White spoke first, about the BCS. He gave a brief history of the NCI case series reviews, mentioning the laetrile review of the mid-1970s, a 1989 Vitamin C review, a 1990 Office of Technology Assessment (OTA) study, and the 1991 NCI BCS program. The laetrile review involved a solicitation of documentation of cancer responses, with nearly half a million letters going out to physicians, other health professionals, and pro-laetrile groups. This resulted in 230 patients with claimed objective responses from laetrile but only 93 authorized releases of medical records. Of the 93, only 67 cases provided sufficient information for review.

The 1990 OTA report noted that the BCS approach could be useful in deciding which alternative treatments warranted further investigation. The report suggested that key to a successful BCS was the active participation or support of the practitioner. The NCI case series reviews were established after the OTA report came out and involved coordination by the NCI's cancer therapy evaluation program, along with internal review of materials. From 1991 to 1998, the program generated about 30 inquiries, 10 requests for review, 5 reviews, and 4 response audits.

In 1999, the NCI Office of Cancer Complementary and Alternative Medicine (OCCAM) began coordinating the BCS program. The current process is that the practitioner contacts NCI or NCCAM and receives an information packet from OCCAM. Documentation of cases goes to OCCAM, with radiology and pathology reviewed at the NIH Clinical Center. The materials are then summarized and presented to CAPCAM. The practitioner is invited to present their cases to CAPCAM and answer questions. CAPCAM advises the NCCAM Director as to whether or not further research is warranted, and if so, of what nature.

Of those who contacted OCCAM for information in the first nine months of 1999, eight were from the U.S and two were foreign. There have been two U.S. best case solicitations and two submissions. OCCAM began promoting this previously unadvertised program in December 1999. Over 150 letters were mailed, information was placed on the OCCAM web site, and there were conference presentations, journal articles and interviews, and advertisements in six journals. OCCAM has had more than 125 inquiries since January 1, 2001.

Dr. Nahin explained that NCCAM is supporting the Agency for Health Research Quality (AHRQ) Southern California Evidence-based Practice Center (SCEBPC), which includes RAND, in a one-year pilot project to put together BCS for designated practices. SCEBPC staff and the practitioner could then present the BCS to CAPCAM.

Dr.Coulter, Principal Investigator for NCCAM's contract to the SCEBPC, explained that the SCEBPC is contracted through AHRQ to provide technical support for NCCAM. Projects include systematic reviews of: 1) mind-body therapies---gastrointestinal problems; 2) Ayuverdic medicine--diabetes; and 3) SAMe--depression, arthritis, and chronic liver problems.

Specific aims for the one-year pilot are to create a BCS for three CAM providers treating cancer, and to determine if there is sufficient evidence for further study of these therapies. NCCAM will identify the three CAM providers, of which two have been chosen so far. The CAM providers will be asked to identify their best cases, and SCEBPC staff will visit the practice and abstract the patient files after first obtaining informed consent. Files will be abstracted from the CAM provider and from mainstream medical providers. This underwent a rigorous IRB review.

After the CAM provider has identified the best cases, the provider will contact patients to be included in the study. Patients will be interviewed regarding health and quality of life. Where the CAM record in incomplete, they will be asked for permission to contact their mainstream medical provider. The mainstream medical provider, in turn, will be asked for a histological report, other documentation of diagnoses, and documentation of treatment. Inclusion criteria will be histological confirmation, the starting point for CAM, exclusive CAM treatment, documented CAM treatment, and a documented end point such as remission, tumor size, or longevity. Dr. Coulter said it will be difficult to find patients who have had CAM treatment exclusively.

The first intervention they are examining, from the Bahamas, is immuno-augmented therapy (IAT). The premise is that the immune system attacks the cancer cells but also controls the rate of the attack by blocking protein to prevent toxic damage to the liver. As immunosuppression and anti-tumor activity occur, the inhibitor system must be reactivated. There are four factors in the immune system failure: a blocking protein, a tumor antibody, a tumor complement, and a deblocking protein. The therapy involves daily injections of human processed blood based on the patient's immune system and the four factors.

The SCEBPC is reviewing cases of cancer patients treated with naltrexone. Naltrexone is an opiate antagonist used to treat heroin addiction and people with HIV/AIDS. It is also thought to cause cell death and tumor regression in some instances. The theory is that a low dose of naltrexone raises levels of beta-endorphins and met-enkephalin, facilitating immune function.

To contact patients, SCEBPC staff must go through the provider. The IRB is allowing them to only review cases where either the patient has given informed consent, or cases where the unique patient identifiers are removed from the records. The research team then identifies the cases they wish to include, at which point the provider contacts the patient to secure their consent. There are three patient consent forms. The first allows SCEBPC staff to review patient files, while the second allows SCEBPC staff to interview the patient. The final consent allows SCEBPC staff to obtain medical records from the patient's other health care providers.

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XII. Closed Session

The remainder of the meeting was closed to the public in accordance with the provisions set forth in Section 552b(c)(4) and 552b(c)(6), Title 5, U.S.C. and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix 2).

The closed session began at 3:00 p.m. A total of 163 applications were assigned to NCCAM. Of these, 134 were reviewed by NCCAM with the rest reviewed by the Center for Scientific Review. Applications that were noncompetitive, unscored, or were not recommended for further consideration by the initial review groups were not considered by Council. Council reviewed 118 applications requesting $117,825,977 in total costs. Council concurred with 108 new research grant applications for a total cost of $73,089,637. Council recommended deferral of thirteen (13) (three were noncompetitive, unscored) Frontier Medicine (P20) grant applications requesting $44,736,368 in total costs.

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XIII. Adjournment

There being no further business, the meeting was adjourned at 6:00 p.m.

1. Members absent themselves from the meeting when Council discussed applications from their own institutions or when a conflict of interest might occur. The procedure applies only to individual applications discussed, not to en bloc actions.

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