CAPCAM Members Present

AD HOC Members

NIH Staff Present

Others Present

I. Call to Order

The meeting was called to order by Richard Nahin, MPH, Ph.D., Executive Secretary of CAPCAM. Dr. Nahin reviewed NIH rules concerning confidentiality and conflict of interest.

II. Best Case Series Presentation: Insulin Potentiation Therapy

This morning session was closed to the public for reasons of patient confidentiality.

III. Lunch

IV. Call to Order and Meeting Procedures

Dr. Nahin explained for those present that there would be a continuation of the morning discussion without specifying the details that made it necessary to close that session. He then reviewed the rest of the agenda. The goal of the meeting was for the panel to make one of three recommendations: that there is sufficient data for further research by NIH; that no further research is warranted; or, that there is insufficient data to recommend additional steps, in which case it might be useful for the presenters to offer additional information.

V. Introductory Remarks

Dr. Hawkins explained that the topic under discussion was insulin potentiation therapy (IPT). That morning, Dr. SGA had made a presentation and the panel reviewed three cases. This therapy employs insulin with low doses of chemotherapy, which, according to Dr. SGA, changes the permeability of cancer cell membranes and makes cells more sensitive to chemotherapy. In two and possibly three of the cases, the panel felt there was evidence of improvement. Given the confounding aspects of chemotherapy administration, it did not appear useful to continue to focus on those three cases. Hence, the remainder of the day would be spentdiscussing the next research steps.

Dr. Hauser explained that his clinic sees 40 to 50 patients each day, as well as two or three new cancer patients each week who are seeking alternative medicine. He said that under the insulin potentiation therapy, the patients do not suffer side effects from chemotherapy, and even end-stage patients feel much better after two or three sessions. So as a natural health care provider, he is comfortable doing this treatment because of the lack of side effects.

When asked about providing patients for a study, Dr. Hauser explained that because many of his patients are in HMOs and PPOs, they cannot receive this therapy, even though the cost is much less than that of conventional treatment. Dr. Hufford suggested that 10 dramatic cases with substantial progress would be convincing. The effects would need to be large to overcome the issue of dosage. Dr. Hauser said that results thus far have been very good, but doing a study would require enrolling many patients prior to their receiving standard therapy. Dr. SGA felt this was doable. He said they could provide a significant numbers of cases of newly diagnosed patients, and would participate in recruitment and provide other help to participating practitioners. Dr. SGA would like to see a safe trial period of three weeks, then if the patients show no improvement, channel them back to conventional treatment. Dr. Hufford said that recruitment should not be specific to the study, as it would be a challenge from an ethical standpoint. They could, however, document current practice.

Dr. SGA added that the FDA might require moment-to- moment blood glucose monitoring. Dr. Hawkins explained that the nature of the study population will influence how the FDA views the study. A study of women who are likely to recover from breast cancer will receive more scrutiny than one of patients who can no longer be cured. Dr. Gordon explained that it will take years to know the results of a study of those who have early stage disease, so a study of end-stage patients would be advisable. He suggested that they could study patients in the late stages of cancer who have not yet been treated, or those who have diseases such as pancreatic cancer, in which treatment does not have much effect. Advanced stage cancer patients will produce the most dramatic results. Dr. Moss added that for pancreatic cancer, chemotherapy is given primarily for palliative effects. The most likely positive outcome would be to show that this therapy is as good as standard chemotherapy but significantly less toxic, which would be a major contribution to humanity and medicine. He did not think they should put resources into a prospective case series. On the other hand, chemotherapy shrinks tumors, so they ought to compare the insulin potentiation therapy with conventional chemotherapy.

Dr. Hawkins said that to do such a comparison requires much more in the way of resources than keeping track of the next 20 patients treated. If six or seven were to have a dramatic response with few or no side effects, a clinical trial could be conducted to compare IPT to conventional chemotherapy. But to leap to a comparison study with the data now in hand now will not work. Dr. Hufford's proposal is the least costly step at this point. Even a 50 percent shrinkage in tumor size would be significant. A key element of this approach would be to identify patients before they are treated with conventional chemotherapy. Dr. Hawkins added that ultimately, they would be looking for anti-tumor activity. They would be able to get an objective measure of shrinkage on CT scans, as well as other standard components. Once they have the experience of 20 patients to examine, they can see where they are and move on. Dr. Weed added that at this point, they are simply interested in documenting what happens, in order to determine if there is enough information to justify proceeding further. It would be helpful to have a prospective study that gathers more information. Dr. Moss agreed, and noted that standard quality of life measurements would test the thesis that this treatment has little or no toxicity. If it has significant toxicity, the appeal is much less.

Dr. Hawkins suggested that animal studies would be simple to evaluate and the least expensive thing they could do. But the others still preferred to see a better case series. Dr. Nahin asked if an institutional review board (IRB) would be needed by the investigators. Dr. SGA said that he has access to an IRB, which approved his protocol back in 1997. Dr. Hammer advised that if NIH were to support a prospective study, some expertise and resources should be devoted to assisting the researchers in doing it so that it meets NIH criteria. Dr. Hufford agreed that it would be best to give guidance now, and not pick apart a proposal later. Others agreed. Dr. White suggested including a mechanism by which NIH can actively participate in the data collection design.

Dr. Hawkins asked if the committee felt there should be efforts to move forward. Approval of such action was unanimous; the committee approved going forward while offering help to make sure the data collected are those NIH needs. Dr. White explained that NCI does not have a formalized process for providing such assistance, but instead does so on a case-by-case basis. Discussion of a concurrent animal study produced no real enthusiasm, although several committee members noted that animal studies could help underpin future studies.

VI. A Systematic Approach to Identifying Case Series of Promising CAM Therapies for the Treatment of Cancer

Dr. Coulter gave a presentation based on his work at RAND, with the premise that a more systematic approach to data collection might yield a larger sample of promising CAM cancer therapies for consideration by CAPCAM. One available method to such an approach is a literature review followed by synthesis and analysis. This begins with a search of databases, then a review of citations and abstracts. Articles receive quality scores, the synthesis leads to a meta-analysis, and finally the researcher reports the evidence. In an example, Dr. Coulter discussed such an approach as applied to oncology and mind-body studies. The literature review produced 110 studies. Of these, there were 19 possible comparative studies, 19 case studies, 17 reviews, 5 historical studies, 1 case report, 47 pieces that were unclear. A quality review entails either giving a Jadad score or conducting a detailed qualitative review.

A second approach is systematic evaluation of random charts at CAM practices. As an example of the approach applied to practice-based studies of CAM, Dr. Coulter told of a chiropractic study that involved 5 sites, 25 practices, and a random selection of files. There were many challenges: identification of providers; recruitment; office format; the state of the files themselves; use of results; and politics. One of the central issues was finding providers, because there was no central source providing a list. Recruitment was also a tremendous task. Each state addresses the issue of chiropractors differently, and there are multiple membership organizations. In addition, the CAM community is a small one; word travels fast, so they had to explain clearly what they were doing to avoid misperceptions. CAM practitioners tend to practice in modest settings, rather than elaborate offices, which meant that their offices were not always easy to work in - sometimes files are kept in a broom closet, for example, and sometimes there is no real waiting room. To obtain a random selection of files, the RAND researchers measured the files as through they were books in book case, used a random table generator to tell which files to take, and accounted for "fat file" bias to avoid taking just the thick files.

The study abstracted every case to acquire the denominators. All of the cases were randomly chosen, to get estimates of the types of conditions represented in the practice. The researchers did complete information extraction on the low back pain cases. They found that the quality of the information in the files varied; workers comp cases were the most complete, because any file likely to be reviewed had more detail. In the end, Dr. Coulter felt that the data RAND acquired were of good quality. In conclusion, he noted that the literature-based search will only capture what is in the literature already, and much CAM information is unpublished. Practice-based research in CAM is possible, but it is difficult, time-consuming, and costly. He also recommended considering foreign language sources in the literature review.

Finally, Dr. Coulter noted that it is naive for researchers to ignore the politics of CAM. CAM providers are sensitive regarding their reputations, and are wary of being seen as quacks. In this chiropractic study, the headlines that reported the results focused on the negative. But RAND has a policy that if the company is misquoted, they will reply to the media in question and even take legal action in order to combat misinterpretation. Therefore, this study was possible because of trust built up through this policy.

Dr. Gordon noted that for many CAM approaches, there is little or nothing in the way of literature, and what does exist is often of poor quality. Dr. White explained that his office has developed a list of direct contacts for the purpose of mailings, and these contacts were gathered from alternative medicine directories. Dr. Coulter noted that RAND preformed the previously mentioned study with a fully dedicated staff of 6 abstracters and 4 investigators, along with volunteers. The research team consisted of 10 during the first year, then about 5 for 2 more years. Dr. Weed suggested that for a case series, it would not take that much effort to find out what already exists. Dr. Hufford added that it would be useful to have a best case series of conventional treatment in order to gauge the results of CAM studies.

Dr. Moss observed that the CAPCAM process is frustrating, because the original purpose of the committee was to find if anything was being missed, and he has a sense that that is still the case. He felt they were drifting further and further from the core purpose to identify treatments that are used by the public and that may have promise. Dr. Gordon suggested that despite the excellent job NCI has done, there should be more people involved in the work of looking at practices and taking next steps. The main advance, in his opinion, is that CAPCAM exists; he feels he can at least refer people to others in the group. He would like to see CAPCAM fortified in order to move ahead and address more of these issues. Dr. Nahin suggested that there might be dissatisfaction with the speed with which the committee is seeing best cases. He felt that Dr. Coulter's presentation illustrated a good model and showed what could be done. One of the issues is getting data from practices to the panel. Even when there is a concerted effort, it does not always produce useful data in the correct volume and quality. Dr. Gordon added that CAM practices need a bridging mechanism that can pull them together. Dr. Hammer observed that the kinds of issues that have been problematic are those that have involved contacting practitioners and working with them to obtain complete cases. It is possible that there is a need for more effort in this area, for they are dealing with people who have gaps in their knowledge, and the result is a lack of follow-through. He felt the committee was really discussing a process issue, and that the concern was missed opportunities.

Dr. White explained that it is hard to assess what the biggest problems are in obtaining data. Just raising awareness is not sufficient. Practitioners do not always know who he is and are not always willing to participate in the process. Dr. SGA agreed, noting that many health organizations are unaware of CAPCAM's existence or efforts. He suggested that an effort be made to attend professional organization meetings and inform the membership. He noted that he belongs to two natural medicine physician organizations, and doctors within those groups were astounded that he was going to NIH. In response to the suggestion of having an audit committee and contacting specific groups, Drs. Nahin and White both agreed that this would be something that could be delegated. Dr. Hufford added that one of the issues is that CAM practitioners lack an equivalent to allopathic medical schools. He would like to see more emphasis on education, resulting in doctoral theses and an established cadre of skilled researchers familiar with the area.

Dr. Coulter explained that one of the key things he learned at RAND is how difficult and important it is to build trust. The effort must be constant, and it is time consuming and not always practical. CAPCAM must therefore make choices and focus. Ms. Holloran asked how his experiences could be transferred to help the committee. Dr. Coulter suggested first identifying case series, then establishing a way to show what works. Dr. Hammer requested that Dr. Coulter provide a blueprint of the steps he took. Dr. Richardson suggested that what is needed is a system or mechanism to assist practitioners in collecting and entering data. She added that NIH could develop an appropriate mechanism to do this. Dr. Moss said that researchers must cultivate contacts and connections, as trust does not happen overnight. The literature gives a false impression of what is exciting and current in the field. Another group is assembling this data, the National Foundation for Alternative Medicine. Dr. Gordon cautioned that the work goes beyond just visiting a practice. There is a tremendous amount of leg work involved. NCCAM and the cancer centers should be encouraged to make efforts in this area. Another issue is that of providing some kind of protection for these researchers. Some are genuinely afraid of being accused of practicing medicine without a license.

VII. Public Comment

Dr. Denise Wiley, a dermatologist from Oklahoma City, said that she was happy to be able to attend. She noted that she found information about the meeting on the NCCAM web site.

VIII. Update on NIH Initiatives for CAM and Cancer

Dr. Richardson reviewed NCCAM cancer activities. Two P50 cancer centers will be funded soon: Johns Hopkins and the University of Pennsylvania. In addition, NCCAM supports several investigator-initiated projects investigating CAM to treat cancer (see the NCCAM web site for a list of funded projects: http://nccam.nih.gov).

Studies in development will address CAM therapies for end of life, and phytoestrogens (PE) and breast cancer. For the former, NCCAM will issue an RFA for R01s and R21s to prevent and/or reduce side effects; prevent and manage symptoms; and enhance psychological, social, and spiritual well-being. The breast cancer studies, done as R01s, will have a strong pharmakinetic component, evaluate PE supplements versus a PE-enriched diet, clarify the role of PE, and gauge dosing.

Dr. Gordon asked about plans for Phase 1 and 2 studies. Dr. Richardson said that this is being left up to the field, to move along in whatever therapies are ready. Dr. Hufford asked about the extent to which the projects underway are linking to the CAM community. Dr. Richardson explained that natural medicine practitioners are very involved with hyperbaric oxygen. Dr. Nahin added that NCCAM has been talking to Dr. Sun since his CAPCAM appearance and has been trying to facilitate his study. Dr. White noted that Dr. Sun wishes to be the principal investigator, and they are helping him line up clinical oncology collaborators. The focus has been on helping him with the quality of the proposal. They have reviewed his protocol plans and made comments about what is necessary for improvement. Dr. Weed raised the issue of prevention. With the large body of NCI research on prevention and diet, he wondered if NCCAM was working with NCI in this area. Dr. Richardson explained that they are working in that area.

One of the requirements of the NCCAM centers is that they do outreach to the CAM community. Dr. Gordon observed that some centers are very good at this, and others do very little. Dr. Hammer asked if any CAM centers have recommended that certain practitioners bring their therapies to NIH. His concern was that things might be falling through the cracks. Dr. Richardson noted that the Texas center has sent groups to NCCAM. Dr. Nahin added that some centers are newly funded, while the Texas center's funding has just ended. Ms. Holloran asked if the specific research questions that arose are the most significant ones. For example, the CAM community argues for foods, not tablets, and many feel that soy supplements are dangerous. She was concerned that the researchers were studying the wrong things in the wrong form. Many CAM practitioners believe that healing action takes place in food, and therefore NIH should study the food as used in these practices. It seems clear that it would be easy to look at both. Dr. Hufford agreed that this is where collaboration with the CAM community comes in. The validity of a study requires that NIH examine practices as they occur. But a parallel point is that collaboration is sometimes problematic, because CAM practitioners often feel proprietary and fear that conventional medicine will take over their innovations.

Dr. White then gave a presentation about Cancer CAM information. The PDQ CAM summaries are available by calling 1-800-Cancer or by going to the CancerNet website (cancernet.nci.nih.gov). Topics include laetrile/amygdalin; cancel/Entelev; shark and bovine cartilage; coenzyme Q10; hydrazine sulfate; and mistletoe. NCCAM/NCI CAM fact sheets are condensations of information from PDQ summaries and will be available online and from other NCCAM and NCI information sources.

A recent NCI/NCCAM initiative solicited CAM cancer pilot projects through NCI-designated cancer centers. Initiative goals include supporting projects with high likelihood of developing into successful R01 applications; facilitating development of continuous CAM research programs; and encouraging and supporting collaborations between conventional cancer researchers and CAM researchers and practitioners.

The NCI best case series program has been moving forward. Between December 14 1999 and September 15 2000, there have been 22 inquiries, 6 planned submissions, and 3 actual best case series submissions. Submission #1 resulted from an initial contact made in September 1999. NCI received documentation on two cases in March, documentation on one more in April and another in June, and expected more cases by July. The first three cases were reviewed in July while NCI waited for the pathology on the fourth case. Since no further information was obtained on subsequent cases, approval was obtained to schedule the presentation of the three complete cases to the CAPCAM. (This was the IPT best case series discussed above.) Submission #2 came from an initial contact in July 1999; clinical summaries and radiology materials were received in May and June of 2000. In this series, four cases have been received and two are eligible for review, with more data on the remaining two forthcoming. The initial contact for the third submission was made in June 2000. NCI received cases in July, but there were no pathology slides; the submitter is obtaining more data. There are also two prospective, single-arm clinical trials NCI has addressed. For one, preliminary data was submitted in September 1999. NCI has requested further documentation of patient responses. For the second, the initial contact was made in June 2000; no data have been submitted yet.

To promote the best case series program, NCI has sent out 152 letters since mid-December 1999. Information is available at the OCCAM web site (occam.nci.nih.gov) as well. Dr. White has made conference presentations, has submitted journal interviews and articles, and has placed advertisements in six journals. NCI is now paying the travel and expenses for practitioners appearing at CAPCAM meetings for the best case series, and is exploring the feasibility of per case reimbursement for expenses incurred in preparing a best case series. In terms of practice outcomes monitoring, there have been difficulties with the Banerji project in Calcutta, India, in that there are ongoing negotiations about the scope of the investigation. Joint NCI/NCCAM CAM cancer clinical trials include a Phase 3 study of liquid shark cartilage and a Phase 3 study of a powdered shark cartilage product. The study of the Gonzalez/Kelley Regimen has had a problem with patients being unwilling to be randomized; there are some remaining administrative issues to work out.

There were questions about the Calcutta and Gonzalez studies, but Dr. Hawkins reminded the committee that they should not discuss the cases openly at this point. Dr. White offered to discuss the details with committee members who contacted him personally. Dr. Nahin added that the issues are details and not global. Ms. Holloran also asked about Mr. Angelo P. John, who left his information at a previous meeting. Dr. White said that the case is inactive because Mr John has not obtained any new data in two years. The difficulties are largely due to the fact that Mr. John is not a practitioner with an office or records, so he must approach practitioners as a consultant. He does not supply documentation of disease and responses, nor does he provide a specific therapy.

In answer to questions, Dr. White explained that there is a template for submitting BCS on the NCI website. In addition, when he attends conferences, he explains the BCS process in detail. While he wants to make materials easily available, he also wants practitioners to contact him directly, for the one-on-one discussion is critical. Several CAPCAM members who had heard Dr. White speak on this subject noted that he does an excellent job, particularly in distinguishing the scientific perspective from the issue of medical practice. A motion was passed to acknowledge and applaud Dr. White's efforts.

Dr. Straus thanked the committee members for their time. He noted that the task before them is not easy. But despite the long and complicated process of ramping up, they now have a level of commitment and substantial resources beyond what they had before. He added that Dr. White has spent many hours working hard on the best case series. They are also asking for hard work and courage from their researchers, and he commended Dr. SGA and Dr. Perez Garcia for their efforts. As NIH develops the sensitivities and sensibilities necessary to move forward in this area, they will rely on collaboration with others to help them understand what is needed. Discussions on the best methods will continue. He challenged the committee to continue to be as optimistic and collegial as they have been, and to try to develop consensus, even though given the necessary diversity, they will not always be unanimous.

IX. Adjournment

No date was set for the next meeting. Dr. Nahin said that members will be contacted about a possible time in winter or spring once two to three additional BCS have been completed. There being no further business, the meeting was adjourned at 5 p.m.