UPDATE: COMMUNITY-BASED TRIALS AND SAN FRANCISCO'S COMMUNITY RESEARCH ALLIANCE

In a development unprecedented in the history of medicine, persons with AIDS or HIV and their physicians have begun to organize and run their own clinical trials of potential treatments, conducting this human research in ways which meet all FDA and other legal requirements. One of about 20 such organizations is the Community Research Alliance (CRA), which AIDS TREATMENT NEWS covered in issue #70, December 1, 1988. This writer is one of the founders of the CRA and is currently a member of the board; we chose to focus our report on this particular organization because we are closest to it and know it best.


WHAT IS COMMUNITY-BASED RESEARCH?

Clinical research traditionally takes place in major medical centers, usually academic institutions, and is paid for by pharmaceutical companies or by the Federal government. Some research, especially tests of new chemicals never before taken by humans, can only be done in specialized institutions. But other studies, such as "monitoring" trials designed to collect consistent, reliable data on a new use of a treatment already well known in medicine, can usually be done more rapidly in the less formal setting provided by a community organization working together with front-line physicians in private practice or at public clinics.

Research initiated by persons with AIDS or HIV or their physicians, and conducted under the professional guidance of physicians and scientific specialists, can:

* Test immediately practical treatment options, which other-wise might not be tested at all if they lack commercial incentive or elegant scientific appeal;

* Design trials which will get results quickly (in contrast to the "body count" designs usually used in mainstream research, which usually take two years or more to produce results, due to the wait for persons not being treated to get sick);

* Negotiate trial designs which are attractive to the participants and their physicians, as well as scientifically sound, greatly reducing recruitment delays and the danger of invalid results due to cheating;

* Build an in-depth knowledge base, allowing the PWA community to make sure its interests are represented when decisions are made in mainstream research.

The public has not realized the extent to which the specific interests of institutions and professionals have shaped medical research in ways which differ from patients' interests. One example came to light over a year ago, when Dr. Anthony Fauci, director of the National Institute of Allergies and Infectious Diseases, which runs most of the Federal government's AIDS treatment research, had to tell a Congressional committee that some of the most promising treatments, including aerosol pentamidine prophylaxis, had been delayed for a year or more due to lack of a single staff person to "shepherd" each one through the research and regulatory labyrinth (see The New York Times, April 30, 1988, page 1). Because the community- based research movement had been small until that time, no one knew what was happening, except those too dependent on the system to make a public issue. Therefore, nobody raised the warning early, and a year was lost. (Aerosol pentamidine received full FDA approval last month, based on data from studies begun by the two oldest community-based research organizations, the County Community Consortium in San Francisco and the Community Research Initiative in New York. Emergency funding was provided by pentamidine licensee LyphoMed, Inc., after the U. S. National Institutes of Health had unexpectedly refused to fund the study.) This incident illustrates the fact that treatment and prevention of opportunistic infections has often fallen through the cracks of mainstream research, as there are usually too few patients to generate much commercial interest, and government scientists have preferred to study high-tech antivirals which relate to genetic research and the growing biotechnology industry.

Today's movement for community-based research exists to make sure that the interests and patients and their physicians are better represented in the future.

The groups developing today are modeling themselves on one of the two pioneering organizations in the community-based trials movement -- the Community Research Initiative in New York, and the County Community Consortium in San Francisco -- the same organizations which conducted the studies leading to the approval of aerosol pentamidine. These original organizations developed separately, creating two different flavors of community-based research:

The Community Research Initiative was first suggested in a position paper by Joseph Sonnabend, M. D., Michael Callen of the PWA Coalition, Dr. Mathilde Krim of the American Foundation for AIDS Research (AmFAR) and others. The organization started with a five thousand dollar grant from New York's PWA Coalition -- beginning the tradition of extensive PWA involvement. Two more physicians -- Bernard Bihari, M. D. and Nathaniel Pier, M. D. -- joined the group in its earliest stages, and administrator Tom Hannan did the lengthy paperwork required to establish an organization meeting all legal requirements to conduct human research.

For the first year the group attracted little attention. But after favorable comments by the Presidential Commission on the HIV Epidemic (see The New York Times, March 15, 1988), the organization and the concept on which it was based attained wide acceptance. Today the CRI has 190 participating physicians, and a scientific advisory committee headed by Donald Armstrong, M. D., Chief of Infectious Diseases, Director of the Microbiology Laboratory, and head of the AIDS Clinical Trial Group (ACTG) at Memorial Sloan Kettering Cancer Center. (Two other members of the scientific advisory committee are also ACTG researchers.) Nine trials are now underway or completed, with over 500 patients participating; the organization has an annual budget of slightly over a million dollars. (For more background on the Community Research Initiative, see AIDS TREATMENT NEWS #70, December 1, 1988.)

The other pioneer in community-based research, San Francisco's County Community Consortium (CCC), did not begin as a research organization, but as a forum for communication between physicians with AIDS practices, and AIDS researchers at San Francisco General Hospital. Almost all AIDS physicians in San Francisco are members of the CCC, although many are primarily interested in sharing information, rather than conducting research.

In addition to its information-sharing function, CCC now has five clinical trials underway, is building an infrastructure to provide research-nurse support to help physicians throughout the San Francisco area participate in research within their practices, and has published a directory of clinical trials in the San Francisco area (see "San Francisco: New Clinical Trials Treatment Directory," elsewhere in this issue for information about the directory and how to receive a copy). (For more back-ground on the history and development of the County Community Consortium, see AIDS TREATMENT NEWS issues # 54, April 8, 1988, and # 56, May 6, 1988.)

These two organizations have established two different styles of community-based research:

(1) The Community Research Initiative emphasizes patient involvement, with PWA participation on the governing board and on the institutional review board (IRB) which must review and approve any trial's ethical treatment of human subjects. Studies can take place either in the offices of primary-care physicians or at a central location, with the physician consulted. Much of the CRI's research takes place at its clinical center, however, as physicians are usually too busy to do the additional paperwork required for research.

(2) The County Community Consortium emphasizes technical support to enable primary-care physicians to conduct AIDS treatment research. Physicians with large HIV practices are usually he first to see the potential of available, immediately practical treatment options. But few practicing physicians have the time, training, or inclination to organize their own clinical research projects without assistance. Technical support provided by organizations like the Consortium allows the knowledge and experience of leading physicians to lead to credible scientific data which can be used everywhere to improve medical practice. Studies take place within the practices of the physicians, with the Consortium providing technical support and assuring quality control of the data.

The CRI model applies when patients want to be involved not only as subjects, but also in the development and decision- making of research. The Consortium model applied when an existing (or new) group of physicians, in private practice or in a public or private hospital or clinic, want to begin participating in clinical trials. Both models are crucially important for organizing practical research to make new treatments available faster.


THE COMMUNITY RESEARCH ALLIANCE

AIDS TREATMENT NEWS described the formation and early history of the Community Research Alliance last December (issue #70). At that time the scientific advisory committee had not met, and the institutional review board had not been formed. This article will focus on current projects, instead of the details of the rapid organization building which has taken place since then. We should point out, however, that developing an organization which meets all legal requirements for conducting human research is not only a matter of completing paperwork and complying with regulations, but more centrally is a process of developing working relationships with scientific and medical professionals, and with other organizations and community leaders. Over 30 volunteers are involved as members of the various boards and committees.

The Community Research Alliance is currently conducting a hypericin monitoring project which has been running for two months and has 30 patients participating. This study went from proposal to operation in three months. It provides a model for what could become a series of studies by the organization.

Hypericin is a substance found in a plant (St. John's wort) long used in herbal medicine. Recently researchers at New York University and elsewhere have found that hypericin appears to be an excellent antiretroviral, not only active against HIV in the test tube, but also against two other retroviruses in mice. (Since animals do not get AIDS, it has not been possible to run a direct animal test of hypericin as an anti-AIDS treatment.) For more background on hypericin, see AIDS TREATMENT NEWS issues numbers 63, 74, 75, 77, 79, and 80; the major scientific report so far was published in the Proceedings of the National Academy of Sciences, USA in July 1988, and five abstracts were published at the Montreal AIDS conference in June 1989 (including number M. C. P. 115, not listed under "hypericin" in the subject index).

But approval and regular human use through the mainstream research system will probably be years away. At this time, chemists are developing better methods for synthesizing large quantities of the pure chemical. Then there must be more animal tests before human trials can begin. The human trials can take years, despite recent efforts to speed the process.

Meanwhile herbal extracts are available. No one is sure if they can be useful. How can we find out?

A randomized controlled trial (today's gold standard of clinical research) would probably be impossible, at least in the United States. Such studies are difficult to run, and expensive -- and herbal extracts have very poor prospects for patent protection and therefore do not attract investors. Besides, it would probably be legally impossible to do the study, as the FDA is very unlikely to give an IND (Investigational New Drug approval) for the herbal extracts available. The FDA does not like crude plant extracts since they are not completely characterized chemically, and vary from batch to batch. The FDA exists to regulate (and protect) the pharmaceutical industry -- not herbalists, who are not taken seriously in the U. S. mainstream. Without an IND, it is not legal to give an unapproved drug to people.

What, then, can be done, besides waiting several years for large-scale synthesis of pure hypericin and animal and human tests of the chemical?

One option is to conduct a survey -- such as the one AIDS TREATMENT NEWS distributed in our June 2 issue, which we are now analyzing. A survey is better than nothing, but it has the major limitation of having no uniformity in data collection. People get different blood tests, or none at all, and on completely different schedules. Because of such problems, our survey will only be a study of peoples' beliefs about whether herbal extracts containing hypericin are helping them. What objective evidence does get reported (such as blood results, or clear appearance or disappearance of symptoms) is so diverse and scattered that it is difficult or impossible to draw reliable conclusions from it.

Between the survey and the randomized controlled trial is the monitoring study, such as the one the Community Research Alliance is doing with hypericin. A monitoring study avoids the need for an IND by not giving anybody a drug. Instead, it only collects data -- by doing blood work, physical examinations, and medical histories. But it collects the data under a strict, scientifically designed protocol, to maintain uniformity and quality control.

In the hypericin monitoring study now being run by the Community Research Alliance, patients are not told what kind of hypericin to use, or how much. They are not told to stop or change any other treatment. Of course they are asked to report every treatment they are using.

As we described in our June 2 issue, which announced the start of this monitoring study, baseline (before starting hypericin) and four monthly blood tests are given. Tests (not all given every month) include P24 antigen, T-cell subsets, the CMI skin test, CBC, ESR, and SMA 25. Before and after physical exams are given, and a medical history is taken. All blood work for all patients is done by the same laboratory, to reduce inter-lab variations.

This kind of monitoring study cannot control or standardize the treatments people are using -- for both legal and ethical reasons. But it can rigorously control the data collection. As as result, it can quickly collect much better data than is available from any other source about many, if not most, of the non-approved treatments now being used.

Since there is no control group for comparison, this kind of study cannot obtain statistical "proof" of whether the treatment works better than no treatment, or better than some other treatment. Instead of seeking such proof, this study aims to keep very good records of what happens to people who are using the treatment. The rationale is that since every patient's health status going into the study is well documented, any major or dramatic effects should be evident to physicians when they compare the histories of these patients, during the trial or afterward, with the histories of other patients they have known.

Therefore monitoring studies do not aim to prove a drug effective, but rather to produce quality information which can support treatment decisions. Note that almost any result of a well-conducted monitoring study can support such decision- making to some degree. If the treatment shows dramatic effects, of course that would be interesting. But if it shows nothing at all, or only ambiguous, debatable results, this information would also be helpful to patients and physicians, in supporting the case against using the treatment.

Monitoring studies are relatively inexpensive and easy to administer, because they do not give treatments, or change what the patient is doing anyway. The main expenses are for blood tests, and staff time. This kind of study can quickly obtain the best information available on treatments which are coming into use but have not been formally studied -- either food supplements, etc. which patients can obtain on their own, or drugs formally approved for other purposes and prescribed by physicians.


FUTURE PROSPECTS

Here are examples of the kinds of projects which the Community Research Alliance may pursue in the future:

(1) The CRA might develop many small monitoring studies, like the hypericin trial currently underway, and focus on doing this particular kind of research well. Funding would come mainly from individual donations, fund-raising events, and foundation or corporate grants, rather than from pharmaceutical company sponsorship of particular projects. The treatments studied would be those already available; and because funding would be from community and other public sources, treatments could be selected only on the basis of medical merit and public-health importance, without regard to their commercial prospects. This research arm of the organization will operate entirely in service to the AIDS community and the larger public.

(2) Some of the most important studies, however, could only be done with pharmaceutical-company sponsorship. Collaboration between pharmaceutical companies and community-based research organizations has worked well in the past, and the companies have been happy with the results. More time may be required up front to negotiate a protocol acceptable to people with AIDS and their physicians, as well as to the other parties involved -- a step usually omitted by academic research centers. But the care taken to include their interests is repaid many times over by easier and faster recruiting of volunteers for the trial.

Community-based organizations have a reputation for getting top-quality results much faster and less expensively than other alternatives. And today there are more drugs to test than research facilities available to test them (for background on this problem, see "The Trials of Conducting AIDS Drug Trials," Science, May 26, 1989). Therefore community-based organizations not only have opportunities to contribute to the mainstream research process, but by doing so they can help relieve a major bottleneck in the system, in addition to the qualitative contributions they can make by being close to the PWA community.

At this time the two most important drugs which could be studied by community-based research organizations are compound Q and DDI. Genelabs, the developer of compound Q, is exploring the possibility of organizing some phase II trials through community-based groups. For DDI, the phase II trials will be through NIAID's ACTG system, but there may be a role for community-based organizations in collaborating with Bristol-Myers to collect data from patients who receive drugs through compassionate use, treatment IND, or (later) the parallel track.

No final decisions have been made at this point, but these are some of the projects the Community Research Alliance is exploring as possible industry-sponsored trials.

(3) A number of other potential avenues are also being examined, including:

* Studying treatments for opportunistic infections, an area which has been neglected by the AIDS research mainstream. The treatments would be used by physicians in their usual practice, with the Community Research Alliance doing paperwork to facilitate access, data collection, and reporting of results;

* Participating in multicenter community-based trials, carried out by a developing network of community-based research organizations around the country, focusing on prophylaxis of opportunistic infections;

* Opening doors for full participation in clinical trials people of color and other groups which so far have been under-represented -- both in the decision-making process and as volunteers -- speeding AIDS trials by reducing recruitment delays, at the same time as the trials are made more equitable.


HOW CAN YOU HELP?

Community-based research organizations need public support. The biggest immediate need is money. The Community Research Alliance, for example, has had its office space and almost all of its office equipment donated, as well as the efforts of many volunteers, but it must have some paid staff in order to move as rapidly as possible to negotiate future trials, as well as com- pleting the one already going. The hypericin study is completely financed by the CRA itself, as there is no pharmaceutical company sponsor for it.

The Community Research Alliance has received a $30,000 grant from AmFAR (the American Foundation for AIDS Research), and individual gifts totalling over $60,000. But expenses at the current rate of growth and activity are about $12,000 per month. The CRA did not originally ask the public for money, as it wanted to establish a track record first. Now it needs contributions within the next two months, or its growth must be greatly curtailed.

The Community Research Alliance also needs volunteers, especially people with professional skills and/or who can develop or manage long-term projects.

If you can help in any way, contact administrator Tom Wilcox or his assistant Drew Catapano at 415/626-2145. Physicians should call the medical director, William Cooper, M. D., at the same number. Contributions can be sent to the Community Research Alliance, 273 Church St., San Francisco, CA 94114.



STATEMENT OF PURPOSE

AIDS TREATMENT NEWS reports on experimental and complementary treatments, especially those available now. It collects information from medical journals, and from interviews with scientists physicians, and other health practitioners, and persons with AIDS or ARC.

Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS TREATMENT NEWS does not recommend particular therapies, but seeks to increase the options available.

We also examine the ethical and public-policy issues around AIDS treatment research.