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AIDS Trestment News
June 5, 1998

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New Guide to Living with HIV Infection


One of the best general resource books for persons with HIV is The Guide to Living with HIV Infection, by John G. Bartlett, M.D. and Ann K. Finkbeiner, developed at the Johns Hopkins AIDS Clinic and published by Johns Hopkins University Press. The revised fourth edition is now available.

This book focuses on the many practical concerns (not only medical ones) that a person with HIV may face. Topics include emotional issues (anger, energy, depression, hope, and others) -- interpersonal situations (such as disclosure about one's diagnosis) -- understanding how medical care is organized and some of the barriers to access, including insurance issues -- the need to have an HIV specialist involved in one's care -- hospital administration procedures -- patients' rights -- finding support, and taking control of your life -- and others. There are discussions on caring for your health, medical symptoms, laboratory tests, considering clinical trials, considering alternative treatments, and some of the major drugs used in the treatment of HIV infection. However, this book does not include in-depth discussion of specific antiretroviral treatments and strategies, since these change rapidly and the information would soon become obsolete.

If you read the "Prologue: To People with HIV Infection and to Their Caregivers," be aware that it is a speech given ten years ago about one person's experience with AIDS. Readers new to this area could be confused if they miss the date in the fine print.

The Guide to Living with HIV Infection, 4th Edition is available in bookstores for $15.95 (paperback), or can be ordered directly from Johns Hopkins University Press by calling 800-537-5487, Monday through Friday 8:30 a.m. to 5:00 p.m.



Medical Marijuana: Largest Provider Closed, Some Alternatives Available

by John S. James


San Francisco's largest medical marijuana buyers' club, the Cannabis Healing Center, was shut down on May 25 due to a court order obtained by state Attorney General Dan Lungren -- creating an emergency for thousands of persons with serious illnesses who were obtaining marijuana from the Center and are unable to get relief from any other treatment.

City officials are exploring ways to help patients obtain marijuana legally when it is medically recommended by their physicians. Meanwhile, three smaller buyers' clubs remain open in San Francisco, and there are others elsewhere in the state -- although these will not be able to meet the needs of everyone, due to limited staff and the intensive checking of documentation required.

The three in San Francisco differ in their documentation requirements and their services:

  • ACT UP/San Francisco, 864-6686, may accept an identification card from the Cannabis Healing Center or Flower Therapy (another medical marijuana group forced to close in San Francisco). Otherwise it requires a letter of diagnosis and a state identification (such as a driver's license).

  • C.H.A.M.P. (Cannabis Helping Alleviate Medical Problems), 861-1040, is the only remaining center in San Francisco that offers a space where patients can socialize with each other and smoke cannabis there if they wish. C.H.A.M.P. requires a physician's letter written within the last 30 days which states the illness diagnosed and which either recommends or approves cannabis for the illness, and states that the physician will continue to monitor the patient; a form letter is available from C.H.A.M.P. Identification can be a current California drivers license or ID, passport, or SSI letter.

  • Market Street Club, 861-1864, requires a photo identification by a state or Federal agency -- for example, a drivers license, passport, or military ID; it also requires a letter of diagnosis, and letter of recommendation, by a medical doctor. A patient can bring the same letters they used at clubs that have closed, even if on the other club's stationery. Documentation must be the original (not a photocopy); the club will make copies for its records and return the originals.

  • Also nearby is the Oakland Cannabis Buyers' Cooperative, 510-832-5346. It requires a physician's letter of recommendation (within the last six months) that can be verified, and a current identification.

On June 1 the San Francisco Board of Supervisors passed a resolution urging the city attorney, with the district attorney, to draft legislation for emergency distribution of medical marijuana. The goal is to develop a system that will have the best possible chance to withstand legal challenge, and especially to minimize legal liability of city employees. Even if everything goes well, it will probably take two months or more for any new system to be set up.


Comment

San Francisco health, law enforcement, and other departments have been working for months on guidelines for medical marijuana, consistent with California Proposition 215 (see text below). Proposition 215 does not override Federal laws against marijuana, but in practice Federal authorities usually leave marijuana enforcement to state or local jurisdictions, unless large quantities are involved.

We hope that official guidelines or supervised distribution systems will make provisions for patients and their caregivers to grow their own marijuana if they choose, as they are allowed to do under Proposition 215 -- including growing collectively in a community garden for those unable to do so at home. Then the price could be reduced to about the cost of garden tools and fertilizer. This is important because many patients are already under severe financial pressure because of their illness.

Also, there is an urgent need for organizations which will consistently help patients to tell their personal stories -- for example, providing professional video feed to national news media, and referring reporters to patients willing to be interviewed.


Election Note

California Attorney General Lungren's closure of the Cannabis Healing Center also shut the campaign office of Dennis Peron, who had founded the previous Cannabis Buyers' Club at that site and was running for governor against Lungren in the Republican primary on June 2. Peron's staff was later given a few hours to remove their campaign equipment and materials. Many phone calls in the critical get-out-the-vote week before the election were unable to get through.



Medical Marijuana Distribution Summit, Sacramento: Video Available


On May 26 we attended the Medical Marijuana Distribution Summit, a three-hour hearing by the California Senate Committee on Public Safety, chaired by Senator John Vasconcellos. Over a dozen doctors, law enforcement officials, political representatives, activists, and other experts were invited to speak, and anyone could sign up for public comment. A videotape of the meeting, available at low cost, provides an excellent background on many of the issues today.

Unfortunately the Federal government refused to participate, citing ongoing litigation. California Attorney General Dan Lungren did send a representative.

It is impossible to summarize such a meeting, but here are a few things we learned:

  • There are many different kinds of medical marijuana clubs. For example, some establish a cooperative garden so that the cannabis is provided for the nominal cost of tools and supplies -- and do not make the patient wait the months required for their plants to mature.

  • Models with local government involvement include the cities of Arcata and West Hollywood. In both cities, cannabis is grown openly for patients, avoiding the need to obtain an underground supply.

  • The county of San Mateo is exploring the possibility of a clinical trial of medical marijuana -- which could be permitted under Federal law, since the drug would be used for research.

  • In some rural areas of California, most of the interest in cannabis is not from persons with HIV, but from patients in wheelchairs who have severe, chronic pain and have not found satisfactory relief with other treatments. They frequently talk about suicide, and sometimes do kill themselves. [The main problem here may be improper pain treatment with approved prescription drugs. Experts agree and have said for decades that severe pain is greatly undertreated. This situation persists, in large part because doctors are afraid that they may be targeted by law enforcement if they prescribe more pain medication. Undertreatment of pain could be worse in rural areas where physicians may be less able to put together a legal defense if necessary.]

  • There is strong opposition against allowing patients to use marijuana at a site were it is dispensed; they must take it away and use it elsewhere, like other medicine purchased at a pharmacy. [This is unfortunate since social isolation is a major problem for patients with chronic illness and severe pain, and the social outlet has been important where it has been tried. Many people were offended by the "party atmosphere" at Peron's clubs; we would urge that seriously ill patients be permitted to choose the atmosphere that works best for them. But most cannabis clubs have had to accept the pharmacy-only model in order to have any chance of being allowed to operate at all.]

  • In most of California, Proposition 215 has not been allowed to work, and patients are still arrested for legitimate medical use. Some rural counties are so poor that county workers may not get their paychecks; the funding they do have available is from Federal marijuana-eradication projects. This dependence complicates efforts to discuss medical use with law enforcement, and sometimes even in local newspapers.

  • "California now has 20 times as many marijuana prisoners as in 1980," according to Dale Gieringer of California NORML (http://www.norml.org/canorml, or 415-563-5858). Persons using cannabis for medical purposes do get caught up in this massive arrest and imprisonment.

  • It is widely agreed that Federal cooperation is necessary for finding a workable solution on medical marijuana. But with both Democrats and Republicans using the war on drugs as a political football, Washington has no interest in a solution at this time.


For a Videotape of the Summit

To obtain a videotape of the Medical Marijuana Distribution Summit, send a request to:

attn: Claudia
Senate Rules Committee
1020 N. St., Room 585
Sacramento, CA 95814

Ask for the three-tape set for the "Medical Marijuana Distribution Summit, Senate Committee on Public Safety, May 26, 1998," and enclose a check for $18. Most orders are filled within a few days. If you have questions, call Televising the Senate, 916-445-4913.


Appendix: Text of Proposition 215

The following proposition was approved by California voters in November 1996. Previous legislation to prevent prosecution of patients had been passed by the state legislature but repeatedly vetoed by Governor Pete Wilson, in 1994 and 1995. The governor cannot veto a proposition passed by the voters.



SECTION 1. Section 11362.5 is added to the Health and Safety Code, to read:

11362.5. (a) This section shall be known and may be cited as the Compassionate Use Act of 1996.

(b)(1) The people of the State of California hereby find and declare that the purposes of the Compassionate Use Act of 1996 are as follows:

(A) To ensure that seriously ill Californians have the right to obtain and use marijuana for medical purposes where that medical use is deemed appropriate and has been recommended by a physician who has determined that the person's health would benefit from the use of marijuana in the treatment of cancer, anorexia, AIDS, chronic pain, spasticity, glaucoma, arthritis, migraine, or any other illness for which marijuana provides relief.

(B) To ensure that patients and their primary caregivers who obtain and use marijuana for medical purposes upon the recommendation of a physician are not subject to criminal prosecution or sanction.

(C) To encourage the federal and state governments to implement a plan to provide for the safe and affordable distribution of marijuana to all patients in medical need of marijuana.

(2) Nothing in this section shall be construed to supersede legislation prohibiting persons from engaging in conduct that endangers others, nor to condone the diversion of marijuana for nonmedical purposes.

(c) Notwithstanding any other provision of law, no physician in this state shall be punished, or denied any right or privilege, for having recommended marijuana to a patient for medical purposes.

(d) Section 11357, relating to the possession of marijuana, and Section 11358, relating to the cultivation of marijuana, shall not apply to a patient, or to a patient's primary caregiver, who possesses or cultivates marijuana for the personal medical purposes of the patient upon the written or oral recommendation or approval of a physician.

(e) For the purposes of this section, "primary caregiver" means the individual designated by the person exempted under this section who has consistently assumed responsibility for the housing, health, or safety of that person.

SEC. 2. If any provision of this measure or the application thereof to any person or circumstance is held invalid, that invalidity shall not affect other provisions or applications of the measure that can be given effect without the invalid provision or application, and to this end the provisions of this measure are severable.





Efavirenz (Sustiva™, DMP 266) and Saquinavir (Fortovase®) Combination: Pharmacologic Interaction


Anyone taking both efavirenz and saquinavir should know that the combination can reduce the plasma level of saquinavir by about 60% -- which will likely result in underdosing of the protease inhibitor. DuPont Merck (soon to be called DuPont Pharmaceuticals), the maker of efavirenz, "strongly urges patients taking Sustiva with Fortovase to talk to their physicians about changing their regimens."

Currently efavirenz is not marketed but is available through clinical trials or through an expanded access program. The company has sent detailed information to physicians in those programs.



If You Are Exposed to HIV: Guidelines Published for Postexposure Prevention


On May 15, 1998 the U.S. Centers for Disease Control and Prevention (CDC) published guidelines for preventive treatment of healthcare workers accidentally exposed to HIV (for example, by being stuck with a contaminated needle). While these official guidelines do not discuss persons exposed through sex or sharing needles, many experts agree that the situations are similar and the same preventive treatment should be used.

The new guidelines call for four weeks of treatment, with either two drugs (AZT plus 3TC) or three drugs (AZT plus 3TC, plus either indinavir or nelfinavir). Whether to use two drugs or three -- or no treatment at all -- depends on the seriousness of the exposure. The guidelines include a procedure for deciding what prophylaxis is needed.

Treatment to prevent infection must be started as soon as possible, preferably within a few hours of exposure, certainly before 24-36 hours, since animal studies suggest that later treatment might not prevent infection When starting drugs immediately is not possible, the guidelines still recommend a later start in some situations, since very early treatment of HIV may be beneficial, even if it is too late to prevent the infection.

For advice in managing postexposure prophylaxis, clinicians should consult local HIV experts, or call the National Clinicians' Postexposure Hotline, 888-448-4911.


References

"Public Health Service Guidelines for the Management of Health-Care Worker Exposures to HIV and Recommendations for Postexposure Prophylaxis." MMWR Recommendations and Reports, May 15, 1998; volume 47, number RR-7, pages 1-33. This publication is available at http://www.cdc.gov/epo/mmwr/mmwr_rr.html; or single copies may be obtained from the Centers for Disease Control and Prevention, National AIDS Clearinghouse, P.O. Box 6003, Rockville, MD 20850, telephone 800-458-5231. It is also available by faxback; have the phone number of a fax machine handy, and then call 800-458-5231 and select the faxback option, which is available 24 hours a day. You can ask for a catalog of dozens of different documents, or get the postexposure prophylaxis recommendations by ordering document #3003.

Also see discussion of postexposure prophylaxis on various AIDS Web sites, including the Center for AIDS Prevention Studies or the Stop AIDS Project.

San Francisco has a post-exposure prevention (PEP) study, which runs a 24-hour information line at 415-502-5PEP.



Medical Marijuana Study in San Francisco: Pays $1000, 25 Days in Hospital


An important medical marijuana study now recruiting will pay $1000 to volunteers who meet the entry criteria and successfully complete the trial. The main drawback is that you must spend 25 days in a research ward at San Francisco General Hospital -- without leaving during that time, and without receiving visitors (due to Federal rules for studying marijuana). You can make unlimited phone calls, have access to a TV and VCR, use the Web, and bring books and a laptop computer.

Volunteers will be randomly assigned to either smoke marijuana cigarettes (4% THC) three times a day, take dronabinol (Marinol) capsules (2.5 mg) three times a day, or take placebo capsules. There is a one-third chance of being assigned to each group.

"Our main goal is to find out what is safe for HIV/AIDS patients," said principal investigator Donald Abrams, M.D., professor of medicine at the University of California San Francisco (UCSF), who has fought for years to get Federal permission to study marijuana. "We know many patients use marijuana to relieve nausea and loss of appetite brought on by the disease and its treatments, but we don't know how THC -- the active ingredient in marijuana -- interacts with HIV drug therapies. For example, protease inhibitors like indinavir and nelfinavir are metabolized by the liver, as is THC. We want to see if THC alters the metabolism of protease inhibitors and therefore changes the concentration of the drug in the blood, either creating a level that is too high, producing toxicities, or is too low, rendering the protease inhibitor ineffective." The study will also look for any effect of marijuana on viral load, the immune system, testosterone levels, appetite, energy intake, resting energy expenditure, body composition, and body weight.

This study is funded by a grant from the U.S. National Institutes of Health. Besides Dr. Abrams, other researchers are: Morris Schambelan, M.D., UCSF professor of medicine; Kathleen Mulligan, Ph.D., UCSF assistant professor of medicine; Neal Benowitz, M.D., UCSF professor of medicine and pharmacology; Francesca Aweeka, Pharm.D., UCSF clinical pharmacist; Joseph M. McCune, M.D., Ph.D., UCSF associate professor of medicine; Joan Hilton, Sc.D., M.P.H., UCSF assistant professor of biostatistics/epidemiology; Tarek Elbeik, Ph.D., UCSF assistant researcher/medicine; Roz Leiser, R.N., Community Consortium study coordinator; and Thomas Mitchell, M.P.H., Community Consortium program director.

To be eligible, you must:

  • Be HIV-positive and taking either indinavir or nelfinavir and no additional protease inhibitors (other antiretrovirals are OK);

  • Have a stable viral load and have been on stable antiviral medicines for at least eight weeks;

  • Have used marijuana previously (at least six times in your life);

  • Be willing to not use marijuana for up to three months;

  • Not have active opportunistic infections or malignancies requiring acute treatment;

  • Not have had unintentional weight loss of greater than 10% in the last six months;

  • Not be a tobacco smoker (currently or within the last 30 days), be dependent on any recreational drugs, be on methadone maintenance;

  • Not be pregnant;

  • Meet certain other medical conditions.

For more information about volunteering for this trial, call the Community Consortium THC Study at 415-502-5705.



Acetylcarnitine and Neuropathy: Call for Information


Over a year ago we published a call for information about acetylcarnitine -- a substance available from health-food stores, and also in clinical trials as a possible treatment for diabetic neuropathy (AIDS Treatment News #267, March 21, 1997). At that time there was very little experience to report, since interest in the HIV community was so new. We did not hear from anyone who believed that acetylcarnitine either did or did not work for them.

We would appreciate hearing from persons with HIV who have used acetylcarnitine for any purpose, either with or without success; this information may be useful in helping to design a clinical trial. Contact John S. James, AIDS Treatment News, 415-255-6259, or jjames@aidsnews.org.



Prison or Discharge Treatment Programs: Funding Available, Proposals Due June 29


Glaxo Welcome has issued a nationwide request for proposals "to fund innovative programs in which incarcerated persons with HIV are linked to treatment programs while in prison or upon discharge." Grant sizes are expected to range from $10,000 to $50,000. These grants can be for new or existing/ongoing projects, in any geographic location in the U.S.

Proposals are due June 29; however, the application process is much simpler than for most grants. The application requires only a three to five page letter (including a description of the project and a description of the organization), with a copy of the organization's 501(c)(3) letter of determination attached.

For a copy of the request for proposals, contact Health Care Coalitions, Glaxo Wellcome, Inc., 919-483-8584.



Correction: Hepatitis C Trial


Our last issue announced a trial of the combination of ribavirin plus alpha interferon for treating hepatitis C in persons co-infected with HIV. It should have described this trial as "the first study of [ribavirin plus interferon for] treating hepatitis C in persons who also have HIV." Due to our error, the words in brackets were omitted.



Email Experts; Librarians: AIDS Treatment News Seeks Expert Advice

by John S. James


We are looking for experts in two different areas who could volunteer to give us some technical pointers -- probably through a few phone calls or email exchanges.

(1) Email compatibility. We are quite familiar with email, and know how to send text-only messages with a short line length so that everybody can receive them correctly. But most people do not send email that way. At the upcoming 12th World AIDS Conference in Geneva (June 28 to July 3) and elsewhere, we will need to provide practical advice on dealing with issues like: different line lengths, software packages, file formats, and relevant standards which are in common use around the world; international alphabets; how to assemble a useful set of file translators (including non-proprietary ones) to read attached files produced by various applications and emailed to lists with no regard to how the recipients' software will read them; under what circumstances are email messages likely to be lost; and other problems such as spam, censorship by governments, maintaining confidentiality, and service providers which charge for each message received.

Also, as a future project, we want to investigate the possibility of reporting about AIDS with a controlled vocabulary, for automatic translation into many different languages.

(2) Library outreach. We need help in developing outreach to get AIDS Treatment News into libraries -- public, university, corporate, and other. We have had no organized marketing to libraries before, and our presence there is poor. We need to know how libraries place orders, what their financial, seasonal, and other constraints are, what listings, catalogs, or Web sites we should appear in, how we should advise library users who want their library to carry AIDS Treatment News, etc.

(3) Database research advice. For over ten years we have used Dialog Information Services (now The Dialog Corporation) for specialized searches; it was expensive but we paid only for what we used. This month Dialog begins charging a minimum bill of $75 per month ($900 per year), so we need to find alternatives. This is a good time to review and update our entire database search strategy.

The information most important to us -- AIDSLINE/MEDLINE, and Web sites and searches -- is already available without charge. We need strategies for occasional specialized searches -- especially for finding available databases, and working with an affordable information broker when necessary.

If you can help us in any of these areas, call or email John S. James, 415-255-6259 or jjames@aidsnews.org.



Prospective Case Series in Clinical Trial Design -- Proposal, and NTZ Example

by John S. James


Recently the drug NTZ was rejected by an FDA advisory committee -- even though it is widely agreed that NTZ appears to be safe and may have value for treating cryptosporidiosis and other intestinal parasites. The rejection happened because the major clinical trial comparing NTZ to placebo in people with cryptosporidiosis had to be canceled recently, since very few patients volunteered. The FDA realized that it would be impossible to run such a trial in the U.S., and allowed UNIMED Pharmaceuticals, the drug's developer, to present what data it had. But this information -- never intended to be the pivotal data for approving the drug -- did not convince the FDA's analysts or the advisory committee that NTZ was or was not effective for treating this disease.

We believe this debacle happened because in modern medical research -- and especially in AIDS -- only one kind of clinical trial is likely to be taken seriously: the randomized controlled trial, in which volunteers are randomly assigned to receive either the drug being studied, or a standard treatment for the illness (or placebo if there is no standard treatment, as with cryptosporidiosis). Certainly this kind of trial has unique advantages, and will continue to be important in medical research.

But what happens when a controlled trial is not feasible? Do we throw up our hands and either refuse to study the drug at all, or try to analyze data which was collected incidentally during medical care, with little or no thought for research? Today there is usually no other choice.

To help stimulate thinking about different kinds of clinical research, we suggest a different kind of trial, a prospective case series -- an organized system of case studies in which the research team does the best it can for each patient, using any available treatments (approved or experimental) and absolutely first class documentation and data collection. The goal would not be statistical proof, but a document in which the physician-researchers tell what they have learned about how to treat the illness effectively, and use the data generated to explain why they have come to believe what they do. The full data itself could also be published, allowing others to suggest different interpretations or conclusions.


Design and Size of Study

A team of physicians and researchers would design the study. They would decide such issues as which patients can enroll, what drugs would be available, what laboratory and other tests could be provided, and how many volunteers could be accepted.

Unlike controlled trials which seek statistical answers, the studies we are suggesting do not have a minimum size which can be calculated mathematically. The number of volunteers might typically be ten to 40 -- but it might be as few as one, or it could depend on the resources available. Patients can be treated and studied as they arrive, and the researchers will not necessarily have to decide in advance on the total number of volunteers.


Entry Criteria

In the case of NTZ, one of the problems with the controlled trial (the one which had to be stopped because it did not recruit) was the time and difficulty of reaching a confirmed diagnosis of cryptosporidiosis. Researchers might avoid this problem by designing clear entry criteria for suspected cryptosporidiosis -- or for diarrhea which is suspected to be caused by unidentified protozoa or bacteria. This approach might be the more practical, since NTZ is probably safe and is one of the broadest spectrum anti-parasite drugs known -- and typically in medical practice, diagnosing exactly which pathogens are causing diarrhea can be difficult or impossible. Instead of waiting for an exact diagnosis, it may be better to treat certain patients empirically for a short time, and discontinue the drug if their symptoms do not improve. (Of course samples would be collected before treatment began, so that changes in microbiology could be recorded, and correlated with changes in symptoms.)


Treatment

The goal of the physicians and researchers running the trial would be to provide the best possible treatment for each volunteer all the time -- using almost anything (of course with the consent of the volunteer, who would have at least one treating physician independent of the trial).

For example, controlled trials typically give a fixed dose of one drug for a predetermined time, then collect statistics on what fraction of patients benefited. In a prospective case series, the researchers would try to control the disease in every volunteer; drug doses could be increased or decreased, as appropriate for that individual. Or the study drug could be combined with other drugs (such as NTZ with azithromycin, which is also broad spectrum, and may have some activity against cryptosporidiosis).

With the volunteer's consent, the researchers might decide to stop treatment early to see if symptoms return, and start treatment again if they do. This kind of rechallenge can greatly increase confidence that the drug is (or is not) active in that particular person.

In some cases the researchers might decide that it was best for a volunteer not to use the study drug at all. The person could still stay in the trial and be monitored, could receive other treatments, and would be included in the analysis.


Data Collection

While the protocol for treatment would be flexible, the protocol for documentation and data collection would be exacting. Such information as laboratory tests, concomitant medications, and rationale for treatment strategies would be recorded at strictly defined times, and with pre-defined procedures for quality control.


Ethical Supervision

How could such a flexible study -- where there is no rigid treatment protocol, and drugs can be changed at any time -- be effectively controlled by an IRB (Institutional Review Board)?

One approach is to have the IRB approve a different kind of protocol which is really an "envelope," defining all the drugs, tests, and treatment strategies which are likely to be used in the trial. In exceptional cases where the researchers want to go outside the envelope, due to new information or to a volunteer's special circumstances, they would need permission either from the full IRB, or from a committee which the IRB had designated for that purpose.

Also, every volunteer should have a treating physician who is unconnected to the research project. This physician would have access to all the information gathered about the patient, and could advise the patient to withhold consent for any treatment or procedure.


Advantages

This kind of trial combines the best available medical care with excellent data collection for research. Here are some advantages:

  • The approach focuses directly on extending the standard of care as a whole -- instead of testing just one drug at a time, due to commercial constraints. It provides a planned, coherent program of many case studies planned in advance and happening at once.

  • Recruitment should not be a problem, since volunteers will be cared for by a team of leading experts who can use all available information and treatments, who can change treatment at any time, and who are always trying for the best treatment for each individual.

  • Total cost should be small since relatively few volunteers are needed. And this kind of study can start quickly without waiting for extensive resources to be assembled, since no minimum number of subjects is needed, and useful information starts being generated with the first one. Also, results from the first few volunteers can provide a database to help justify additional funding or resources if necessary.

  • Results can be released as they are generated. There is no need for secrecy -- unlike conventional controlled trials, where information learned early can threaten later adherence to the treatment protocol. Here it is intended that treatment will change as new information becomes available. The goal is always the best treatment of the individual, using all existing information toward that end.

  • Even if it fails to produce definitive or convincing proof of drug efficacy, a prospective case series can provide highly reliable information about what leading physicians are doing, what problems they face, and some of the results they are seeing -- information which can help in the design of subsequent controlled trials.

  • This approach does not produce statistical proof like controlled trials do. But it may lead to comparable or even better confidence in the conclusions drawn. When a controlled trial reaches the p=.05 statistical significance level which is usually acceptable, there is (by definition) one chance in 20 that a worthless drug will pass as effective. In the design we suggest, well-informed physicians will gain experience with the drug under research conditions -- including seeing how symptoms respond to repeated rechallenge, if appropriate. Although it is impossible to calculate an exact probability, it seems likely that after such a trial, a worthless drug may well have less than a one in 20 chance of being considered effective.

  • Instead of organizing study design around p-values, statistical analysis can focus on broader issues of using available information to assist decision making under uncertainty.

  • Medically, this kind of trial focuses on exactly the issues that treating physicians face. Treatment is contemporaneous, meaning that the strategies being tested are the ones which leading medical experts are using that day. In contrast, conventional controlled trials test strategies which were current when the trial was designed, often several years before. And they test treatment by protocol, which usually differs greatly from medical practice.

We believe these advantages justify serious attention to this kind of trial -- a planned yet very flexible case series which is designed prospectively and run under research conditions. Such studies could be used when controlled trials are not feasible, as with NTZ today. Also, a prospective case series could rapidly provide practical information useful in designing randomized controlled trials which are well focused on provable and clinically relevant questions.



ISSN # 1052-4207

Copyright 1998 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.




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