Subject: AIDS Treatment News #140 Date: Dec 06 1991 (850 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& copyright 1991 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS Issue #140, December 6, 1991 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: [items are separated by "*****" for this display] Endocrine Complications in HIV Progression 3TC Trials Recruiting: NIH, Boston, Vancouver New Lymphoma Immunotoxin Study FDA Reform: White House Proposals ***** Endocrine Complications in HIV Progression by Denny Smith Certain disturbances of the endocrine system may represent a new marker for HIV progression, as well as a treatable cause of some AIDS-related debilities. The endocrine system is a complex of glands and their hormone messengers which regulate the body's metabolism. This system interacts closely with the nervous system; both serve as information pathways, and they share some common mechanisms. The endocrine system maintains everyday internal functions, and is primed as well to deal with external stresses, whether they be traumatic or gradual. Consequently, endocrine activities are involved in any chronic disease process, like HIV infection, as well as episodes of acute illness, such as AIDS-related opportunistic infections. Several recent reports describe how HIV might affect, or be affected by, the endocrine system. Endocrine problems can also be consequences of opportunistic diseases like CMV, PCP, or Kaposi's sarcoma, and of some drugs used in AIDS care, like pentamidine or ketoconazole. The signs of endocrine disorders, depending on which gland is affected, can include fevers, low blood pressure and blood sugar, decreased libido, electrolyte imbalances and prolonged recovery from acute illnesses. Unfortunately, these symptoms are not very specific, and are commonly attributed to a variety of causes. An experienced HIV clinician will be able to identify drug and disease-specific symptoms; then follow questions of whether an endocrine dysfunction can be diagnosed, or corrected. If endocrine imbalances are contributing to symptoms, the results could be significant. For example, one report from Albert Einstein College of Medicine in New York suggested that "failure to thrive" in children with HIV may be due to problems with thyroid regulation. Thyroid problems are commonly treated in non-HIV infected people with thyroid hormone supplements. Example: DHEA At the Sixth International Conference on AIDS in 1990, a phase I study of dehydroepiandrosterone (DHEA) in 13 patients showed some dose-dependent immune function improvement and no toxicities (abstract S. B. 488). A modest increase in T4 cells was seen in the five patients who were given more than 750 mg daily. A more recent report, from the San Francisco Men's Health Study, describes an association between HIV progression and decreased levels of DHEA. This steroidal hormone is derived from cholesterol and contributes to the synthesis of testosterone. We asked the primary author of the new report, Mark Jacobson, M. D., if supplements of DHEA could correct the deficiency or even be directly useful against HIV progression. Dr. Jacobson said this study showed only that low DHEA levels preceded progression to AIDS in HIV-infected men with T4 helper cell counts below 500. He feels that further interpretation is speculative: perhaps low DHEA levels reflect HIV-induced damage to the adrenal glands, and so only represent a marker for HIV progression; or perhaps, before its levels are depleted, DHEA actually does inhibit HIV. Dr. Jacobson is currently looking for more conclusions from another clinical study he conducted in which participants were given DHEA; he does not think there is now a solid basis for people with HIV to spend money and risk side effects trying it on their own. He does think that more intensive studies are warranted, including studies of how DHEA, which is an androgenic hormone, affects women with HIV. DHEA levels are naturally higher in men than in women. Some protective effect on the part of DHEA in HIV infection would not be inconsistent with other activity already connected to this hormone. As Dr. Jacobson's report noted, DHEA has been associated with in vitro inhibition of viral expression, including that of HIV; it is also associated with a decreased risk of cancer and heart disease. His report concludes by noting that DHEA and its sulfate derivative, DHEA-S, have been administered orally in other clinical situations for months or years at doses up to 1600 mg a day, with no serious side effects -- leading to the suggestion that DHEA be investigated as a potential therapy in HIV infection. [Some readers may remember that DHEA provoked a flurry of community excitement almost four years ago as an underground treatment, after AIDS TREATMENT NEWS reported positive news of a DHEA trial in Paris (issue #48, January 15, 1988). Its popularity faded, but DHEA has remained occasionally available through AIDS community buyers' clubs. The work of Dr. Jacobson and his colleagues has resurrected some good questions about DHEA. We hope that the search for answers this time takes less than four years, and does not fail to account for the role of DHEA in women with HIV.] Example: Cortisol Probably the most common endocrine dysfunction documented in HIV infection is insufficient adrenal production of the hormone cortisol. Ordinarily cortisol is one of the most important of the many endocrine secretions, and a number of studies have documented a blunted response to cortisol stimulation in people with HIV. During episodes of acute illness, such as moderate to severe bouts of Pneumocystis pneumonia, corticosteroids are often administered to help the body cope with the extreme stress. As with DHEA, the implications of adrenal insufficiency might seem to extend to all people with HIV, symptomatic or not. Some published reports (see references) lend weight to that idea, others appear to downplay it. Most conclude that while a number of hormones are slightly imbalanced even in early HIV infection, they don't ordinarily present clinical symptoms that warrant replacement therapy. Every researcher or clinician we spoke to said that the whole issue requires more attention, and that it would be premature to begin hormone replacement therapy in HIV infection, except when an opportunistic infection like CMV is causing identifiable symptoms. Interview With Edward Biglieri, M. D. For additional information we interviewed Edward Biglieri, M. D., a Professor of Medicine at San Francisco General Hospital who has long studied adrenal insufficiency. It may help the reader to know that cortisol production, while associated with the adrenal glands, is actually generated by a series of messages which are passed along a circuit from the hypothalamus through the pituitary to the adrenals. DS: So many of the body's systems are well-known to be affected by HIV, now the endocrine system as well? EB: The endocrine system is clearly involved with AIDS, but there is no clear and uniform disturbance that we've identified. Pituitary problems and thyroid abnormalities are common in the general population anyway, so it can be hard to link these conclusively to an HIV infection. The literature gives the impression that it's sporadic at most. We have focused on the adrenal gland because it seems to be implicated in HIV more than the others. We followed adrenal function in over one hundred patients. DS: How would the adrenal glands be expected to function in regard to AIDS? EB: The adrenals release stress hormones during an illness or injury, to help regulate blood pressure, blood sugar, etc. We were first intrigued when we saw certain features in patients on PCP therapy that resembled adrenal insufficiency, such as low blood pressure and elevated potassium levels. Of course, they were also on a drug, pentamidine, that can produce those effects through the kidneys. So we had to ask ourselves, is it the disease, or the therapy, or something else? We monitored people right after an acute illness episode by giving them an ACTH test. ACTH is the normal regulator of cortisol production. We found that 25% of these patients didn't respond normally when given ACTH. Their pituitary was not sending sufficient impulses to the adrenal gland to sustain a normal response. Also, the hypothalamus sends an ACTH releasing factor to tell the pituitary, in turn, to stimulate ACTH and the adrenals. A defect in the pituitary was demonstrated when the releasing factor failed to increase ACTH or the adrenal. DS: Is this a direct result of HIV infection, or something secondary? EB: It seems as though one of manifestations of HIV generally can be this insufficient hormonal production. Perhaps one out of four people with AIDS will experience this insufficiency. When these people are diagnosed with something serious like PCP, we can give them what we call "stress doses" of steroids, to facilitate their response to the primary treatment. DS: Is the pituitary implicated in other endocrine problems in AIDS? EB: I'm not sure there's convincing evidence of that. Sometimes other hormones are low, including testosterone. But I haven't seen studies of these situations involving 100 or more patients like ours. The pituitary obviously could be involved; I haven't seen compelling evidence of it. DS: But it would make physiological sense? EB: Yes; in any event, it appears that 25% of those experiencing AIDS-related illnesses exhibit an adrenal insufficiency. But you don't have the luxury of testing someone for adrenal insufficiency when they are in respiratory distress. So we can presumptively give stress doses of steroids for three or four days. This has helped correct some of the metabolic abnormalities seen at that time. DS: How do the endocrine system and immune system communicate with each other? EB: Actually, they tend to contradict each other. High doses of cortisol can suppress the immune system. So of course we avoid massive, extended doses. We just want to help people over the critical days of an acute illness, even if the immune system is insulted briefly. Also, there is some speculation that HIV-infected cells secrete something like ACTH; perhaps to circumvent any inadequate production by the pituitary. DS: Does adrenal insufficiency become more likely as HIV progresses? EB: You need to watch for the typical clinical signs -- low blood pressure, low blood sugar, high potassium. As with any debility, you have to consider the role of pituitary hormones. DS: Is there a patient group you would particularly recommend testing for adrenal insufficiency? EB: Unless there is some concrete suspicion, I wouldn't do it on asymptomatic patients. It may be a marker in asymptomatics, but even then, there are other markers to follow. DS: So theoretically, if there is HIV involvement of the pituitary or adrenals in someone with no apparent symptoms, then AZT, ddI or ddC could reverse it or stabilize it? EB: Yes, if HIV is the problem. Otherwise, I would wait until some symptoms develop. It's an interesting situation that's still evolving, but it shows the diffuse nature of this virus, and the many different systems affected. The endocrine involvement certainly is secondary, but by correcting an insufficiency you can make someone feel a lot better and even shorten an acute illness. Endocrine System and HIV: Technical Articles Jacobson, MA and others. Decreased Serum Dehydroepiandrosterone Is Associated with an Increased Progression of Human Immunodeficiency Virus Infection in Men with CD4 Cell Counts of 200-499. The Journal of Infectious Diseases, volume 164, pages 864-868, November, 1991. Mollison LC and others. Hypothyroidism due to destruction of the thyroid by Kaposi's sarcoma. Reviews of Infectious Diseases, pages 826-827, September-October, 1991. Spitzer RD and others. Case report: hypothyroidism due to Pneumocystis carinii thyroiditis in a patient with acquired immunodeficiency syndrome. American Journal of Medical Science, volume 302, number 2, pages 98-100, August 1991. Marks JB. Endocrine manifestations of human immunodeficiency virus (HIV) infection. American Journal of Medical Science, volume 302, number 2, pages 110-117, August, 1991. Strauss KW. Endocrine complications of the acquired immunodeficiency syndrome. Archives of Internal Medicine, volume 151, number 7, pages 1441-1444, July, 1991. Schwartz LJ and others. Endocrine function in children with human immunodeficiency virus infection. American Journal Diseases of Children, volume 145, number 3, pages 330-333, March 1991. Raffi, F and others. Endocrine function in 98 HIV-infected patients: a prospective study. AIDS, volume 5, number 6, 1991. Aguilar, X and others. The use of corticosteroids in the control of the adverse effects of cotrimoxazole in AIDS patients suffering from PCP. AIDS correspondence, volume 5, number 6, 1991. Cobbs, R and others. Adrenocortical insufficiency with normal serum cortisol levels and hyporeninaemia in a patient with acquired immunodeficiency syndrome (AIDS). Journal of Internal Medicine case report, pages 179-181, 1991. Poretsky L and others. Endocrinologic and metabolic manifestations of the acquired immunodeficiency syndrome. Mt Sinai Journal of Medicine, volume 57, number 4, pages 236- 241, September 1990. Verges B and others. Anomolies endocriniennes au cours de l'infection par le VIH. Presse Med, 1990 volume 19, number 27 pages 1267-70, July 7-14. Merenich JA and others. Evidence of endocrine involvement early in the course of human immunodeficiency virus infection. Journal of Clinical Endocrinology and Metabolism, volume 70, number 3, pages 563-565, March 1990. Murphy TA and Aron DC. How to approach endocrine complications of AIDS. AIDS Medical Report, volume 2, number 11, pages 117-128, November 1989. Dobs AS and others. Endocrine disorders in men infected with human immunodeficiency virus. American Journal of Medicine, volume 84, number 3, pt 2, pages 611-616, March 1988. Membreno L and others. Adrenocortical function in acquired immunodeficiency syndrome. Journal of Clinical Endocrinology and Metabolism, volume 65, number 3, pages 482-487, September 1987. ***** 3TC Trials Recruiting: NIH, Boston, Vancouver by John S. James 3TC, a new anti-HIV drug being developed by Glaxo Inc., is now in a phase I/II trial at three North American sites: the U. S. National Cancer Institute near Washington, D. C., Boston City Hospital, and St. Paul's Hospital in Vancouver, British Columbia; a different trial is also underway in Paris, London, and Amsterdam. The drug is a nucleoside analog (in the same class as AZT, ddC, or ddI); laboratory studies suggest that it may be less toxic than these drugs. The North American trial is open to volunteers with advanced ARC or AIDS. Six different dose levels will be tested, from 0.25 mg/kg twice daily to 6.0 mg/kg twice daily, with ten to 15 volunteers in the trial at each level. The lowest dose is already fully enrolled. The trial will last for six months, and there are provisions for continuing the drug beyond that time if it appears to be safe and effective. All doses are given orally, with volunteers remaining for 12 hours after the first dose (this is the only hospitalization required), and returning to the clinic for later tests -- monthly after the first two months, more frequently before that. Volunteers must have T-helper counts of 300 or less, and be off antiretrovirals (AZT, ddC, ddI) for at least 21 days before the first T-cell test. There are also other entry criteria, including the usual laboratory tests for hematological, liver, and kidney function, and exclusions for certain conditions (such as ongoing treatment for most infections, or Kaposi's sarcoma which is likely to require treatment in the next three months), and exclusion for certain concurrent drugs treatments. For more detailed information about this trial, including names and phone numbers of contact persons at the three North American sites, call the AIDS Clinical Trials Information Service, 800/TRIALS-A. Comment There is more interest now than a few months ago in new nucleoside analog drugs, since the non-nucleoside reverse- transcriptase inhibitors which had been expected to replace them (such as the Merck "L-drugs" and Boehringer Ingelheim's BI-RG- 587) have encountered major problems with rapid development of viral resistance. We have not seen any data on 3TC, but there seems to be significant enthusiasm for it. Glaxo is one of the world's largest pharmaceutical companies (although not well known to the public in the U. S.); it has the resources and ability to develop the drug rapidly. ***** New Lymphoma Immunotoxin Study by Michelle Roland A small study testing a new kind of lymphoma treatment will be opening soon at San Francisco General Hospital. People who have failed standard radiation or chemotherapy will be eligible for the trial. The specific agent being studied is one of a group of compounds called "immunotoxins." Immunotoxin molecules consist of two parts: a specific antibody which targets the molecule to a certain kind of cell, and a toxin which kills the cell. The drug being studied in San Francisco is called "ricin-A chain conjugated anti-CD22." It was designed to bind to the CD-22 marker found on many of the B-cell lymphomas seen in people with AIDS, allowing the toxin (ricin-A chain) to enter and kill the cells. This immunotoxin approach has been studied in HIV-negative people with lymphomas which have been unsuccessfully treated with the standard medical approaches of chemotherapy and radiation. It appears to be a promising concept which will eventually be used in combination with other immunotoxins and chemotherapy drugs. It is extremely important that new and creative approaches are pursued in developing treatments for lymphoma, as those which are currently available have both limited effectiveness and substantial side effects. The study at San Francisco General Hospital will include approximately 25 patients who have not responded to, or have relapsed after, standard therapy. Biopsies will be required to make sure that enough of the lymphoma cells have CD22 receptors on them to make it likely that the immunotoxin will be effective. The side effects of this therapy, as seen in studies in HIV- negative volunteers, appear to be limited. The most common side effects seen so far include muscle aches, reversible weight gain, and accumulation of fluid in the tissues (edema). When edema occurs in the lungs it can be very serious; in past studies people have died from pulmonary edema. Therefore, people with lymphomas involving the lungs will not be allowed to participate in this study. Volunteers will be excluded if, in addition to lymphoma, they also have certain active opportunistic infections which require treatment, or are using the growth factors G-CSF or GM- CSF. If an opportunistic infection develops while on the study, the study medication will be stopped until the infection is treated. Maintenance or preventive treatment for MAC, cryptococcal meningitis, and tuberculosis are allowed. The study has two components. First, a dose escalation phase will find the maximum tolerated amount of the drug. This will be done by starting with a very small dose in three people, and increasing the dose in subsequent groups of three. The maximum tolerated dose will be used in the next phase, which will include about thirteen additional people, to evaluate the effectiveness of the treatment. The drug will be given by IV infusion four times over a period of eight days. The study requires eight to nine days of hospitalization in the clinical research center at San Francisco General Hospital. The cost of hospitalization, the drug, and all tests directly associated with the study will be covered. However, costs of exams and tests associated with the standard care of a person with AIDS-associated lymphoma will be billed to the participant's insurance company, MediCal, or other third party payer. According to Lawrence Kaplan, M. D., the principal investigator of this study, billing for the costs of standard care of a person with lymphoma within the context of a clinical trial has not presented a problem at San Francisco General Hospital in the past. For more information about this study, Dr. Kaplan can be reached at 415/476-4082, extension 84190. Another Lymphoma Study: Sites Throughout U. S. People with lymphoma should also be aware of another large, multi-center study called ACTG 142, which is testing a more conventional treatment approach. ACTG 142 is comparing high- dose versus low-dose chemotherapy, in combination with the growth factor GM-CSF, to determine if high-dose chemotherapy will be more effective than a more conservative low-dose regimen. This study is enrolling patients at 22 sites around the country. ACTG 142 is typical of most of the studies available today which involve the use of varying doses and combinations of chemotherapy, radiation, and growth factors. Often they do not offer drugs which are not available through a clinic or doctor's office; therefore, private physicians may not refer their patients to these studies. While a major incentive for participating in clinical research is often the opportunity to try experimental therapies which are otherwise unavailable, it is also important to systematically collect information about less exciting, but often important, treatment questions. For example, all of the drugs in ACTG 142 (or very similar ones) are available through clinics and private physicians. But the only way to reliably learn how well different regimens work is to collect data in a consistent and coordinated manner through a clinical trial. ACTG 142 is enrolling volunteers very slowly. It is mentioned it here because there are two very important components to AIDS lymphoma-related research. The more exciting, and potentially much more useful, is to develop completely new approaches to lymphoma treatment. The immunotoxin therapies are one such novel approach which should be pursued actively and quickly. Treatment advocates should be aware of the development of these compounds so that, if they are shown to be safe and somewhat effective as single agents, they can be pushed as quickly as possible into combination trials. The second (less exciting) research direction seeks to help people with AIDS-related lymphomas and their physicians define the best way to use the drugs which are available to us today. This will happen only if doctors and patients participate in trials like ACTG 142, and if these trials are designed to be attractive to potential participants. For more information about this and other AIDS-lymphoma trials, excluding the immunotoxin study described in this article, call 800/TRIALS-A. ***** FDA Reform: White House Proposals by John S. James On November 13 the Council on Competitiveness, chaired by Vice President Dan Quayle, announced a major package of proposed reforms designed to make new-drug development and approval more efficient. The ideas themselves are not new; they are largely based on the "Lasagna Committee" report, which had been well received in the AIDS community but then largely ignored (Final Report of the National Committee to Review Current Procedures for Approval of New Drugs for Cancer and AIDS, issued August 15, 1990). But the new proposal goes further in also addressing treatments for non- life-threatening conditions. What is new is that the White House is now putting its weight behind implementing some of the reforms -- which is the good news, and especially welcome since the AIDS community has long been asking for White House leadership in fighting the epidemic. The bad news is that the new proposals have become involved in a major non-medical controversy -- an ongoing bitter dispute involving charges of political abuse of the regulatory process, and questions of the relationship between the legislative and executive branches of government. Most of the Competitiveness Council proposals appear to be largely noncontroversial. But on some there will be different perspectives even within the AIDS community. We should accept different views as legitimate. [Note: This article does not address the political background of this dispute -- such as the controversies involving the Council on Competitiveness, secret influence on the regulatory process, and political use of implementing regulations to nullify the intent of Congress. To cover these areas well would take us too far afield from the central focus on this newsletter. But we should be aware that these issues exist, because they color most of what is happening in the debate about FDA reform.] The Council on Competitiveness Proposals A ten-page fact sheet released on November 13 lists eleven specific reforms: #1: Allow outside organizations to review certain new-drug applications, subject to FDA approval; #2: Expand use of advisory committees, using them earlier than now in the drug-development process; #3: Allow phase I trials to be approved by institutional review boards (IRBs), without necessarily having FDA review; #4: Flexible interpretation of the efficacy standard. "FDA will make a deliberate effort to interpret the statutory requirement of efficacy in a manner that maximizes rather than limits a drug's potential for approval and takes into account the risks to human life and health that may result from delay of new treatments;" #5: Accelerate development and approval of drugs which either (a) treat life-threatening, very serious, or seriously debilitating conditions (examples given are cancer, HIV disease, and cystic fibrosis), or (b) treat any condition which lacks satisfactory alternative therapy -- provided that "the drug's effectiveness can be measured by appropriate surrogate endpoints or other appropriate indicators of effectiveness." #6: U. S. recognition of foreign approvals. "The Administration and the FDA will place high priority on achieving harmonization with other industrial countries that will enable the U. S. to recognize foreign approvals of drugs, in order too provide American patients with faster access to a broader variety of important therapies." #7: Enhance computerization of new drug reviews. #8: Classify all new-drug applications as either "routine" or "expedited," and review applications within each category in the order received. (This would replace the current system of six priority levels based on potential therapeutic benefit.) #9: Use internal management systems to monitor the progress of each application submitted, and to reduce the use of clinical holds on investigational new drug (IND) applications. #10: Reduce product liability costs by Congressional passage of S. 640, which protects drug companies from punitive damage when their product has FDA approval. (They would still be liable for actual damages, despite FDA approval.) #11: Increase FDA staff and resources for new-drug review, (a) by directing all new expanded staff to drug approval until goals there are met, and (b) by "a concerted, one-time industry effort to pay for computerization for FDA through the use of the government's gift authority." The Controversy A November 13 letter to FDA Commissioner David Kessler from three members of Congress, all leading Democrats -- Edward M. Kennedy, Chairman, Senate Committee on Labor and Human Resources, John D. Dingell, Chairman, House Committee on Energy and Commerce, and Henry A. Waxman, Chairman, House Subcommittee on Health and the Environment -- strongly supported efforts to speed drugs for life-threatening conditions, but found serious problems in three of the eleven Council on Competitiveness proposals. Because of the importance of this issue, and the difficulty of summarizing the complex arguments briefly, we quote the letter in full: "We have reviewed a summary of the report on the drug approval process issued today by the Vice President's Council on Competitiveness, and we are writing to express our serious concerns. "We strongly support steps to expedite the approval of drugs for AIDS, and other life-threatening diseases and serious conditions. To the extent that the Council recommends expediting decisions on the approvals of these drugs while preserving the statutory requirement that there be substantial evidence of a drug's safety and efficacy, we would enthusiastically support those recommendations. "Three proposals, however, raise particularly troubling questions. They are the proposals: (1) to allow private contractors to review the safety and efficacy of drugs proposed for FDA approval; (2) to move toward permitting the United States to accept foreign government approvals of drugs; and (3) to use private review boards in place of the FDA to evaluate animal studies before allowing an experimental drug to be used in the first stage of human testing. "In our view, under these proposals, the FDA appears to be abdicating its statutory responsibility to make key decisions on the safety and efficacy of drugs. These proposals appear to be directed largely toward the development of drugs that are not designed to treat life- threatening diseases or other serious conditions. Unfortunately, they do not adequately account for the fact that the use of any prescription drug entails a risk of life-threatening adverse reactions. These risks will be compounded if decisions about safety and efficacy are delegated to private contractors or foreign governments. "Respected experts are concerned that the proposals to use private contractors, foreign governments, and private review boards to make critical decisions currently made by the FDA are thinly veiled efforts to weaken the agency and would undermine the very purpose for which it was created and that it is uniquely qualified to fulfill -- the protection of the American public from unsafe and ineffective drugs. We are concerned, at a minimum, that the proposals will lead to inconsistent and uncertain standards for review and could permit commercial interests to override the objectivity that is essential in evaluating drugs. "The proposals are particularly troubling in light of the Administration's historic refusal to request adequate funding for the FDA. In our view, the Administration should seek greater resources for the FDA rather than attempting to supplant it with less credible alternatives. "We intend to make a thorough review and evaluation of the proposals as expeditiously as possible. While we are undertaking that evaluation, we respectfully request that you not take any action to implement the three recommendations that we have identified as being of particular concern. "We look forward to receiving your prompt response to our request." Comment Here is our understanding of the issues behind the three points of controversy. More analysis, discussion, and debate is appropriate, but should not delay implementation of at least the noncontroversial parts of the proposals. The most controversial recommendation seems to be #1, allowing the FDA to contract with private organizations to review certain new-drug applications. The reason for this proposal seems to be that due to government red tape, as well as salary scale, the FDA cannot hire enough physician/scientists to review the drug applications it receives. The major concern seems to be that allowing companies to contract with private organizations "to review their clinical data for a fee," as is proposed, could open a Pandora's box of potential abuses -- especially since these review companies would know that they would inevitably be judged by their clients (pharmaceutical companies) on their history of positive vs. negative reviews. It may be fortunate that this most controversial recommendation may not be a major issue for persons with life- threatening diseases. For technical reasons, outside review would probably not be used for the most important drugs. What matters most is making sure that critical drugs do get evaluated quickly. Just how this work gets done may not be our issue. Proposal #6, U. S. recognition of foreign approvals, is important because a number of critical drugs have been in widespread use abroad long before they were generally available in the U. S.; notable examples have included fluconazole, clarithromycin, and azithromycin. In addition, we are all affected by the cost of medical care, and duplication of expensive testing certainly adds to this cost. This proposal calls for negotiating with selected countries to develop common standards for clinical trials, a common format for submission of drug-approval applications, common requirements for animal testing, and common manufacturing and inspection standards, as well as for country-by-country agreements to accept each other's drug approvals. The objection seems to arise because the United States has had the world's most meticulous standards for drug approvals; therefore, accepting others' approvals would seem to imply lowering standards. And yet it is widely recognized that the U. S. approval system has become too expensive and cumbersome; also, the world is rapidly moving toward more international commerce. In negotiation of international drug-approval standards, the U. S. will have much leverage to insist on high standards when they are supported by evidence -- and it can, of course, reject any proposed agreement not to its satisfaction. Pilot Studies: The Need for Change Proposal #3, to allow institutional review boards to approve most phase I trials, may ultimately be the most important of the eleven proposals. But the case against it is strong, and unfortunately the case for it has not been well stated by the Competitiveness Council. The text of the recommendation is: "Reform No 3 -- Expanded Role for Institutional Review Boards "FDA will immediately permit sponsors of new drugs to submit their applications for Investigational New Drugs (INDs) involving Phase I studies of patients for commercial drugs and all INDs for non-commercial drugs to the appropriate Institutional Review Board (IRB) for approval and will not require additional agency review. "IRBs currently provide valuable assistance to investigators in the design and review of clinical studies, particularly in regard to ethical issues and informed consent. "Pursuant to this reform the FDA will rely upon the IRB's expertise to allow sponsors to begin research in human subjects. At present, both FDA and the IRB must review such Investigational New Drugs (INDs). "The expanded role for the IRBs will enable FDA to be less involved in the early stages of clinical research where a significant number of drug studies are discontinued. As a result FDA can focus its resources only on drugs that survive the early stages of investigation and appear to have potential as new therapies for human treatment. This reform will promote creativity in clinical research by eliminating regulatory constraints in the early phases of investigation." Incidentally, this writer spoke recently with a researcher from Australia, which allows such IRB approval for phase I studies of drugs which are already approved for human use elsewhere, without additional review by their equivalent of the FDA. He told us that many IRBs were reluctant to get involved, since they were not experienced in evaluating the pharmacology and toxicology data on drugs. One had recently solved the problem by hiring a toxicologist to evaluate that information; the toxicologist wrote a letter to the IRB saying that he found no problem with the proposed trial. It is easy to argue against this proposal. The FDA is far better qualified to evaluate early drug data and clinical-trial plans than IRBs, which are not set up for this purpose but rather an as ethical check, for protecting the volunteers in the trial. We suspect that pharmaceutical companies interested in getting their drugs approved would in almost all cases choose to go through the FDA, since otherwise their data would be unlikely to meet all of the FDA's standards and the company would be sent back to do the trial over again. In fact, a company with an important drug should consider meeting with the FDA even before its application for an IND (permission to test the drug in humans) is completed. The argument that letting IRBs approve phase I trials would save time for the FDA was not thought through -- especially since human lives can be at risk in these trials. But the proposal is vitally important in allowing trials by smaller research groups without pharmaceutical support -- such as community-based organizations or university medical centers. Often these early trials would not be intended as a direct step toward drug approval, but rather to bring an important treatment possibility to the attention of the research mainstream. Again and again we have seen promising AIDS treatments delayed for years before they get to the first human trials, because the cost of getting an IND, even for drugs already in common use abroad, is prohibitive for community-based or university organizations; required animal studies alone can cost hundreds of thousands of dollars. When a drug has no human data (from tests with the disease in question), it usually takes it several years to generate enough interest among corporate financial officials to meet the high hurdles now in place -- hurdles which make sense for routine, non- emergency drug development. If community organizations could legally do the first small pilot studies, then any drugs showing good indications of efficacy could move into mainstream research much more quickly. At present, such pilot studies must be done underground or not at all, and it is hard to fund underground studies and to get reliable and credible data from them. Unlocking the research system to avoid shutting out community, physician, and university research organizations would also be important for pilot studies of drug combinations. Combination studies are notoriously difficult to negotiate when the drugs come from different companies, as is usually the case. It could be argued that the right way to solve this problem is to get the national will to deal with AIDS as a major emergency -- instead of lowering the hurdles so that those who are interested can generate research by themselves, without serious mainstream support. But there is little sign of such national seriousness after ten years of the epidemic. We cannot wait indefinitely for it, but must pursue other promising approaches -- including opening up the research process to the creativity of smaller organizations. And even aside from AIDS, our medical-research system is very poor at mobilizing the critically important early exploratory followup of practical opportunities (for potentially lifesaving treatment advances) as they present themselves. It usually takes years for even a completely sound idea to mobilize the commercial or professional momentum required to reach even a small pilot human trial. Those who do understand a new idea and are committed to it could carry it to credibility years ahead of today's system, which usually blocks all but well-financed corporate sponsors. Expeditious testing could greatly speed the most important practical medical advances, to the immense benefit of the public. [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display