Subject: FDA Drug Approval Reform, AIDS Drug Testing Date: Aug 12 1988 (522 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& copyright 1988 by John S. James; permission granted for non-commercial use. Articles by John S. James are from AIDS Treatment News unless otherwise indicated. John may be contacted by telephone at (415) XXX-XXXX. AIDS TREATMENT NEWS issue # 62, August 12, 1988. CONTENTS: [***** appears here at each new item] FDA Drug Approval: Major Reform Considered AIDS Drug Testing and Access: Interview with Nathaniel Pier, M. D. CD4 Treatment Test Near? PCR Test Cautions Roads to Recovery: Resource Book for Persons with AIDS AmFAR Guide to AIDS Educational Material ***** FDA Drug Approval: Major Reform Considered A behind-the-scenes effort to reform the Federal drug- approval process has recently become public through an editorial in The Wall Street Journal (August 2), and a major article in The New York Times (August 7). The effort, spearheaded by Vice President George Bush and his Presidential Task Force on Regulatory Relief, apparently seeks the following changes: * Regulatory hurdles could vary with the severity of the disease. For example, a treatment for AIDS, cancer, or Alzheimer's disease could be approved more quickly than a new cold remedy or sleeping pill. * For life-threatening diseases, the current "phase III" testing (large-scale efficacy trials) could be eliminated. This phase takes the longest, yet it contributes the least, since the great majority of drugs which begin phase III are eventually approved (after several more years) for marketing. These drugs have already been proved safe in phase I, and probably effective in phase II. * The FDA would be allowed to require a "phase IV", or post-marketing monitoring of the drug. This step is important because one of the current obstacles to earlier approval is that once approval is given, the FDA loses control of the drug and the company has no further incentive to complete its research. Instituting phase IV could allow the FDA to let patients get the drug while the research continued. (The importance of finishing the research is illustrated by the problems in surgery, where new procedures do not need to prove efficacy. Some experts believe that a large fraction of operations are unnecessary, and that some accepted procedures may not be effective or do more harm than good. The issue isn't whether drugs should prove efficacy, but whether drugs that prob- ably work should be denied to patients in an emergency, pending lengthy, final proof.) * The FDA would also work more closely with companies during phase I and phase II, to design trials which could lead quickly to approval, and avoid the need to redo trials because of ambi- guities in the results. Comment These reforms could be very important -- or they could fail, in many ways. The AIDS community must be vigilant to see that the needs of persons with life-threatening illnesses are addressed. The forces which wrecked previous reform attempts like the "treatment IND" could sabotage this one too. A process as com- plex and delicate as drug approval inevitably leaves room for obstructionism. Could the proposed reforms deal with the depth of problems which have occurred? Time and again the AIDS drugs closest to approval have had extraordinary bad luck: * Going into the recent Stockholm conference, the only drug close to approval was Imreg-1. Four days later it was so vili- fied by exaggerated criticism that the researchers were terrified of loss of their professional reputations. Criticism of the research design was legitimate. But the crowd lost the perspec- tive to ask whether, even if all the criticism were true, the drug still should be available to patients. * A year and a half ago, ribavirin was closest to approval. Early release of questionable data led not only to justified cri- ticism, but to extraordinary vilification of leading researchers who were completely innocent of wrongdoing. * Imuthiol (DTC) looks good in every way. But the U. S. trial results on which U. S. approval depends are being kept secret, for about a year, pending the completion of the last straggling arms of the multicentered trial. Apparently the developers feared that what happened to ribavirin could happen to them if they did not wait for full completion. What they are doing makes sense if the existence of an emergency is ignored. * DHPG (ganciclovir), the only accessible treatment for AIDS-related blindness, got caught in regulatory limbo long ago because after compassionate use in thousands of cases everybody knew that it worked -- and that scientific trials to "prove" it worked would require deliberately letting people go blind. When the FDA acted against this drug, apparently to punish the company for not doing the scientific trials, other compassionate-use treatments such as fluconazole for cryptococcal meningitis sud- denly became less available. It is well known that the FDA does not like compassionate use for AIDS drugs. The common factor in each of the cases above is that the drugs were close to approval. All were threats to AZT, which takes in more money than anything else in AIDS, and therefore has more clout. The corporations victimized by these abuses seldom dare to speak out, for fear of retribution not only against the drug in question, but against their non-AIDS drugs as well. Government agencies will not speak out. Researchers dare not, for doing so would damage their career prospects with almost any potential employer, public or private. Funded AIDS organizations have feared loss of funding if they speak about treatments not already approved by the FDA. In short, no major institutions nor any of their employees can tell the public what is wrong -- which is why these problems were not recognized, addressed, and corrected long ago. For these reasons we are only cautiously optimistic about the proposed reforms. The AIDS community must be cautious about fine print which could destroy the goal of faster approval -- such as the rumored proposal to start the reform by moving all AIDS drugs back to phase I, requiring that all the trials be redone. In particular we should note whether the new policy has written standards specifying the conditions under which a drug can be released. The "treatment IND" system had no such stan- dards, meaning that drug companies set their course depending on their reading of internal FDA politics. The real decisions were made privately, with public scrutiny excluded. The U. S. drug-approval process was deliberately designed to be impervious to outside pressures and influences. Clearly a case can be made for setting up the system that way; for other- wise, powerful companies could buy or pressure their way to approvals not medically justified. But this system has also resisted scrutiny and challenge of the ill-concealed, de facto public policy decision to write off those already ill or infected with HIV. The FDA is not the whole problem. The NIH, and private drug companies, have done no better. Few major drug companies even have an antiviral program. Almost all of the ballyhooed business interest in AIDS research concerns only new tests or other non- treatment products -- and much of the rest is stock manipulation. The fundamental problem has been a pervasive lack of politi- cal will to save the lives of people with AIDS. During the last year we have seen the beginning development of this political will. But still it must overcome the legacy of previous years -- the inertia of legions of officials and professionals less inclined to do the job than to argue why it can't be done. Ultimately this battle will be won; this country will not sit still while hundreds of thousands die from public neglect. The question is how long victory will take, and that depends on the effort we bring to the struggle. ***** The Emperor Has No Clothes: Notes on AIDS Drug Testing and Access by Nathaniel Pier, M. D. The following comments were edited from an August 5 tele- phone conversation with Nathaniel Pier, M. D., a New York physi- cian treating several hundred patients with AIDS and related con- ditions: "We have lost something in the struggle to find therapies for AIDS. The individual patient with the counsel and guidance of his or her physician must have the right to make choices, to have options. People with AIDS and at risk for AIDS have abdicated their responsibility far too much to the medical establishment and the research establishment to make this decision for them. "The primary role of a clinician such as myself is to syn- thesize a course of action with a patient that makes sense. That means every patient is offered the opportunity of choosing from the options that are available, under the careful guidance of their clinician. This should not be a major issue. "The current system of doing drug studies has failed. It has bureaucratized to the point where it takes two to three years to test a drug that should be tested in two to four months. There is no proof that this system works. So let's go back to the old system where individual clinicians are given the oppor- tunity of synthesizing a course of action. "Under supervised protocols from a national group, we should get access to drugs that are in phase II trials, including drugs that have not had efficacy demonstrated, and clinicians should be allowed to authorize the option of trying these drugs if patients want to. (Editor's note: drugs in "phase II" testing have already passed the "phase I" test for dosage, toxicity, and safety.) It should be up to the patient with the clinician's guidance to make such decisions. The fact that we have to wait two to four years for a drug like lentinan or dideoxycytidine to come down as a potentially useful drug is not fair to the patients who have no other options, who are simply going to die. "The system is essentially telling patients with immune deficiency disease, 'We don't care about you, go home and die. We will cure this disease in our own time with our designer drugs.' Every patient should demand that anybody with HIV disease should have access to a number of experimental options through their clinician, and these options should be offered to them as super- vised protocols. "A good example is the multi-drug protocols for cancer. If you're diagnosed with colo-rectal cancer, for example, your oncologist ties in to a national computer where your statistics are kept confidentially; out the other end comes a protocol. Not only are you allowed to participate in a potentially lifesaving drug regimen, but the data that's collected from you goes back to a center that very quickly will collect information as to whether this particular combinations of drugs works. "We should be doing this in AIDS. There is no reason that after 18 months of AZT, we shouldn't be allowed to combine other drugs for both antiviral and immunomodulatory effect. We could do this on thousands of patients overnight if there were a national registry and a system for doing it. "We wouldn't need to do complex virological or immunological tests. The studies requiring such tests should be done in smaller protocols at major medical centers. Otherwise, once a month the physician would do the blood work specified in the pro- tocol, and send the data to the NIH, and the physician will fill in clinical data. Probably within three or four months we could find out which treatment combinations are best. People with AIDS should be demanding that the system be reformed to allow anybody at risk access to these drugs under supervised protocols. "It seems that groups advocating for people with AIDS have lost this primary goal, that it should be the patient's option, to use experimental drugs under guidance, supervision, and moni- toring. "The system now in place for developing and testing and dis- tributing AIDS drugs is not working, it is not producing new therapeutic options. In the last two years all we've had is AZT. AIDS advocates need to start saying that the emperor has no clothes. So let's start a system that is going to work -- one where people with AIDS-related problems get rapid access to experimental drugs in protocol, on a routine basis through their clinicians, whether private physicians or at a clinic. "Let's stop wasting time. I have done my rounds of researchers, and there is nothing, there are no new drugs close to approval. It's a scandal that our system with its funding still isn't producing. "The system claims to be working, but isn't. Why aren't more people demanding access to these drugs which are potentially effective and are safe to use? We must stop this idea that test- ing drugs on a small number of patients, then on a slightly larger number of patients is a reasonable approach when people are dying. We want to make experimental therapies available to people as a matter of course, as a matter of therapy, so that clinicians caring for AIDS patients can get access to these drugs under supervised protocols. Not only would patients have more options, we also would learn quickly what works. "It is completely unreasonable that two years after AZT there is no new drug, and combination therapies using antivirals and immunomodulators are not available. It is unreasonable that Frank Young of the FDA says that very few drugs are likely to be approved between now and 1991, when we're losing 48 people a day to this disease. "It's not working, so let's come up with a new system. Let's use experimental treatments as potential therapy for ailing patients, and do it in a manner that's going to provide useful information. Set up a national registry, check out protocols of combination therapies, and let people use them. Similar systems have been used for cancer and heart disease. "For example: "At the recent Stockholm conference, information from NIH demonstrated that an AZT and dideoxycytidine on alternating weeks may be an effective alternative for people who can no longer take AZT continuously. Why isn't this drug combination available to these people, who have few other choices? "NIH made dextran sulfate a top priority drug in January 1988. It has taken eight months since then to get ready to start its first study, a multicenter trial with all of 60 patients. When thousands of people have no other choice, it's inhuman not to make such a safe drug available to patients through their doc- tors, as part of a study. "Where are new antivirals such as DDA or DDI? NIH has been recruiting for clinical trials for about six months. "My problem with the treatment underground is that for the last two and a half years we have tried naltrexone, AL 721, anta- buse, dextran sulfate. Something has come along every few months that has offered people hope, and access to therapy that they couldn't get other places. That's very important. But I as a clinician am tired of my patients not knowing which of these therapies is the best to choose, tired of patients being bamboo- zled by people into taking this or that or the other thing, tired of not being able to assess whether or not an approach or combi- nation is really benefitting the patients. We need a system so that when a therapy comes along, we can evaluate the efficacy very quickly. "What I'm proposing is very clear. We need a national registry, and if a patient has an AIDS-related problem at any stage of the illness, and if that patient elects to try to inter- vene, there should be protocols available to that patient's clin- ician. There should be multiple protocols for every stage of the disease, so that we can quickly assess which intervention might in fact make a difference. "These protocols should be available not just through a few selected centers, not just to the lucky few who can afford to go to doctors who can get them into these studies. They should be available to every physician who treats AIDS patients, not just in the major cities. We know enough about this disease to develop a logical approach involving antiviral, immunomodulatory, prophylactic, and anti-inflammatory therapies. "There are enough drugs to be tried so that we could develop these protocols in a few weeks and make them available to clini- cians through a national computer. The data from these combina- tion trials could start pouring in, and we would know within a few months which of the available combinations are working best, rather than the years and years that it's currently taking. "This approach will give patients hope, and access to humane, well-supervised medical treatments, instead of allowing them to live in fear or desperation, or search for the few trials available. At the same time it will allow them to participate in a larger effort, to find what therapies work best for everybody, making their situation meaningful not only for themselves but for the world. "We want to participate, to know what is happening with the research and what the future plans are. We want to reduce the secrecy, the sense that scientific data is proprietary or exclusive in the face of this epidemic. "The current system simply has not produced the goods. And if Dr. Frank Young's prediction (of few new drugs approved by 1991) is any indication, it will not produce the goods for a long time to come. This consigns large numbers of people to death without giving them a dignified chance to fight back. This is not an acceptable human or reasonable approach to doing research in this epidemic. "After five years of being on the front lines, my heartfelt feeling is that the top priority for people with AIDS and people who care about AIDS is to demand access to experimental therapies to try to save their lives. "I appeal to people to organize this effort immediately, to bring it forward in their local groups, then present the case to their political people, and to the people who are running the present medical system of testing drugs. It's time we told them that the emperor has no clothes, that the current system is not working. It's time to insist on wider access to promising thera- pies, and rapid testing of existing drugs to develop better treatment options." ***** CD4 Treatment Test Near? An article in the August 9 San Francisco Chronicle first reported that Genentech, a biotechnology company in South San Francisco, had been granted permission for human tests of CD4, its genetically engineered AIDS treatment. The company applied for permission in January. In the week before the article, two people who were consid- ering volunteering had asked us what we knew about the treatment. CD4 is the protein found in the CD4 receptor site on T- helper and certain other cells. In the laboratory, manufactured CD4 provides an alternate target for HIV, preventing it from infecting new cells. There will be a risk for the first person or first few per- sons who try this treatment, however. Some experts fear that injecting CD4 could cause the body to develop antibodies against its own T-helper cells, making AIDS symptoms worse. Animal and laboratory tests have been successful, but because this drug is so specific for the human immune system, these tests cannot rule out the possible danger. Despite the risk, CD4 represents an important potential treatment for many people. It should be tested quickly. San Francisco General Hospital and other medical centers are now preparing to run initial trials. ***** PCR Test Cautions Issue #60 of AIDS Treatment News described the new PCR test, a very sensitive biochemical test for HIV. After reading the article, Joseph Sonnabend, M. D. called to alert us to the con- troversy over whether this research test is ready for clinical diagnostic use, because of the unknown risk that it could produce false positives or false negatives. Dr. Sonnabend and others, some speaking off the record, alerted us to the following infor- mation and concerns: * The PCR test is so sensitive that sometimes it can detect a single molecule of the DNA being looked for. Therefore it is also extremely sensitive to even the tiniest contamination of laboratory glassware, reagents, etc. * Even small variations in the chemicals used in the test can cause large differences in the result. And no one has yet made sure that the test works in a standard way when performed in different laboratories. * Although about 200 people at least have already been tested with the PCR, this number is too small to provide very accurate data on the risk of false positives or false negatives. * It is too early to be sure of the clinical meaning of a PCR test. Most experts seem to agree (1) that the PCR should not be used by itself for diagnosing patients, and that (2) this very important research test may also be useful for diagnosis after more is known about it. Whether the PCR should be used at all at this time for diagnosing patients remains controversial. ***** Roads to Recovery: Resource Book for Persons with AIDS Roads to Recovery, an 860-page looseleaf compendium of AIDS information from a PWA perspective, has been compiled by Jeremy Bell and published by Face to Face, an AIDS service organization in Sonoma County, California. The articles selected represent many points of view -- including mainstream medicine, minority medical views such as some of the syphilis theories, and spiritual approaches. Most of the material concerns treatment options, especially non-approved or alternative treatments. Chapters on "AIDS 101" (basic back- ground information), coping, doctor-patient relationships, legal issues, a glossary, and resource lists also are included. The high price, mainly to pay for photocopying over 800 pages, and the mass of material and mixture of different viewpoints will deter some from using this book. We think that Roads to Recovery will be most useful as a reference. Libraries, service organizations, support and study groups, and individuals who want in-depth information or who have limited information available in their localities may want a copy. Roads to Recovery, provided in looseleaf form to allow future updating, is available for $50. donation ($65. for hos- pitals, institutions, or physicians) from Face to Face, Roads to Recovery Project, P. O. Box 1599, Guerneville, CA 95446. Please include $6. for shipping and handling. This project is a fun- draiser for the PWA Emergency Fund. For more information, phone (707) 887-1581. ***** AmFAR Guide to AIDS Educational Material The American Foundation for AIDS Research (AmFAR) has pub- lished the AIDS Information Resource Directory. It includes descriptions of over 1,000 AIDS brochures and pamphlets, video- tapes and films, curricula and instructional programs, posters, public service campaigns, manuals, and periodicals. A panel of 34 experts reviewed the material for medical accuracy, appropriateness to the target audience, and production quality. The directory divides material by target audience, for example, "Gay and Bisexual Men", "Black Community", and "Health Care Professionals and Service Providers". The AIDS Information Resource Directory costs $10., and can be ordered by calling 800-992-2873. Persons outside the U. S. can call 212-333-3118. ***** [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display