Date: 11 Apr 1996 23:07:05 From: FRSHAW@delphi.com Subject: Compound Q + Martin Delaney = Murder Subject: Compound Q + Martin Delaney = Murder Martin Delaney's Compound Q Odyssey Transcribed and commented by W. Fred Shaw (frshaw@delphi.com) The following is a transcript from the PBS broadcast of the Winter 1990 AIDS Quarterly program, narrated by Peter Jennings. This transcript concerns the part of the program dedicated to Compound Q, and the unofficial study directed by Project Inform's Martin Delaney. In response to Martin Delaney's March 28, 1996 posting on sci.med.aids, some commentary - in parentheses ( ) - is added in response to selected statements to help guide the reader and provide some historical insight into these disturbing events. The similarities between this trial and other AIDS drug trials are quite striking. The PBS program begins on May 23, 1989 with Martin Delaney speaking with men in front of immunologist Dr. Alan Levin's San Francisco medical office: DELANEY (speaking to the men): Project Inform is NOT the supplier of this (Compound Q) but I AM acting as the courier to get it to you guys from the people who brought it into the country (from China). (Delaney doublespeak - Martin Delaney IS Project Inform. Later in the transcript Delaney forgets his courier status and claims that the patients are the distributors) PETER JENNINGS (narrating): Martin Delaney is one of the most influential AIDS activists in the country. For years he's been challenging the FDA to speed up its drug trial procedure. DELANEY: I think it's been shown time and again in AIDS, when you got a crisis, a national emergency going on, you have to take a shorter path to your goal. (This story exemplifies how a "shorter path" can worsen a crisis). PETER JENNINGS (narrating): Trichosanthin, better known as Compound Q, a Chinese abortion and cancer drug. It was tantalizing because it killed HIV-infected cells in the test tube. The FDA promised human trials. But for activists like Martin Delaney, trials administered by the FDA would take too long. So Delaney joined forces with Dr. Alan Levin, a San Francisco immunologist, who was prepared to conduct an accelerated trial ... illegally. LEVIN: Now it's not a simple treatment, and its not a safe treatment, and the odds are very good someone's going to die of this treatment. We're not kidding ourselves - this is not a magical panacea. (These initial warnings by Levin are soon to be lost in the enthusiasm) PETER JENNINGS: Dr. Levin was prepared to put his reputation on the line, because many people had imported it from China and were taking unsupervised doses. Levin asked for volunteers from among his own patients. He and his staff chose 3 who had advanced cases of AIDS. LEVIN STAFF MEMBER (interviewing trial patient): Do you understand that Dr. Levin does not guarantee that trichosanthin treatment will slow down or stop your AIDS. Do you understand that this is not necessarily a cure for AIDS? (Aren't these patient warnings much different than Levin's previous statement that "someone's going to die of this treatment"? It becomes quite clear later in the program that, in fact, patients held on to the false belief that Compound Q was a "magic bullet".). PETER JENNINGS: One of them, 41 year-old Tandy Valou. TANDY: I'm in my seventh year of dealing with this and I'm tired of all the symptoms. I'm willing to take the risk to wipe it out completely. Of course, my main hope is that it is going to eliminate the virus completely and I really believe it is. In terms of hopes for myself, I'm a survivor, I feel like that now. If it doesn't work for me that's not the end of the road for me. But I think it may be for a lot of people. So many people are counting on this drug. (As in other trials, patients are frequently led to believe that they will "wipe it out completely", whatever the risk) PETER JENNINGS: Day 1: The patients receive their first infusion with Compound Q. The trial consisted of 3 doses over 3 weeks. LEVIN: I can tell you that we're going to see benefit, or lack or benefit in hours, certainly in days. (Here, the immunologist believes that the "benefit", in this case an increase of CD4 cells, seen in a matter of hours or days, is the result of the drug killing virus-infected cells. Aren't such responses an obvious response of the immune system to Compound Q - similar to the "flushing out" of existing CD4 cells by AZT in the same time period?). PETER JENNINGS: Dr. Levin was looking for an increase in T4 cells, the white blood cells that fight disease. He was worried about side- effects. He was most concerned about MTD, the maximum tolerated dose, that signals when the drug is about to overpower the body. Besides Andy Valou, the other patients were 39 year old Norman Watkins and 41 year old Ron Fisher. PETER JENNINGS (as the first infusion was started): Dr. Larry Waite assisted Dr. Levin. WAITE: We needed people who had tried previous therapies and who had failed those previous therapies. They have tried virtually everything and everything is failing them and they are at the point now where they are trying this as literally... it is their last resort. ( The "last resort" school of thought - no consideration given to the acceleration of a patient's death ) PETER JENNINGS: They waited anxiously for the drug to take effect. TANDY (receiving treatment): I was thinking about so many of my friends that have died. And I felt their presence. RON FISHER: I'm going to survive this and get over it. I'm committed to it. I believe that I'm going to survive and get over it. (Ron Fisher would die less than four weeks later from "pulmonary cancer", more likely fulminating Kaposi's Sarcoma of the lungs, undoubtedly due to the profound immune suppression of Compound Q. Norman Watkins died months later). PETER JENNINGS: They were kept overnight for observation. The activist (Delaney) and the doctor were anxious too. DELANEY: Let's say the drug worked. Let's say it knocked out all these infected cells. Would the immune system recover? (This question not only reveals Delaney's limited knowledge of immunology, but isn't this a basic science question that should be answered BEFORE starting a clinical trial involving an immunosuppressive and toxic drug?). LEVIN: I'm going to speculate. The guy with high supressor cells will respond because he has a lot of bone marrow reserves. The guy with low total T cells and low suppressor cells might have more trouble. My sense is that the guys whose bone marrow is damaged by AZT won't do as well as the guys whose bone marrow's haven't been damaged by AZT. I'm speculating again that there is going to be a dramatically clear result one way or the other. (As seen later, what does a 12 hour, 35% increase of CD4 cells have to do with "a lot of bone marrow reserves"? Clearly the increase was a flushing effect. Further, the trichosanthin research that is cited after this transcript clearly shows that the CD8 CTLs would be expected to decline together with a suppression of IL-2 and a decreased lymphoproliferative effect). DELANEY: I hope you're right. (Hope? ) LEVIN: I'm also speculating that we're going to run into big trouble with some guys. PETER JENNINGS: The next morning the first set of results was encouraging. LEVIN: In the main everybody did very well. In the one patient that we have the data on right now, we see about a 35% increase in the white blood cells in 12 hours, that's pretty impressive. Medically, scientifically and ethically, it should be made available to every HIV-positive person by the end of the year if it works. And we'll know that within six weeks to two months. (CD4's increase by 35% in 12 hours? This is the flushing response to the drug). PETER JENNINGS: A very accelerated trial. Across town, at San Francisco General Hospital, Compound Q was undergoing an official FDA trial, and it would take at least 18 months, under the direction of Dr. Paul Volberding. VOLBERDING: Even though there was some prior experience with this drug in China, there wasn't any experience any of us had any direct involvement with, and we expected that the drug would be more toxic in the setting of AIDS. So when we designed the initial trials, we said we don't really know what dose to use, we don't know what side- effects to expect, so we'll do a very careful study, it's called a dose-escalating study, where we start out with very low doses of the drug and build up as we get more comfortable with the drug. PETER JENNINGS: Patients in Dr. Volberding's trial initially received only a fraction of the dose that Dr. Levin was administering to his volunteers. VOLBERDING: A traditional way that we've used new drugs - drugs for the first time in people - the plan for this drug is really comparable to the plan we have used for drugs in the past. PETER JENNINGS: Dr. Volberding did not know that the secret (Levin) trial was taking place. On the seventh day of his trial, Dr. Levin was optimistic. LEVIN: In every patient we've seen at least a doubling, if not a tripling, of the white blood cell count, and these people have run very low white blood cell counts for years, or for at least the year that we've been tracking them. So something very dramatic is happening to them. There are a lot of questions as to whether to double the dose next time or even to increase it by 10%, but we just don't know. So right now, to be on the safe side, we're just going to expand the population at this dose level and monitor them. (Clearly, a dramatic CD4 flushing response - but this was seen as "good" because Delaney and the good doctor were focusing on the CD4 surrogate marker. It was way too soon to expand the trial after only seven days with the first group) PETER JENNINGS: So the next day, Norman, Andy and Ron received their second infusion. The same amount as the first time. While four new volunteers began in the trial. DELANEY (hunched over the lab results): That's remarkable (referring to the increases in white blood counts). (As usual, Delaney is fixated on the singular CD4 surrogate marker). PETER JENNINGS: On the 8th day, the experiment took a turn for the worse. After his second infusion, Tandy's mental capacity was seriously impaired. TANDY (disheveled and tearful): I'm scared, very, very much scared right now. I've been here all day, since, oh what 8:30 or 9:30. The doctor wanted to see what's happening with me. He's given me some medication (mumbling) ...so difficult ...and it's scary. I'm pretty scared (mumbling, tearful). (All prospective patients of toxic drug clinical trials should see this tape). LEVIN: Well, Tandy, as you saw, had an episode where he has a lot of confusion. He has difficulty gathering words and Organic Brain Syndrome. And of course, most of our guys have described some level of feeling confused and inability to think well. He happens to be the worst. He's had the worst reaction of any of the guys regards his problems with the drug. (Organic Brain Syndrome (dementia) only eight days after starting a toxic, immunosuppressive therapy like Compound Q? Interestingly, this "Syndrome" later disappeared two days after the patient stopped taking his drugs). PETER JENNINGS: At this point Dr. Levin speculated that Compound Q might be killing brain cells, leading to temporary dementia or even coma. Then Levin's assistant Clark Housman learned that Norm was also ill. The drug was taking over his body. It appeared they had reached maximum tolerated dose, MTD. HOUSMAN (Levin's assistant - excerpted): Norm has to come in today anyway for blood work, we have to check him out. If he can't walk, we have to get him in by ambulance. PETER JENNINGS: A worried Dr. Levin made a decision. LEVIN: I'm not going any further with anybody. (Excellent moral and ethical choice, but one that unfortunately was short-lived) HOUSMAN: What does this mean for (the) Thursday group? LEVIN: You mean in terms of the second infusion? No second infusion on anybody as far as I'm concerned. RECEPTIONIST (on Telephone Intercom): Can you take a call from Martin Delaney? LEVIN: Hi Marty. We're hitting the wall. Well Tandy has marked phages which are chronic, he has atrophy and dirty white matter. Well, he's got AIDS dementia. In his case we have to wait and watch. Norm Watson is in here with a temperature of 103.2 which is coming down. The problem with him is we don't know what antibiotic to use because he's been on all of them. I really don't like hurting people. But, you know, obviously these guys had no alternative. I just don't want to be the one that accelerates their demise. But, you know, we might be able to pull them through. (Was Norm's fever a result of the emergence of a copathgen due to further immune suppression by Compound Q?). PETER JENNINGS: Hours later, Levin wanted to cancel the trial, Delaney wanted to proceed. They argued. LEVIN: Next question though is the way to go with the second infusion on the second group. DELANEY: See, on that one I'm more inclined to think "yes" but maybe rethinking the dosage question. I know some of those guys are very upset (about the prospect) of not doing it too. (What had Delaney told "those guys" about Compound Q that made them so very upset at the thought of not being able to use it? Clearly, Delaney is not expressing any sense of compassion for these patients, since he clearly thinks these patients are going to die anyway - a mindset that has pervaded all of the AIDS clinical trials.) LEVIN: But they're so sick. DELANEY: Yeah. Well what about making some individual choices then? Letting them call it. I mean they're sort of calling it anyway so what is the difference here? (Individual choices? Based on what information - that which is spoon- fed by Delaney?) LEVIN: Cause I'd feel guilty about hurting them no matter what they say. (The doctor has to EXPLAIN this to Delaney?) DELANEY: See there is nothing in any of the lab work I've seen right now that suggests a problem with anybody. I mean the only stuff in the lab work suggests some fairly significant benefits in fact. Now it's too early to make any kind of conclusion from that but I didn't see any evidence of harm in any of the blood work, do you? (These patients are as sick as dogs, yet Doctor Delaney "didn't see any evidence of harm" - he knew that the CD4 marker was the single key to health and long life. One must ask, where is Delaney's compassion?). LEVIN: I just see the evidence of harm walking in the door. DELANEY: Yeah clinical, right (laughing) PETER JENNINGS: By this point the trial was no longer a secret - work had leaked to the FDA. But the agency did not intervene. (discussion about FDA history and policy, thalidomide, etc.) PETER JENNINGS: ...But the agency (FDA) was unprepared to deal with the sudden onslaught of the AIDS epidemic and the highly politicized gay community. (more FDA discussion about the agency being on the defensive). PETER JENNINGS: (Picture of Norman and Dr. Levin at Norman's home). By the end of the second week, Norman was unable to leave home and come for a checkup. Compound Q had apparently further weakened his immune system. Dr. Levin went to him. NORMAN: All three of us got sore, and tired and fatigued, and I had trouble with fevers for two years so I didn't know if it was from another infection or from the drug itself. This has been a bad week. (If) I die, I was going to die anyway, probably. (Tearful) it's hard ... hard. (Norman dies in the months to follow) PETER JENNINGS: Tandy's condition was troubling. TANDY: (tearful, confused, disheveled, shaky voice) I was doing OK for a while, then completely lost it, completely lost my capacity (drifting off) very, very out of it. Very much out of it. DELANEY: Well this comes back to the question that always comes up with me, and that is do you treat the very sick people who desperately want to get treated, because they feel they have to, or do you try to treat people at an earlier stage of the disease? (Showing no compassion for Tandy's condition, Delaney is looking for another target - healthy persons at "an earlier stage of the disease". When does it make sense to treat healthy, asymptomatic patients with toxic, immunosuppressive therapies?) LEVIN: Well this is a Phase I trial. That's what you do in the first place, establish MTD on the basis of the sicker patients. (So that's what the "sicker patients" are for in clinical trials! Humans are cheaper than Chimps) DELANEY: But so often they're the wrong patients to try treating. I mean the history of this disease has been that every drug that's come along has worked better at earlier stages, rather than later. (Delaney's "logic" ignores the fact that healthier patients outlast sicker patients) PETER JENNINGS: Then Tandy and Norman stop taking Compound Q. For the next two months, the trial continued with healthier patients, altogether 19 men were taking Compound Q. Then in late June, Ron Fisher died of pulmonary cancer. Days later, another patient died. And suddenly the news was everywhere. The secret that had been debated only behind the closed doors of the FDA was suddenly very public. VOLBERDING: Well I think first of all, the Project Inform study is playing more than a passive role, they're encouraging by being involved, patients to use drugs out of desperation that haven't been tested for safety. (As Volberding confirms, Delaney's " career" has been built on the fear and desperation of AIDS patients). DELANEY: We face the situation here that have been typical throughout the AIDS epidemic in that patients have been gearing up for large scale importation and distribution of this drug because it appears to be so promising. (As admitted in his opening remarks of the program, Delaney said HE was "gearing up" for distribution - not the patients) PETER JENNINGS: Six weeks later the FDA, which had known about the trial almost from the beginning, felt obliged to respond, it sent a letter to Martin Delaney. ELLEN COOPER (FDA Director of Antiviral Products): the letter was, basically, told Mr. Delaney that certainly we did not approve of the protocol, that it was illegal. (Elinor Burkitt's recent book, "The Gravest Show on Earth" reveals much about how Delaney, especially his interaction with Ellen Cooper in the spirit of "working together") PETER JENNINGS: But the letter had a curious turn of phrase. Although it said "we feel that you should discontinue any further unapproved experimentation", it closed with "we look forward to working with you". An unprecedented invitation to an AIDS activist. DELANEY: I never expected (the) FDA to, you know, come down on us and lock us up, I think they understood the good faith and intentions of what we were doing and that once they had the opportunity to look at how we did it, I think they could understand that we were scientifically responsible as well. (Scientifically responsible? Good intentions? Good faith? Ignoring the patient's clinical presentation and lacking in compassion? Volberding's earlier commentary should be reviewed in this regard. Delaney's previous experience as a public relations hack is quite obvious here.) FDA EXPERT: The AIDS drugs are treated in a wholly separate category, and the FDA is developing separate rules for those drugs. The long term question is to what extent, when they get those rules in place, those rules will become the rules for drugs for arthritis, and ulcers, and diabetes, and asthma and so forth. PETER JENNINGS: By the Fall, Dr. Levin had assessed his findings from the trial, and claimed that the drug might keep the AIDS virus from reproducing. So he thought his experiments were justified. (What happened to the CD4 counts? Clearly, trichosanthin causes the suppression of IL-2 and the suppression of cellular proliferation - this immunosuppression is NOT specific to infected cells but negatively affects the immune system as a whole). LEVIN: I've got to tell you that the obligation between the doctor and the patient is above the law of any land. Period. And if the Nazis say "throw the Jew in the oven", as a doctor I would be obligated to say "no". I don't care what any regulatory affairs - any governmental institution tells me - if this is going to save lives, I'm going to do it. And I'll tell ya I'll do anything scientifically, medically and morally correct and somebody else has to make it legal. (Levin, now the hero, confuses the role of the Nazi and the doctor - using the unfortunate Jew/oven metaphor. Aren't Levin and Delaney the ones throwing the Jew - represented by the sickest patients - into the oven - represented by this trial? How simple it is to justify the killing of patients through the twisting of metaphors) PETER JENNINGS: But by the end of the year, it was clear that Compound Q was NOT the miracle cure. Norman Watkins died of complications from AIDS - Compound Q may have contributed to his death. By then, one of the patients in the San Francisco General trial had died as well. Dr. Volberding had a different view of Dr. Levin's efforts. VOLBERDING: We felt quite strongly that this was not a good idea to do this kind of a study in a non-academic setting, without the review - the external review of institutional review boards, the FDA, and a drug company sponsor. And I still feel that that's true. I feel what's changed is that, I appreciate again that our goals are the same and that we've learned too over time that we really do have to look at our ways of approaching things to make sure that we're not slowing things down. It's not fair to criticize someone else if, in fact, we are part of the problem. (During this same time period (1989), Volberding was advocating high- dose AZT for "early intervention" - today Volberding admits that this was a failed strategy from the outset) PETER JENNINGS: But he (Levin) also had some good news, Tandy Valou had rallied. Tandy: I actually thought I was dying, I woke up one morning, I said to myself "Tandy, this isn't working, I think you're dying, stop you're medications. Stop everything right now." So I did, stopped it all. And in two days time I knew I was coming back. (Here Tandy - two days after stopping the drugs - looked fine - not disheveled, confused or depressed - suddenly the Organic Brain Syndrome diagnosed earlier by Levin has disappeared. Perhaps, after all, the problem wasn't the "atrophy and dirty white matter" speculated by Levin earlier) PETER JENNINGS: In December, Tandy began taking Compound Q again. TANDY: I was disappointed when it wasn't like the miracle cure right away, wasn't the magic bullet. But continued with it, I think it's working. I see other friends of mine who that are doing quite well on it. (With the other two participants in the trial (Ron and Norm) now dead, exactly what hype led this patient to believe that Compound Q was the "miracle cure" or "magic bullet"?) PETER JENNINGS: So is Compound Q effective against AIDS? There are still no clear answers. The official FDA trial isn't over yet. Delaney is planning another study of Compound Q, but this time with official approval. END OF PBS PROGRAM TRANSCRIPT ON COMPOUND Q The following studies were available PRIOR to the Delaney Compound Q study of 1989, yet this information was replaced by hype - many patients believed that Compound Q was the "magic bullet". Clearly, trichosanthin is a very strongly immunosuppressive agent that strongly inhibits the production of IL-2 as well as the Cytotoxic T Lymphocyte (CTL) lymphoproliferative response. The single-minded fixation on CD4 counts in the Compound Q, AZT and other drug trials proved to be a very dangerous clinical goal. Obviously, Compound Q contributed to the immunosuppression of the study participants, and for some of them, their death. The following abstracts represent the type of information that Delaney refers to as "laughable" in his March 28, 1996 sci.med.aids posting. Yeung HW; Poon SP; NG TB; Li WW. Isolation and characterization of an immunosuppressive protein from Trichosanthes kirilowii root tubers. Immunopharmacology and Immunotoxicology, 1987, 9(1):25-46. Abstract: An immunosuppressive protein was isolated from Trichosanthes kirilowii root tubers by a procedure involving acetone fractionation and ion exchange chromatography on CM-Sepharose. Homogeneity of the protein was demonstrated in immunoelectrophoresis, SDS-polyacrylamide gel electrophoresis, gel filtration, high performance liquid chromatography and a single NH2-terminal sequence. The protein had a molecular weight of 26,000, aspartic acid as the NH2-terminal amino acid and no cysteine or carbohydrates in its molecule. It inhibited ConA-induced transformation in lymphocytes isolated from spleens of CBA mice. The protein was also potent in inducing mid-term abortion in mice. Leung KN; Yeung HW; Leung SO. The immunomodulatory and antitumor activities of trichosanthin-an abortifacient protein isolated from tian-hua-fen (Trichosanthes kirilowii). Asian Pacific Journal of Allergy and Immunology, 1986 Dec, 4(2):111- 20. Abstract: Trichosanthin, a basic protein purified from the root tuber of Trichosanthes kirilowii, has been used effectively in China to induce midterm abortion in humans. In this paper, we show that trichosanthin at non-cytotoxic concentrations markedly inhibited the mitogen-induced lymphoproliferative response and the generation of a primary alloreactive CTL response in vitro. Similarly, the production of IL-2 by Con A activated splenocytes and the in vitro effector functions of macrophages were also significantly suppressed. In contrast, the cytolytic activity of CTL and NK cells was unimpaired. Moreover, the in vivo activation of NK cells was not significantly altered by a single injection of a non-toxic microgram amount of trichosanthin into mice. However, other immune reactivities such as the induction of a DTH response and the humoral antibody formation to SRBC were markedly depressed. Our data suggest that trichosanthin is a potent immunosuppressive protein that could affect humoral immunity and a variety of cell-mediated processes. In addition, our preliminary results show that this abortifacient protein could also inhibit the growth of a murine malignant tumour (MBL-2), both in vivo and in vitro.