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Friday, August 17, 2012

John Lauritsen-AZT ON TRIAL


AZT ON TRIAL
By John Lauritsen
New York Native 19 Oct. 1987

I argued in a previous article (Native #215) that the theory behind AZT (now known by its trade name of Retrovir) was false, inasmuch as the hypothesis that HIV causes AIDS has been refuted by Prof. Peter H. Duesberg, a world-renowned molecular biologist at Berkeley; that AZT's alleged benefits were not backed up by reliable evidence; that its toxicities were firmly established and severe; and that therefore the drug should not be prescribed, recommended, or used.
In his interview with me (Native #220), Prof. Duesberg referred to AZT as "a poison" and as "cytotoxic" (lethal to body cells). Duesberg said that the theories behind AZT were false, that there was "no rationale for treating with AZT", that prescribing AZT was "highly irresponsible", and that AZT was "guaranteed" to be harmful:
AZT hits all DNA that is made. It is hell for the bone marrow, which is where the T and B cells and all those things are made. It's hell for that. It has a slight preference for viral DNA polymerase compared to cellular DNA polymerase, and that's based on in vitro studies only, but that's certainly not absolute. It kills normal cells quite, quite extensively.
At the time these articles were published, the only reports on the Food and Drug Administration (FDA) trial that was the basis for granting government approval to market AZT, were in the popular media or a promotional film produced by AZT's manufacturer, Burroughs-Wellcome. Doctors who prescribed AZT did so on the basis on very limited information, along with the assurances of the Public Health Service that AZT represented the "best hope".
This appears to have changed. The 23 July 1987 issue of the New England Journal of Medicine (NEJM) contains a two-part report on the FDA's "Double-Blind, Placebo-Controlled Trial"-"The Efficacy of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS -Related Complex" and "The Toxicity of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-Related Complex". Margaret A. Fischl, M.D. is identified as the primary author of the first article, and Douglas D. Richman, M.D., of the second.
It quickly became clear to me that there were serious problems with the reports. The description of methodology was incomplete and incoherent. Not a single table was acceptable according to statistical standards-indeed, not a single table made sense. In particular, the first report, on "efficacy", was marred by contradictions, ill-logic, and special pleading.
In the meantime, I received about 500 pages of material which Project Inform in San Francisco had obtained from the FDA under the Freedom of Information Act. This material showed the dark underside of the double-blind, placebo-controlled trial-falsification of data, sloppiness, confusion, lack of control, departure from accepted procedures-things not even hinted at in the NEJMreports. Martin Delaney of Project Inform gives a fair summary of what emerges from the FDA material:
The multi-center clinical trials of AZT are perhaps the sloppiest and most poorly controlled trials ever to serve as the basis for an FDA drug licensing approval. Conclusions of efficacy were based on an endpoint (mortality) not initially planned or formally followed in the study after the drug failed to demonstrate efficacy on all the originally intended endpoints. Because mortality was not an intended endpoint, causes of death were never verified. Despite this, and a frightening record of toxicity, the FDA approved AZT in record time, granting a treatment IND in less than five days and full pharmaceutical licensing in less than 6 months.
After reading through the FDA material several times, I called Drs. Fischl and Richman, and spoke with each of them for about half an hour. The conversations were not very enjoyable for any of us. Neither one of them could explain the tables in the reports that they themselves had supposedly written. They both repeatedly said that I should call Burroughs-Wellcome to find out how the tables were developed or to obtain answers on other questions. Dr. Richman became quite truculent at one point, saying that I was "fixated" on the tables; that I should "forget about the tables"; that the report would be "just as good without them". Their ignorance regarding these tables is really amazing. As a market research analyst, I am accustomed to working with tables, and I can say that I have never written a report containing even a single table I could not explain and interpret.
Despite abundant reports of the horrible physical consequences of taking AZT, several of the New York City physicians most prominent in treating AIDS and ARC patients are not only prescribing AZT, but actively proselytizing for it. I think that history will judge these doctors harshly. This article will argue that no credence should be placed in the NEJM reports, that the "benefits" attributed to AZT remain unsubstantiated.
But first, an update on the central question: What causes AIDS?
HIV is not the cause
AZT (Retrovir) is officially defined as a drug for "symptomatic HIV infection". Its label states it is for the "management of certain patients with serious manifestations in infections caused by the human immunodeficiency virus (HIV)." Therefore it is crucial to know whether or not HIV really is the cause of AIDS, or whether HIV infection is even harmful. According to Duesberg, HIV is a benign passenger virus, and HIV "infection" is nonpathogenic. If so, prescribing a poisonous drug to attack a harmless virus would be utter madness.
Colleagues in the sciences have told me that we should now consider it highly probable that HIV is not and could not possibly be the cause of AIDS. I agree. Not only are the arguments compelling that are put forward by Drs. Peter H. Duesberg, Joseph A. Sonnabend, Nathaniel S. Lehrman, and others-but no attempt to rebut these arguments has been made by any of the leading HIV champions, including Drs. Robert Gallo, William Haseltine, Myron Essex, or their faithful colleagues in the Public Health Service.
The HIV edifice appears to have collapsed, and the "AIDS virus" crowd have resorted to stonewalling. A British television team recently attempted to interview Gallo. They were informed by National Cancer Institute (NCI) officials that it would first be necessary to submit in writing a list of all questions he would be asked, and that under no circumstance would the world's premier "AIDS researcher" discuss etiology, or whether or not HIV was the cause of AIDS.
Secrecy and censorship versus science
Ideally science is supposed to be a public activity, where scientists verify each other's work in a mutual endeavor to establish the truth. Scientists are expected to describe their experiments precisely, and to make their data available, so that other scientists working independently could replicate their experiments and verify their findings. Likewise, scientists are expected to enter into scientific dialogue, to respond to the criticisms and arguments of other scientists. It is therefore disgraceful that the NCI scientists refuse to respond to Prof. Duesberg's arguments.
Censorship is also incompatible with the ideals of science.
Government agencies, like the FDA, ought to be willing to make their materials public, so that their work can be verified independently. Although the FDA did release material under the Freedom of Information Act, it was heavily censored. As many as a dozen pages at a time were missing. Individual pages had words, lines, or paragraphs whited out. And most of the pages were entirely or almost entirely illegible-they looked as though the copy machines had been badly out of focus. There is no excuse for this. We live in the age of the copy machine, and the FDA could have produced legible copies. The lives of thousands of people are affected by the AZT trials, and it is wrong to treat information about these trials as though it were classified military secrets.
The aborted trial
The "double-blind, placebo-controlled" trial of AZT was conducted by the FDA at twelve medical centers throughout the United States. Although the patients did not enter the study all at one time, each patient was intended to undergo a full 24 weeks of "treatment"-either with AZT or with a placebo.
Midway through the study it was observed that only one patient on AZT had died, whereas more than a dozen on placebo had. According to the received version, it was then decided it would beunethical to continue the study, since AZT was so spectacularly (if unexpectedly) prolonging the lives of those who took it. The study was terminated; all patients were told whether they had been taking AZT or a placebo, and all were given the opportunity to take AZT. As I'll argue later, there are good reasons for being skeptical of the mortality data, as well as the motives for prematurely terminating the study.
Owing to the early termination, only 15 patients (5% of the total) completed the full 24 weeks of treatment. Twenty-three patients were treated for less than four weeks. On the average, patients had received treatment for about 17 weeks at the time the study was aborted. (See Table 1.)
TABLE 1
Very Few Patients Finished the Full 24-Week Protocol
 
Total
Patients
AZT
Treatment
Placebo
Treatment
Base: Total Who Began Trial(282)(145)(137)
Finished Trial (24 Weeks)5%6%4%
Did Not Finish Trial95%94%96%
    "Still Participating" (But Finished Less Than 24 Weeks Of Treatment)
73%79%67%
    Dropped Out Of Study
22%15%29%
Weeks Of Treatment (Mean)(17.3)(17.6)(16.9)
As might be imagined, the premature termination invalidated the original study design and caused chaos from an analytical standpoint. Tables which would have been entirely straightforward if all patients had finished their 24 weeks of treatment had to rely upon controversial statistical projections. For example, instead of showing the percentages of patients in each group who experienced opportunistic infections during the 24 weeks, it became necessary to develop a projected probability of their experiencing opportunistic infections within 24 weeks. This is analogous to estimating the probability of developing arthritis by the age of 70, using a sample in which only a few people had reached this age, and in which some were still teenagers. The method used (Kaplan-Meier Product-Limit Method) is a statistical attempt to estimate what results would have been if the study had not been terminated. Like mopping up milk, it may be the best thing to do-but it would be better not to spill the milk.
With poignant restraint, an FDA mathematical statistician registered his misgivings over the early termination:
There are a number of disquieting aspects concerning this NDA. It contains only one controlled clinical trial, and thus there is no independent confirmatory evidence for that study's results. It contains a relatively small number of patients (<200) who have been treated with AZT. The controlled clinical study is relatively short (i.e., 24 weeks) and WAS TERMINATED EARLY ON THE BASIS OF UNANTICIPATED FAVORABLE RESULTS IN A MANNER THAT HAS NEVER BEEN ADEQUATELY DEFINED IN TERMS OF ITS IMPACT ON THE SUBSEQUENT STATISTICAL ANALYSES. [Emphasis added.]
The unblinded trial
The study was planned as a "double-blind" trial, which means that the drug was supposed to be labelled and the study conducted in such a way that neither doctors nor patients knew whether AZT or a placebo was being administered.
In practice, the AZT trial became unblinded rather quickly.
An FDA medical officer writes: "the fact that the treatment groups unblinded themselves early could have resulted in bias in the workup of patients".
The study became unblinded among the patients as a result of differences in taste between AZT and the placebo:
Initially the placebo capsules, which were indistinguishable from the AZT capsules in appearance, were distinguishable in taste. This difference was corrected and the placebo capsules replaced with new ones after early reports were received of patients breaking the capsules and tasting the medication.
Anyone who has spent time with PWAs is aware of the keen interest with which they compare treatments. And anyone who has observed the gay grapevine is in awe of the speed with which information can travel around the world. I can well believe that from the time the first two patients compared notes on how their capsules tasted, it was only a matter of days until many or most of the patients knew whether they were getting AZT or a placebo.
Other patients discovered what medication they were receiving by taking their capsules to chemists for analysis.
In some instances patients pooled and shared their medication, thus ensuring that all of them could receive at least some AZT. Other patients, who found out their medication was only a placebo, took Ribavirin that had been smuggled in from Mexico.
From the standpoint of the doctors, the study unblinded itself through the strikingly different blood profiles of the two treatment groups. (See "Toxicity" below.) No attempt was made to blind the blood results from any of the doctors in the medical centers at which the trials were held. According to an FDA analyst:
The treatment groups may have unblinded themselves to a large extent during the first two months due to drug-induced erythrocyte macrocytosis.
There are very good reasons why blind studies are required for the approval of a new drug. The potential biases are so great, for both patient and doctor, that a drug-identified trial would be scientifically useless.
Many patients entered the trial out of desperation, believing that death was immanent without the intervention of a new "wonder drug". For these patients, the psychological consequences of finding out that they were receiving only a placebo must have been devastating. A sense of despair and hopelessness may well have contributed to the high mortality in the placebo group.
Doctors, and scientists in general, are often extremely gullible people. In their book, Betrayers of the Truth: Fraud and Deceit in the Halls of Science, William Broad and Nicholas Wade devote an entire chapter to "Self-Deception and Gullibility". Scientists unconsciously see what they want to see. Even the most absurdly crude hoaxes, like the Piltdown man, were believed for many years by eminent scientists. With high expectations engendered for AZT, it is not unreasonable to assume that unconscious biases affected not only how data were interpreted and recorded, but also how patients were treated. The shockingly high death rate among the placebo patients suggests that these patients may not have been managed well by their attending physicians.
When I spoke to Drs. Fischl and Richman, they both vehemently denied that the trial had become unblinded before it was terminated. This suggests that they had little control over, or knowledge of, what was happening-or, that they were not telling the truth. As FDA analyst Cooper stated, it was fact that the study became unblinded early on. And since the AZT trial was not blinded, the entire study was invalid and worthless. On this basis alone, FDA approval of the drug was neither proper nor legal.
Sloppiness, improprieties, false data
The AZT trial was characterized throughout by sloppiness and lack of control. Recording forms were poorly designed, leading to confusion when doctors were asked to make judgments. For example, doctors were asked to record 10 subjective symptoms "often associated with HIV infection", and to decide whether they were symptoms of AIDS or adverse reactions to the drug treatment. Understandably it was hard to differentiate among "malaise, fatigue, and lethargy", let alone to decide whether these were caused by drug or by disease. Midway through the trial the "sponsor" (Burroughs-Wellcome) substituted a 33-item "AIDS-related signs and symptoms" sheet, at which point confusion became utter chaos. Most of the medical centers were unable to relate one form to the other, or even to comprehend the 33-item form, and so in the end the incomplete data on the 10-item form served as the patients' only baseline data.
When FDA analysts reviewed the Case Report Forms, numerous improprieties were observed:
* Symptoms previously checked off on the 10-item sheet were crossed out or otherwise changed, usually without the principal investigator's initials, and sometimes with a date of change much later than the date the form was originally filled out, without explanation as to why changes were made.
* "Transcription" of data from 10-item symptom form to the 33-item form was performed, sometimes without date of initials of who did the transcribing. Sometimes the original form was not submitted.
* Adverse experiences were sometimes crossed out months after initially recorded, even though "possibly related to test agent" had been checked off originally by the investigator or his designee.
The last set of improprieties is especially serious, as it appears to be tendentious, favoring AZT by reducing the cases of adverse reactions to the drug. If done deliberately this would constitute cheating and fraud, things that people controlling and directing studies must constantly be vigilant against. If there can be cheating in little things, there can be cheating in big things as well.
Having detailed these various improprieties, the FDA analyst insouciantly dismissed the whole mess with a sentence that caught me completely off guard:
Whatever the "real" data may be, clearly patients in this study, both on AZT and placebo, reported many disease symptom/possible adverse drug experiences.
"Whatever the 'real' data may be..."! I can't get over this phrase. Is this an expression of bureaucratic cynicism, a sardonic form of humor, simply indifference, or what? Do FDA analysts even care whether their data is "real" or not?
Serious problems were uncovered at one of the 12 medical centers. According to an FDA analyst:
The FDA inspector found multiple deviations from standard protocol procedure, and SHE RECOMMENDED THAT DATA FROM THIS CENTER BE EXCLUDED FROM THE ANALYSIS OF THE MULTICENTER TRIAL. [Emphasis added.]
The FDA inspector's report did not reach an appropriate department until late December 1986, three months after the trial had been terminated. The decision was then made...
...to request inspection of all twelve centers which participated in this trial, due to the importance of this drug, its high public visibility, and because one of the early inspections had revealed "significant deviations" from FDA regulations regarding the proper conduct of clinical investigations.
At this point inspecting all 12 centers was like locking the barn after the horse was stolen. Of grave concern is the fact that one of the problems noted in the delinquent center had to do with "drug accountability", perhaps the most serious impropriety that could be imagined. If there is even the slightest reason to doubt that all "AZT patients" really were getting AZT, and all "placebo patients" really were getting placebos, then the study has fallen apart at its very core.
In addition, there were numerous cases of "protocol violations". When the study was designed, various conditions were defined as constituting "protocol violations", as a result of which a patient's data would be excluded from the data base. Most of the protocol violations concerned the unauthorized use of other drugs in addition to the treatments administered in the study. These restrictions were necessary in order to avoid drug interactions, confounding results, and so on. At an FDA in-house meeting convened to decide what to do about the patients in whom protocol violations were noted, one FDA officer commented that "if exclusion of all patients with protocol violations were strictly applied, quite a few patients would probably be deleted from the database."
After a certain amount of agonizing over the "highly visible, potentially inflammatory issue" of whether to exclude data from the delinquent center or from patients with protocol violations, it was decided to exclude nothing. False data were retained. Garbage was thrown in with the good stuff. These appalling decisions were made with the following rationalization:
Because the mortality analyses were so strongly in favor on the drug, any slight biases that may have been introduced when minor 'protocol' violations occurred were highly unlikely to influence the outcome."
This is egregiously beside the point. It is irrelevant whether or not throwing in bad data with good data will "influence the outcome". The point is that you don't do it on principle. It is an absolute and iron-clad principle of research that you don't use bad data. No principled analyst would ever proceed to interpret data that he knew were contaminated.
One may note that not a hint of these problems appears in the NEJM reports by Drs. Fischl and Richman.
Mortality
The mortality data that so dazzled the FDA that they terminated the AZT trial prematurely and accepted bad data are shown in Table 2.
TABLE 2
Mortality
Double-Blind, Placebo-Controlled Trial
 
AZT
Treatment
Placebo
Treatment
Bases: Total Who Began Trial(145)(137)
Cumulative Deaths During Trial1%14%#
Weeks Of Treatment (Mean)(17.6)(16.9)
# Significantly higher than AZT at the 99% confidence level.
Only 1% of the 145 AZT patients, compared to 14% of the 137 placebo patients died during the course of the trial. Statistically, this is highly significant-the probabilities are better than 99 out of 100 that the difference (1% vs. 14%) is real, as opposed to being a product of chance.
One must caution, however, that these mortality data reflect a very short time period-only 17 weeks, on the average. It would be fallacious to assume that the death rate would have continued to be higher in the placebo group if the time period were 30 weeks, or a year, or two years.
In addition, there are good reasons to be skeptical of the mortality data. For one thing, the death rate in the placebo group is shockingly high. According to doctors in New York with extensive experience in treating AIDS patients, with good patient management, nowhere near this many patients ought to have died in such a short time.
In addition, the death rate in the AZT group is suspiciously low when compared with other trials of AZT. After the "double-blind, placebo-controlled" study was terminated, all patients were informed which treatment they had been receiving, and were offered the option of receiving AZT. (See Table 3)
TABLE 3
Mortality
Open-Label Trial Following Termination of Double-Blind,
Placebo-Controlled Trial (18 September 1986 - 13 February 1987)
 
Received AZT in Extended, Open-Label Trial
 
Total
Original Treatment AZT
Original Treatment Placebo
Bases: Total Participating(227)(127)(100)
Cumulative Deaths During Open-Label Trial (21 Weeks Of Treatment)10%8%12%
A total of 227 patients accepted the offer, and continued or began to receive AZT (127 who were originally treated with AZT and 100 who were originally treated with placebo). AZT no longer prevented patients from dying. In the 21 weeks of the "open-label" trial, 10% of the patients died. Curiously, not only deaths but also opportunistic infections increased in the original AZT group as soon as the first study was terminated. There is no good explanation why this should be so.
Another trial of AZT occurred prior to the "double-blind, placebo-controlled" trial. (See Table 4) This was a "Phase I" trial, intended to give a preliminary estimate of the drug's toxicities. In the Phase I trial, 12% died during a time period of only 6 weeks. The four patients who died were replaced, and all 33 patients continued to take AZT in an "extended trial", during which an additional 21% died. It is unclear from the FDA material exactly how long the extended trial lasted-but at any rate a cumulative total of one-third (33%) of the patients died, either in the phase I or in the extended trial.
TABLE 4
Mortality
Phase I Trial of AZT (No Placebo Control)
Base: Total Receiving AZT(33)
Deaths During 6-Week Trial12%
Deaths During Extended Trial21%
Cumulative Deaths33%
Burroughs-Wellcome provided data to the FDA on deaths which occurred among patients who began taking AZT following release of the drug. The information was in incredibly garbled form, but I was able to ascertain at least the deaths that occurred during the first 8 weeks of treatment. During this short time period 6% of the patients died. Table 5 shows a comparison of these four studies of AIDS or advanced ARC patients who were treated with AZT.
TABLE 5
Mortality Comparisons
(Four Studies Of AIDS/ARC Patients Treated With AZT)
 
Double-Blind Placebo Controlled Trial
(Mean: 17 Weeks)
Extended Open-Label Trial
(21 Weeks)
Phase-I trial
(6 Weeks)
Following Release of Drug
(8 Weeks)
Bases: Total Patients Participating In Each Trial(145)(227)(33)(2552)
Deaths During Trial1%10%#12%##6%#
# Significantly higher than the Double-Blind, Placebo-Controlled Study at the 99% Confidence Level or more.
## Significantly higher than the Double-Blind, Placebo-Controlled Study at the 95% Confidence Level.
It can readily be seen that the death rate in the "double-blind, placebo-controlled" trial (the first column) is significantly lower than in any of the other studies, especially considering that the trials in columns three and four represented much shorter time periods. In other words, the mortality data from the "double-blind, placebo-controlled" trial are almost certainly wrong, based on comparisons with mortality data from other AZT trials.
In addition, and I regret having to say this, skepticism is warranted by virtue of the stakes involved-hundreds of millions of dollars-and the participants: big business and the FDA. The materials released by the FDA show that Burroughs-Wellcome was quite willing to bend rules or stretch interpretations if doing so would facilitate approval for their product.
The FDA did not come to the AZT trials with clean hands. In fact, the FDA has a long history of collusion with industry. A number of examples can be found in the book, How to Get Rid of the Poisons in Your Body, by Gary Null and Steven Null.
Another example where the FDA catered to the needs of big business can be found in a crude propaganda piece, "Evaluation of Health Aspects of Sugars Contained in Carbohydrate Sweeteners", recently circulated by the sugar industry, and prepared by the Division of Nutrition and Toxicology, Center for Food Safety and Applied Nutrition, Food and Drug Administration. This report, which strives to exonerate sugar from any connection with obesity, diabetes, hypertension, tooth decay, etc., uses pseudo-scientific language and tables, but is conspicuously short on references. It is not hard to imagine that the authors of the sugar report were motivated by something other than scientific ideals.
One more example of the FDA's tainted past: For more than a decade, the FDA has been asked to recognize the fact that poppers are drugs, and to regulate them as such. The FDA has repeatedly refused to do so, claiming that poppers are "room odorizers", since they are labelled as such. This is preposterous, for the FDA has traditionally been concerned with truth in labelling. They would certainly take action if snake oil were labelled as an "AIDS remedy", or if cocaine were labelled as a "nasal decongestant". Why should they accept at face value the cynically ridiculous claim that poppers are used as "room odorizers"?
I am also distrustful of the mortality data because of the fact that problems with "drug accountability" were among those found at the delinquent medical center. Suppose that some of the placebo deaths were really AZT patients who had been posthumously reassigned? There are a number of ways that this could have been done. As a check it would be desirable to have some way of verifying that the placebo patients who died really had been placebo patients. Unfortunately, the causes of death were listed in perfunctory and even incorrect ways ("AIDS", "pneumonia [unspecified]", "suspected TB or CMV" or "suspected MAI or CMV"). Since death was not an endpoint of the study, many of the causes of death were not verified. No autopsies were performed. These might have yielded useful information, and would have verified whether or not there were traces of AZT or other drugs in the bodies of the "placebo" patients.
Project Inform requested copies of the medical records of the patients who died. It would have been possible to determine from these, with considerable accuracy, whether or not the patient had been treated with AZT. The FDA refused to release the medical records, claiming that they were "confidential". It is hard to see why the records would have been "confidential" if the FDA had whited out the names of the patients. And the FDA knows well enough how to white out things. What exactly is the FDA afraid of?
The inadequate descriptions of causes of death, the lack of verification of death causes, the lack of autopsies, the refusal to release medical records-these things are even more suspicious in light of the stringent procedures that the FDA laid down for trials of other drugs. In a recent trial of Ribavirin, autopsies were obligatory, and a Death Report form of more than 30 items had to be filled out for each patient who died.
Efficacy
The mortality data are even more suspect in light of the fact that the "double-blind, placebo-controlled" trial failed to demonstrate that AZT had any benefits, relative to the placebo group. Slight increases in the T-4 cell counts in the AZT group did not persist over time. There is no known mechanism by which AZT could produce benefits sufficient to account for the dramatic differences in mortality.
AZT was found to have "no significant antiviral activity against a variety of other human and animal viruses, including herpes simplex virus type 1, cytomegalovirus, adenovirus type 5, measles virus, rhinovirus 13, bovine rotavirus, and yellow fever virus. It has been shown to inhibit the replication of Epstein Barr virus (EBV)...though the clinical significance of this finding is unknown."
Although AZT (Retrovir) is officially defined as a drug for "symptomatic HIV infection", it was no more effective against HIV than the placebo was. Several measures of viral activity were used, and "no statistically significant changes in the percent of positive cultures or time to detection of virus in culture were observed." After reviewing the failure of AZT to prove efficacious in any known way, an FDA analyst concluded that AZT treatment is likely to be worse than the disease in the long run:
Of particular concern is the possibility that the hematologic toxicity of the drug when administered over a prolonged period of time may eventually debilitate patients to such an extent that they may become less able to resist opportunistic infections and other complications of HIV-disease [sic] than if they had been left untreated.
Toxicity
In summarizing adverse reactions to the drug, the FDA medical officer states, "The majority of patients who were randomized to receive AZT in this trial experienced significant toxicity." This is, if anything, an understatement, especially considering that many AZT patients were treated with the drug for only a few weeks. If all AZT patients had been treated for 24 weeks, as originally planned, the percentages experiencing various toxicities would undoubtedly have been even higher.
AZT patients suffered from many adverse reactions to the drug, the most severe involving blood toxicities. These are summarized in Table 6. In less than 18 weeks of treatment, on the average, almost one-third (31%) of the AZT patients required at least one transfusion; one-fifth (21%) of them required multiple transfusions.
TABLE 6
Blood Toxicity
(Double-Blind, Placebo-Controlled Study)
 
AZT Treatment
Placebo Treatment
Bases: Total Who Began Study(145)(137)
Experienced During Trial:  
ANEMIA
Moderate (Hb <7.5)
Severe (Hb <3.5)
Hemoglobin decreases >2g.

25%#
13%#
38%#

4%
2%
2%
TRANSFUSIONS
Had at least one transfusion
Had multiple transfusions

31%#
21%#

10%
4%
MARROW SUPPRESSION
Grade 3 marrow suppression (Hb <7.5g./deciliter, neutrophile <750, or white cells <1500)
45%#12%
MACROCYTOSIS (Associated With Pernicious Anemia)
Mean corpuscular volume
<100 cubic angstroms
Mean corpuscular volume
<110 cubic angstroms


69%#

41%#


-

-
LEUKOPENIA (white blood count <1500)27%#7%
NEUTROPENIA (neutrophile counts <750)16%#2%
Weeks Of Treatment (Mean)(17.6)(16.9)
# Significantly higher than Placebo at the 99% Confidence Level or more.
Marrow suppression was experienced by 45% of the AZT patients, but only 12% of the placebo patients. Macrocytosis (enlarged red blood cells, associated with pernicious anemia) occurred in 69% of the AZT patients, but in none of the placebo patients. This measure, which clearly distinguished AZT from placebo patients in over two-thirds of the cases, played a major role in the unblinding of the study among the doctors.
In addition to the "double-blind, placebo-controlled" trial, many experiments were performed, which further demonstrated the high toxicity of the drug. The results of the Cell Transformation Assay suggested:
AZT may be a potential carcinogen. It appears to be at least as active as the positive control material, methylcholan threne.
The FDA analyst who reviewed the pharmacology data, Harvey I. Chernov, succinctly summarized the effect of AZT on the blood:
Thus, although the dose varied, anemia was noted in all species (including man) in which the drug has been tested.
Chernov concluded his review of the pharmacology data by recommending that AZT should not be approved:
In conclusion, the full preclinical toxicological profile if far from complete with 6-month data available, but not yet submitted, one-year studies to begin shortly, etc. The available data are insufficient to support NDA approval.
Ethical issues
There is no doubt that AZT is a highly toxic drug, that it will be harmful to patients, many of whom are already severely debilitated. On the other hand, there is no scientifically credible evidence that AZT has any benefits whatsoever. The "double-blind, placebo-controlled" trial of AZT is unworthy of credence. Assurances from representatives of the pharmaceutical industry or the Public Health Service, that AZT represents the "best hope", are also unworthy of credence.
I submit that it is malpractice for physicians to prescribe AZT, a poison which can only harm the patient.
I submit that it was unethical for AZT to be approved on the basis of research which was, to put it as generously as possible, invalid.
The nation's blood supply belongs to all of us. If AZT continues to be administered to thousands of patients-apparently there are almost 10,000 patients on AZT, at last count -- this will mean an intolerable drain on the blood supply, with many AZT patients requiring transfusions as often as every other week. It is one thing when someone becomes seriously ill or has an accident or major operation. Such a person is entitled to receive blood. But AZT is now creating entirely another category of patient-those whose bone marrow becomes irreversibly damaged. A category of iatrogenic vampires. And this is gratuitous, the result of a drug that should never have been administered in the first place. In this sense AZT harms all of us, not just the patients who are being poisoned by it. *
Postscript: 9 March 1988
After I wrote the above article, I learned of a California lawsuit that charged collusion between federal agencies and Burroughs-Wellcome, the manufacturer of AZT. If such collusion did indeed take place as early as February of 1985 (a year before the AZT trials began), then of course it is likely that there was collusion in the trials as well.
Details of the lawsuit are found in an article in the Bay Area Reporter (5 November 1987) by Ray O'Loughlin, under the headlines, "Lawsuit Charges Collusion Between Feds, AZT Maker:
Company Donates $55,000 for Research; Special Status Granted for Marketing Drug". Following are some excerpts:
The two federal agencies which approve and regulate AIDS treatments are accused of colluding with drug manufacturers. The National Institutes of Health (NIH) and the Food and Drug Administration (FDA) are accused of expediting the approval of AZT in exchange for a $55,000 donation by the AZT manufacturer, Burroughs Wellcome. In July 1985, Burroughs received exclusive rights to market AZT for seven years.
The allegation is part of a class action lawsuit filed in June by San Francisco-based Gay Rights Advocates. The suit accuses the NIH of failing to spend $47 million appropriated by Congress for experimental drug treatments. In response to the government's motion to dismiss the suit, NGRA released a series of letters indicating that certain medications are put on a "fast track for approval." They charge that there are unethical conflicts of interest in the agencies' operations.
"If the judge allows this case to go forward, we will prove that government officials have been engaged in unethical and illegal conduct resulting in serious delays of promising new AIDS medications," said NGRA's legal director, Leonard Graff.
According to documents filed in U.S. District Court in Washington, D.C., Dr. Samuel Broder of the National Cancer Institute, part of NIH, encouraged Burroughs Wellcome to fund three research positions in his laboratory.
Shortly after that Burroughs applied to the FDA for "orphan drug" status for AZT. Two weeks later Broder's office received the check for $55,000 from Burroughs. That same day FDA granted the company exclusive rights to market AZT. Originally developed as a cancer treatment, AZT has been in existence for over 20 years.
"We're alleging a special cooperative relationship between sister agencies that put certain drugs on a fast track for approval," said Graff.... Broder's action, he said, "violates conflict of interest as set out in an executive order" issued by Pres. Lyndon B. Johnson in 1965. At the very least, it "indicates a cozy relationship," he said, between the agencies and the drug firm.
Regardless of whether or not there was collusion, the AZT trials were invalid, worthless, and fraudulent. "Fraudulent" is by no means too strong a word to use in describing a study in which false data were knowingly retained, and in which improprieties and violations of protocol were knowingly ignored. It is fraudulent to describe an unblinded study, which the AZT trials most certainly were, as being a "double-blind" study, as Margaret Fischl and Douglas Richman did in their NEJM reports. Either Fischl and Richman were unaware that the study had become hopelessly unblinded, in which case they are guilty of incompetence, or they did know and covered it up, in which case they are guilty of fraud.
On 27 January 1988, Perri Peltz of NBC news did an expose on AZT, which closely followed some of the points of my article (without giving me credit). NBC investigators independently found that:
- The test became unblinded early on. Everyone knew who was getting what.
- A chemist admitted analyzing medications for patients in the trials.
- Patients in the trials shared medications.
- There was mass tampering with the rules of the test-Patients took other medications. Such violations of the rules of the test took place from coast to coast.
- A government memo recommended that Boston be dropped from the study because of gross improprieties. Nevertheless, the bad data from this center were retained. The memo observed that if all patients with protocol violations were dropped, there wouldn't be enough left in the study.
Representatives of the NIH and the FDA resorted to stonewalling. According to Perri Peltz:
"When preparing this report we repeatedly tried to interview Dr. Anthony Fauci at the National Institutes of Health. Both Dr. Fauci and Food and Drug Administration Commissioner Frank Young declined our request for interviews."
[NOTE: ALL TABLES IN THIS ARTICLE ARE MY OWN; THEY ARE NOT TAKEN FROM THE NEJM REPORTS.]
References:
1. Peter H. Duesberg, Ph.D.; "Retroviruses as Carcinogens and Pathogens: Expectations and Reality"; Cancer Research, 1 March 1987. John Lauritsen; "Saying No to HIV: An Interview With Prof. Peter Duesberg, Who Says, 'I Would Not Worry About Being Antibody Positive'"; New York Native; Issue #220.
2. Duesberg, op. cit.; Lauritsen & Duesberg, op. cit.
3. J.A. Sonnabend, MRCP and Serge Saadoun, M.D., M.S.; "The Acquired Immunodeficiency Syndrome: A Discussion of Etiologic Hypotheses"; AIDS Research; volume 1, number 1, 1984.
Joseph A. Sonnabend, MD; "Looking at AIDS in Totality"; New York Native, Issue #129.
4. Nathaniel S. Lehrman, M.D.; "Is AIDS Non-Infectious? The Possibility and its CBW Implications"; Covert Action, Number 28. Nathaniel S. Lehrman, M.D.; "A 'Natural' Epidemic?"; New York Native, Issue # ?.
5. Lawrence Hauptman, Ph.D.; "Statistical Review and Evaluation"; NDA# 19-655/Drug Class 1A, Burroughs-Wellcome Company, AZT Capsules; p. 17.
6. Ellen C. Cooper, M.D., M.P.H.; "Medical Officer Review of NDA 19-655"; p. 70.
7. Ibid. p.6.
8. Ibid. p. 70.
9. Ibid. pp. 77-78.
10. Ibid. p. 78.
11. Ellen C. Cooper, M.D.; "Addendum #1 to Medical Officer Review of NDA 19,655"; p. 1.
12. Ibid. p. 1.
13. Ibid. p. 2.
14. Ibid. p. 3.
15. John Lauritsen and Hank Wilson, "DEATH RUSH: Poppers & AIDS", Pagan Press 1986.
16. Cooper, "Medical Officer Review...", p. 128.
17. Ibid. p. 34.
18. Ibid. p. 131.
19. Ibid. p. 39.
20. Harvey I. Chernov, Ph.D.; "Review & Evaluation of Pharmacology & Toxicology Data", p. 4.
21. Ibid. p. 7.
22. Ibid. p. 8.

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