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FDA Action Handbook





Meanwhile, the government could have been proceeding with its own trials of aerosol pentamidine. As with any new drug, the safest and most effective dose levels, as well as, in this case, the most effective method of administration (the best nebulizer and droplet size) had to be established.

In March, 1987, aerosol pentamidine was declared a "high priority" by the National Institutes of Allergy and Infectious Diseases (NIAID). 13 months later, when he testified to the Weiss subcommittee, NIAID Director Dr. Anthony Fauci admitted he had still not begun testing aerosol pentamidine for lack of a single staff person. 60% of PWA's get PCP; it is the leading cause of death in AIDS. How many thousands might be alive today if the government had started aerosol pentamidine trials in March, 1987?!?

As the AIDS caseload mounted, companies hitherto uninterested in drugs for the epidemic suddenly sought entry in the drug trials process. Fisons, Inc., a giant British multinational pharmaceutical, began aerosol pentamidine trials in England, Canada and the USA. The London trial, in which an ill-designed nebulizer delivered particles too large to penetrate the lung sacs (3.5 microns average), had gruesome results, with some subjects hemorrhaging on the machine and all dying from PCP.

Even now, Fisons is conducting trials at 2 Boston hospitals. It refused to tell ACT UP/Boston which nebulizer was being used. ACT UP/Boston staged a highly successful demonstration at Fisons' Bedford MA, headquarters. This and media attention put an end to Fisons' corporate stonewalling; Fisons' representatives said they'd never met with a group as well-informed as ACT UP/Boston. Because Fisons has the resources necessary to conduct lengthy clinical trials and present them in proper statistical form, they may well beat the smaller, less efficient LyphoMed to the FDA license. another competitor, according to an FDA source, is Rhone-Poulenc, the very manufacturer who was unwilling to guarantee the CDC a supply 3 short years ago.

LyphoMed is having problems unrelated to pentamidine. Factories in Florida and Illinois have been raided by the FDA which, claiming poor quality control, shut them down. One official said, "what came out was they were really in bad shape." LyphoMed transferred much of its manufacturing work to Puerto Rico.

LyphoMed is supplying its aerosol pentamidine to New York's Community Research Initiative (CRI) and to Boston's Fenway Community Health Center. Hundreds, if not thousands, of subjects are being effectively protected from PCP. LyphoMed's product uses the efficient Respigard untrasound nebulizer, which delivers small enough droplets (1.2 microns average). yet neither insurance companies nor Medicare will pay for the treatment, since it is still experimental. This affluent patients enjoy longer and healthier lives, while the poor die as fast as before.

Pentamidine this stands as a graphic indictment of the uncoordinated anti-AIDS efforts of the CDC, the FDA and NIH's NIAID. It proves the drawbacks of private enterprise in providing life-saving treatments to everyone affected by a deadly illness. It exposes the inadequacies of both large pharmaceuticals and small generic drug makers. It shows that in this election season of 1988, health care in America is still not a right, but a privilege. (MH)


The only AIDS drug released thus far under the Treatment IND program has been Trimetrexate. Studies suggest Trimetrexate is a more potent inhibitor of PCP pneumonia, the leading cause of death in AIDS, than either standard therapies, Bactrim or IV-pentamidine. Yet the FDA, out of alleged fear for Trimetrexate's side effects, limited its use under Treatment IND to patients who had had serious or life-threatening toxic reations to both Bactrim and IV-pentamidine. The Treatment IND did not include PWA's who had found both drugs merely ineffective (as opposed to toxic). Thus, in order to use Trimetrexate, a pneumonia patient must be virtually at death's door, delivered there not only by pneumocystis but by toxic drugs and heartless regulations. By July, 1988, only 89 patients had received Trimetrexate. In August, after substantial pressure from the AIDS community and a threatened lawsuit from the Lambda Legal Defense & Education Fund, the FDA expanded access to trimetrexate. Currently, trimetrexate is available under a treatment protocol to those patients who experience no response to approved PCP therapies and who do not qualify for NIAID studies. Trimetrexate will be available free of charge to patients in the treatment protocol. It is an open protocol in which 100 subjects whose PCP is refractory (resistant) to other treatments will get trimetrexate for 21 days. If the treatment seems effective, the open protocol will be expanded. (MH/MM)


Now that Phase 3 data on the promising immunomodulator Imreg-1 is available, it would seem an ideal candidate for Treatment IND status; such status would indeed seem past due. No side effects have been reported. Even the least favorable reading of available data indicates that treatment with Imreg-1 yields a modest, appreciable, sustained improvement of immune response in a great majority of the symptomatic HIV-infected people treated with it. Its sponsors credit with curtailing the progression of HIV infection to more serious stages.

Yet, as has happened so often over the course of the AIDS epidemic, the system has failed. Due to FDA bias either against the drug or against the company which developed it, the small New Orleans-based research in Imreg, or to the company's reluctance to apply for Treatment IND status, or its ignorance of how to (a reluctance and ignorance many pharmaceuticals privately admit to), HIV-infected people are once again deprived of a promising agent.

In a flurry of charges and counter-charges made by the company, rival clinical investigators, a Congressional subcommittee and the FDA concerning manipulation of stock, data and the press, the central issue has been obscured. There is currently no immunomodulator approved for HIV-infected people. Few immunomodulators are currently in drug trials. Yet most experts agree that, for the foreseeable future, the best way to treat symptomatic HIV-infected people is with a combination of an anti-viral (which attacks HIV at some point in its life cycle) and an immunomodulator (which helps rebuild an infected person's weakened system).

When ACT UP visited the Republican Convention in New Orleans in August 1988, it took a side trip to Imreg headquarters to call attention to the delay and demand its end. This demonstration put both the drug company and the FDA on notice that thousands across the country are following their inaction and will not be silent about needless delays in speeding essential treatments to HIV-infected people. (JE)


Even now, 26 years after the Kefauver amendments, many companies do not know, do not care, and are not advised by the FDA, how to execute will-designed and scientifically valid clinical trials. For drugs with promise, there is little excuse for the conflicting signals the FDA provides manufacturers. One salient example is Syntex, manufacturer of DHPG (Ganciclovir), which effectively combats CMV-retinitis and colitis in people with AIDS.

Syntex first developed DHPG as an anti-herpes drug, but lost the licensing battle to Burroughs-Wellcome's acyclovir. Cytomegalovirus (CMV), which can cause blindness and diarrhea in up to 20% of people with AIDS, is closely related to the herpes viruses, so Syntex began testing the drug against these infections, with notable success. Intravenously administrated, DHPG halts progression of blindness, but must be taken weekly for life to prevent CMV from advancing.

Emboldened by the drug's success, Syntex botched the next stage, well-planned clinical trials. There were two problems. Since DHPG was the only know substance effective against CMV retinitis, the problems with using placebo in an AIDS-related drug trial were even more glaring than usual. But DHPG also is bone-marrow suppressive, like AZT, and can cause anemia.

According to an FDA source, Syntex "knew it had a winner on its hands," so it simply issued the drug, under Compassionate Use IND, to doctors. Other sources say the FDA flip-flopped, initially approving Syntex's plan, then turning down the data after it was collected. As a result of poor communication between FDA and Syntex, and due to poor FDA oversight, no clear data bout the most effective, least toxic dosages were gathered. Without knowing the safest and most effective dose level, the FDA claimed it could not approve the drug. But the FDA had originally approved the Compassionate Use IND as a way to get DHPG approved. Blame rest on the FDA for 1) failing to set proper standards for collecting data and 2) changing its mind about the data collection process after the data had been collected. (MH/MM)

The Invasive IVIG Pediatric AIDS Trial

The National Institutes of Health (NIH), which oversees the Federal ACTG (AIDS Clinical Trials Group) seems to have finally realized that it is impossible to enroll large numbers of HIV-infected people in trials using placebos (inactive substances against which test drugs are sometimes measured) because such trials require many people who are ill to relieve no treatment. Many who do enroll in such trials quite understandably continue taking drugs outside the trial and thus skew trial results. This realization has not diminished the passion of the NIH for employing placebos in trials for HIV-infected children who cannot speak out for themselves and lack enough vocal advocates: the new batch of NIH AIDS trials has no fewer than three placebo-controlled trials.

Up to now, children with AIDS have been almost wholly excluded from drug trials, and therefore, from experimental treatment. Of the more than 100 AIDS drug trials listed in AmFAR's May 1988 Directory, 4 trials are for children. It is ironic indeed that the only such trial that is not small and preliminary is, ironically a placebo-controlled one dangerous to its subjects.

Over 1,000 children have AIDS and as many as 10,000 are thought to be HIV-infected. 65% of those with AIDS have died. Since 1980, Dr. Ayre Rubenstein, a NYC Pediatrics Professor, has treated immuno-deficient children with intravenous immunoglobulin (IVIG), a blood-derivative. Dr. Rubenstein reported that over 2 years, only 7% of IVIG-treated children developed bacterial infections, while 78% of those untreated developed them.

Other doctors questioned those results, a national trial was designed and $3.8 million was allocated for a double-blinded, placebo-controlled study. For many children with AIDS, whose parents are most often people of color, poor, IV drug users and HIV-infected themselves, participating in a drug trial offers the best chance of receiving quality treatment. Babies have no chance of giving "informed consent" and the prospect of better care for children may be an un-planned coercion of their parents or guardians.

The IVIG trial compares two groups of children; the treatment group of 200 children will receive the test drug IVIG, the control group will receive a placebo, in this case IV-administered albumin (egg white). Usually the placebo in a drug trial is harmless, a sugar pill. But this trial is invasive. The method by which placebo is administered (IV) threatens to infect the control group with the very infections it seeks to prevent in the treatment group. Moreover, the injection takes from 2-8 hours, biweekly; some infants must be restrained while being injected.

Monthly injection and infusion of 2-6 hours exposes the untreated immune-suppressed children on placebo to possible bacterial infections. Although designers of the trial acknowledge this in their written protocol for the trial, the consent forms that parents or guardians must sign fail to mention the danger. This is unethical and illegal. Some infants, in addition, must be restrained during injection.

It is unethical to use any placebo in a group of seriously ill subjects. ACT UP opposes the use of a placebo in an AIDS drug trial when the drug is available -- as i IVIG -- outside of the trial. That some have access to a sure supply of a promising drug when others have to take their chances raises serious question of equity.

Despite the protest of AIDS activists, ethicists and community clinicians over this trial, the NIH has decided to design another placebo-controlled IVIG trial for 260 children; in this trial all subjects will receive AZT. AIDS activists in New York are gearing up for another battle with the NIH. The same activists are demanding that the FDA, which has in the past approved such trials, stop this one. (JE)




Back to beginning of FDA Handbook > > >

Introduction: WHY THE FDA?

The Federal Health Bureaucracy

___Who's Involved with AIDS
___The NIH and AIDS
___AIDS & the FDA
___FDA: Who Does What
A Brief History of the FDA

___Elixir of Sulfanilamide
___The "Golden Age" of Pharmaceuticals
___The Kefauver Amendment
The FDA and Drug Companies:
___Incest and Competition
___The Orphan Drug Act

The Standard Drug Approval Process:
___Clinical Trials: Phase I, II and III
___Protocols, IRB's and Informed Consent
Extraordinary Release:
___Treatment IND
___Compassionate Use IND
___Post-Marketing Surveillance and De-Regulation:
___Combined Phases II-III and a new Phase IV?
The Underground Market

Pentamidine Wars
Trimetrexate: Treatment IND Hoax
Imreg-1: Treatment IND Omission
DHPG: Bad Oversight Delays Sight-Saving Drug
IVIG: A Pernicious Placebo
Exclusion of Women, People of Color, Poor People,
___People in Rural Areas, IV Drug Users, Hemophiliacs,
___Prisoners & Children from Drug Trials
FDA & Discrimination in Drug Trials
The Rights of Drug Trials Subjects:
___Drug Trials are Health Care Too
ATR: AIDS Treatment Registries, Local & National

Federal Drug Law Timeline

Federal AIDS Bureaucracies
AIDS Drug Development Flowchart



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