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FDA Action Handbook



Combined Phases II-III and a new Phase IV?

Concern that data was not being collected on rare reactions after drugs were approved for marketing spurred Senators Ted Kennedy and Jacob Javits to introduce a bill in 1977 requiring post-marketing surveillance. Elements of this idea are currently being incorporated into Bush-Young regulatory reforms and would result in a so-called "Phase 4," which would collect data after drugs are marketed.

Early in the Reagan administration, Vice President Bush was named Chairman of the President's Task Force on Regulatory Relief. Stymied by a divided Congress and an indifferent public, this august body had little impact on most industries, with the exceptions that larger trucks increased highway carnage and economic exploitation of Federal land increased pollution.

Imagine the surprise of AIDS advocates, therefore, when institutions such as the Heritage Foundation and the Wall Street Journal, never hitherto friends to the AIDS community, began issuing reports and editorials critical of the FDA's deadly AIDS drug delays.

Unexpectedly, AIDS provided a smokescreen for pharmaceutical interests favoring deregulation of this heavily regulated (and highly profitable) sector. Certainly, if Kefauver were repealed it would be devastating for American consumers, and we must keep very focused on our goal of early release of drugs for life-threatening illnesses. The drug industry is very wealthy and fundamentally interested in maximizing its profit margin. coupled with the "deregulationism" of the Reagan Administration, AIDS activists find themselves in the ironic position of reading recommendations to suspend "the drug-approval requirements of the Kefauver Amendments for AIDS drugs in The Wall Street Journal (6.15.88) and listening to George Bush advocate the early release and marketing of drugs for life-threatening illnesses. Some of these suggestions will not require new legislation, but only a rewriting of current Federal regulations governing the FDA.

AIDS advocates must be careful to keep their agenda, supporting earlier access to promising life-saving drugs for life-threatening disorders, from becoming confused with the Bush deregulation/Wall St. Journal/Heritage Foundation agenda of sweeping drug industry deregulation. It would be a disaster for all American consumers, including people with HIV infection, if the Kefauver amendments were repealed and drug companies were no longer required to prove safety and efficacy for most drugs. It is important to recognize that the FDA already has much of the regulatory authority to expand access to the drugs we need. (SS/MH)

Now the FDA is talking about combining Phase 2 and Phase 3 testing, ostensibly to streamline the approval process for AIDS drugs. This might shorten the approval process, but it might also narrow the number of people in drug trials, from thousands to hundreds. Not by coincidence, the initiative followed a July 29 meeting between Commissioner Young and the Bush Task Force. Just as the orphan drug licensing of IV-pentamidine was announced by HHS Secretary Margaret Heckler in the midst of the 1984 election campaign (in October, to be exact), so, it seems, does the 1988 Republican campaign want to have an AIDS feather in its rather tattered cap.

According to the FDA proposal, a drug could be approved after joint Phase 2-3 trials if it met established standards of safety and efficacy. If it was almost there but not quite, the drug could go into additional studies and Treatment IND. If the Phase 2-3 was not a good study, the drug company would have to do a regular Phase 3 study, further delaying approval. The FDA claims problems in the system will be worked out by working more closely with drug companies -- hardly an encouraging prediction, given their shabby oversight and contradictory feedback to Syntex, Imreg and others.

Another possibility being discussed is a possible Phase 4, in which new drugs would continue to be monitored after marketing began. This was originally proposed by Senators Javits and Kennedy in 1977. They wanted to ensure that rare side reactions (often 1/20,000 - 1/200,000, neither of which would turn up in a typical Phase 3 test of 2,000 subjects) would be recorded. The Bush initiative, spearheaded by a spring Heritage Foundation report and a series of editorials in The Wall Street Journal, seems to be using AIDS as a wedge to open the door to a less regulated drug market -- and a bonanza for pharmaceuticals. AIDS advocates must not let their agenda of early release of some drugs for life-threatening conditions be confused with the business community's hopes for a deregulated drug market. We must fight for mandatory Treatment IND, open books for orphan drug monopolies, price controls on orphan drugs, post-approval monitoring for new AIDS drugs, Medicare and insurance coverage of experimental treatments.


The underground market is the way people gain access to possible treatments outside the normal and extraordinary procedures described above. Substances available on the underground market include AL-721, egg lecithins, German enzymes, ribavirin, dextran sulfate and DNCB.

The FDA has control over the underground market through the Food, Drug & Cosmetics Act. under this law, the FDA can prohibit the sale, manufacture and interstate distribution of any unapproved substance which is marketed as or believed by the customer to have a drug-like effect. This applies whether or not it is a "food substance" like AL-721 or a "drug" like dextran sulfate.

The law applies whenever the substance crosses state or national boundaries. This means the FDA governs transactions in which a customer goes from New York to New Jersey to buy a drug, or sends an out-of-state check mail order, or when a drug ingredient comes from out of state even if the drug is manufactured and sold within New York State, or when the drug is imported abroad -- from Mexico (ribavirin), France (Imuthiol), Israel (AL-721) or Japan (dextran sulfate).

It is illegal to advertise therapeutic effects of unapproved drugs. From time to time, local FDA offices, particularly on the West Coast, have sized shipments designated for the underground market. But, after the inevitable protests, the national office in Rockville, MD, has always told them to lay off. The FDA is a master of the bureaucratic pressure-game known as nice-cop/tough-cop.

In Boston at the Lesbian and Gay Health Conference in July, Frank Young announced a new policy: US residents may bring in unapproved drugs from foreign countries as long as the drugs are for personal use and not for profit. If the customs officials seize such a drug, the patient must produce a doctor's letter recommending the substance. People may import only a three-month supply of such a substance for personal use.

The FDA's policy on the underground market has been confused, but it seems to be becoming a basically "hands-off" one. this is different from the situation with laetrile for cancer, when manufacturers, distributors and people with cancer were prosecuted criminally and the substance seized. (MM)


Part 3:

How the FDA Betrayed Its Trust
And Intensified the AIDS Crisis

If the survival of humanity were up to bureaucracies such as the FDA in 1980s America, undermined by a strange and tortuous epidemic, the continuance of the species would be very much in doubt. The bureaucracy, however, could be counted on to continue in some vestigial form, perhaps in a convoluted cybernetic circuit. For whatever their stated original purpose, bureaucracies soon come to recognize their own survival and expansion as their primary mission. Like corporations, they consider the data of lives as raw material and grist for a perpetual-motion papermill. Human need, suffering and death count for very little when compared to the imperatives of orderly process and well-maintained policies.

Virtually everything that could go wrong in the FDA's response to AIDS did go wrong. Their well-trained publicity network continually beats the tiresome drum of praise for the rapid approval of AZT, the most expensive drug ever marketed. Burroughs-Wellcome profits jet AIDS researchers to cozy conferences around the world, subsidized by the sick and the dead. The benefits accruing to a giant pharmaceutical by close cooperation with its regulatory Agency were never clearer.

To other companies, however, the Agency proved more intractable. It buried Ribavirin under a flurry of noisy objections quietly withdrawn once the market had collapsed. It delayed DHPG by a set of zig-zag approval and disapproval maneuvers. It limited Trimetrexate to an absurdly small fraction of the people who could have benefited from it. IT sanctioned the injection of immune-suppressed babies with an invasive dangerous placebo. It played havoc with hopeful data from Imreg, then accused the company of stock manipulation. It sanctioned careerist infighting over rival antivirals, Peptide T and rCD4, while tacitly favoring the latter, in whose camp the university and corporate Big Guns were arrayed. It excluded the most dispossessed of the afflicted from any participation in AIDS drug trials.

Space is too short to document here all the outrages. Let what follow suffice. And let the AIDS communities no longer tolerate such malfeasance.


The story of pentamidine, the only drug known to be effective both in preventing and in treating Pneumocystis Carinii Pneumonia (PCP), the leading cause of death in people with AIDS in the USA, is a textbook case of the uncoordinated Federal response to AIDS, of underfunded agencies, of an FDA preoccupied with regulating drug companies rather than delivering effective drugs to PWA's, and of drug companies preoccupied with competition, price-gouging, and denying information and treatment to PWA's, in order to win the race for licensing.

Before the 1981 outbreak of AIDS, the need for pentamidine in the USA was so slight that the Centers for Disease Control (CDC) kept the entire supply (manufactured by a subsidiary of the French pharmaceutical, Rhone-Paulenc) in Atlanta. On occasion an organ transplant patient would contract PCP as a result of being chemically immuno-suppressed in order to prevent the immune system from rejecting the transplanted tissue. Repeated requests from New York doctors for pentamidine in the early 1980's were among the signals that warned CDC epidemiologist of the impending epidemic.

According to phamacologist Dr. Iris Long, pentamidine isethionate is "a very simple organic salt easy to manufacture." Nonetheless, as the epidemic spread, the CDC found its imported supply dwindling and the overseas manufacturer unwilling or unable to provide a reliable supply.

The 1983 Orphan Drug Act offered companies tax incentives and a limited monopoly on drugs for rare disorders, and the CDC shopped around the major drug companies hoping to find one to manufacture pentamidine. None would; they were blind to the skyrocketing AIDS caseload and convinced no profits lay there, an ironic conclusion in light of their later rush to compete for AIDS drugs.

So in 1983 the CDC approached LyphoMed (Melrose Park, IL), a "small company devoted principally to the manufacture and sale of generic injectable pharmaceutical products," according to its Vice President, Brian Tambi, testifying at the Weiss subcommittee hearings on April 29, 1988.

It took until October 1984 -- just before the Presidential elections, an interesting coincidence -- for Secretary of Health & Human Services Margaret Heckler to announce FDA approval of IV-pentamidine and the issuance of an Orphan Drug license guaranteeing LyphoMed the exclusive right to market intravenous and intramuscular pentamidine until 1991.

Injected pentamidine has severe side effects, including abscesses at the injection site, persistent nausea and appetite loss. This led to a search for a more specific, less toxic method of delivery. In early 1986, physicians began experimenting with aerosolized pentamidine, in which a nebulizer machine sprays tiny droplets of the drug directly into the lungs. The precise size of the droplets was critical to ensure they fit into the lungs' millions of tiny air sacs. Aerosolized administration delivers the drug directly to the endangered tissue. This eliminates injection site abscesses and other side effects. Finally, by reducing the side effects by aerosolizing pentamidine, it could be more safely used as a prophylaxis (preventive treatment) for PCP.

A 15-subject San Francisco trial reported in The Lancet on August, 1987 reported that 87% (13) were protected from PCP and remained healthy for several months. There were no controls in this trial, but the success rate was considered "equal or better than" established treatments such as Bactrim, Dapsone and injectable pentamidine.

These results could have led to thousands of saved lives in 1987 and 1988 had they not immediately been caught up in a maelstrom of corporate competition and bureaucratic torpor.

Orphan Drug licenses cover only the specific administration and indication they are issued for. This, LyphoMed only has a monopoly on injectable pentamidine for PCP treatment. A whole new Orphan Drug monopoly could be given to another company for aerosolized pentamidine used for PCP prophylaxis (prevention), since that was both a different method of delivery and a different treatment purpose.

LyphoMed chose to compete in the race for approval of aerosol pentamidine, and it chose, unusually for a drug company, to charge the patients receiving IV pentamidine for the research into aerosolized pentamidine. Usually trial drug research is covered by anticipated future trial drug revenues. This, and the cost of developing a corps of salesmen (called "detailmen" in the drug industry jargon) to sell pentamidine to physicians around the country, resulted in a 300% price increase for IV pentamidine, from $24.95 a vial to $99.95.

This prompted outrage in the AIDS community and a demonstration at LyphoMed's headquarters by C-FAR (Chicago for AIDS Rights). Cynically, the company offered to provide pentamidine at no charge to anyone C-FAR knew who need it. C-FAR rejected this offer and demonstrated. LyphoMed removed its corporate logo from the headquarters lawn before the protest



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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