Treatment Access - Activists' Philosophies

 

Parallel Track and Accelerated Approval
by Raan Medley

 

The "History of Treatment Activism ..." essay (see link below) concerns the internal struggles within the treatment activist community in the days, weeks and months leading up to the approval of the new class of antiretrovirals called protease inhibitors. In it, I use the terms "expanded access" and "accelerated approval" interchangebly to illustrate ACT UP's core belief in treatment options for people with AIDS and HIV. But, in actuality they are two very different concepts and for readers wishing to distinguish them it is useful to remember that "Accelerated Approval" refers to drugs within the FDA pipelline while "Expanded Access" refers to delivering drugs outside the traditional FDA approval process.

ACCELERATED APPROVAL

A New Drug Application (NDA) may be in Phase I or Phase II and III testing, and depending on the stringency of the criteria may be using either clinical endpoints or some substitute to determine whether a drug is working.

Traditionally, clinical endpoints have been defined as death and or sickness, In other words, a drug would not be approved until over time a certain number people were shown to get sick and die--or not. In the case of AIDS such Phase II and Phase III could conceivably take many years to complete. Phase I is usually a shorter trial used to determine whether the drug has any blatantly unacceptable toxic effects.

In November, 1991, in direct response to the concerns of ACT UP and Project Inform, the FDA initiated several reforms designed to shorten the approval process. One was to farm out much of the design and execution of clinical trials to private research groups. Another was to encourage the replacement of clinical endpoints with a series of substitutes--or surrogate--markers in each trial design.

The result was that by 1992 the overall number of drugs approved was the highest since 1986, and ddi and subsequently, ddc were approved in record time.

However, surrogate markers were and remain a controversial topic. Merely counting t-cells did not accurately predict disease progression. P-24 antigen detection (someone described them as little footprints left by the virus) while helpful were not much more predictive in the short-run. These difficulties led to a questioning of the entire Accelerated Approval process by some quarters of the community. Some of the feuding described in "A History of Treatment Activism..." has been dampened with the advent of fairly accurate viral load testing--but, not all.

EXPANDED ACCESS

Expanded Access addresses the problem of how to deliver experimental drugs to people who for various reasons cannot participate in FDA monitored post-Phase I trials while those trials are underway.

The following is suggested as a companion piece to "A History of Treatment Activism: ACTUP and TAG..." Briefly, it describes the negotiations leading up to Parallel Track, sometimes referred to as Expanded Access, probably ACT UP's signature contribution to treatment activism in the late 1980s:

THE PARALLEL TRACK: AIDS DRUGS NOW (excerpts from the ACT UP/New York Treament Decisions Handbook, written in Autumn 1989 by John Bohne, Tom Cunningham, Jon Engbretson, Ken Fornataro and then member, Mark Harrington)

"After ACT UP joined with activists from around the country to besiege the FDA on October 11, 1988, the previously monolithic Federal agency became sensitive to its public image and took steps to reverse its previous bad acts.

"In summer 1988, FDA Commissioner Frank Young publicly estimated only 2 new drugs for AIDS would be approved between then and 1991, saying "We can't approve drugs that aren't there," the pace of new drug approvals has since stepped up markedly. In December 1988, alpha interferon was approved for treatment of Kaposi's sarcoma. In June 1989, FDA approved aerosol pentamadine for PCP prophylaxis, and DHPG for CMV retinitis. It also approved EPO for kidney disease and granted it Treatment IND status for treatment of AIDS and AZT- related anemia.

"But making up for past erors will not be enough. The regulatory system must become flexible enough to avoid repeating these mistakes in the future - to avoid making them in the first place.

"In June 1989, ACT UP presented its National AIDS Treatment Research Agenda at the FIfth International Conference on AIDS in Montreal, Quebec. This document had and extraordinary impact. Not only was it the first time an activist group had put forth a comprehensive plan to prioritize AIDS treatment research -- it was the first time anyone had done so.

"Upon its return to the US, ACT UP embarked upon a round of intensive negotiations with FDA Anti-Viral Drugs Division director Ellen Cooper, NIAID Director Anthony Fauci, and representatives of Bristol-Myers Co., the licensees of ddi, a new antiretroviral drug with less apparent toxicity than AZT.

"These discussions focused on several elements of the Treatment Agenda -- "full participation of people with AIDS and their advocates in every level of trial design and execution," "an end to the quarantine of the AZT intolerant," -- with a view towards implementing several of the ACT UP demands in the Phase II ddi trials which were scheduled to begin in September 1989.

"The expanded access program for ddi (and hopefully, other drugs) which came out of these discussions came to be referred to as the Parallel Track. That is, it would be a second track, parallel to the controlled clinical trial, available to those who could not participate in the controlled trial, either because they were too sick, lived too far away, could not tolerate one of the drugs being tested, or were otherwise ineligible for the trial but needed the drug.

"Congressman Henry Waxman held hearings on the Parallel Track proposal on July 20. The FDA NIAID gave vaguely supportive statements. Assistant Secretary for Health James Mason was equally evasive. Jim Eigo of ACT UP and Martin Delaney of Project Inform gave the most thorough outlines of the need for the program and what it should entail.

"Mason subsequently asked an FDA advisory committee -- the Anti-Infective Drugs Advisory Committee -- to hold a public hearing on the Parallel Track. ACT UP formed a coalition with about 20 other AIDS and gay rights groups form around the country. They agreed upon a consensus statement about the reasons for and structure needed for the Parallel Track. Elements from that consensus statement and ACT UP' s longer document on which it was based are printed below.

 

"GUIDELINES FOR THE PARALLEL TRACK PROGRAM FOR AIDS AND HIV-RELATED TREATMENTS"

August 17, 1989

TO:

James Mason, M.D., Dr. P.H.
Assistant Secretary for Health
Department of Health & Human Services

FROM:

AIDS Action Council
AIDS Coalition to Unleash Power (ACT UP)/New York
AIDS Coalition to Unleash Power (ACT UP)/ San Francisco
AIDS Project Los Angeles (APLA)
American Association of Physicians for Human Rights
Amerian Foundation for AIDS Research )AmFAR)
Community Research ?Alliance
Gay Men's Health Crisis (GMHC)
Human Rights Campaign Fund (HRCF)
National Association of People with AIDS (NAPWA)
National Gay Rights Advocates (NGRA)
Project Inform
San Francisco AIDS Foundation

 

INTRODUCTION

The concept of Parallel Track permits the treatment use of experimental drugs while controlled efficacy trials are ongoing, thus offering earlier access to promising new treatments to people with AIDS and HIV-related conditions. This concept has been widely hailed. The AIDS commnity is eager to work with FDA, NIH, pharmaceutial sponsors and researchers to rapidly define and implement the Parallel Track.

Parallel Track offers the best hope to address some of the most urgent problems posed by the AIDS epidemic: the rapidly expanding caseload, the proliferation of new promising treatments, the inability of traditional research institutions to test each promising therapy, the inability of most HIV-infected Americans to enroll in controlled clinical trials, and the use by many patients, out of necessity or choice, of other medications.

The importance of Parallel Track lies in its potential to offer the widest possible access to new drugs for people who lack other-than-experimental treatment options, and to make it possible, at the same time, to proceed efficiently with drug licensing.

Existing mechanisms to widen availability of new treatments outside of controlled trials, such as Treatment IND and Compassionate Use IND, have met only a fraction of existing needs. Parallel Track may resolve access needs, provided, we believe, the principles outlined below guide the implementation of the Parallel Track concept.

1. ACCESS

Parallel Track should encompass post-Phase I open-label treatment protocols for people unable to participate in controlled clinical trials for AIDS and HIV-related treatments. Drugs should be eligible for Parallel Track as soon as a tolerably safe dose range has been defined and preliminary evidence of efficacy has been obtained. Drugs qualifying for Parallel Track should be accessible nationwide to qualified physicians in private practice, community hospitals, communtiy-based health institutions, and public health clinics in addition to academic research institutions.

Adverse reaction data should be gathered on all Parallel Track subjects. Whenever possible, efficacy data should be gathered as well, through organizations such as community-based research groups. The resulting data on interations between the Parallel Track drug and concomitant medications forbidden in controlled trials would provide valuable real world information at earliest possible time.

2. ELIGIBILITY

Patient's eligibility for treatment under Parallel Track should be determined by qualified physicians on a case-by-case basis. However, the same access criteria should apply under different circumstances. The following groups of HIV-infected individuals should have access to treatment under Parallel Track:

Because of the generally large number of people with AIDS and HIV disease and because most of them will be unable to particiapate in controlled clinical trial, it is anticipatedthat the existence of Parallel Track will not compete with, but rather complement, more formal studies.

 

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The FDA Anti-Infective Drugs Advisory Committee gave its endorsement of the consensus statement and the Ad Hoc Parallel Track Working Group first met on August 30, 1989. ACT UP is represented on this group and will be represented on NIAID's AIDS Research Advisory Committee (ARAC) which will define and implement the Parallel Track program.

Parallel Track may help solve the problem of access to certain vital experimental AIDS treatments, but it will not itself solve the problems of controlled clinical trials. Activists will have to continue their close scrutiny of the entire clinical trial system to ensure that better treatments are developed fast."

 

see also: ACT UP and TAG ... Brief History of Treatment ACTAGanism

 


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