E-mail the Coalition
"Generic"
proposal for expanded access programs, with research principles
The Coalition for Salvage Therapy (CST) is an ad-hoc group of AIDS treatment advocates. It was formed in 1998 to respond to the lack of clinical studies of promising new antiviral drugs in patients with a history of treatment failure and limited options. Although there had been various working groups of AIDS activists dealing with protease inhibitors, amprenavir, abacavir, and human growth hormone, there was no ongoing national coalition. A letter to Abbott Laboratories from Spencer Cox of New York's Treatment Action Group formed the basis for a sign-on consensus statement from AIDS activists and motivated a group of activists to form the new coalition.
CST members include co-founders Lynda Dee of AIDS Action Baltimore and Linda Grinberg of the Foundation for AIDS and Immune Research; Carlton Hogan of the Community Programs for Clinical Research on AIDS; AmFAR's Dave Gilden; Martin Delaney and Ben Cheng of Project Inform; Jules Levin of the National AIDS Treatment Advocacy Project; Ron Baker of HIV and Hepatitis.com, Mark Milano of ACT UP/New York and many others who jump in from time to time.
The initial focus of the CST was to convince Abbott Laboratories to develop an expanded access program for their new protease inhibitor, ABT378 (lopinavir, Kaletra). In addition, in some cases building on the work of previous activist efforts, the CST has been involved with:
CST members meet by conference call to discuss drug development issues and to prepare for face to face meetings with manufacturers. The CST has not raised any outside funding. Member individuals or their organizations have paid for conference calls, and pharmaceutical companies have reimbursed CST members for their expenses in attending meetings.
Although the CST started with a focus on antiviral therapies that would be useful to people with few or no remaining treatment options, its scope has broadened to include issues around the development of all new HIV antiviral drugs. Most CST members remain convinced that new product development must include studies in patients whose virus has already developed resistance to several drugs.
There are no requirements for CST membership beyond access to e-mail. The best way to get involved is to sign up for the CST e-mail list so that you can participate in discussions on new product development and sign up for conference calls or face to face meetings with various pharmaceutical companies.
To sign up for the CST e-mail list, send an e-mail message as follows:
TO: [email protected]
SUBJECT:
MESSAGE: subscribe cst <your name>
To leave the CST e-mail list, send an e-mail message as follows:
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SUBJECT:
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GENERIC PROPOSAL
FOR EXPANDED ACCESS PROGRAMS
(includes Research Principles)
Last revised November 21, 2002
EXPANDED ACCESS (EA) PROGRAM PROPOSAL
The Coalition for Salvage Therapy (CST) believes that the best
and most compassionate expanded access programs follow the model
established with pharmaceutical companies in the last half decade
or so, including Gilead Sciences' Adefovir program, GlaxoSmithKline's
Abacavir and Amprenavir programs, Abbott's Kaletra (ABT-378) program
and most recently
Gilead Sciences' Tenofovir program.
We agree that the intent, purpose and principle behind any expanded access program is to provide drug to individuals based on need. Almost without exception, these programs ultimately made drug available based solely on need, without arbitrary inclusion/exclusion criteria based on CD4+ count and viral load, addressing the needs of the more advanced or treatment-experienced patient, who might otherwise not qualify for the clinical trials.
The operative definition and principle behind all recent EA programs is and should always be:
To provide an investigational new drug to any HIV positive person who, in the opinion of his health care provider, needs this drug in order to construct a viable treatment regimen.
However, under extraordinary circumstances, or when it has been established that the drug supply initially requires limiting the scope of the program, we have agreed to accept a triage approach for a short period of time -- a two-tiered program, beginning with a "compassionate use" phase, which initially places the neediest patients at the head of the line. As soon as production and manufacturing processes ramp up or quality assurance procedures are acceptable, the CST expects the implementation of a broader expanded access program. We believe that both stages of the program should be predicated on patient need, rather than based on theoretical or proven efficacy of the drug in specific populations (as outlined below).
A. First Phase - "Compassionate Use" Program - if required by limited drug supply or quality assurance issues.
1. Initiation - Timing based on the availability of safety
data;
2. Estimated size - Based on demand by qualified patients; limitations
based on any pre-ordained number of patients would be unacceptable;
3. Not site-based, but open to all qualified physicians and healthcare
providers;
4. Based on immediate, "urgent need", not on proven
efficacy;
5. "Urgent Need" defined as:
a. Any HIV positive person who has virologically failed/is failing
or is intolerant to more than one HAART regimen
b. Has a CD4+ count < 200 and/or an active opportunistic infection
which is not exacerbated by the investigational drug,
c. And who, in the opinion of his healthcare provider, needs the
investigational drug in order to construct a viable treatment
regimen.
B. Second Phase - Broad Expanded Access (EA) Program
1. Initiation - As soon as safety data, drug supply and quality
assurance concerns permit. Manufacturers will keep the CST apprised
regarding the proposed initiation date based on the foregoing
or other unforeseeable events, including FDA requirements.
2. Estimated size: Based on actual demand by qualified patients,
not a pre-ordained number. If demand outstrips supply, program
accrual may be staged while supply catches up. Limitations based
on any pre-ordained number of patients would be unacceptable.
3. Not site-based, but open to all qualified physicians and health-care
providers;
4. Based on need, rather than "proven efficacy";
5. Eligibility: Any HIV positive person who, in the opinion of
his health care provider, needs the investigational drug in order
to construct a viable treatment regimen, irrespective of CD4 count
or viral load.
While it would undoubtedly be advantageous if patients receiving
the investigational drug could simultaneously have access to one
or more additional new or experimental agents at the same time
to create the "freshest" possible safe regimen. This
does not need to be a requirement of the program. No one can guarantee
that two or more experimental agents can be made available through
expanded access in a particular time frame. The need to construct
a drug regimen with previously unused agents, however desirable,
must be addressed as a matter of education and recommendation,
and not as an inclusion or exclusion requirement.
While it is the goal to successfully bring two or more agents
into use simultaneously, access to the investigational drug should
not be delayed in pursuit of this goal. The company should direct
physicians to the Health and Human Service (HHS) guidelines which
advise against adding only one new drug to any proposed new regimen.
II. SALVAGE PROTOCOLS
The CST has considered many different examples of clinical trial
designs for salvage therapy. Obviously this is not a trivial issue.
The complications of treatment and research in persons who have
failed multiple antiretrovirals affect all aspects of trial design,
including the nature of appropriate controls, blinding, treatment
allocations, on-trial clinical management, eligibility, appropriate
endpoints, duration of follow-up, and many other aspects. Trials
in heavily pretreated patients have some unusual accrual issues
as well. Patients have great motivation to try and get experimental
treatments, yet their health is more precarious, so the risk/benefit
balance seen in any clinical trial has some unusual features.
Although patients urgently need new therapies, there are concerns
about "using up" the few new options out there by combining
them with sub-optimal background therapy. When patients have "one
shot", it is prudent to try and make that effort as
effective as possible. This especially complicates designs. Control
treatments are harder to construct and potentially may not just
be ineffective, but may prejudice later care.
For the sake of this synopsis, we will call heavily pretreated, and failing patients "salvage patients". We recognize that this term is unpopular, and will probably change at some point in the future. The CST has concluded that salvage protocols for heavily pretreated patients should include other promising experimental agents in clinical development. Thus, we strongly encourage manufacturers to begin discussions to explore and design collaborative studies as soon as possible with both approved and experimental antivirals.
III. RESEARCH PRINCIPLES
Rather than propose individual and somewhat arbitrary individual protocols, the CST instead asks that manufacturers agree to several general principles regarding the development of future protocols.
A. Salvage patients should not be exposed to monotherapy of any kind, or to "virtual monotherapy", where one new drug is added to a failing regimen for any appreciable length of time. We recognize that pharmacokinetic studies, especially of regimens containing more than one experimental drug are important. But we urge that whenever possible, PK should be done in HIV negative volunteers. When the participation of salvage patients is required, exposure should be restricted to no more than two weeks.
B. We are very encouraged by various sponsors' consideration of collaborative research, where more than one approved or experimental agent might be used. Such treatment strategies offer the best hope for salvage patients. We recognize this to be a difficult strategy to implement. Corporate dynamics and regulatory barriers have made this virtually impossible in the past. The Coalition is committed to help build those bridges where necessary, and to work with FDA and other regulatory bodies to help facilitate this cooperation.
C. The Coalition recognizes that a wide variety of research designs are necessary to get a full picture of any treatment's risks and benefits. Studies looking at both activity and efficacy provide a fuller picture of a treatment or strategy's attributes. Without prejudicing other designs, there is a minimal set of data we would like to see in regard to any new treatment.
1. Evidence of in-vitro activity against ex-vivo isolates from
salvage patients;
2. Phenotypic and genotypic resistance studies, including serial
passages in presence of drug of isolates derived from salvage
patients;
3. Integration of phenotyping and genotyping into all salvage
therapy clinical studies. Patients should be given those results
as soon as they become available so they can construct a viable
regimen;
4. PK interaction studies with all major HIV and OI medications,
methadone, oral contraceptives, psychotropic drugs, replacement
hormones, lipid lowering drugs, anti-hypertensive treatments,
antiseizure medications, specifically phenytoin (Dilantin), anticoagulants,
specifically warfarin
(Coumadin), anti-tuberculosis drugs and, if possible, street drugs;
5. Lipid abnormalities, at every stage of the development program;
6. In Phase III trials, data on patient Quality of Life.
7. Any efficacy data should include presentation of "intent
to treat, non-completer equals failure" analyses. This does
not preclude other explanatory analyses. Partial or incomplete
data sets should not be presented;
8. All HIV RNA viral load studies attempting to describe the number
of percentage of patients "below the limit of detection"
should be done with "ultrasensitive" assays. However,
we recognize that tests which attempt to describe viral load in
terms "log drop or HIV RNA" may require use of the standard
assays, which are more accurate at higher ends of the scale. Virologic
results should be summarized in as many ways as possible, including,
but not limited to, percent below the limit of detection -- median
change, mean change, and normalized area under the curve;
9. When considering studies of combination experimental treatments,
we would like emphasis to be placed on two classes of combinations:
those most likely to be successful, and those most likely to be
used in the "real world". We would like to offer our
assistance in helping to design accurate, intelligible, and culturally
sensitive informed consent documents. The unique challenges of
research in this population make the quality of informed consent
even more critical.
We realize that any investigational drug will present many new challenges and look forward to an ongoing dialogue on development issues, including input into Stage II and III trial designs and EAPs. We are happy to discuss all relevant issues with you on a regular basis. Communication may occur at meetings or by conference calls, which may be more practical in many instances. We look forward to a continuing dialogue and a productive relationship.