Tat Drug: Parallel-Track Negotiations Status

[Editor's note: there is intense scientific and community
interest in drugs to inhibit the HIV tat gene and the tat
protein it produces (for background, see AIDS TREATMENT NEWS
#166, January 1, 1993, and #153, June 19, 1992). Only one
company, Hoffmann-La Roche Inc., now has a tat-inhibitor
drug in human trials. Information about how well it is
working should be available by this summer.]

Meanwhile, ACT UP/Boston has taken the lead in negotiating
with Hoffmann-La Roche to get the company to develop a parallel-
track program (to go into effect if the trial results are
promising), to allow some patients to get the drug before it is
approved for marketing. AIDS activists have found it difficult
to work with this company. David Peck of ACT UP/Boston, who has
been most closely involved in negotiating with Hoffmann-La Roche,
has professional experience as a management consultant and brings
these skills to his activist work. Two years ago he negotiated
successfully with Burroughs-Wellcome to set up a program for
early access to their experimental pneumocystis drug, 566C80, for
patients who had exhausted other options. (The drug, re-named
Mepron, has since been approved.)

Two weeks ago, David Peck wrote the following description of
the current status of parallel-track negotiations with Hoffmann-
La Roche.]

During the last five months ACT UP/Boston has been working
with Hoffmann-La Roche to arrange pre-FDA-approval access to its
novel drug, RO 24-7429 (tat inhibitor). During this time, ACT
UP/Boston has sought access to the drug via parallel track for
HIV, and compassionate access for KS for people who have
exhausted all treatment options. During this time Hoffmann-La
Roche has negotiated positively, despite intense pressure from
community organizations nationwide.

Although they acknowledge the tremendous need for access to
the tat drug, on April 16 Hoffmann-La Roche stated that parallel
track cannot be implemented until fall 1993 at the earliest, even
though the interim safety monitoring from the current trial
showed "no undue safety problems." In addition to the current
human trial which is gathering safety and efficacy data (ACTG
213), Hoffmann-La Roche believes a purely phase II trial (in
addition to ACTG 213, which is "phase I/II") must be underway
before parallel track can begin. Each new trial takes a great
deal of time and coordination, and is subject to a large number
of potential unexpected delays, both sides agree. As a result,
the promise of fall 1993 could easily become mid-1994.

In addition Hoffmann-La Roche has said "No" to compassionate
access for those with severe, immediately life-threatening KS who
have exhausted all existing therapies, including chemotherapy.
Compassionate use is a humane, patient-by- patient program
intended to make promising, theoretically helpful drugs available
to immediately life-threatened people whose only choice is to
die, or to take a chance on a new drug. In a letter dated April
16, 1993, Gail Levinson of Hoffmann-La Roche addressed the KS
issue to ACT UP/Boston:

"Currently, there are no data available which show the tat
antagonist to be effective against Kaposi's sarcoma. As you
know, we will shortly be initiating a KS protocol which will
evaluate the drug's effectiveness against this disease. The
prospect of making the drug available on a compassionate plea
basis is unwise at this time given the lack of data on the drug."

ACT UP/Boston responds: There is theoretical evidence to
suggest this drug may be of use against KS. Compassionate use is
a de facto industry standard in the AIDS crisis, often in the
absence of controlled activity or efficacy data. Many lives have
been saved by such programs, which offer those with no hope a new
option. This potential for control of one's options alone can
mean the difference between life and death.

Ms. Levinson's letter also addressed the parallel-track
issue:

"As we reviewed in detail, the interim analysis of ACTG 213
showed no undue safety problems. However, we will not know
activity nor dosage information until this stage of the
study is complete and the data analyzed. We anticipate this
activity to be completed during the summer months. At that
time, assuming the data are favorable, drug will be
formulated at the required dosage strengths for availability
to patients on an expanded access basis during the fall
months. Activity data and a recommended dose are essential
information before the raw compound can be converted into
final form. However, to manufacture a dosage form that may
not be effective is not a responsible way to respond to the
needs of the patient population. Therefore, after carefully
reviewing this situation, we have determined that we will be
unable to compress the time line for initiating the expanded
access program."

ACT UP/Boston responds: Activity data will be available in
June -- why wait until the fall? While ACT UP/Boston and its
consensus signer organizations agree that parallel-track
guidelines do not require activity data, we were willing to
concede on this point as long as Hoffmann-La Roche agreed to
implement parallel track in July -- immediately following the
review. Hoffmann-La Roche refused, citing the dosage form as the
primary rationale, and the need for a second efficacy trial to be
underway as a secondary reason.

[Note: In early May, ACT UP/Boston learned that ACTG 213
added a higher dosage arm, 200 mg three times a day, to that
trial. The previous highest dose had been 100 mg. This increase
confirms that no major safety problems have been found.]

In the short term, the parallel-track dose is unlikely to be
vastly different from the study dose, which Hoffmann-La Roche is
fully capable of making in its "final form." ACT UP/Boston
believes that even now Hoffmann-la Roche has enough data to
select an appropriate starting dose (i.e., the lowest ACTG 213
dose) for parallel track (as opposed to a proven "effective"
dose), which meets the requirements of parallel track.
Hoffmann-La Roche disagrees, believing that an effective dose is
required. History has shown that identification and manufacture
of the effective dose form is often a revisionist (and
responsible) process; if a better dose is discovered during the
trials, patients can, for example, be told to take two pills as
opposed to one. ACT UP/Boston feels that Hoffmann-La Roche has
not presented a valid reason to delay access to tat.

Underground production of tat on a large scale is now
underway, at great risk and expense to the community. This
should show Hoffmann-La Roche the overwhelming need of those who
have exhausted all their treatment options. These people would
rather try something than do nothing -- and there are thousands!
Hoffmann-La Roche's acknowledgment of this fact, coupled with
their refusal to take immediate steps to address it, is
incomprehensible.

We acknowledge Hoffmann-La Roche's willingness to carry on a
dialog on these issues. We believe they view these delays as
critical steps that must be taken before the drug can be made
available. But what Hoffmann-La Roche misses, despite numerous
conversations and even a video presentation by people who have no
options left, is this: It is not Hoffmann- La Roche's
responsibility to protect people from a drug that may save them.
That's what the federal guidelines say, that's what other
companies are doing, and that's why the community is making the
drug for themselves -- we just can't wait any longer. Questions?
Comments? Contact: David Peck of ACT UP/Boston, 617/776-2534.