<In other words could IMNR use the Spanish study in the domestic approval process?>
That's the impression I got from the 5/20 conference call. If the results are positive, AGPH/IRC/WLA will include it as part of the NDA. Whether the FDA accepts it, who knows. I believe other drugs have been approved or not approved on the basis of clinical trials that have included results from European trials.
The FDA does need two trials.
Agouron/IRC/WLA are hoping that the viral load data from the remaining 2250 patients will count as another trial, as it was a very large trial, much larger than most these days.
They would like to submit an NDA on the basis of:
1.the data from the 250 patient cohort
2. the viral load data from the other 2250 patients
3. the data from the 300 patients in the Spanish trial.
They don't know yet if it will be accepted by the FDA; it will certainly be discussed. They still have to get the data from the 2250 patients.
IF the data is not sufficient for an NDA; then they will proceed with two other trials, 48 weeks long, unless it is accepted for accelerated approval, then it would be 24 weeks.
It would certainly validate Remune's usefulness if patients who were successful at maintaining undetectable viral loads under HAART plus Remune did not show viral load rebound when taken off HAART.
FYI, - Very interesting discussions in the proceedings of an Open Session of the "Antiviral Drugs Advisory Committee"
held on July 14th and July 15th, 1997.
The topic was "Plasma HIV RNA as an endpoint in HIV clinical trials."
fda.gov
Dr. Fred Valentine was a consultant to this Antiviral Drugs Advisory Committee, and apparently is a former chair of this Committee.
Dr. Valentine was one of several who raised the question of "What would you do with the dissociation between CD4 and RNA?" that is patients who fail virologically, but still retain good CD4 responses.
Here are some of Dr. Valentines comments. Remember, this is July 1997.
(pg 251-254.)
"A couple of papers would note immunologic improvements do occur as evidenced by what happens to patients, they do better, evidenced by what happens to some of the immunologic measurements. No one yet really has defined full immunologic reconstitution even with prolonged suppression of HIV. That is, CD4 cells come back up to normal. Some of the analyses of T cell repertoire indicate gaps still remain and function does not return to all what we call microbial antigens. There is very minimal return of or initiation of immune response to HIV itself. "
"My own private definition of immunologic cure would be when this viral disease is treated by the immune system like any other viral disease, that is, when the immune system finally and belatedly starts to mount effective immune responses against HIV itself, and we just haven't seen that. "
"That is asking a lot of an anti-HIV agent, that is, to correct the situation sufficiently, so that the immune response responds to HIV itself, but you can always hang that out in front of you if you think you know something is a long term goal to keep you motivated, so we are not there yet."
I listened to Dr. Valentine's presentation at Geneva again; the latebreaker on July 3rd, 1998 at the World AIDS conference.
webcast.aids98.org
Then go to REVIEW FRI JULY 3
Latebreakers: "Effect of HAAART compared to immunogen HAART plus an inactivated HIV on lymphocyte proliferation response (LPR) to HIV antigens" Dr. Fred Valentine
Requires Real Player, although the slides aren't there any more.
Dr. Valentine began by saying: "It is clear that with in most infectious diseases, the immune system ultimately controls the disease with an effective immune response. It is clear that does not happen with the majority of cases with HIV. When one looks at the type of immune responses associated with control of the disease almost without exception you find lymphocyte proliferative responses, which is a memory response recognizing that the immune system has seen that antigen before, and the lymphocyte proliferative response is usually very vigorous.
However with HIV disease it has been known for at least 10 years that lymphocyte proliferative responses are either missing or of a very small magnitude at all stages of the disease. Lymphocytes will proliferate well to CMV or tetanus but do not proliferate to any substantial degree to HIV antigens.
Dr. Valentine concluded that talk by saying
"In subjects who are suppressed with antiretroviral therapy, immunization (with Remune) can induce HIV-1 specific responses, comparable to and in some cases exceeding those seen in long term non-progressors. These HIV specific responses are cross-clade and show responses to a more conserved region, to p24.
The initiation of HAART alone results in a decrease of HIV RNA but does not effect cell-mediated immune response to HIV antigens.
Dr. Valentine added that "in other data from much longer follow-up, with up to three years of complete viral suppression; they have not seen any responses to any HIV antigens of this panel in those who were NOT immunized.
______________
Also of interest at the same FDA meeting in July 1997 were some comments by David Scondras, representing Search for Cure. fda.gov
(pg. 120-124)
"A third concern of ours is that we really hope and we assume that if, indeed, you find that viral load is an applicable surrogate marker to approve with therapies, are we referring to all therapies, not just antivirals?
"It would be extremely disturbing if it turns out that there was a therapy that had implications for viral load that was not approved or supported because it was not a drug. There are a lot of folks who at this point do not see any reason they will benefit a great deal from the new therapies, people for whom drugs have failed, people in whom the immune system damage is such that it will not be reconstituted with antiretrovirals".
"The FDA decision to use viral load could very well have the unintended consequence of reducing research under development of immune-based therapies, including those to restore immune function. Scondras suggested that the FDA "convene an assemblage of immunological experts to identify and cause data to be assembled on immunologically relevant surrogate markers."
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