At the recent meeting of the NIH's AIDS Vaccine Research Working Group (May 27-28, 2004), there were discussions of two important developments in the HIV vaccine field. Firstly, Merck publicly announced plans for a "phase IIB" efficacy trial of their adenovirus-based HIV vaccine candidate. Secondly, a subcommittee of the AVRWG presented a series of recommendations aimed at improving the highly controversial phase III vaccine efficacy trial that the U.S. military HIV research program recently launched in Thailand.

IIB Is To Be
Details of the Merck trial were presented by Robin Isaacs, who has replaced Emilio Emini as the Executive Director for vaccine research at the company (Emini has joined the International AIDS Vaccine Initiative and is a also a new member of the AVRWG). Isaacs outlined the phase IIB trial design, which is intended to answer the question of whether the HIV-specific CD4 and CD8 T cell responses induced by the adenovirus vaccine can provide protection against HIV infection and/or reduce post-infection viral load in vaccinees that subsequently become infected. Isaacs emphasized that this represents a "proof-of-concept" study and is not designed to lead to licensure of the vaccine—an additional efficacy trial would be required for Merck to seek FDA approval. The trial will be a collaborative effort between Merck and the NIH-sponsored HIV Vaccine Trials Network (HVTN) and the slated start date is the end of 2004.

The trial will recruit 1,500 individuals aged 18-45 years at a high risk for sexual exposure to HIV infection; individuals whose primary risk factor is intravenous drug use are excluded. Merck is aiming to enroll at least 350-450 women and study sites will be located in the Caribbean and South America in addition to North America. Immunizations with the adenovirus construct (most likely containing gag, pol and nef antigens from HIV—a final decision on which antigens to include had not been taken by Merck at the time of the meeting) will be given at weeks 0, 4 and 26.

A total of 50 events (HIV infections) are anticipated over the 3.5 year duration of the study; Isaacs reported that 30 events would provide 80% power to detect a >1 log difference in post-infection viral load between vaccinees and placebo recipients. A total of 50 events would provide 80% power to detect 60% efficacy of the vaccine in preventing persistent HIV infection (essentially protection against HIV infection). These assumptions are based on an anticipated incidence of HIV infection of 2.5% per year among gay male trial participants and 1.25-1.5% among heterosexual women enrollees. The predicted drop-out rate is 10% per year for the first year of the study and 5% per year thereafter.

The rationale for the trial is based on the relatively impressive immunogenicity results obtained in Phase I and II studies of the adenovirus construct. There is, however, a significant caveat to these data. Because adenoviruses of the serotype used in the vaccine (serotype 5 or Ad5) are common in nature, many people have been exposed to the virus (which causes severe colds) and therefore have high levels of anti-Ad5 neutralizing antibodies. In the phase I and II studies, the ability to mount a T cell response to the HIV gag antigen contained in the Ad5 construct was severely compromised in individuals with anti-Ad5 neutralizing antibody titers greater than 200. Conversely, 63-75% of individuals with titers below this cut-off were able to mount a sustained gag-specific T cell response, representing the best results seen to date with any vaccine aiming to induce T cell immunity (as a comparator, ALVAC typically induces HIV-specific T cell responses in around 20-30% of recipients and these responses are often not sustained).

These observations have led to an additional entry criterion for the phase IIB trial: individuals with baseline anti-Ad5 neutralizing antibody titers over 200 will be excluded. It is estimated that about a third of the population in North America falls into this category; in the developing world the proportion may be upwards of 90%. While it may seem mystifying that Merck has taken such pains to develop a vaccine candidate that will be essentially useless in most of the world, this is due in part to macaque data that suggested that giving a DNA vaccine as a prime followed by the Ad5 vector as a boost could surmount the problem of anti-Ad5 antibodies.

Unfortunately, as Isaacs showed, studies in humans failed to duplicate these findings: among individuals with anti-Ad5 antibody titers over 200, 7/20 (35%) that received DNA priming followed by Ad5 boosting mounted a gag-specific T cell response versus 5/18 (28%) that received both Ad5 priming and Ad5 boosting. In light of these facts, Isaacs stressed that the purpose of the phase IIB study is to answer the question of whether HIV-specific T cell responses can play a useful role in preventing or ameliorating HIV infection, under conditions that are deliberately designed to maximize the potential for vaccinees to develop such T cell responses.

Given that the vast majority of current HIV vaccine candidates are intended to induce T cell immunity, data from Merck's phase IIB trial could clearly have a broad impact on the vaccine field as whole. Merck is also developing adenovirus vectors using rare serotypes that are less susceptible to the problem of pre-existing neutralizing antibodies; a successful outcome to the phase IIB trial would provide additional impetus to advance these candidates.

Members of the AVRWG soundly endorsed the concept for the trial, although Jerry Sadoff (head of the Aeras Global TB Vaccine Foundation and formerly at Merck) expressed concern that the study may be statistically underpowered to achieve its goals. Bette Korber (Los Alamos HIV Database) felt that the statistical plan was workable but "marginal," which suggests that the study could be undermined if assumptions regarding the number of events and drop out rates prove incorrect.

Hammering the Thai Trial Design
At the previous AVRWG meeting in January, committee members recommended that a subcommittee—chaired by Scott Hammer and comprising Larry Corey, Jerry Sadoff and ad hoc statistics adviser Steve Self—review the design of the recently initiated phase III vaccine efficacy trial in Thailand and suggest improvements. The study is comparing a prime-boost combination of Aventis Pasteur's weakly immunogenic ALVAC vCP1521 canarypox vector and VaxGen's seemingly inert gp120-containing AIDSVAX construct to placebo in a low-risk rural cohort of 16,000 Thais. The idea came from the U.S. military HIV research program which was recently reintegrated into the Division of AIDS at the NIH; unfortunately part of the politicking that surrounded the reintegration involved DAIDS committing to support this $120 million trial to completion.

At the May AVRWG, Scott Hammer presented the recommendations of his subcommittee to the larger group (the trial's co-principal investigator Debbie Birx was also in attendance). Hammer broke down the subcommittee's discussions into four key questions and presented their suggested answers:

1. Should the primary (acquisition) and the secondary (amelioration of infection) objectives be switched or should the amelioration of infection objective be made co-primary?
   → Yes, the amelioration of infection objective should be made co-primary -50 viral load endpoints would provide 90% power to distinguish a 1 log difference in viral load and 80% power to distinguish protective efficacy of 60% (compared to 90% power to distinguish protective efficacy of 50% in current design). This would result in at least a 50% reduction in sample size.

   Should the HIV-1 RNA and CD4 secondary endpoints be included in a composite endpoint?

   → Not necessary for this trial, but the viral load endpoint in infected volunteers is crucial and should be better defined; e.g., the geometric mean of 2-3 HIV-1 RNA values post-infection to define early 'set-point.'

   Should immunogenicity data in real time be generated and supplied to Data Safety Monitoring Board (DSMB)?

   → Yes, data from 200-300 vaccinees and 100 controls would provide information on the activity of vaccine during the trial and should concentrate on T cell responses. Such data, however, should be used for background and not be part of any guideline for prematurely stopping the study.

   Should the DSMB take an earlier look at interim efficacy? Should a futility analysis be framed (e.g., for slower accrual, lower HIV incidence, or higher lost to follow-up rate than predicted)?

   → Earlier or multiple looks at interim efficacy will not provide an advantage but it would be reasonable to consider outlining operational futility for the trial (criteria for early termination of the trial if it is not going to meet its goals).

There followed a lively and occasionally heated discussion of what such changes might mean in terms of logistics and finances. Although most AVRWG members supported Hammer's recommendations, some concern was expressed regarding the need to obtain revised informed consent from the approximately 3,000 individuals that have already enrolled in the trial. Jerry Sadoff countered that such extensive reconsenting had been successfully performed in at least one prior vaccine efficacy trial. John Moore asked about the potential cost savings that would accompany a reduction in samples size from 16,000 to 8,000 volunteers. Both Debbie Birx and DAIDS vaccine director Peggy Johnston suggested that the cost savings would be minimal while Jerry Sadoff argued that they would likely total at least $30 million.

At the time of writing, the principal investigators of the Thai trial are planning to discuss the AVRWG's recommendations with their Thai colleagues during the upcoming XV International AIDS Conference in Bangkok (July 11-16). A final decision on implementing the suggested changes to the trial design will not be made until these discussions are completed. ¤

As if there were ever any legitimate doubt, it is now official: the three-in-one generic HAART pill ("Triomune," manufactured in India by the huge generic outfit Cipla) has proved just as safe and effective as its branded components: nevirapine, d4T, 3TC. Results of the six-month study, ANRS 1274, were published in the July 3 issue of the journal Lancet, just in time for release at the international AIDS conference in Bangkok, July 11-16. Mike Barr prepared this summary.

Results of the six-month study reported that viral load drops (the study's primary endpoint) and CD4 rises among the 60 Cameroonian volunteers were equivalent to those expected with the branded products: median viral load change at 24 weeks was -3.1 log copies/mL with 80% of people showing viral loads below the limit of detection (400 copies/mL). CD4 cell counts rose from a baseline median of 118 to 201. There are, however, two key differences: the generic 3-in-1 costs a mere $20 a month; also, since there are no dueling Big Pharma marketing departments to contend with, all three drugs (of BMS, GSK and Roxane/BI) can be combined in a single pill instead of three separate ones. Perhaps it should come as little surprise, then, that adherence rates for the trial logged it at an incredible, if self-reported, 99%. (Of course, the people enrolled in the study were characterized as having advanced HIV disease, and regimen adherence is often best among those with symptomatic infection.)

But just when it would seem all spurious quality assurance concerns could be laid to rest, advocates for brand name meds criticized the joint French-Cameroon study for its short duration (six months) and lack of a control group. Eric Delaporte, lead author of the paper, doesn't see it that way. "Thanks to these results," he said in a July 1 press release, "it is no longer credible to cast scientific doubt on the large-scale use of these fixed dose generic ARVs." So far as adherence is a factor in the long-term sustainability of viral control, long-term follow-up is likely to show the generic three-in-one combination regimen superior to its separate and branded counterparts. After all, who wouldn't find it easier to pop two pills a day rather than six?

Rachel Cohen, of Médecins Sans Frontières, one of several co-sponsors of the study, was quick to mock the disingenuous caution on the part of the generics' detractors. "A controlled study was not necessary," she told veteran Wall Street Journal AIDS reporter Marilyn Chase. "The [generic fixed-dose combination] regimen was already proved safe and efficacious through the WHO pre-qualification program."

Not surprisingly, the Bush administration has spearheaded the effort to sideline WHO's pre-qualification of generics ARVs. Since the release of George W's Emergency Plan for AIDS Relief, the U.S. global AIDS coordinator and former C.E.O. of Eli Lilly, Randall Tobias, and other Bush administration officials have made public remarks that question the quality of generic antiretroviral drugs and undermine international quality standards set by the World Health Organization.

In March, the Bush administration informed the first organizations to receive money from its Emergency AIDS plan that they could not spend the funds on foreign-made generic drugs until those drugs undergo further evaluation-even though they have been tested and approved ("pre-qualified") by WHO, which uses the same standards as the FDA.

In the meantime, these groups would be forced to buy the much more costly U.S.-made, name-brand drugs. Which means that many people with HIV/AIDS in the developing world will have to wait longer to initiate antiretroviral therapy-until either the Bush administration approves the use of generic drugs or it allocates more money so they can afford the pricier brand-name ones. UCSF's Dr. David Bangsberg portrayed the situation to National Public Radio as a "choice between generic therapy and no therapy."

Meantime, MSF's Essential Medicines Campaign director, Ellen 't Hoen, blasted the Bush administration's hypocrisy in a strongly worded letter in April:

"There is no medical or scientific basis for the Bush administration's attacks against WHO prequalified medicines, and the United States is isolated in its view that WHO-prequalification standards are not sufficient. We call upon the United States to join the international consensus by allowing its grantees to procure quality generics, including fixed-dose combinations, and by supporting the WHO prequalification project. We cannot stress enough how disruptive it will be if the United States fails to do so."

"The only possible explanation we can imagine," she adds, "for the Bush administration's current position on procurement of quality-assured generic medicines is that it is more interested in protecting the interests of the pharmaceutical industry than it is in expanding antiretroviral treatment to the largest possible number of people. We would like to be proven wrong." ¤

The fixed-dose generics equivalency study was conducted at two hospitals in Yaoundé, Cameroon, by Drs. Eric Delaporte and Christine Laurent of the University of Montpellier (France) and collaborators at the Agence National de Recherches sur le Sida (ANRS), Doctors without Borders (MSF) in Switzerland, and the University Hospital Center of University Bichat Claude Bernard in Paris. African collaborators included the Pasteur Center of Yaoundé, the Yaoundé Mobile Laboratory of Health and Hygiene, and the National AIDS Program of Cameroon.

From: rastern@racsa.co.cr [mailto:rastern@racsa.co.cr]
Sent: Tuesday, June 15, 2004 9:47 AM
To: polly@sjsadvisors.com; yanick; walter; vera; vera; vera; sheryl; rita; ramon; rajan; paul; marie; Marie; lester; kathleen; kalesa; julio; iris; henry; george; freier; edith; doris; diana; dennise; daisy gely; daisy; christopher; carmen; afonseca; adeline
Subject: Pfizer Working Session in Bangkok—Invitation to Richard Stern and Dr. Stern's reply

(Please disseminate widely)

15 June 2004
Ann Prochilo
Pfizer and Company
San Francisco, California

Dear Ann:

Thanks for this invitation [posted below this response] to participate in a forum in Bangkok with company representatives of Pfizer. Your invitation makes me wonder to what extent Jackson Peyton accurately conveyed my true sentiments about Pfizer which I expressed in my telephone interview with him several months ago.

1. During a period of several years I have tried to communicate with Pfizer's Central American General Manager, Sylvia Varella, and she will not even return my phone calls. That it is to say it seems odd, in fact quite ironic, that I am invited to a Forum in Bangkok, Thailand when I am not even permitted to speak to the person in charge of Pfizer for the region in which I live and work. The Central American headquarters of Pfizer are just a few miles away from where I live, here in San Jose, Costa Rica.
   (My first contact with Pfizer was a letter sent to Ms. Varela on January 4th, 2000, subsequently forwarded to Jim Brigatitis of Pfizer's New York office, who promised to reply to my request for a reevaluation of Pfizer pricing policies in Central America, but to this date (4 years and six months later) has never replied. Subsequently, I have left at least 20 messages for Ms. Varela, during the past 4 years, but have yet to receive a return call.)

   I made it clear to Jackson Peyton that, to me, Pfizer's pricing policies in Central American have been particularly cruel and, in my opinion, border on genocidal. I have witnessed or been told about the deaths of dozens of People Living with HIV/AIDS that I have known and cared about because they were unable to purchase Pfizer's Diflucan because of its outrageous prices in Central America. Such deaths continue to occur regularly TO THIS DAY not only in Honduras, Nicaragua, Panama, but also in Bolivia, Ecuador and Peru, as well as Jamaica and other Caribbean countries because the price of Diflucan ranges from $18-30 per day for the dose necessary to cure life-threatening opportunistic infections such as oral candidiasis, and cryptococcal meningitis. People who are poor and sick with AIDS and out of work do not have $18 to $30 a day to buy Pfizer's pills and consequently perish from these horrible opportunistic infections.

   The issues that patents may or may not exist in some of these countries is irrelevant, since in many areas of these countries, urban as well as rural, no generic companies have marketed their products, meaning that Diflucan is the only product available. Pfizer's local representatives are well aware of this de facto monopoly.

   As you are well aware, the death of a 12-year old Honduran boy was documented on British television on April 18th of 2003, by the True Vision documentary company. The boy died (literally on camera) of starvation due to esophageal candidiasis because his family could not afford the $28 per day that the local pharmacies were charging for Diflucan in San Pedro Sula, Honduras. Ann, can you as a human being, imagine what it is like for a 12-year old boy to die of starvation over a period of weeks, strangled by oral candidiasis, a disease that would have been perfectly curable with 15-20 pills if his impoverished family had been able to buy them?? We cannot show this film in Central America because it also shows desperate Honduran People with AIDS attempting to smuggle generic versions of Diflucan into Honduras from another country in order to save the lives of dying people, and they are terrified of reprisals.

   At one point I was told that many of Pfizer's leading company officials receive salaries of $5 to $10 million yearly, which probably accounts for the high prices that Pfizer needs to charge. This corporate greed contributes to the death of impoverished and innocent people.

   Pfizer has donation programs in other countries, but not in Latin America. Why not? Why is it that the version of Diflucan manufactured generically can cost as low as 25 cents per tablet, when your own product sells for as much as 100 times that amount?? Whether in South Africa or Ethiopia or Peru or Honduras or Jamaica, Diflucan is still too expensive for most poor people already sick and out of work.

   Please note that I refused to accept the $100 payment which Pfizer's paid consultant, Jackson Peyton, offered me for the interview, but suggested instead that a donation of $100 be made to a leading generic company. As long as you and Pfizer management staff can accept all of the points made above, I will be happy to accept your invitation, but I would be much more interested in hearing what Pfizer is willing to do about prices of Diflucan in the countries I have mentioned above.

As the only way to deal with a situation such as this is to publicize it, I am making this correspondence public.

Sincerely,

Richard Stern, Ph.D.
Agua Buena Human Rights Association
San Jose, Costa Rica
Tel/Fax 506-234-2411
www.aguabuena.org

TEXT OF ORIGINAL PFIZER INVITATION
----- Original Message -----

From: Ann Prochilo
To: rastern@racsa.co.cr
Cc: Andy Schmeltz
Sent: Monday, June 14, 2004 9:57 PM
Subject: Invitation: Pfizer Working Session in Bangkok

Dear Richard,

I am writing to you on behalf of Pfizer. Firstly, I'd like to thank you for speaking with my colleague, Jackson Peyton, earlier this spring. Your broad-ranging inputs and follow-up helped us better understand key issues and concerns and increased Pfizer's awareness of critical issues and advocates to work with in Latin America and beyond.

As you know, Pfizer has two antiretrovirals in Phase II clinical development—capravirine, an NNRTI, and UK-427,857, a CCR5 co-receptor antagonist. As Pfizer begins evaluating strategic alternatives to maximize access to these compounds in developing countries, they are grappling with critical structural issues that challenge not only the least-developed countries, but the remainder of countries that do not meet formal least-developed criteria.

In anticipation that you will be in Bangkok, Pfizer would like to invite you to participate in a small working session on the evening of Tuesday, July 13th comprised of Pfizer personnel and 10-15 HIV community advocates. The objective of the working session is to share preliminary thoughts and gather information on expectations, perceived best practices, advocate considerations, etc. These discussions will inform recommendations for Pfizer's HIV developing markets strategy for non least-developed countries.

Pfizer recognizes that country/regional-specific situations vary widely in regards to functional infrastructure, supply chain/distribution integrity, pricing policies and intellectual property positions. Pfizer also recognizes that these are highly complex, high-stakes issues that go far beyond Pfizer's pipeline focus and will require an ever-broadening, active partnership with HIV advocates to forge a path to meeting unmet needs. This working session will provide one opportunity to gather inputs to inform approaches in middle markets/developing countries. It is Pfizer's intention to engage advocates in a variety of venues to expand the scope of discussion and participation at local, regional and international levels going forward.

Please let us know as soon as possible if you are interested and able to participate. If you have questions, please do not hesitate to contact me directly at aprochilo@prochilo.com or 1-415-378-3175. Thank you in advance for your consideration.

Details follow:
DATE: Tuesday, July 13, 2004 (6:00 PM to 9:30 PM)
FORMAT: Dinner with facilitated small (roundtables) and large group discussion
LOCATION: Upon confirmation, we'll send full details

Best regards,
Ann Prochilo