Its Rapid Rise & Fall
June 2001
by Mark Harrington

From the Introduction

If you don’t have the survival data, how are you exercising your clinical judgement?… I find it hard to understand how anyone could feel that it is not important to know… Of course [the doctor] needs to know that. This is life or death. Why isn’t that important?
– Robert Temple, MD, FDA Lasagna Committee1, February 1, 1989

If you are going to have accelerated review it is important to expose the [FDA advisory] committee to the Phase Three protocols before they are actually executed. The educational process and the consensus process that they represent are not trivial.
– Thomas C. Merigan, MD Lasagna Committee, February 1, 1989

We are not against all drug regulation of any sort. We don’t want ourselves or our friends to die from taking unsafe drugs and we disagree with the radical deregulators of the right who would abolish all efficacy requirements, and risk flooding the market with safe, but ineffective, AIDS drugs…
– Jim Eigo, ACT UP/New York Lasagna Committee, May 2, 19892

This is a story of desperation, expediency, compromise, and misfortune – the desperation of AIDS activists in the early and mid-1990s fighting with the government, with the drug companies, and with each other over how best to move new drugs forward through the testing and approval process to save the lives of those sick with AIDS and to figure out how to extend the health of those with HIV; the expediency of drug companies trying to bring forth new anti-HIV drugs as quickly (and often, as cheaply) as possible; compromises imposed by the government agencies that were most involved, the Food & Drug Administration (FDA) and the National Institutes of Health (NIH), and by the academic scientists who worked with NIH funds and played by FDA rules; and the misfortune of thousands of people with AIDS and HIV who suffered because of inadequate drugs, inadequate studies, and inadequate information – and, ultimately, because the drug in question, Roche’s saquinavir, turned out to be a big disappointment.

It seems like a good time to tell this story again because there is so little institutional memory in the AIDS treatment activist movement, and the story of the last fifteen years is hardly the unblemished forward march of scientific progress it is sometimes portrayed as. The story raises issues which are always timely, illustrating unavoidable tensions between speed and care, thinking and feeling, common ends and contested means.

In mid-1992 I was the second community representative on what was then known as the AIDS Clinical Trials Group (ACTG) Primary Infection Committee (now dubbed the HIV Research Agenda Committee, or RAC). The committee, then as now, was the bastion of scientists who only grudgingly met the incursion of the activists into the ACTG starting in 1989, and were not used to dealing with us as equals. At one meeting, something bizarre took place. We were discussing the proposed study of an exciting new drug – the first protease inhibitor to enter clinical trials – called Ro 31-8959 and later to be known as saquinavir. There were some anomalies in the proposed study. Roche, which had done the phase I study, had not tested the drug up to the maximum tolerated dose (MTD). Most of the drug did not, it appeared, get into the bloodstream. This was of concern because it might weaken the drug’s effect, or even lead to drug resistance. Moreover, the statisticians’ report on the proposal stated that the study as designed would be unable to detect a moderate effect, if in fact the drug had one. Now we were sitting around the table discussing the proposal, and I kept bringing up uncomfortable questions about the dose and the design. There was an embarrassed silence and some shuffling of papers. Eventually Dr. Thomas Merigan – then the committee chair – and Dr. Ann Collier, who was to be the study principal investigator (PI) – left the room with the Roche representative and huddled in the hallway looking over some papers which displayed the preliminary dosing and potency information. Then they came back into the room and told us that everything was OK, the dose proposed for ACTG 229 looked just fine.

While I have the utmost respect for Drs. Merigan and Collier, this was simply no way to go about deciding to invest taxpayer dollars and commit hundreds of people with AIDS in a publicly-funded study. But Roche insisted and the ACTG was as desperately eager then as now to get its hand on the hot new drug du jour (or d’année, as the case may be). The letter I wrote to Dr. Collier expressing my concerns was politely brushed off. ACTG 229 duly moved forward and the ACTG randomized 302 AZT-experienced individuals to receive AZT plus ddC, AZT plus saquinavir, or all three drugs together.

Some of us were worried. Back in April 1992 we had gone through the grueling FDA Antiviral Drugs Advisory Committee hearings on Roche’s HIVID brand zalcitabine (ddC). I had the misfortune to be the community representative on that occasion. My journal entry for the day, April 20, notes, From 4-7 [p.m.] the lame Roche presentation of their ddC NDA. Everyone is appalled at their pathetic evidence of safety and efficacy. While I’d seen nothing whatever to convince me that the drug had any useful activity in the body, it was widely used on an extensive underground in the community (as Roche had refused to establish an expanded access program), and was being touted by many prominent researchers as perhaps the most potent drug to use in combination with AZT. The night before the hearing we held a large meeting of community activists in a hotel room and debated the issue for a long time. Eventually I decided that, as my role was to represent the community, I would vote in favor of approval for ddC even though I saw no evidence that it was safe and effective. My misgivings were strong but in those days there was so little to offer people with AIDS that it seemed better to go along with majority sentiment. (I assuaged my conscience by voting “no” on the monotherapy indication and “yes” on the combination therapy one.)

Over the following two years the misgivings which I felt at that hotel room in Bethesda, and which were shared by many of my colleagues at AIDS Action Council, AIDS Action Baltimore, Community Research Initiative on AIDS, Gay Men’s Health Crisis, the People with AIDS Health Group, and others, grew into a feeling that the AIDS community, in its understandable desperation, was being manipulated by industry to demand the expeditious approval of inadequately tested drugs. The deal was that industry would provide the proof of safety and efficacy after approval. But with ddC, Roche failed to generate that evidence.

In early 1994 my ex-lover, Jay Funk, died of a virulent pulmonary Kaposi’s sarcoma after living with AIDS for more than four years. My own immune system was still fine, but I no longer felt like going along with majority sentiment in my activism. My colleagues in TAG felt the same way. Rather than being expedient or going along with mainstream sentiment it seemed better to think through what we really thought would be best for AIDS research, and for people with HIV, and put that forward as policy – to try and change the way protease inhibitors were developed, to get more information faster with bigger studies that would provide more access and better answers.

All year we had passionate discussions and debates about ddC, d4T, and saquinavir and the new protease inhibitors. How could we avoid, or at least learn from, the mistakes which had been made in studying the nucleoside analogues? How could the new programs of expanded access and accelerated approval, for which we had fought so passionately, fulfill their promise rather than degenerating into tools by which industry could manipulate us – We give you Parallel Track, you give us Accelerated Approval?

Eventually in mid-1994 we decided to go public with our concerns. The story that you are about to read describes some of the main events of that struggle. After the dust had settled, the field moved rapidly and unexpectedly forward into the era of highly active antiretroviral therapy (HAART), although whether or not saquinavir-containing regimens ever really were “highly active” remained somewhat controversial. Thanks in part to our intervention, saquinavir was not approved in mid-1994. By the time it was released, in fall 1995, two other much more potent protease inhibitors were not far behind. This was fortuitous, for had saquinavir been on the market a year earlier, thousands of people would have taken it, failed to suppress their virus, developed resistance to the drug, become cross-resistant, and not been able to benefit from the much stronger ritonavir or indinavir which came onto the market in early 1996.

Even though saquinavir benefited from being the first protease inhibitor on the market, it never was a big seller. When the U.S. HIV treatment guidelines panel put out its first post- HAART antiretroviral treatment guidelines in spring 1997, Roche’s Invirase was not among the drugs in the preferred category for first-line therapy. The company instigated a massive letter writing campaign to the panel, which had no effect.

In late 1997 Roche finally introduced the much more potent soft gel capsule formulation, Fortovase. But it had a high pill count and never really caught up.

Later in the 1990s Roche began to move on. Practically no one was using ddC anymore. Sales were too low to figure in the company’s annual reports. Invirase was receding into the past. In its first quarter 1999 report Roche touted recent regulatory approvals received for Fortovase in the US, the EU, Australia, Canada, Switzerland and elsewhere, and claimed that “market reception has been very good”, noting that worldwide Invirase/Fortovase sales that year amounted to some 350 million Swiss francs (SFr), or about $197 million. Luckily the company had licensed Viracept brand nelfinavir from Agouron for sale in many countries; Roche’s worldwide 1999 Viracept sales amounted to 430 million SFr or about $242 million. As late as the first quarter of 2000, Roche reported that “sales of Viracept . . . continued to show double-digit growth.” But by the first quarter of 2001 the company reported “sales of the anti-HIV medicines Viracept and Fortovase were down for the quarter as a result of increasing competitive pressure.”

Regardless of the future of ddC or saquinavir, Roche will remain a presence in HIV research and care as 1) it is co-developing the fusion inhibitors T-20 and T-1249 with Trimeris; 2) its anti-CMV drug valganciclovir (Valcyte) received FDA approval; 3) it’s RTPCR test kits are the standard of care for viral load testing; and 4) its pegylated antihepatitis C virus (HCV) interferon alpha Pegasys is poised to become the standard of care (when used with ribavirin) for HCV in both HIV-positive and negative individuals, at least for the near future. To its credit, Roche also appears to have learned to be more open and constructive with the community than was once the case.

Are there any lessons from the saquinavir saga? Perhaps there are.

• It would have been better if Roche had discovered the maximum tolerated dose (MTD) of saquinavir before rather than after moving into phase II. While this would have required a larger investment upfront, it would have had the effect of letting them market Fortovase rather than Invirase in late 1995, and they could have become a market leader.
• Moreover, it would have been better if Roche had studied the effect of suboptimal dosage on viral drug resistance earlier. Again this would have resulted in a higher dose moving into phases II-III.
• Similarly, it would have been better if Roche had designed larger phase III studies earlier. They ended up doing so anyway, and the studies showed what at the time was regarded as acceptable activity.
• Roche also didn’t bother opening expanded access programs with either ddC or saquinavir until just weeks before approval. This highly cynical maneuver helped build demand for licensure while holding people with advanced AIDS hostage to its commercial needs.

Other lessons apply to academic scientists, regulators, and activists.

• It would have been better for all concerned if the Primary Infection Committee had insisted on transparency rather than secrecy in deciding why it was moving forward with a suboptimal dose in 1992.
• At the same time researchers and regulators were complicit in allowing Roche to impose a shoddy dose and a shoddy design on the ACTG, and many activists went along with it at the time, fearing that otherwise “companies would leave the field.”
• We must not allow the implicit or explicit threat that a drug company will take its resources and go elsewhere to allow us to condone poor study design or the infliction of suboptimal drugs onto the market.

I am sympathetic to the dilemma of Dr. Kessler in 1992-1994, caught as he was between the not always consistent demands of AIDS activists, the opportunism of industry, and the need to provide incentives for drug companies to stay in AIDS research so that there would be better new drugs.

In the post-HAART era it is time for the FDA to firmly insist that promised post-marketing studies and monitoring of long-term effectiveness and safety actually take place.

Finally, there are several lessons for activists. We in TAG made a mistake by not consulting more widely in the community before writing our incendiary letter to Dr. Kessler in July 1994. Had we shared our viewpoint more widely and earlier with other activists they may have been more understanding of the fact that we were not trying to stop accelerated approval, deny access, or delay the development of protease inhibitors as a class. Rather, we were trying to make accelerated approval fulfill its promise, utilize the pivotal efficacy trials themselves to provide access (and answers) and ensure that protease inhibitors were developed faster and more intelligently than the nucleoside analogues.

One more lesson for activists. I do not recall that anyone in TAG or amongst our allies publicly attacked or impugned the motives of any of those in the community who disagreed with our positions. The opposite was not the case. Too often many in the community have listened to divisive rumors from drug companies or have resorted to personal attacks rather than engaging other activists in serious discussion and debate. My hope is that by revisiting the long and dispiriting saga of saquinavir, treatment activists today and tomorrow can reflect on what has happened and apply the lessons to the changing and very different situation in the post-HAART era as HIV treatment moves into global settings where it has never been used before, and where the research issues in contention will be debated with as much passion and urgency as ever.

To read the rest of the report, please download the pdf.