Anthony Brink: The trouble with nevirapine

PART TWO

I therefore claim to show, not how men think in myths, but how myths operate in men’s minds without their being aware of the fact.

Claude Lévi-Strauss 

Boehringer Ingelheim had a bit more trouble pushing past the medicines regulators in Canada than it did in the US and Europe. Its licensing application filed on 13 June 1996 had bombed. A second one was wallowing. The Therapeutic Products Programme of Health Canada, a division of the Health Protection Branch, couldn’t see any benefit. Only terrible toxicity. But the company wasn’t used to taking no for an answer. Who do you red coat naffs think you are? Telling us to bugger off. So its surrogates got the politicians to interfere. Knowing how to get things done. On 5 March 1998, a mob of Treatment Action Campaign types – the Treatment Information Project, an arm of British Colombia People with AIDS – gatecrashed a meeting attended by Health Minister Allan Rock at St Paul’s Hospital in Vancouver and began mouthing off that his drug regulators didn’t know what they were doing: they “do not understand how the drugs work”, unlike the US FDA which has a “superior understanding.” Not only stupid but too independent too – characterised, in the BCPWA’s report of the day’s fun, as “ineffective in coordinating its work both internally and internationally. Drug company representatives express enormous frustration that there is little consistency in the personnel [that Health Protection Branch] assigns to work on a given file. As well, there seems to be little opportunity for fluid, ongoing dialogue during the review process. Add to this the fact that components of a review that could be done concurrently such as clinical and chemistry/manufacturing are instead done sequentially. There are also opportunities for international co-operation that Canada takes little advantage of.”

Hell of impressed by the activists’ pitch, Rock was full of it when stirring things up down at the TPP. A week later, taking a sudden interest in the drug approval process, he asked the guys how it worked, specifically wanting to know what the hold-up with nevirapine was, since it was already approved in America, Europe and elsewhere. Five days later he got his answer: It mentioned that nevirapine was in the final stages of the review process (in a renewed application). It explained that, “Differences in the regulatory status of antiretroviral drugs in Canada as opposed to the United States, relate to several factors, namely: differences in submission filing dates [the trick being to file in the US first and later in the secondary markets to pressurise the latter’s regulatory authorities into conforming with the US, where just about any shit goes down – 80 per cent of all licence applications approved nowadays], restrictive regulatory provisions [slightly higher standards in Canada – drug regulators being edgy there in the wake of the thalidomide disaster, particularly bad in that country thanks to regulatory inertia and laxity at the time], and limited resources. …Differences in submission filing dates stem from the tendency of pharmaceutical manufacturers to file their new drug submissions in the United States (US) first, primarily to get access to and secure a wider market share.” Working the system in other words. The memorandum pointed out that in Canada there was none of this ‘conditional approval’ business, with manufacturers coming up with evidence of clinical efficacy only after the release of a drug. But they were looking at developing such a scheme. To keep up with the Americans and Europeans. It then went on about how hard we’re trying, but we’re low on dough. Concluding with the canniness of a cat pitching for cream: “There has been a continual erosion of the appropriated funds…required for sustaining and enhancing regulatory review activities related to drugs. … Without infusion of additional resources, the TPP will not be able to respond to the continuing demand for shorter review times for HIV/AIDS drugs.” Nothing if not upfront about their pork-barrel demands, these blokes. The bureaucrats playing the politician like a banjo. Scratch our backs and we’ll scratch yours.

On 9 April 1998 Rock replied: Get the new conditional approval regime in place. Without delay. We’ll worry later about drawing up some regulations to deal with drug companies not complying with their obligations to come back with the evidence that their drugs out in the market actually worked. That’s what he said – sure did. Now we recall that according to ‘AIDS experts’, nevirapine’s benefits, if any, are very modest indeed. Modulating CD4 cell counts slightly better in combo with older drugs than the older drugs alone, but only in the case of people with low CD4 cell counts. Certainly no clinical benefits shown in terms of improved health. But that’s not what the lobbyists told him. A swallower evidently, the politician enthused: “As the Department is no doubt aware…the new antiretroviral drugs are able to cut death and disease rates dramatically… With respect to the drug Viramune (nevirapine), I am told that this drug is available in 75 countries but not in Canada. I am also told that the drug has been rejected once by HPB and is now under second review. Please advise whether this is true, and if so, the circumstances.”

On 22 April 1998 Rock got his next answer, confirming that a conditional approval regime was being implemented. Also that nevirapine had been approved elsewhere but not at home. The interesting bit was why: “…the review of the new drug submission for Viramune did not reveal any conclusive effects on clinical end points nor on surrogate marker end points to support the benefit of Viramune in treating patients with HIV disease [i.e. even the latter were too flimsy]. The efficacy of Viramune was not clinically significant when evaluated against internationally recognised standards of efficacy for drugs used in the treatment of HIV. There are, in addition, safety concerns associated with Viramune use in clinical trials. On March 6, 1997, a Notice of Non-Compliance (NON) was issued by the Therapeutic Products Programme. On July 2, 1997, the manufacturer filed a response to the NON. In the absence of scientific evidence of efficacy and concerns relating to safety, the data available for Viramune are judged to be inadequate to support the clinical benefit of the drug.”

On 23 April 1998 Rock’s office addressed further questions to the regulators. Their answer the following day reiterated adamantly, “The review of the drug submission for Viramune by the Therapeutic Products Programme found that there was an absence of scientific evidence of efficacy and that there were also concerns about safety. The data available for Viramune were judged to be inadequate to support the clinical benefit of the drug and a Notice of Noncompliance (NON) was issued on March 6, 1997. This review decision will be forwarded to the Expert Advisory Committee on HIV Therapies for further review.”

Doing as bidden, the Therapeutic Products Programme rushed a new conditional approval system into place. The next development was – you guessed it – nevirapine was back on the table for “a priority review ... a quick response would be much appreciated” (per Joyce Pons, Submission Screening Officer in the Bureau of Pharmaceutical Assessment, in an internal memorandum dated 8 September 1998). Following which it was conditionally approved. With pleasing alacrity, on the 17^th, just over a week later. But only for use in combination with other old antiretrovirals, not on its own. No good for that. We speak of a drug found to be useless after two unharried assessments – the manufacturer having been unable to come up with any evidence of clinical benefit. Or any significant effect on laboratory test markers. Despite ample time and opportunity to come up with the goods. In not one but two licence applications. But approved for consumption by the public under the new rules. The process being a quick one. Because look, this is an emergency. The activists say so. So there’s no need to show a drug works anymore. As long as you promise to come back and show us later.

A condition was duly attached to the licence, being, that’s right, that Boehringer Ingelheim come back with some evidence of clinical efficacy. Fine, it promised. Just one snag. In the headlong rush to oblige the Germans, the Canadians hadn’t got around to writing the rules concerning the enforcement of such undertakings. Internal communications reveal the confusion: Chris Turner, Manager of the Continuing Assessment Division asked, “Who is responsible for following up the conditions? … We do not have the review staff at present to accept such an assignment…” Ann Sztuke-Fournier of the Advertising and Promotions Unit replied, “As discussed this is still not clear. The conditions are unknown to me and the regulatory impact as well.” Eric Ormsby, Acting Director of the Office of Science-Risk Management Methods in the agency noted, “We still do not know whether we have the authority to remove an NOC [Notice of Compliance] if they do not provide the information agreed upon. Sheila Hills in BPA is writing a guideline or something regarding information required. I don’t know much more.” Chris asked, “Is the NOC with conditions actually finalised yet? I thought there was to be a guideline. What is the regulatory authority for such ‘limitations’ at present?” Ann wrote to Eric: “As mentioned by Chris…do we have a regulatory authority for these limitations? I am not aware of any formal commitment or agreement to conduct post-marketing surveillance for this drug or under what conditions this drug has been approved.”

Vicky Hogan, Head of the Monitoring and Evaluation Unit, set out her agency’s “concerns.” Nothing was being done to “educate the medical community” about the new conditional licensing policy, she said. In Boeringer Ingelheim’s release about the drug to physicians, “information about the conditions was not highlighted and the prescribing physicians [who] received that information were NOT informed about the outstanding concerns about efficacy associated with this drug. …physicians are under the impression that this drug…is considered…to be both safe and effective.” There was “deep concern,” she said, “that we do not have [an] active surveillance program in place yet…” She wondered what “compliance action” will be taken if manufacturers do not comply with the conditions imposed on their provisional licences, and concluded by suggesting that “the programme needs to act fast to communicate this new policy to the medical community and to develop some operational infrastructure around it. I am particularly concerned that the vast majority of the medical community does not know the significance of a [provisional licence] and so is left to make prescribing decisions without the benefit of this knowledge and that there seems to be a good deal of confusion in terms of who, in TPP, does the follow through on monitoring conditions set forth in [a provisional licence].” Never mind the Mounties. More like the Keystone Cops.

Once Boehringer Ingelheim had succeeded in stiffing the Canadian government too, its whores began to sing on cue: Julio Montaner, driving a nice new Beamer, no doubt, on his nevirapine trial supervison fees, enthused: “We are extremely pleased to see this valuable new treatment alternative in Canada…” International AIDS Society President Mark Weinberg (at the time), his back pocket similarly stuffed from overseeing nevirapine clinical trials, applauded: “Nevirapine is a wonderful antiviral drug and its approval now means that Canadian patients, and their physicians, will have increased options for the treatment of HIV disease. I fully expect that people will live longer and enjoy an increased quality of life as a result of this long-overdue decision by Health Canada to approve nevirapine.” I watched this guy with his Colgate smile glad-handing several dazzled women at a lunch table at Durban’s AIDS Conference in 2000 a couple of paces from where I sat. The International AIDS hero. And I couldn’t help recalling that timeless summation of Eichman: “The banality of evil.” (Four months earlier he’d proposed that troublemakers like me be arrested and imprisoned.) Our very own nevirapine fan, Supreme Court of Appeal Judge Edwin Cameron enthused about the drug in similar vein during an interview on the M-Net television programme Carte Blanche on 4 November 2001. Nevirapine, he said, “is a very good drug. It’s been offered free to our government to give to mothers who are about to have babies and our government has not yet taken up that offer, which is a tragedy I think.” The tragedy of it we’ll examine in Part Four. The tragedy of Edwin Cameron you can read in Just say yes, Mr President: Mbeki and AIDS.

Hot on the heels of its licence grant in Canada, Boehringer Ingelheim spokesman Fred Harris announced a quick marriage of convenience. To a sugar daddy. And golly, guess who: “Boehringer Ingelheim (Canada) Ltd, recognising Glaxo Wellcome Inc. as a leader in the development and marketing of products for the treatment of HIV/AIDS, has decided to enter into a marketing agreement to provided a quicker and more focussed introduction of the product into the Canadian community.” So we can get it out there. Like people are dying.