AIDS TREATMENT UPDATE, August 1995
Keith Alcorn

Unfortunately these experimental drugs are in very short supply, and in the short term this problem will not get any easier. At the moment only three drugs are licensed in the UK for use as anti-retrovirals: AZT, ddC and ddI. Virtually all other anti-retroviral drugs are available only through clinical trials. Inevitably this creates problems for people who don't want to join trials, or who don't qualify for those trials.

Drug companies often deliberately exclude people with advanced HIV disease from their trials because they have a higher likelihood of becoming ill, and they consider that this would make the results harder to interpret. Tony Whitehead is one of those who doesn't qualify for the existing trials of 3TC. "The exclusion criteria of these trials prevent many of the most seriously ill people from participating. My partner is on one of these trials, but I was unable to join" he says. For people like Tony, the only way of obtaining experimental treatments is if the company decides to make them available through expanded access schemes. A full account of the situation of Tony and others like him is published on page 5.

Expanded access schemes may also be helpful to those such as Dominic Gough, former editor of Positive Times, who suffers from peripheral neuropathy (nerve damage in his legs and feet). Drugs such ddI, ddC and stavudine (d4T) might worsen this nerve damage, so he began looking around for other options after his blood counts suggested that his current treatment might be diminishing in its effectiveness.

"I spoke to a doctor at the anti-viral clinic at the Kobler Centre about the options available to me and it became clear that for someone in my position the Abbott protease inhibitor was the best option, and it was going to be available through an expanded access programme which functioned as a trial."

Unfortunately that scheme didn't go ahead, leaving Dominic without any information on how he could get the drug. "It's very annoying after you take the trouble to find out all the options to have it snatched away at the last minute. Of course it's important for drug companies to run trials to test drugs properly, but it's also important that people like me can get access to the drugs where necessary."

Expanded access programmes present a number of dilemmas to doctors, drug companies and people with HIV. Should expanded access programmes provide experimental drugs only to people who have exhausted other treatment options, even though the lack of early trials among people with advanced disease means that there is often no evidence that the drug will have any benefits for them? Or is it more ethical to give a scarce but promising drug to those who might get the biggest benefit from it - namely, those who have previously taken little or no anti-HIV treatment and still have a relatively healthy immune system?

3TC - FALSE HOPES?

Some doctors have told AIDS Treatment Update privately that they expect the current excitement about expanded access to 3TC will soon fade. To be eligible to join the expanded access scheme you have to have taken AZT previously, and trials have shown that AZT-experienced people are the least likely to experience substantial benefits from the AZT plus 3TC combination. One doctor told us "Perceptions will change when word gets around about people who start 3TC but still deteriorate and die. The people who are most likely to benefit from this combination - those who haven't taken AZT before - aren't eligible for the expanded access scheme."

If you haven't taken anti-HIV drugs before, and your CD4 count isn't too low, you may be able to obtain 3TC by joining a clinical trial. For more information, see the article in AIDS Treatment Update issue 26.

EXPANDED ACCESS VERSUS TRIALS

In the past, there have been concerns that expanded access schemes might harm the scientific effort to find out how best to use new treatments. Some researchers fear that if experimental drugs are made available too early, it will be impossible to conduct formal trials to study their long-term safety and effectiveness.

Dr Janet Darbyshire, head of the Medical Research Council's HIV Clinical Trials Centre, agrees that expanded access schemes are important for some people. "The thing I never have any doubt about is prioritising people who cannot tolerate any other drugs because of toxicity. But for people who are considered to be running out of treatment options because they have a falling CD4 count despite taking other drugs, I'm not so sure about the wisdom of expanded access.

"The priority with any drug is to find out how effective it is and how toxic it is, which means you want as many people as possible to join controlled trials to prove as quickly as possible whether the drug has any effects on the progression of disease. Expanded access may reduce recruitment to such trials, but should, if possible, be available to those unable to join trials."

She also points out that the supply problems are often a consequence of very complex manufacturing processes such as those required to make the protease inhibitor drugs saquinavir, ABT-538 and MK-639. This means that compared with 3TC, all the protease inhibitors are in very short supply and virtually all the supplies that can be produced are already earmarked for current and future clinical trials.

OUTSIDE LONDON

Outside London, the options for people who want access to new anti-retrovirals are even more limited. Dr Bibat Mandal of North Manchester General Hospital is concerned that people with HIV attend large centres outside London like his clinic are at a disadvantage when it comes to getting access to experimental drugs.

"We are not a trial centre which runs a 3TC trial, for instance, so the only way patients can get the drug is through the expanded access programme. Some of our patients have been forced to go to hospitals in London, which creates obvious problems for them, and for us."

Although he accepts that there is a limit to the number of trials which can be run at one clinic, he points out, "Ours is the largest centre outside London. We have just as many patients in the North West region as the South West region, but the drug companies tend to centre their activities in London. There are also patients willing to participate in trials outside London."

AMERICAN LOTTERIES

Even if you are eligible to join an expanded access scheme, you may still experience problems. The rationing of 3TC earlier this year was just the most visible example of the shortage in supplies of experimental drugs. In the United States Roche and Merck have recently announced that they will use a lottery system to decide who will get access to their experimental protease inhibitors. People who meet the entry criteria for the expanded access schemes will be put into a draw, and the drug will be given only to those who are lucky enough to have their names picked. Roche has decided that anyone with a CD4 count under 300 and failing on other drugs will be eligible to join the lottery. The company has already received more than 10,000 calls from people chasing 2,280 places on its scheme. David Barr of Gay Men's Health Crisis in New York said that Roche had completely ignored the consensus of advice from community organisations when fixing the criteria, and that the company would have done better to prioritise people with CD4 counts below 50.

Neither company plans to use a lottery system when they begin expanded access schemes in the UK this autumn. Instead, they will set very strict entry criteria so that only people with the most advanced disease and no other anti-retroviral options will be eligible.

BOX OUT - Why do expanded access schemes exist?

Expanded access schemes exist largely as a result of pressure from AIDS activists. Although arrangements have existed in some countries for several decades which allowed some people to have access to promising new drugs on a 'compassionate' basis, it wasn't until the late 1980s that any drug companies developed formal policies on access to experimental drugs.

In 1986, following the completion of a trial which showed promising results, Wellcome made AZT available to 4,500 people in the six months before the drug was licensed. Syntex, manufacturers of the anti-CMV treatment ganciclovir, had been providing the drug on a compassionate basis for five years before its use was formally approved in people with AIDS.

However in 1989 the idea of expanded access took a quantum leap forward with the decision by US regulators to approve 'parallel track' a system whereby a drug could be tested in carefully designed trials, and also made available to people who were suffering more advanced disease through a 'parallel track'. This group would be monitored for drug toxicities and survival information. It was hoped that this system would get drugs to people running out of options more quickly. In fact, the first drug to be distributed by this route swiftly demonstrated the potential dangers of expanded access. Within months of making ddI available through parallel track, manufacturers Bristol-Myers were confronted with evidence that life-threatening pancreatitis occurred much more commonly than expected in people taking ddI, especially those who were already very ill. Whilst it is arguable that if it were not for the expanded access scheme this information might not have come to light until after the drug had been licensed, it's also clear that wide, early access to experimental drugs always widens the potential for harm before proper tests have been conducted.

AIDS activists have always argued that people with HIV should be allowed to choose for themselves whether or not to take that risk, and that people without other treatment options, often excluded from clinical trials, should be first in the queue when experimental drugs are being distributed.

But why is it in drug companies' interests to give away large quantities of free drugs in expanded access schemes, when they are under no legal obligation to do so? Stephen Whitehead of Glaxo-Wellcome says that they're simply responding to the community's demands. "This doesn't happen in any other area, and it's entirely down to pressure on drug companies from patient groups."

But some suggest that to drug companies, expanded access schemes are simply a shrewd marketing move, familiarising doctors and patients with the potential benefits of a drug.

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