TRIALS WITHOUT TRIBULATIONS
Gus Cairns presents a guide to clinical drug trials
As you read through this magazine or other HIV publications, you may come across mention of many new drugs or other treatments for HIV and related conditions which are not yet widely available.
This means they have not been through the statutory process of stringent clinical trials and so have not yet been licensed by the regulatory authority (in Europe this is the European Medicines Evaluation Agency). This means they can’t be prescribed by just any doctor.
You may feel that one of them might be particularly useful or even vital to your health. To take a few random examples: have you got lipodystrophy, with sky-high blood lipids (fats), and want to try that new protease inhibitor that doesn’t raise lipids? Have you got hepatitis C or B and want to try the new treatments you’ve heard of? Do you have multi-drug-resistant HIV and have heard that there’s a new drug that can maybe overcome it? Are your T-cells refusing to budge and you’ve heard about that new ‘vaccine’ that raises CD4 counts?
Then you may need to join a clinical trial to get it.
About clinical trials
A word of warning first. Clinical trials aren’t designed to get experimental drugs to anyone that needs them. They’re designed to test, as quickly and efficiently as possible, new drugs to find out if they work. So there is no guarantee that the treatment will work for you. It is in the nature of trials that it could even possibly turn out to do you harm, though they are designed to make this unlikely. It is also unethical for a clinical trial to be designed in a way that prevents you getting a necessary treatment that you otherwise would.
Access to a new drug via a clinical trial is not guaranteed anyway. This is for several reasons:
- Exclusion criteria. Most clinical trials only ‘recruit’ certain
types of people and exclude others. This is for several reasons. Firstly, to
ensure that a representative mix of different people are on the trial. Second,
to exclude people who could possibly be harmed: a very common exclusion is
pregnant women and sometimes all women, to exclude the possibility of harm
to unborn babies. Third, because many trials are designed to see only if the
drug benefits certain kinds of patient, such as those with particular CD4 counts
or drug resistance.
- Numbers and location. Many phase I/II trials are quite small (see below). Most clinical trials only happen at certain clinics, though large phase III trials may take place at many clinics in many countries. If it’s not your clinic, you can generally refer yourself and book an appointment if it is a GUM or HIV clinic. But otherwise you will need a letter of referral from your own GP or clinic doctor.
- Randomisation. Clinical trials generally compare new drugs either against a pre-existing drug - maybe the one you’re already on - or against an inactive substance called a placebo. The trial is divided into two or more ‘arms’ or groups of people, only one of which may get the new treatment, or get it at the dose which turns out to work. Trials choose which arm people go into via a process called ‘randomisation’ because the selection is made to eliminate bias. Trial designs can be quite complex and in most there is only a 1/2 to 2/3 chance you will end up taking the new drug,
- Blinding. In many cases you won’t even know if you are taking the new drug. This is to eliminate the ‘placebo effect’ whereby patients - and their doctors - experience improvements purely because they expect the drug to work. So you’ll get identical pills whether you’re on the new drug, an old drug, or a placebo. If your doctor knows what drug you’re on but you don’t (you will be told when the trial ends), the trial is ‘single-blinded’. If your doctor doesn’t know either, it’s called ‘double-blinded’. If it’s not blinded, it’s an ‘open-label trial’.
For all these reasons, you may want to think twice before starting a trial. Trials also require more frequent hospital attendance and testing than usual. However some people find the increased attention benefits their health and in some cases you may be willing to take the chances in order to get a lifesaving or beneficial medicine.
Trial phases
Trials are carefully structured so that only medicines which are safe, effective, tolerable and - as is becoming increasingly important - cost-effective get licensed.
- Phase I Safety trials. Small trials in which the experimental drug is given for a short time (usually a few days/weeks) on volunteers to see if it is toxic, establish the maximum safe dose, and measure the way the body deals with it. Phase I trials of HIV drugs are usually tested on HIV negative volunteers or people not on combination therapy.
- Phase I/II (or IIa) Dosage trials. Small trials, done on people actually with the condition (i.e. HIV positive in the case of HIV), designed to establish the most effective dose.
- Phase II (or IIb). Effectiveness trials. This is when, in the case of HIV, the drug starts to be tested on larger number of people in clinics. Phase II trials usually last for 24-48 weeks. The idea is to see if the drug has an effect on the ‘clinical endpoint’. This means, according to the trial design, whether it reduces deaths, reduces illness, is more effective at raising the CD4 count/lowering the viral load, produces less of a certain side effect, etc.
- Phase III Population trials. If phase II indicates the drug is beneficial, there will be a much bigger trial on hundreds or thousands of participants, often in many different clinics, to show whether its effectiveness is maintained in a ‘real world’ setting. Phase III trials may last at least a year. In the case of something like a vaccine, it is only at phase III stage that it can be shown if it actually reduces the spread of a disease; this may take several years to prove. If a product already exists for the condition, it will be compared with the new one to see which works better. An example of an HIV drug currently in a phase III trial is Boehringer Ingelheim’s protease inhibitor tipranavir; centres are recruiting suitable patients now.
- Expanded/early access programmes. In some cases, the drug company may decide that it is so likely the drug will prove beneficial for some patients that it makes it available to a wider group of patients, at more clinics. But it is still part of the phase III trial and patients will have to meet certain selection criteria. Because the drug is still on trial the manufacturers have to supply it free of charge. As a result, costs make a big difference to the size of expanded access programmes. Recently, for instance, the expensive new HIV drug T-20 only became available to a few thousand patients before it was licensed. In 1994, however, the cheaper drug 3TC was made available to 44,000 patients in Europe before it was licensed. An example of a drug on an early access programme is Bristol-Myers Squibb’s new protease inhibitor atazanavir, which is already licensed in the US but is currently available to patients who fit the trial criteria at 27 clinics across the UK.
- Phase IV Post-licence reporting. In theory, any new treatment should continue to be monitored by clinics for unexpected side effects. Though this is called ‘phase IV’ the drug can be freely prescribed and in many cases phase IV remains incomplete. l Comparison trials. An increasingly high proportion of HIV drug trials seems to consist of trials of, or between, products already licensed. Recent examples include ones to see if taking abacavir instead of d4T or AZT reduced lipodystrophy or comparing nevirapine with efavirenz, and seeing if the former could be taken once a day. This development has been criticised in some quarters as useful only to companies who aim to establish their product as market leader. Companies in turn point to the spiralling cost of developing totally new drugs. But comparison trials are useful. They help reduce the likelihood of harmful side effects and provide guidance to doctors as to best prescribing practice in the complex field of HIV therapy.
Named patient programmes
If you are excluded from a trial for one reason or another, and/or there is no expanded access programme, you may still be able to get the drug, especially if it is at the later stages of development. This is called prescribing the drug on a ‘named patient’ or ‘compassionate release’ basis. Legislation exists to exclude the doctor from liability for prescribing an unlicensed product in such cases. News stories periodically surface about patients affected by conditions like certain cancers or CJD who are attempting to obtain new treatments on this basis.
Drugs may be prescribed on a similar basis for patients never studied properly in trials. A common example is children. Too few initial drug trials - including HIV drug trials - are designed for children, but a doctor faced with a child who may benefit from a particular drug can ask for it to be prescribed ‘off-label’, i.e. outside the criteria that say who should get it. A surprisingly large number of prescriptions are ‘off label’ ones.
Named patient prescribing is done outside the clinical trial structure. Your doctor makes the decision to prescribe it, not the trial researchers, which means that if you attend a small clinic your own research may be key to letting a doctor know that a treatment is available. Your doctor has to be sure an equivalent product is not already available.
The manufacturers are entitled to charge an ‘administration fee’, which covers the cost of supplying the drug, though they’re not allowed to make a profit from it. In some cases the administration fee may be more than the likely eventual cost of the bulk-manufactured drug, and some clinics have refused to prescribe certain drugs on a named patient basis for this reason. It may in this case be possible to get it from another clinic.
An example of an HIV drug currently available on a named-patient basis is GSK’s protease inhibitor 908 or fosamprenavir.
What’s available now?
There are too many trials currently underway in the UK to list in detail here. There are over 35 listed on Aidsmap alone. Just a few examples of the varied questions they are asking include:
- Will taking abacavir instead of d4T improve fat wasting?
- Is intermittent HIV therapy, with or without the immune booster interleukin-2, better than continuous treatment?
- Are the new drugs DPC 083, TMC 125 and the fusion inhibitor UK 427857 effective?
- Does isoniazid stop people with HIV developing TB?
- Does imiquimod prevent cervical cancer in women with HIV?
- Can you use the anti-Hep C drug pegIntron to stop highly drug-experienced HIV patients getting Aids?
- If you fail therapy on Kaletra, will fosamprenavir/ritonavir work?
- If that doesn’t work, will mega-HAART combos of five, six or seven HIV drugs?
- What are the right doses of HIV drugs for children?
- hypnosis
More information on clinical trials, including ones currently recruiting, can be found on www.aidsmap.com : do a text search on ‘clinical trials’.
NAM also publish a booklet giving more information about trials: phone NAM on 020 7840 0050. Thanks to Michael Carter of NAM for his help with this piece.
