EUROPEAN ACTIVIST POSITION ON SALVAGE ACCESS

Despite therapeutic advances there are still a large number of people dying of AIDS in developed countries.

As an example, in Spain, the official statistics put the latest number of deaths yearly at approximately 2,300, although this number would undoubtedly explode if Hepatitis C was considered an opportunistic infection. Thousands of people are at risk of health deterioration and thousands more of death. All of them could be helped by quicker access to experimental drugs, although this is not happening because there are no products available.

Drug-developing processes require that companies go through different consecutive study phases. It all starts with laboratory and animal tests (pre-clinical phase), which are followed by human trials (Phases I, II and III). The reason for this process is that it is unethical to give an experimental drug to people if the risks outweigh the possible benefits. Going through these different investigational phases makes it possible to determine whether or not this might happen. In the case of HIV, the possible benefits are nothing less than saving a life. Therefore the risk that someone could be ready to assume who has no other treatment options available and whose health is in a critical condition, is very high.

Usually, with HIV, compassionate and expanded accesses to an experimental drug comes around the end of Phase III, when the regulatory process is in a very advanced stage and the drug is just a few months away from commercialization. This, however, is far too late for many people at risk of having their health seriously deteriorate or even dying.

Why is expanded access not available earlier? Generally, at the end of the second phase of development of an antiretroviral drug we already know the recommended dose, what the possible side effects are, at least in the short-term, and how possibly efficient the drug is in a limited number of people. Certainly, before approving a drug it is necessary to do tests on a large number of people (Phase III) but even before then, the data is sufficient to consider that it could save lives. This last element compensates for the risks of unexpected side effects or a lower efficacy than expected.

You would imagine that people in a salvage therapy, when no other ARV drug works due to either resistance or toxicity, would have access to the experimental drugs they need through Phase III trials. Unfortunately this is not the case. These studies are conducted on an inclusion (people who may participate) and exclusion (people who may not participate) basis in order to select a population group in which the drug can show a higher efficacy than the one observed with other drugs. This is the reason behind excluding or limiting the number of people with a serious diagnosis in Phase III studies. If most of the participants in these studies were in a salvage situation it would be difficult for the new drug to show better results than those of the other drugs available.

Although this is understandable, it has its limits. By excluding patients, Phase III studies do not collect all the data in respect to all the different people who will use the drug once it is approved. This creates a gap in the knowledge of the true efficacy of the drug.

Clearly, what is absolutely not understandable is that there is no alternatives for those in desperate need of experimental drugs who are excluded from the studies. For this reason, different activist groups have decided to demand that the EMEA establish some type of system where pharmaceutical companies are obligated to open expanded access to antiretroviral studies as early as the end of Phase II or the beginning of Phase III.

The multinationals claim that at this stage of development it is not so easy to produce a sufficient amount of product for the study, let alone for a large expanded access. What happened recently with T-20 and is now occurring with tipranavir are examples of this shortage. In the past with T-20 and currently with tipranavir, there were and are barely a few hundred treatments available for the thousands of Europeans who were or are in clear risk of death.

Activist groups understand that it is the companies’ responsibility to plan ahead of time so that at the start of Phase III there is also enough product available for expanded access. They also know that the availability of such a vital drug cannot be left in the hands of the companies and there should be a mandate from regulatory agencies to make sure it happens.

On the basis of these arguments, the European AIDS Treatment Group (EATG), the Spanish Forum of Treatment Activists (FEAT), the Spanish HIV/AIDS Coordination Group (CESIDA), the Portuguese Treatment Activist Group (GAT), the Italian Community Advisory Board (ICAB) and the French Interassociative Group on Treatments and Therapeutical Studies (TRT5), have addressed a letter to Daniel Brasseur, President of the EMEA’s (CPMP) to demand that action be taken on this issue. We hope that it will happen soon.

Two Examples: T-20 and tipranavir
In the letter to the EMEA, the activists describe the recent Phase III studies of enfuvirtide (T-20, Fuzeon) and ritonavir-boosted tipranavir (TPV). In the first study, which has already been completed, patients were excluded through a selection process because they were too ill and the study might not have shown the drug’s efficacy had it included too many people in dire need of alternative treatments. The second study is still running and the patients were excluded based on the results of a genotypic test: exclusion came after more than three mutations on the protease were found. According to community representatives, this selection of the study population was carried out in such a way that tipranavir would surely show more efficacy than the other available drugs.

The activist groups understand that the companies Roche (T-20) and Boehringer-Ingelheim (tipranavir) need to show the efficacy of the drugs, and therefore exclude some patients from the studies. But in some cases the rate of exclusion reached very high levels: in the Phase III study of tipranavir for instance, it went up to 55%. It is true that some of the people excluded were offered to enter another study but the number of places were very limited. The excluded patients run the risk of seeing their health deteriorate or of dying, as is happening in this case.

For many patients who need alternative treatments, participating in these studies is the only way to have access to a new drug. Including if they are randomized in the control arm, in trials for drugs such as T-20 and TPV, access to the experimental antiretroviral was allowed if the patients’ regimen failed after 8 weeks.

Other patients are enrolled in studies but do not make it past the first selection process. They are rejected with no alternatives offered, after going through a long process of discussing with a doctor the trial’s advantages and disadvantages, offering themselves for enrolment, signing the informed consent form, having blood samples extracted and waiting for the results.

The Community Proposal
Activist groups refuse to hear again the excuse of production limitations to justify the lack of experimental drugs. What we want is for the companies to be obligated to plan ahead of time that at the necessary moment there is enough product available.

The proposal is that regulatory agencies, such as the EMEA or including national bodies, establish that parallel to the Phase III efficacy studies a compulsory tolerance study be opened in which those rejected from the first may participate in the second.

These studies would be known as Phase IIIb. They would allow the risk-benefit ratio of these antiretrovirals to be demonstrated in people excluded from the efficacy study. Along with offering access to those who need it, they would also provide efficacy and tolerance results for this population.

Another option would be that public agencies give authorization for a pre-launching of the drug to a very limited number of patients who are in a dangerous situation. This surely could only be after sufficient data is collected on the safety of the drug.

The third option would be to obtain a formal commitment from the pharmaceutical companies, but activist groups doubt that this would be put into practice. In fact, they declare that when the situation was brought up to the people accountable for it, the result was good words but no actions. This is why, according to activist groups, it is preferable that there be a legal obligation that the pharmaceutical industry will not be able to ignore.

Joan Tallada
based on an ECAB presentation