ECAB: History & vision

History
The first meeting of the European Community Advisory Board (ECAB) took place in spring 1997 near London, and the formation of ECAB was the result of a process by Community Advisory Board (CAB) work along with extensive discussions about the format of such CABs within EATG. In the early 1990’s, when the European AIDS Treatment Group was founded, CABs in Europe existed as company-associated CABs like the Community Company Consultancy Group (CCCG) at BurroughsWellcome or the CAB with Vienna based pharmaceutical company Immuno AG. In addition, pharmaceutical companies presented new research results and plans for the clinical development of substances at the annual EATG ”AIDS & Medication“ meetings. Apart from these annual meetings, companies called for ad hoc CABs, inviting a limited number of EATG members to meetings when new questions or roblems arose.

These early models of CABs were unsatisfactory for various reasons: In many CABs, pharmaceutical companies (and not the EATG or another community-based organization) would decide on the structure of the CAB, including number and choice of invited attendees. Especially ad hoc CABs did not provide a satisfactory way of communication, as there was not always a commitment by companies for continuous cooperation.

The community depended largely on the kindness of strangers. At ”AIDS & Medication“, held in Budapest in fall 1994, the idea of creating a European Community Advisory Board (ECAB) was first mentioned [ref 1]. Three major areas of activity were identified:

• research and development

• marketing issues, including pricing

• ethical issues.

As important goals in the field of research and development, the active involvement of CABs in clinical trials design and development was identified. Pricing issues played an important role not only in Eastern European countries, but also within the European Union. In addition, Eastern European countries experienced very restrictive standards of clinical care due to a lack of resources. Different marketing strategies by pharmaceutical companies resulted (and still do today!) in different levels of access to treatment in various parts of Europe.

At the 1994 ”AIDS and Medication“, members of EATG reconfirmed an earlier decision that they did not want to be seen as representing individual communities rather as representatives for a community based activist’s approach to clinical research and science in Europe. A European Community Advisory Board would be independent from individual pharmaceutical companies, its composition was to be decided upon by the EATG, and it is accountable to EATG and the community.

It took additional years of work and experience to establish the model of the ECAB which is still the basis of today’s work. A fundamental point was the implementation of a working structure of 10-20 (and nowadays even more) members who would meet several times a year to discuss clinical trials with pharmaceutical companies, organize trainings for new members and provide information about ongoing research to the EATG [ref 2].

Objectives,structure and working procedures were described early in 1998 [ref 3] as follows:

• review the design of clinical trials during the process of protocol development

• promote best practice procedures

• suggest / initiate trials according to community needs

• review informed consent procedure

• monitor ongoing trials as far as adverse events, compliance and community needs

• be informed of interim results

• interact with other involved entities such as investigators, Data and Safety Monitoring

Boards (DSMBs) etc.

• be visible to all involved parties and in particular to the community of patients participating in the trials.

Some basic working models have been established (and later been reconfirmed): Work for a CAB should be volunteer (ie, unpaid). Meetings and communications with sponsors of clinical trials or investigators as well as other activities should be documented in (internal) minutes or articles in the EATN.

Past and / or present challenges
Simultaneous development of therapies

A major goal for EATG when it was founded in 1991 was the simultaneous development of therapies in Europe, including not only antiretroviral therapies, but as well as treatments for opportunistic infections and other AIDS related conditions. In the second half of the 1980’s, pharmaceutical companies which developed AIDS medicines ran trials primarily, if not exclusively, in the United States. Trials in other countries would start only after approval was gained in the U.S. This situation resulted in a large delay in access to treatments in Europe and elsewhere. It was the rule, and not an exception, that antiretroviral and other medicines were filed in Europe for approval with a delay of up to 2 years. In addition, compassionate use programmes in Europe started with a similar delay.

This time gap has changed over time, due to the demand of AIDS activists in various countries, due to the establishment of clinical research networks, and an increasing awareness by the pharmaceutical industry of the importance of the European market. Today, major clinical trials are starting simultaneously in Europe, Australia and the U.S. (still leaving other areas on the wait), and in recent years, antiretrovirals were filed simultaneously in the U.S. with the Food and Drug Administration (FDA) and the European authorities (EMEA).

Access to the best available treatments
Access to the best available treatments is a major goal for the EATG. This includes:

• Access to all people who could benefit from the treatment, including so-called ‘sub-populations’ like drug-users, women, children, migrants, people with hepatitis or tuberculosis co-infection, haemophiliacs and other.

• Access for patients in all stages of HIV infection (including first-line, salvage)

• Access to treatment in all European countries (according to WHO definition of Euro region)

Clinical trials and research have been, and continue to remain a major tool in achieving this goal. However, certain patient groups have been traditionally not included in clinical trials (e.g., drug user), or are badly underrepresented (e.g., women). The inclusion of all patient groups who may benefit from new therapeutic developments, as well as the participation of patients from all European countries remains a challenge for the ECAB.

With an uneven distribution of trial sites, for example, access to new antiretrovirals may be limited to patients in a few countries (mostly in Central or Western Europe), and if Expanded Access Programs are running only through sites which have participated before in the clinical trial, this illustrates the access problem for the majority of HIV-infected people in Europe.

Important tools of access to new treatments are: Clinical trials (1 in 20 HIV+ people in the UK could participate in a trial on antiretrovirals in 1991, as compared to 1 in 1,000 in the U.S. [ref 4]), Parallel track or Fast track programmes (as for ddI and d4T), Compassionate Use or so-called Salvage Programmes. Today, early access programmes run mostly under the label of Expanded Access Programmes (EAP) or, depending on legal regulations, Named Patient Programmes (NPP). It remains a challenge to find appropriate inclusion criteria for these programmes to provide sufficient access for those who are in urgent need of new treatments. Lotteries (which were conducted in the past by several pharmaceutical companies) for a slot in an EAP are unacceptable. It is the manufacturer’s responsibility toprovide enough drug supply once efficacy and safety have been sufficiently demonstrated and an EAP is approved by the authorities.

Access to new treatments must be provided as fast as possible. Obstacles and obstructions are: Long duration of drug development (e.g., first publication on Saquinavir in 1989, approval 1997; first publication on Tipranavir in 1996, approval 2005). Regulatory procedures can be time-consuming. Initially, this procedure could easily take more than 200 days in Europe, it is now within 120 days with the centralized approval procedure through London-based EMEA. Approval by local authorities which may be required not only in countries which do not participate in the centralized approval procedure, adds additional bureaucratic procedures which can be time-consuming and, sometimes unclear.

Regulations concerning reimbursement through health insurances may be responsible for delays in access, as is in the Belgium case of Atazanavir (tradename Reyataz) illustrates: This protease inhibitor is officially approved, but not yet available in Belgium because the health care system does not pay for it.

Such delays require communication, discussion, and sometimes protests from community organizations.

Patient safety
Patient safety has been a topic for CABs ever since it beginning, but issues have changed over time. In the early days, a placebo arm in clinical trials was unacceptable when an approved therapy was already available. Trial designs comparing a new antiretroviral versus AZT versus placebo were as unacceptable as a trial design comparing pentamidine for treatment of Pneumocystis carinii pneumonia (PcP) versus placebo, because patients who received the placebo would be put in an unnecessary life threatening stituation.

After results from Delta trial and ACTG175 study were made public [ref 5], monotherapy in antiretroviral trials seemed no longer acceptable since these trials had demonstrated the superiority of a combination therapy (with two NRTIs). Combination therapy was the concept which later made HAART (with three, and sometimes even more antiretrovirals) possible. But in the future antiretrovirals could emerge which have a potency that could allow a new discussion about monotherapy concepts.

The time line of clinical trials is a constant issue. Typically, clinical trials in the past were moving forward too slowly, producing yesterday’s research results for today’s treatments. Maintenance therapy trials which compared different regimens were in the past frequently overcome by the introduction of new treatment options. However, clinical trials cannot simply be speeded up - if trials, in particular phase IIb/III trials, are moving forward too fast, there is a risk of a lack of adequate analysis and inherent risks are not recognized before the new phase is entered (and more people join the trial). ECAB had most recently to deal with protocols which proposed what can be considered a ”fast-lane“ approach, and expressed concerns about these trial designs.

Not only in clinical trials, but in ”daily“ therapy, additional questions arise, concerning the safety in populations with specific physiological or medical conditions (e.g., women, children, co-infected persons, haemophiliacs), about the initiation of antiretroviral therapy (early versus deferred), the efficacy of long-term treatment and last but not least patient information: Are all relevant data for treatment decisions communicated to physicians and patients? Is information about a clinical trial understandable, can patients understand informed consent forms, and is patient information on long-term treatments adequate?

Design of clinical trials
The design of clinical trials changed considerably from the early AZT trials to the latest TORO, RESIST and POWER studies. A major change has been the use of surrogate markers instead of clinical endpoints, sometime during the early 1990’s, but questions remain: Which surrogate markers are the best to use? When should surrogate markers be used? Or when should clinical endpoint studies be done? Which endpoints are acceptable?

Methods of statistical analysis have been refined over the years: new methods for trials which were not placebo-controlled have been introduced, statistical tools for the analysis of two or three treatment arms were developed. But: What are statistics telling us? Is a statistical ”non-inferiority“ good enough for treatment decisions in real life? Are there better, more reliable and more powerful statistical methods?

This problem relates to the question whether registrational trials (studies done during the approval process of a drug) really provide us with the answers which we need? Certainly not in every case. In addition to registrational studies, long-term strategic trials are necessary to answer questions on long-term survival, adverse events etc. These studies are not easy to put up since infrastructure for conducting such a trial, and long-term funding are not easy to secure. And why should people with HIV participate in long-term trials if additional treatment options could become available in the near future?

Improvement of treatments
Prior to approval, new drugs should be tested in drug-drug interaction studies, which is still not yet done in a sufficient way always. Bad experience with full-dose ritonavir has demonstrated the necessity of extensive drug-drug interaction studies 10 years ago. As well, food-drug interaction studies are needed, and if interactions are documented, a clear and understandable advice for patients is needed (not only saying: ”Take it with breakfast“, but indicating the type of the breakfast, since an English breakfast consisting of ham and eggs may contain much more fat than a French breakfast with a cup of black coffee and a Gauloise). Pharmakokinetic studies are needed to assure the frequency of dosing, and adequate dose finding must be undertaken. Traditionally, phase I trials test how much of a new drug is tolerated in (healthy) volunteers, and much too often, too high doses are used in consequent phase II and III trials. This resulted in approval of AZT, but also of other antiretrovirals, in a higher recommended daily dosing than needed.

After approval, medicines need continuous quality improvement: better pharmakokinetics are almost always possible, resulting in less adverse events, better taste of the pills, no food restrictions, or no temperature limits in storage etc. It is not acceptable that pharmaceutical companies improve their products only reluctantly and slowly after approval, thus trying to avoid additional cost and expenditure. ECAB will point to problems with approved drugs and is continuously asking pharmaceutical companies to improve their products.

Community input provides a ”reality check“ not only in clinical trials design (as a Glaxo virologist put it a few years ago), but also in everyday treatment reality. It remains a challenge for ECAB to express the concerns and needs of the community in the process of development of new treatment options as part of community-based AIDS treatment activism.

Stephan Dressler

Based on a presentation given during an ECAB training session, January 26, 2006, Bruxelles. This article expresses the individual opinion of the author.

References
1 see Matthias Wienold: AIDS and Medication. In: European AIDS Treatment News (EATN) Vol 3, Nr 3 (1994), p 1-4, esp. p 3

2 François Houÿez: The future of CABs. A proposal for moving forward. EATN Sept/Oct

1997, p 16-17

3 The ECAB: The European Community Advisory Board. EATN March/April 1998, p 15

4 see Simon Watney: Treatment Issues in Store for European AIDS Activists. European

AIDS Treatment News (EATN) Vol. 1, Nr. 1 (1991), p 4-6

5 First communicated at ICAAC and EACS 1995. Published in print version: Delta trial:

ZDV vs ZDV+ddI vs ZDV+ddC. Lancet 1996;348:283-91; ACTG175: ZDV vs ZDV+ddI vs ZDV+ddC vs ddI. New England Journal of Medicine 1996;335:1081-90.

EATN - European AIDS Treatment News, Volume 15, I – Spring 2006

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