Patients Involved – HIV DUET Phase III trials

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Introduction

A patients involved case report of patient advocacy in HIV DUET Phase III trials for a novel treatment regime using a combination of two investigational compounds: TMC125 (etravirine) and TMC114 (darunavir). Consultation between the AIDS Treatment Activists Coalition Drug Development Committee (USA), European Community Advisory Board of the European AIDS Treatment Group (ECAB EATG), and the pharmaceutical company Tibotec (now Janssen Therapeutics).

Description of the case

The pharmaceutical developer Tibotec (now Janssen Therapeutics) designed the DUET 1 & 2 studies in 2005. The DUET Phase III trials involved the concurrent use of TMC125 (etravirine) and TMC114 (darunavir) in a HIV treatment experienced population. The unique feature of the trial was that both compounds used had not been licensed at the time of use (2006). This was the first occasion that two yet unlicensed compounds were used in a trial in a treatment experienced setting, albeit only in one arm, while the other arm of the trial remained placebo-controlled.

HIV infection is a yet incurable but manageable disease that requires a relatively rigorous regime of anti-retroviral medication (ART) for the patients in order to avoid resistance. Resistance to certain medicines or classes of medicines is more common with treatment experienced patients who therefore need novel or more complex regimens to control virus reproduction in the body.

The patient community played a key role in achieving that –for the first time –a trial involved the concurrent use of two unregistered compounds. Standard procedure is to use a single new compound in a trial.

The objective of this intervention of the patient community was to make sure that a potent novel combination of ART is available as salvage therapy for heavily treatment experienced patients. Compassionate use of the novel treatment regime through the trial was advocated for.

Type(s) of patient (advocates) involved

• Patients with personal disease experience.
• Expert patients / patient advocates with good expertise on disease, but little R&D experience.
• Expert patients / patient advocates with good expertise on disease and good R&D experience.

Benefits of patient involvement

Consultation between the patient community and the pharmaceutical developer matured and evolved during this process significantly. The patient’s organisations (POs) involved could successfully demonstrate to the industry and the regulators that the knowledge and experience of the patient community can yield substantial input into the development process. The innovative approach of the community infused the development process with a certain degree of ‘courage’ to go apply unconventional strategies when preliminary results from previous trials are convincing enough (both new compounds were already known to be safe and well tolerable at the time).

This new approach led to lasting results and trust between the stakeholders involved. The collaboration of two POs from both sides of the Atlantic entered a new, more intensive phase, thus allowing exchange of experience across the communities of people living with HIV. The DUET study resulted in overcoming accumulated multidrug-resistance (MDR) for thousands of heavily pre-treated patients.

Challenges and barriers

Providing compassionate use of novel compounds to patients with reduced treatment options was and remains a challenge. The participation in clinical trials is an effective tool for patients to access new medicines.

The use of two experimental compounds was not common practice. Substantial advocacy (political) input was required from the patient community to convince the developer (and in turn the US Food and Drug Administration (FDA), European Medicines Agency (EMA) and National Competent Authorities (NCA)) of this new strategy.

An important meeting was held with ATAC-DDC, EATG/ECAB and the pharmaceutical company in Antwerp in 2005.The specific objective of the meeting was to convince the company of the usefulness of and need for a new approach to help patients in need.

However, one main challenge remained that the pharmaceutical company decided to design the trial with one placebo-controlled arm, meaning that 50% of the patients received placebo + one investigational compound rather than both new medicines.

Learnings

The involvement of patient organisations and expert patients in pharmaceutical development is no longer unique. However, new strategies and uninterrupted work, complemented with continuous self-education and rigorous knowledge of the field by the community are needed in order to navigate the complex setting of medicine development and research.

More intensive interaction with regulators is required to leverage the political objectives and pressure that POs want to exert to achieve their objectives; in this case the availability of new treatment options.

Despite all efforts, the POs could only achieve a partial result: a placebo-controlled arm remained part of the trials concerned. Improvements in this area could, however, be achieved in later study designs developed with patient involvement.

Even better coordination between POs and a more regular exchange of experience within and outside a specific disease area should improve the effectiveness and efficiency of patient involvement in research.

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