Written by Gianluca Quaglio with Sophie Millar,
Drug development: heavily ‘drug-focused’ rather than ‘patient-focused’
For a drug to be prescribed to a patient, it must first be rigorously tested for efficacy and safety and subsequently be approved by relevant authoritative bodies, such as the European Medicines Agency (EMA). However, it has been underlined that the current framework of drug development is heavily ‘drug-focused’ rather than ‘patient-focused’. This means that the end users of the drug, the patients, are not generally placed at the centre of the drug development paradigm. In other words, achieving regulatory approval is seen as the ultimate goal, eclipsing somewhat the use of a drug in its real-world setting. This is not helped by the lack of regulatory demands or incentives for gathering such real world data.
Clinical trials generally recruit a very specific set of participants with small variability, who do not ultimately fully reflect the target population to receive the novel therapy under investigation. The resulting ‘research gap’ highlights the disconnect between the pre-approval development of medicines and their post-approval use in real-world contexts (Figure 1). In Europe, most clinical research focuses primarily on drug development for regulatory approval, instead of addressing patient and public-health needs.
Establishing treatment optimisation as part of personalised medicine development
A shift in drug development is emerging, with momentum towards greater recognition of precision or personalised medicine and patient-centred approaches. The Council of the European Union, while accepting that there is no common definition of the term precision (personalised) medicine, noted that this is generally understood to refer to a medical model that uses the characterisation of individuals’ phenotypes and genotypes to tailor the right therapeutic strategy for the right person at the right time and/or to determine the predisposition to disease and/or to deliver a targeted prevention strategy (Council of the EU, 2015).
A patient-focused approach, termed treatment optimisation or applied research, would bridge the gap between the first stage (regulatory approval) and the second stage (real-world application) of drug development, giving strength to the direction of personalised medicine development.
Numerous drugs are authorised on the market, with limited knowledge on how to use them for dose, sequence, combination and duration of treatment. The treatment optimisation approach could answer questions such as: whether a lower dose of the drug could produce the same results with potentially fewer toxic side effects; how the drug performs in terms of patient-relevant outcome measures such as quality of life and overall survival; and long-term use effects. There is therefore a need for investigation of the optimal way to use medicines.
Role of key stakeholders in the current drug development system
Developing a drug and bringing it into clinical practice is a complex process involving multiple partners in several areas, namely: (i) pharmaceutical industry; (ii) regulatory agencies; (iii) payers (in healthcare, this term generally refers to entities other than patients that finance or reimburse the cost of health services); (iv) Health Technology Assessment (HTA) agencies; (iv) clinicians; (v) patients; (iv) academia. Although they have a common goal (the benefit of the patient), they work with different priorities and methodology. For example, while pharmaceutical companies seek – among other things – profit, researchers want to develop their medical tools and academic career, regulators assess the therapeutic efficacy, and payers make sure that the medical innovations are worth the public investment (Figure 2).
The presence of different actors in the drug development process does not help to narrow the research gap between the first stage and the second stage of drug development.
The STOA study
How do we move to more patient and society-centred drug development, taking all stakeholders’ perspectives and needs into account? It is about bridging the gap between two dimensions that are often misunderstood: (i) efficacy, which is demonstrated under controlled conditions in classical clinical drug trials, and (ii) effectiveness, defined as how a drug performs in the real world of widely varying patients and doctors in different types of hospitals and clinics.
To provide direction in enabling the implementation of treatment optimisation, 26 experts across 5 stakeholder groups were interviewed for a study carried out by the European Parliament Panel for the Future of Science and Technology (STOA) and entitled ‘Treatment optimisation in drug development’. The report was carried out in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC). The interviewees represented patient organisations, regulator and payer authorities, the pharmaceutical industry, health technology assessment agencies, and academic clinicians.
The majority of interviewees agreed that there are insufficient patient-centred approaches and real-world evidence, and a lack of adequate patient involvement during the design stage of clinical trials. The report highlights that both patient-centred and drug-centred approaches are needed and should indeed complement each other.
A number of important recommendations from interviewees regarding how to implement treatment optimisation strategies emerged, covering the process, funding, timing, design and setting for the conduct of studies. Interviewees either proposed that the process should be led by a consortium of all key stakeholders, or by academia and not-for-profit organisations with input from industry (e.g. drug supply). There was some agreement on funding, in that it should come from a combination of public and private sources. Setting-wise, interviewees either did not have a strong preference (case-by-case basis), or suggested that it should take place at a national level with possible international oversight.
In regard to the design of treatment optimisation methods, the following key features emerged from the interviews: fewer inclusion and exclusion criteria; standard of care or best available treatment as comparators; use of patient-relevant outcome measures; and publication of all results. No clear consensus was reached on blinding (whether participants or study staff should know what treatment is being followed) or randomisation.
Policy options arising from this study centred on when in the drug development ‘pipeline’ the treatment optimisation process should take place, and by which legal mechanism. Three main policy options emerged. Briefly, these were: (i) making the conduct of treatment optimisation studies part of the requirements that manufacturers have to satisfy in order to obtain marketing authorisation for their products; (ii) including treatment optimisation studies as part of the post-authorisation commitments; and (iii) conditional reimbursement mechanisms employed to compel the manufacturers to carry out treatment optimisation studies.
Whatever policy approach prevails, it is clear that significant political effort will be needed for the current legislative frameworks to be modified, at both European and national level.