Opportunities and challenges for the inclusion of patient preferences in the medical product life cycle: a systematic review

Increasingly, the patient's perspective is considered essential on all levels of decision-making throughout the lifecycle of drugs and medical devices (i.e. the medical product life cycle (MPLC)) [1, 2]. This is demonstrated by a growth of literature on the roles of patients’ perspectives in drug and medical device development [3‐5], regulatory benefit-risk assessment (BRA), Health Technology Assessment (HTA) [6‐9] and clinical practice guideline development [10, 11]. The term ‘medical product’ will be used hereafter as an umbrella term for drugs (or human medicinal products) and medical devices as defined by the European Commission [12, 13] and the US Food and Drug Administration (FDA) [14].

A particular area of interest is the measurement and use of patient preferences (PP) [15, 16]. Although no unique definition exists for PP across research fields and disciplines [17‐20], the FDA refers to PP by defining patient preference information as “qualitative or quantitative assessments of the relative desirability or acceptability to patients of specified alternatives or choices among outcomes or other attributes¹ that differ among alternative health interventions” [14]. PP can be investigated through qualitative and/or quantitative methods [19]. While qualitative methods (e.g. interviews) generate information about patient experiences and perspectives, quantitative methods (e.g. discrete choice experiments) collect numerical data [21].

The initial search identified 1015 documents. Seventy-two documents were included (Fig. 1, Additional file 2). Most were: i) original research (32%) or reviews (24%), ii) focused on PP in BRA/MA decision-making (35%), HTA/reimbursement (21%) or both (17%) and iii) written from an academic perspective (61%) (Table 1).

Using a systematic approach, this review identified the potential roles and reasons to use PP (desires), as well as the expectations, concerns and requirements regarding their use across industry processes, BRA/MA, and HTA/reimbursement decision-making.

The three potential roles that were identified in all three decision-making contexts involved the use of PP to increase understanding of: i) how patients value (clinical) outcomes of a medical product, ii) how patients make the trade-off between benefits and risks and iii) how preferences may differ across patient subgroups (preference heterogeneity). This finding raises the question of whether a single PP study with the primary objectives of investigating these three issues could inform all three decision-making contexts and address the needs respectively, of industry, HTA/reimbursement and regulatory BRA/MA stakeholders. One could for example imagine a PP study consisting of: i) a qualitative phase, where patients are asked openly about what their needs are regarding treatment for their disease and what treatment attributes they find important, and ii) a quantitative phase, where patients are asked to choose between hypothetical treatment options that differ in how they perform on these treatment attributes. Both the results from the qualitative phase as well as the selected attributes and attribute weights derived from the quantitative phase could assist industry in: i) developing a medical product that targeted patient needs and the attributes that patients found most important and ii) subsequently selecting those clinical trial endpoints based upon the attributes patients indicated as most relevant. The selected attributes and the attribute values from the quantitative phase could also be used by regulators and HTA/reimbursement decision-makers to assess the clinical relevance of the outcomes of a medical product being evaluated for MA and reimbursement for the disease of the included patients in the PP study. Furthermore, the attribute values could be used to calculate the minimum required benefit (the minimum benefit respondents expect in order to tolerate a specific level of risk) and the maximum acceptable risk (the maximum risk respondents are willing to tolerate for a given benefit). This minimum required benefit could be used as a reference by regulatory and HTA/reimbursement decision-makers, to evaluate whether or not the clinical benefit of the medical product, as demonstrated in clinical trials exceeds this value, i.e. whether patients would accept the risks of the product under evaluation in return for its benefits. If these calculations indicated that a subgroup of patients accepted the risks in exchange for the benefit, this could inform regulators and HTA/reimbursement decision-makers on the marketing authorization or reimbursement for that subset of patients respectively. These preferred outcomes could also be incorporated in a novel patient relevant outcome (PRO) instrument as, for example, explained by Evers et al. [32], that could be used during clinical trials to evaluate how the medical product in clinical development performed on these PROs. Results from such a hypothetical clinical trial could then inform: i) regulators and HTA decision-makers regarding the performance of that medical product in terms of those PROs as observed during clinical development and ii) the developer of that medical product on how to redesign and improve the medical product in subsequent development. After the MA and reimbursement decision, the PRO instrument could be used to assess how the medical product performs on these PROs outside the clinical trial environment. This information could then inform industry on product redesign and regulatory and HTA/reimbursement stakeholders on continuation of MA and reimbursement. Finally, if these PRO measurements indicate that the medical product only performs well for a subset of patients outside the clinical trial environment this could inform continuation of MA and reimbursement for that subset of patients only.

Despite the array of potential opportunities for the use of PP in the MPLC listed in Table 2, there are few published examples of the actual use of PP study results in industry, regulatory and HTA decisions [45, 82]. As highlighted in Tables 4 and 5, a number of concerns and gaps need to be addressed in order to advance the measurement and use of PP in these decisions. More specifically, efforts need to focus on providing and encouraging: i) recognition of the importance of including PP in industry, regulatory and HTA decisions, ii) guidance on when and how to measure PP aiming to inform these stakeholder decisions and iii) increased familiarity with performing and evaluating PP studies. To promote the development of guidance, more best practice PP studies and more PP studies investigating the methodological concerns this review identified are needed on such questions as: i) how to select, apply and validate different preference methods, ii) how to choose a representative sample in order to satisfy the needs of different stakeholders and iii) how to increase understanding of the reliability and cognitive burden of different preference methods.

Although efforts to address methodological issues are crucial, they are not sufficient alone. Efforts are also needed to address how results from a PP study could be incorporated and aligned with current decision-making processes. More clarity on how results from PP studies would be used in regulatory and HTA decisions together with guidance on how such studies should be conducted could motivate stakeholders to conduct and submit a PP study (Table 5). Table 5 highlights additional concerns regarding the use of PP in HTA/reimbursement. Among the multiple ways in which PP could inform HTA/reimbursement (Table 2), the potential role of PP to inform QALY calculations in countries with publicly funded healthcare is under ongoing debate. As in these countries, HTA guides the allocation of public resources (including but not limited to patients only), it is unclear whether public versus patient preferences should be used. Incorporation of PP in HTA/reimbursement bodies of such countries would therefore not only require solving methodological questions, but also structural and political discussions on the current HTA process in those countries.

This review identified numerous operational and quality requirements involved in performing and evaluating PP studies (Table 5), including: i) ensuring a transparent description of PP study and results when communicating about the study, ii) applying the principles of ‘good science’ when conducting a PP study, iii) paying attention to the heterogeneity of PP and cognitive challenges of preference methods, iv) ensuring patient understanding of the questions asked in the PP study and v) ensuring a representative and diverse sample.

Remarkably, only 18% of the included documents focused on the use of PP in industry processes, leading to sparse results on the use PP in industry processes. As a result, further research is warranted regarding the use of PP for industry purposes, e.g. by consulting sources other than the peer-reviewed literature, including those sources that use qualitative methods such as interviews or focus groups. It was beyond the scope and aim of this review to: i) explain reasons why certain concerns or requirements exist and ii) grade the results (e.g. the identified concerns and requirements) into a hierarchy indicating their importance. Therefore, research aiming to address these issues could complement the current review, e.g. by using qualitative methods to explain the reasoning behind certain issues or differences or by using quantitative methods aimed at ranking and prioritizing the identified requirements and concerns. No literature was found that described the patient’s, caregiver’s, reimbursement agency’s or (practicing) physician’s perspective, which may have led toward a more methodological and scientific result. Therefore, research aiming to assess the perspectives of these different stakeholder groups on the measurement and the use of PP in the MPLC would complement the current review.

The main strengths of this review are its comprehensiveness and novelty in using a systematic approach to search and identify literature relevant to this topic; to the best of the authors’ knowledge, this is the first systematic review that provides an overview of the specific roles and the expectations, concerns and requirements associated with using PP in different decision-making contexts across the MPLC and for different stakeholders, including industry, BRA/MA, and HTA/reimbursement. This review also has limitations. The selection criteria led to the exclusion of: i) literature focused only on PP within individual treatment decision-making, ii) non-English literature, iii) literature from outside the US/EU and iv) literature that did not explicitly mention the use of preference methods. These criteria might have resulted in the exclusion of literature dealing with issues relevant to this review. Further, the broad time span of included literature may be viewed as a limitation since the described concerns and requirements mentioned in earlier published work might at this time already be (partially) resolved and therefore this information might not be as accurate as more recently published studies. During coding, it was sometimes unclear to what specific decision-making context a particular piece of text pertained or whether a particular piece of text needed to be coded as a: i) desire or expectation or ii) concern or a need. This difficulty resulted in this text being coded into multiple domains, which in turn led to some of the results being repeated.

This review highlights the numerous opportunities for using PP in industry, BRA/MA and HTA/reimbursement decisions, from early development decisions through pharmacovigilance activities and post-marketing decisions. However, exploiting the full potential of PP in these decision-making contexts is currently hampered by remaining methodological challenges and lack of specific (regulatory) guidance on how to address these challenges when designing and performing PP studies aiming to inform decisions. To support the development of such guidance, more best practice PP studies and PP studies investigating these methodological issues are critically needed.