A checklist for managed access programmes for reimbursement co‐designed by Canadian patients and caregivers

Abstract Introduction Reimbursement decisions on orphan drugs carry significant uncertainty, and as the amount increases, so does the risk of making a wrong decision, where harms outweigh benefits. Consequently, patients often face limited access to orphan drugs. Managed access programmes (MAPs) are a mechanism for managing risk while enabling access to potentially beneficial drugs. Patients and their caregivers have expressed support for these programmes and see patient input as critical to successful implementation. However, they have yet to be systematically involved in their design. Objective The aim of this study was to co‐design with patients and caregivers a tool for the development of managed access programmes. Methods Building upon established relationships with the Canadian Organization for Rare Disorders, the project team collaborated with patients and caregivers using the principles of participatory action research. Data were collected at two workshops and analysed using a thematic network approach. Results Patients and caregivers co‐designed a checklist comprised of six aspects of an ideal MAP relating to accountability (programme goals); governance (MAP‐specific committee oversight, patient input, international collaboration); and evidence collection (outcome measures and continuation criteria, on‐going monitoring and registries). They recognized that health‐care resources are finite and considered disease or drug eligibility criteria for deciding when to use a MAP (eg drugs treating diseases for which there are no other legitimate alternatives). Conclusions A patient and caregiver‐designed checklist was created, which emphasized patient involvement and transparency. Further research is needed to examine the feasibility of this checklist and roles for other stakeholders.


| INTRODUC TI ON
Reimbursement decisions on orphan drugs (ie medicines for treating rare diseases affecting less than 5 in 10 000 people in the European Union 1 ) carry significant uncertainty. 2,3 Uncertainty typically arises from a lack of high-quality information on (i) clinical benefit, (ii) value for money, (iii) potential adoption/diffusion and (iv) affordability. 4,5 The natural histories of many rare diseases, which tend to be lifethreatening or severely debilitating, remain poorly understood, and high-quality randomized clinical trials are often difficult to conduct because of small patient populations and limited validated outcome measures. 5,6 As uncertainty increases, so does the risk of making a "wrong decision." Patients may be harmed and resources may be wasted when a treatment provided turns out to be ineffective or unsafe or when a treatment not provided turns out to be effective. 4 Therefore, to manage risk while enabling access to potentially beneficial drugs, innovative ways of introducing these drugs have been developed, [7][8][9] one of which may be referred to as managed access programmes (MAPs). 4 MAPs provide patients with a drug while information needed to address uncertainties is collected to inform a definitive coverage decision. As an outcome-based arrangement, they resemble complex patient access schemes offered through NHS England. 10 In Canada, patients, caregivers and patient organizations have expressed support for MAPs. Further, they perceive their input to be critical to successful implementation, should such a policy option be adopted. However, they have yet to be systematically involved in their design. 4,11

| OBJEC TIVE
The aim of this study was to co-design with patients and caregivers a tool for the development of managed access programmes.

| ME THODS
A participatory action research (PAR) approach was used. PAR requires the active involvement of researchers and participants in co-constructing knowledge; promoting self-and critical awareness (which leads to individual, collective and/or social change); and building alliances for effective planning, implementation and dissemination of the research. 12 In Canada, the Canadian Organization for Rare Disorders (CORD) represents the rare diseases community. It is comprised of more than 80 patient organizations and is recognized as the national voice of this community, advocating for appropriate access to care.
In this study, we built on established relationships between CORD and members of the study team. At the same time, recent research from our group had demonstrated that there was strong interest in the CORD community in a possible role for patients and families in developing innovative approaches, such as MAPs, to improve coverage for orphan and ultra-orphan drugs. 13 Two workshops were held using the methods described below.

| Study population
All patients and caregivers at two CORD Regional Forums were invited to participate in the workshops, which were part of the main Forum programme (ie no other sessions were scheduled at the same time). The Forums focused on strategies for sustainable access to therapies and explored personalized approaches to drug access.
Presentations were made on assessing therapies for real-world use, strategies for responsible use and different pathways for access, including MAPs. Prior to the Forums, participants had participated in two CORD conferences focused on improving access to therapies for rare diseases and efforts to accomplish this in other countries. They also included presentations on the challenges faced by decision-makers in Canada and discussions around the feasibility of applying international experience to the Canadian context. CORD travel grants were provided to patients and families for the conferences and Forums, minimizing financial barriers to attendance.

| Data collection
Workshops built upon findings from research previously undertaken in collaboration with CORD (deliberative discussions with multiple stakeholders and then patients and caregivers, followed by webinars and priority-setting exercises with patients and families) (see Figure S1 in Appendix A for the diagram of research progression).
Questions focused on the 4 main types of uncertainty that decisionmakers face (listed in the Introduction) and sought to elicit information from participants on additional sources of uncertainty and aspects of MAPs important to them (see Table S1 in Appendix A for the list of questions). Two experienced researchers facilitated both workshops, which began with a presentation on MAPs and examples of their use. Both workshops were audio-recorded and transcribed.
No training was provided prior to the workshop, but all of the participants had attended the Forum and CORD conferences.

| Data analysis and interpretation
Transcripts were analysed using a thematic network approach, 14 a tool for organizing the different levels of themes that emerge in a thematic analysis of qualitative data. Transcripts were first coded inductively using open coding methods. 15 Codes were then clustered into "basic themes," describing the premise of the coded data (eg no legitimate drug alternatives). 14 Basic themes focusing on similar issues were further grouped into "organizing themes" (eg drug priorities for MAPs). 14 Finally, organizing themes were grouped into "global themes," capturing what they meant as a whole (eg best practices for an ideal managed access programme). 14 Constant comparative analysis was used to organize codes into themes, 15 which were subsequently mapped onto an uncertainties matrix, reflecting their link to a specific type of uncertainty. Finally, by considering how the themes could be operationalized in the implementation of a MAP, an "ideal" MAP checklist was created similar to commonly used critical appraisal tools.
The checklist was reviewed by workshop participants, minimizing opportunities for bias in the interpretation of data. It was then presented to a broader group of stakeholders who comprise members of the research and advisory teams of Promoting Rare-Disease Innovation through Sustainable Mechanisms (PRISM; a Canadian research network through which this project was funded) for further feedback. These teams include clinicians, regulators, provincial drug plan decision-makers and industry representatives. Based on comments received, a final version of the checklist was prepared.

| RE SULTS
All patients and caregivers who attended the Regional Forum participated in the workshop. They represented a range of disease types (eg cancer, non-cancerous tumour disorders, blood disorders, metabolic disorders, connective tissue disease, endocrine disorders, lung disorders and epileptic encephalopathies) and differing levels of experience within their rare disease communities. Nine patients and three caregivers (10 females; 2 males) participated in the first workshop, and five patients and three caregivers (7 females; 1 male) participated in the second.
Through the workshops, four global themes reflecting "notions" were identified. A notion is an individual's impression of something known, experienced or imagined 16 The notions related to patients' and caregivers' experiences living with a rare disease and accessing appropriate therapies (eg orphan drugs). Collectively these appeared to guide their views on what they considered a MAP that they felt would provide the necessary, but missing information on a new therapy. In addition to these notions, patients and caregivers also identified specific aspects of an ideal MAP. Overarching the four notions and the aspects of an ideal MAP was "sentiments," capturing why patients valued MAPs and wanted to be involved in their design.
Further details on each notion, including examples from the transcripts, can be found in Appendix A (Tables S2 and S3).

| Research on rare diseases and orphan drugs is challenging
Patients and caregivers reiterated the challenges involved in conducting research on rare diseases and orphan drugs, the most significant of which remains the poorly understood natural histories of rare diseases ("Well finally, at least we know I'm not the only one…" -P5, W2) and its impact on the discovery of effective therapies. They emphasized the importance of on-going collection of natural history and clinical outcomes data. They recognized that while registries may play a role, they require significant resources to implement and maintain. "Many drugs can't support that type of registry" and there are "the physicians as well…they don't have time to fill out the paper work" (P3, W2) for on-going data collection.
Patients and caregivers also identified challenges involved in conducting clinical trials on orphan drugs in Canada. In their view, trials are "not likely to be happening in Canada" (P4, W2), which is a concern, as they represent an important means of obtaining early access to new therapies. Regardless of location, trials are limited by small patient sample sizes ("we didn't have 99 patients that were going to enroll"-C2, W2) and a lack of validated outcome measures.

| Challenges around coverage decision-making processes affect access to orphan drugs
Patients and caregivers discussed challenges in Canadian coverage decision-making processes that affect their ability to access orphan drugs. They appreciated that coverage decision making is complicated by the significant uncertainties that exist around the clinical benefit of orphan drugs when one is "not quite sure how it's going to be used and what the outcomes will be…" (P1, W2).
However, they questioned why such processes do not routinely involve specialist physicians "who know something about the disease and the drug" (C1, W2). They also acknowledged the high cost of orphan drugs as an added challenge for decision-makers, as well as desperate demands from patients and families for access to treatments with "no data to support [them] whatsoever…" (P4, W1). These demands are often exacerbated by "inequality [in access] across Canada" (P7, W1), which they blamed on the lack of a national health-care system. They believed that provincial control of health-care budgets has hindered the implementation of nation-wide programmes, like the pan-Canadian Pharmaceutical Alliance (pCPA; established to conduct joint drug plan negotiations for brand drugs in Canada), which could directly affect access to orphan drugs.
There is also a lack of transparency in drug coverage decision making. One participant wondered: "Why don't they have accountability? Why is there no transparency there?" (P6, W1). Patients and caregivers felt that they were purposefully kept in the dark by those involved who "don't want [patients/caregivers] to know" (P1, W1).
Finally, patients and families discussed how Canada represents only a small share of the global drug market and is "not a friendly place for [pharmaceutical companies] to come to" (P8, W1). As a result, there is a need for the government to introduce policy mechanisms for bringing new drugs into Canada that provide some security for companies "around how long they have to recoup that money" (P8, W1).

| All patients are unique
Patients and caregivers explained that no single patient can represent the views of the entire disease group because all patients are "unique" and do "not [

| Aspects of an ideal MAP
Additionally, patients' and caregivers' described the components that a MAP should contain. Six aspects of an ideal MAP were identified. In considering how to operationalize these components, a checklist was developed, which organized the aspects into three categories relating to accountability, governance and evidence collection (Table 1).
An annotated version of this checklist can be found in Appendix B, which maps the notions onto the checklist components (Table B1).

Programme goals
While patients and caregivers viewed MAPs as enabling earlier access to potentially effective therapies, they wanted to ensure that this option is used appropriately or "for the right purpose" (C1, W2)-it must be able to address research questions aimed at determining the right dose of the right drug for the right patient. Individualized treatment protocols, which involve "trying [

MAP-specific Committee
Patients and caregivers indicated that MAPs should be overseen by a MAP-specific committee with "a stipulation that there's patient representation" (P9, W1) from three patient members who: They also agreed that committees should include a physician who specializes in the specific rare disease-"somebody in the medical field who understands [the specific disease]" (P4, W1) and the patient community should select that physician. Finally, there was a widely held view that committee meetings should be "open to anybody" (P7, W1) so that all patients/caregivers have the opportunity to provide input into the programme. This is discussed in detail below.

Individual patient input
The importance of providing opportunities for individual patient and caregiver input in the development of a MAP was

Outcome measures and continuation criteria
Patients and caregivers believed they should have an opportunity to provide input on the outcome measures selected and used as continuation criteria to ensure they are meaningful. They felt that patients should be asked, "What do you think? What else can you tell us?" (C1, W2). With respect to continuation criteria, where these could not be

| Disease/drug priorities
Patients and caregivers recognized that health-care resources are finite and that it is infeasible to have a MAP for every drug. As such, they also considered possible disease or drug eligibility criteria for deciding when to use a MAP. They included drugs that treat "life-threatening or chronically debilitating conditions" (P2, W1) and those for which there are no other legitimate alternatives (ie when an alternative exists but is not an option for all patients, eg, due to intolerance). Drugs that are innovative (ie offer a new mechanism of action) or high cost were also seen as priorities. When asked whether disease prevalence alone is a sufficient criterion to make a drug a priority for a MAP, patients and caregivers both responded "no." While there was broad agreement from patients and caregivers on these criteria, some wondered "why we…are even thinking about excluding [drugs]" (P4, W1), arguing that the use of MAPs for all drugs may make the health-care system more efficient.

| The role of MAPs
In addition to the 4 notions described above, 3 overarching "senti- what they would see as success"-P1, W2) and contributing to decisionmaking committees. should look like, general discussions around the current context of orphan drug access, the challenges that patients and caregivers face and, ultimately, why MAPs was viewed as an appropriate solution also took place. The three sentiments identified from these discussions (trust, hope and desperation) have been documented in published literature. One study found that patients with lower levels of trust in their physician were more likely to want an autonomous role in treatment decision making. 21 Another study which involved a qualitative analysis of cancer patients' conversations demonstrated that hope often served as a justification for action. 22 Finally, a recent ethics paper argued that it is a combination of desperation and hope that motivates patients with untreatable diseases to drastic measures to find potentially effective therapies. 23 It was also recognized that MAPs will not address all of the is-

| Limitations
Both workshops were held at national events hosted by CORD, and it is possible that the individuals who chose to participate in these events were not representative of the rare disease population in Canada. However, CORD is comprised of over 80 different rare disease patient organizations and covers travel expenses for patients and caregivers to attend their events, reducing the likelihood of bias.

| CON CLUS ION
The MAP checklist co-designed by patients and caregivers offers a tool for informing the development and evaluation of such policy options, which aim to improve access to drugs where there is a high degree of uncertainty in the available evidence. Future research is needed to examine the feasibility of this checklist and roles for other stakeholders.

ACK N OWLED G EM ENTS
The authors are grateful to the Canadian Organization for Rare Disorders and the participating patients and caregivers for making this study possible.