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Increasing Patient Involvement in Drug Development

Open AccessPublished:May 24, 2016DOI:https://doi.org/10.1016/j.jval.2016.04.009

      Abstract

      Background

      To ensure the creation of treatments that maximize value at the lowest cost, all aspects of the health care system need to align with patient needs and preferences. Despite growing efforts to engage patients in research and regulatory activities, the pharmaceutical industry has yet to maximize patient involvement in the drug development process.

      Objective

      To gain a better understanding of the present state of patient involvement in drug development.

      Methods

      Through a semistructured interview methodology, we sought to identify opportunities, barriers, and examples of patient involvement in the drug development process. Telephone interviews were conducted with six senior leaders of evidence generation within the pharmaceutical industry and four patients. These interviews were supplemented with interviews with a research funder, a regulator, a patient advocacy group, and a caregiver.

      Results

      Although our interviewees spoke of the potential benefits of aligning research around the needs of patients, there were few examples they could share to suggest this was occurring at scale. A number of barriers were identified including the added burden associated with adverse event reporting, concerns about patient representativeness or their ability to participate in drug development conversations, and the costs in time and resources involved relative to returns on investment.

      Conclusions

      As health care systems continue to evolve and establish patients as the primary stakeholder in their health care decision making, the pharmaceutical industry will need to be innovative to demonstrate the value of their products relative to the outcomes experienced by patients. Pharmaceutical companies should recognize the value of involving patients across the entire product life cycle and work to transform present perceptions and practices throughout their organizations.

      Keywords

      Introduction

      Pharmaceutical companies are tasked with developing life-changing products that meet the needs of patients, physicians, and payers while adhering to regulatory standards, managing health technology and payer scrutiny, and performing to satisfy investors. In addition, in a time when total health care costs are being scrutinized by government and private payers alike, providers must maximize the quality of care by using interventions that provide the most value while minimizing cost. While drug prices seem to be continually rising, many health plans are shifting more of the burden of cost sharing to patients. As a result, the patient is becoming more of a “consumer” in the traditional sense. This shift demands that the pharmaceutical industry begin to use the types of consumer research that are a mainstay of other industries in which the true value of a product is defined by those who will ultimately use it. Notably, in these industries, the input of consumers is sought throughout development, from product conception through market entry and beyond.
      Developing a treatment that can truly help to improve the lives of patients should be rooted in a firm understanding of the challenges those patients face in their daily lives, their needs, and the trade-offs they are willing to make to gain relief [
      • Hoo A.
      • Anderson J.
      • Boutin M.
      • et al.
      Partnering with patients in the development and lifestyle of medicines: a call for action.
      ]. To ensure the creation of valuable treatments, all aspects of the health care system, including research prioritization, product development, trial design, regulatory approval, access, reimbursement, and treatment decisions, will need to align with the needs of patients. This realignment has started to take place on the payer side with the use of health technology assessments (HTA), which stipulate that patients’ preferences or perspectives be integrated in value demonstration. Such HTAs are presently in use in several European countries, and similar value frameworks are beginning to emerge in the United States, bolstering hopes that these nascent efforts to increase patient involvement in various aspects of health care will continue to develop and expand in scope.
      Despite this paradigm shift toward incorporating patient perspectives, pharmaceutical companies have yet to maximally engage with patients to learn what they value before developing a product. Advocacy and market research groups, which have networks and skills in patient “outreach,” exist in most pharmaceutical companies; these departments, however, tend to focus more on the commercial aspects of launch and postlaunch activities such as disease awareness and education. Thus, individuals working in these areas often have different objectives for engaging with patients than their colleagues in clinical development. Because they may also lack the scientific or technical skill set necessary to collect patient input in a meaningful way that will result in actionable insights for their clinical development programs, many decisions in clinical development are made without patient input.
      At present, limited data exist that describe the scope and overall benefit of existing patient-centered drug development activities [
      • Getz K.A.
      Establishing return-on-investment expectations for patient-centric initiatives.
      ]. Nevertheless, the following story of the inhaled insulin product Exubera® illustrates how a better understanding of patient needs can inform the development of a more valuable product and prevent costly missteps. Exubera® (insulin human [rDNA origin]) inhalation powder was approved by the Food and Drug Administration (FDA) in January 2006 for use as a mealtime insulin, but the makers of the product withdrew it from the market in October 2007 [

      Exubera® [package insert on the Internet]. April 2008. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021868s016s017lbl.pdf. [January 16, 2014].

      ,

      Herper M. Pfizer kills Exubera. Forbes [Internet]. 18 October 2007. Available from: http://www.forbes.com/2007/10/18/pharmacuticals-pfizer-exubera-biz-sci-cx-mh-1018pfizer.html. [Accessed January 16, 2014].

      ]. The goal of this product was to offer the convenience of an alternative, less invasive route of administration over injected insulin. Unfortunately, the delivery device was found to be too cumbersome and patients did not find it appealing enough to stop using injectable insulin. As a result of the failure to gain the interest of patients and providers, pharmaceutical company Pfizer made the decision to voluntarily withdraw Exubera®, a decision that cost the company $2.8 billion [

      Herper M. Pfizer kills Exubera. Forbes [Internet]. 18 October 2007. Available from: http://www.forbes.com/2007/10/18/pharmacuticals-pfizer-exubera-biz-sci-cx-mh-1018pfizer.html. [Accessed January 16, 2014].

      ,
      • Mack G.S.
      Pfizer dumps Exubera.
      ].
      Outside the pharmaceutical industry, however, engagement with patients is increasing. Patients have been invited by regulators such as the FDA, the European Medicines Agency, and the National Institute for Health and Care Excellence to provide their perspectives and advice during decision making [
      • Mann M.K.
      Partnering with patients to help heal healthcare.
      ]. In the Prescription Drug User Fee Act V spanning fiscal years 2013 to 2017, the FDA launched the Patient-Focused Drug Development initiative designed to gain the patient perspective in certain disease areas and in turn to more effectively inform the FDA’s evaluation of the risks and benefits of new therapies [

      Mullins TM. FDA’s patient-focused drug development initiative [presentation]. April 2013 [Accessed 17 December 2015]. Available from: http://c-path.org/wp-content/uploads/2013/09/PRO_Consortium_FDA_PDUFA_V_PatientFocusedDD.pdf.

      ,

      US Food and Drug Administration. Enhancing benefit-risk assessment in regulatory decision-making. Available from: http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm326192.htm. [Accessed November 8, 2015].

      ]. The British Medical Journal now includes patients in its peer review process and encourages authors to coproduce articles with patients. Researchers submitting grants to the Patient-Centered Outcomes Research Institute are also encouraged to work with patients [
      • Godlee F.
      Towards the patient revolution.
      ,
      • Fleurence R.
      • Selby J.V.
      • Odom-Walker K.
      • et al.
      How the Patient-Centered Outcomes Research Institute is engaging patients and others in shaping its research agenda.
      ]. Participant-led research using patient-powered research networks and social media is challenging our traditional views of what “a participant” is truly capable of doing [
      • O’Connor D.
      The apomediated world: regulating research when social media has changed research.
      ]. Medical conferences take steps to self-accredit as “#PatientsIncluded™” by involving patients in planning, as presenters, and in the audience, whereas medical journals can accredit themselves by inviting patients to join their editorial boards, submit content, and act as peer reviewers [

      Patients Included. Patients Included: a charter for conferences. Available from: http://patientsincluded.org/. [Accessed April 12, 2016].

      ]. Such patient-centered activities differ from mere tokenism [
      • Arnsterin S.R.
      A ladder of citizen participation.
      ] because patients themselves are making decisions with real consequences, instead of merely being asked for opinions that can be arbitrarily used or ignored by decision makers.
      These efforts to increase patient involvement in various facets of health care highlight a growing need for the pharmaceutical industry to shift its approach to proactively engage with patients during drug development. If pharmaceutical companies remain unengaged with patients, they risk not only falling behind what FDA learns as a result of the Patient-Focused Drug Development initiative but also misunderstanding the concerns of their customers and thus ultimately breaking their social contract with patients [
      • Wicks P.
      • Vaughan T.
      • Heywood J.
      Subjects no more: what happens when trial participants realize they hold the power?.
      ]. Given the time and money required to develop a new drug, any misstep is likely to have significant financial ramifications. Because engaging patients in the drug development process is not yet commonplace for most pharmaceutical companies, there is an opportunity to develop recommendations to guide the inclusion of patients in this process going forward. To inform the creation of such recommendations, we first sought to learn how patients are presently involved in drug development and the generation of evidence.

      Methods

      To gain a better understanding of the present state of patient involvement in drug development, a number of industry, regulatory, research, and patient advocacy thought leaders were interviewed. The interviews aimed to identify previous, present, and potential areas of patient participation as well as the corresponding benefits, barriers, and challenges to such patient involvement. Interviewees were identified via previous contact with PatientsLikeMe either as members of the Website or through personal networks. They were invited to participate with the understanding that their information would not be attributable to them personally, that they were free to withdraw at any time, and that they would receive no compensation except early access to a final report. To guide the conversation, each interview was conducted using a semistructured interview format over approximately 60 minutes using the questions and topics listed in Appendices I and II in Supplemental Materials found at doi:10.1016/j.jval.2016.04.009. Key themes for health care thought leaders included the interviewee’s experience with including patient voice in drug development, their feelings about the role patients could potentially play in different aspects of development, specific examples including what worked well and what did not, and potential challenges and barriers to incorporating patient voice. Key themes for patients included their experience of working with researchers and with other stakeholders such as the FDA, their thoughts on the skills needed to be effective, and their thoughts for the future of patient engagement in drug development. Interviews were conducted between June 2014 and August 2015. The authors compiled transcripts and analyzed major themes and concepts upon completion of all interviews.

      Results

      A total of 14 interviews were conducted: 8 with health care thought leaders, 5 with patient thought leaders, and 1 with a disease-specific patient advocacy foundation. For the purposes of this analysis, the results of the interview with the patient advocacy foundation will be included with those of the patient interviews because all these interviewees represented patient interests. Of the 8 health care thought leaders interviewed, six worked in the pharmaceutical industry, one for a regulatory agency, and one for a research institute. Interviewees of the pharmaceutical industry were at either the vice president or director level and represented various departments, including health economics and outcomes research, medical evidence, global outcomes, epidemiology, evidence science and innovation, patient-reported outcomes (PROs), and research integration. Of the five patient thought leaders interviewed, all represented the experience of patients with incurable, chronic illnesses with significant impact on daily life.

      Health Care Thought Leader Interviews

      Our health care interviewees all expressed the belief that incorporating the patient voice into drug development and evidence generation is a positive development. They reasoned that “being more patient-centric is always a good thing,” particularly as a way to better understand heterogeneity of disease and identify unmet needs: “Patients often bring a refreshing perspective on what matters … things that doctors might not have talked about.” Our interviewees felt that incorporating the patient voice into drug development is not only part of a corresponding responsibility to do right by patients, but it can help inform the development of important therapeutics and even help avoid costly missteps in the development process.
      The industry interviewees identified five main areas in which patients are presently involved: informing product strategy, informing clinical trial design, developing PROs, generating evidence, and participating in company/regulatory meetings. The interviewees were able to cite a number of specific examples, but also stated that these represented exceptions rather than established practice, and patient input was not incorporated consistently. The interviewees also provided a number of areas in which patients could potentially be better involved in the drug development process (Table 1).
      Table 1Present and potential future areas of patient involvement in the drug development and evidence generation process, as described by health care thought leader interviewees
      Focus areaPresent examples of patient involvementFuture potential for patient involvement
      Product strategy•Small number of invited patients participate in focus groups to inform product strategy•Gather input more uniformly from patients (including their experiences, needs, and expectations) and quantitatively assess their needs and insights to guide the product agenda
      •Product development teams hold meetings with patient advocacy groups during product development process
      Clinical trials•Patients may be called upon to provide input on trial protocols and study design, particularly if recruitment is going poorly•Include patients as partners in the process charged with ensuring patient centricity of study protocols, study hypotheses, recruitment materials, and end point selection to increase patient interest in participating, and avoid problems with study recruitment and retention
      •Patients may provide qualitative feedback throughout trial participation that is fed back to the company via health care professionals•Leverage patients outside of the clinical trial setting to better understand the real-world settings patients live in
      •Systematically listen to patients participating in clinical trials to better manage the trial and inform further development
      PRO development activities•Patients participate in activities such as qualitative interviews and concept elicitation•Include patients as partners in the design of PRO instruments
      •Provide patients self-monitoring PRO tools outside of clinical trial context to better manage their conditions
      Evidence generation•Patients participate in clinical trials or have their health care claims data analyzed•Develop tools to support participant-led research
      •Patients’ burden-of-illness assessments•Increase connectivity between patients and medical/pharmacy claims data or health care use to support economic modeling
      •Involve patients in evidence dissemination to their peers
      Patients as meeting participants•Patients may speak at company meetings to help set the tone and provide employees with the patient perspective•Utilize appropriate training and safeguards, and recruit patients as pharmaceutical staff to serve as company employees and internal subject matter experts to change culture from the inside
      •Patients may be included as full voting members in regulatory committee meetings
      PRO, patient-reported outcome.
      In contrast, the regulator and research funder we spoke to both worked at organizations that took a systematic approach to including patients throughout the research process. Training was included to increase skills and build the capacity of patients to contribute. In some cases, patients had specific responsibilities such as writing reports, reviewing grants, writing lay summaries, or conducting their own research studies. Both organizations were funded by national governments and had requirements for patient inclusivity explicitly written into their mandates.
      The health care thought leader interviewees cited a number of barriers and challenges to expanding patient involvement in drug development (Table 2). Two of the greatest challenges identified were timing and budget impact. Legal, compliance, and regulatory challenges were also frequently mentioned by industry representatives when it came to talking to patients: “We can talk about patients, but not with patients.” One interviewee cited an example when their company convened an advisory board that included patients; the interviewee recalled that industry colleagues found it hard to move past the concern that they were “somehow breaking the law by having patients in the room.” Another common theme was that the pharmaceutical industry and other health care decision makers, such as physicians, are slow to adapt and often resist change to the status quo. Those who endorse expanding patient involvement in drug development activities have an uphill battle to enact change. Last, concerns were expressed regarding the lack of evidence to suggest that patient participation in drug development would deliver sufficient tangible benefits to justify the costs, expressed in terms of sufficient “return on investment.”
      Table 2Barriers to increasing the level of patient involvement in the drug development process, as described by health care thought leader interviewees
      Timing and budget concerns
      Unknown return on investment for increasing patient involvement
      IRB approval
      Rapidity of drug development
      Compliance and regulatory challenges
      Adverse event reporting
      No industry guidance on interacting with patients
      Regulators slow to adopt patient-generated data and real-world data
      No regulatory requirement to involve patients in the drug development and evidence generation process
      Methodological challenges
      Lack of uniform, repeatable, scientifically rigorous methods for involving patients
      Clinical trials may become unblinded
      Patient views may conflict with regulators, clinicians, and scientists
      Organizational and clinical inertia
      If it is not broken, why fix it?
      Existence of inconsistent practices within and across companies
      Clinicians and researchers resistant to change
      Development and validation of PROs slow and expensive
      Uncertainty regarding feasibility of involving patients
      Uncertainty regarding ideal methods for involving patients
      Negative perceptions about patients’ ability to participate
      Belief that patients cannot be representative as a result of being biased by their own experiences (in contrast to key opinion leaders who might have cared for hundreds or even thousands of patients)
      Patients do not always have the knowledge required to participate in complex drug development conversations
      IRB, institutional review board; PRO, patient-reported outcome.

      Patient Thought Leader Interviews

      In addition to various members of the health care industry, we interviewed five patient thought leaders and one patient advocacy organization to gain their perspectives. In general, these interviewees reported sensing an increased desire on the part of drug developers to include patients, but reported that significant progress is needed. They all emphasized that whatever challenges or barriers may be encountered along the way, patients are eager and willing to be involved but they need to be invited to the table. One interviewee described it not as patient involvement or engagement, but as patient integration: “Invite me to be on your team … Show me that you appreciate and value me.” Another felt that patients and drug developers are both interested in the same things: “We all want better treatments developed more quickly.”
      One of the most prominent themes present was that patients should be involved from the start. It is too late to bring a patient in at the end to simply react to or sign off on work that was done without them. The interviewees felt this could be improved by getting patients involved in setting the research agenda and product development plan for a given product or disease state: “Patients should be engaged early and often and there is a place at each step from conception all the way to FDA approval.”
      Interviewees felt that patient involvement does not mean having patients necessarily inform the science behind drug development, but rather it should focus on the experiences of patients living with an illness. Patients are best suited to provide insight regarding their perceptions of benefits and risks, relevance of an issue being studied, what symptoms matter most, and overall impact on daily life. One patient commented, “It just seems kind of funny to me that you can go through the whole process of getting a clinical trial underway and never include a patient in the process.” Patients felt that decision makers, particularly regulators, do not always have a complete understanding of the risks that patients with some illnesses are willing to accept, and that this benefit-risk assessment will vary by disease. Patients also expressed that they may be willing to accept more risks to get the right treatment sooner.

      Discussion

      We sought to characterize the present state of patient involvement in drug development to inform the development of a set of recommendations to aid pharmaceutical companies in more proactive and consistent engagement of patients. The results of our interviews revealed little evidence that patients are routinely involved during drug development or that their involvement in the drug development process is widely sought beyond a few champions. Some of the examples of patient involvement provided by our interviewees would sit quite low on Arnstein’s ladder of citizen participation [
      • Arnsterin S.R.
      A ladder of citizen participation.
      ], frequently cited by the Patient-Centered Outcomes Research Institute as a useful framework to understand engagement. For example, involving patients as participants in research studies to better understand their disease for PRO development is, at best, consultative rather than a reflection of true partnership. Inviting patients to act as speakers at meetings may have the appearance of patient centricity, but this risks co-opting the experience of patients to boost morale without actually inviting them to participate in decision making.
      Our interviews also confirmed the existence, whether real or perceived, of many of the same barriers to consistent patient involvement in drug development identified by Hoo et al. [
      • Hoo A.
      • Anderson J.
      • Boutin M.
      • et al.
      Partnering with patients in the development and lifestyle of medicines: a call for action.
      ], such as inconsistency and fragmentation of approach. The health care thought leader interviewees cited a range of concerns, not least of which was the widespread perception by employees of pharmaceutical companies that patient interaction constitutes a regulatory violation. Some concerns shared regarding this issue represent real challenges, such as the need to report adverse events reported by patients, whereas others were representative of more imagined barriers, such as regulatory or legal statutes prohibiting direct interactions with patients.
      These findings support the notion that the availability of existing engagement frameworks has not been sufficient to encourage and inform more widespread patient involvement in drug development; thus, the creation and validation of such a framework is an important next step to guide the development of better drug products [
      • Hoo A.
      • Anderson J.
      • Boutin M.
      • et al.
      Partnering with patients in the development and lifestyle of medicines: a call for action.
      ,
      • Domecq Garces J.P.
      • Prutsky Lopez G.J.
      • Wang Z.
      Eliciting Patient Perspective in Patient-Centered Outcomes Research: A Meta Narrative Systematic Review.
      ,
      • Forsythe L.P.
      • Szydlowski V.
      • Murad M.H.
      • et al.
      A systematic review of approaches for engaging patients for research on rare diseases.
      ]. For any proposed framework to be successful, it needs to be specific in identifying areas of the drug development process in which patients can become more involved, it needs to describe and recommend how patients could become involved in such activities, and it needs to be accepted by all stakeholders in this process [
      • Hoo A.
      • Anderson J.
      • Boutin M.
      • et al.
      Partnering with patients in the development and lifestyle of medicines: a call for action.
      ]. Drawing upon what was learned from these health care and patient thought leader interviews, we would like to propose a framework for increasing patient involvement in drug development, beginning with the principles outlined in Table 3.
      Table 3Principles for increasing patient involvement in drug development
      Acknowledge the importance of patient involvement and define what it means to truly incorporate patients as partners.
      Take inventory: Review existing efforts and work with patients to determine when patients should be more included.
      Be transparent: Own up to instances when this could have been done better, both internally and to external stakeholders such as patients, payers, and regulators.
      Trust patients: Invest in them and take the time to educate them on issues and needs.
      Involve patients continuously, early, and often: Encourage involvement across all phases of product development.
      Treat patients as collaborators: They should be seen and treated as equal stakeholders and not as a target market.
      Display leadership: Be ambassadors for this cause for the rest of the industry.
      Be the change you want to see: Proactively provide patient-generated perspectives and evidence to regulators, payers, and market access gatekeepers.
      Share your lessons learned: Document failures as well as successes.
      Collaborate to develop best practices: Share tool kits with your peers.
      On the basis of the findings of our patient thought leader interviews, we support the recommendation to use the phrase “patient involvement,” because it conveys a more active role on the part of the patient [
      • Hoo A.
      • Anderson J.
      • Boutin M.
      • et al.
      Partnering with patients in the development and lifestyle of medicines: a call for action.
      ]. By defining what constitutes patient involvement at the company level, drug developers can then create company-specific values and priorities for including patients as partners throughout this process. We recognize that for meaningful patient involvement to become more commonplace, real and perceived barriers—structural, cultural, and regulatory—will need to be overcome. At present, patient involvement is not uniformly recognized as valuable in drug development by those in the pharmaceutical industry. This is why we feel it is important for leadership within companies to champion this effort and to be the change that they wish to see. This leadership needs to be focused both internally to all aspects of company operations and externally to set an example for others within the industry. We believe that it is equally important that payers and HTAs give adequate weight to patient preferences in their valuation of treatments. Doing so will likely serve as an incentive for pharmaceutical companies to face these barriers head on and involve patients in drug development activities in meaningful ways.
      Best practices for patient involvement are still in development and further experimentation will be required to identify what techniques work best. Companies will need to experiment with different methods to learn what works best and try to build on the successes of others in the industry [
      • Wicks P.
      • Lowe M.
      • Gabriel S.
      • et al.
      Increasing patient participation in drug development.
      ]. Pharmaceutical companies have an opportunity to achieve a strategic advantage by building internal expertise of the most impactful strategies for patient involvement, to guide development of industry best practices, and to anticipate changes to regulatory requirements.
      To help facilitate these changes, we have also proposed a range of solutions to overcome the barriers identified by our interviewees (Table 4). It is important to note that patient involvement may take many forms: patients may serve on advisory boards during protocol development, provide guidance on early product development strategies or specific areas of clinical trial protocols, serve as coinvestigators, and coauthor articles. Inspired by the work of the PatientsIncluded group, which invites voluntary self-accreditation against a crowdsourced set of criteria, we also propose some practical steps that senior leadership could take within their organization today to bring patients into their business as true partners (Table 5) [

      Patients Included. Patients Included: a charter for conferences. Available from: http://patientsincluded.org/. [Accessed April 12, 2016].

      ].
      Table 4Barriers and proposed solutions for increasing the level of patient involvement in the drug development process
      BarrierExample(s)Solution(s)
      Timing and budget concernsProviding sufficient support for patient involvement increases time and resources needed for development of the specific studies, thereby prolonging drug development and increasing costs.Factor these additional costs in earlier, model the potential benefits later down the line in terms of approval or trial accrual—“You save time by making time.” By involving patients early and often throughout drug development (specifically in the design of clinical trials), time may ultimately be saved by preventing difficulty with recruiting and retaining patients in clinical trials.
      Compliance and regulatory challengesConcerns over adverse event reporting requirements and the lack of regulatory guidance on interacting with patients.Pharmaceutical companies can create an open dialogue with regulators to avoid pitfalls, model engagement on existing mechanisms, and develop best practices.
      Methodological challengesConcerns on both sides about “tokenism” or “nonparticipating observers of technical discussions.”Ensure that patients are included in decisions as equal partners and ensure they see rapid evidence of their efforts. Proactively solicit patient feedback and respect the thoughts and opinions they provide.
      Patient partners may have strong opinions that are not scientifically feasible (e.g., breaking equipoise).Be open and honest with patients about what is expected of them and about the potential impact that their input can have. Treat them as a valued partner in the process. Be honest and transparent if feedback is provided that would not be directly actionable. Do not dismiss patients as not helpful and address potential conflicts or differences of understanding constructively.
      Concerns about external validity of involved patient group to wider population.Develop a set of patient characteristics of importance for the issue at hand to guide population selection or try to match patient participants against best available epidemiological data for the patient population.
      One patient may not be representative enough.For many drug development activities, it may make sense to include more than one patient. Involving more than one patient in each activity may increase patient comfort in taking a more active role. Patients serving as the sole representative of their disease community may not feel valued or supported and this may negatively impact their ability to be productive participants in these processes.
      Regardless of the number of patients involved, encourage each to connect with others in their disease community to gain more insight into the experience and opinions of others. Patients are likely making these connections with one another already; encouraging such connections can provide an additional source of learning and maximize the impact of involving a small number of patients in drug development.
      Uncertainty regarding how to find the right patients.Develop “personas” describing the types of patients who could be helpful across the entire drug development process for a given disease state and narrow patient selection on the basis of these personas and the specific activity that patients will be getting involved in. Using these personas, drug developers can adopt an approach similar to empaneling a jury to identify a small, but representative, patient sample.
      Some characteristics to look for in patients who will thrive when taking on a more active role include training from an advocacy group regarding drug development or research processes, comfort with public speaking, comfort with voicing opinions in group meetings, and basic understanding of study design and drug development.
      Patients are ready and willing to help and there are plenty of advocacy groups and patient interest organizations that are available to help prepare patients for this role and facilitate connections. These organizations can also provide expertise and guidance with respect to working with patient representatives and may even offer various training programs to prepare patients for the various roles they may play in the drug development and research processes.
      Getting the right information from patients.Trust patients. Do not assume they are not capable of understanding what they need to. Invest in them and take the time to educate them on issues they need to understand to become involved in various activities.
      Make questions answerable; keep them simple and remove ambiguity.
      Ask the right questions and be ready to listen. If you ask the right questions, patients will answer them. Even if a patient is not skilled in science/research, there are still things that can be learned by speaking with them about the right things. Patients have valuable insight into their experiences, regardless of the questions being asked.
      Use both qualitative and quantitative methods to collect information from patients. Quantitative techniques will allow you to measure trends but qualitative methods will help inform further dialogue with patients.
      Researchers may influence involved patients to further own agenda.Patient selection could be tasked to a neutral third party such as a nonresearcher or patient. Similarly, such third parties could be used to guide and facilitate patient discussions if concerns exist regarding the partiality of researchers or other members on the drug development team.
      Organizational and clinical inertiaPatient involvement is not as great a “win” as other methods of protocol optimization (e.g., six sigma).Patient involvement does not preclude other forms of trial improvement research and should focus on framing questions rather than serving as the sole technique for optimizing solutions.
      Researchers are interested primarily in optimizing trials and not involving patients in earlier phases of decision making such as outcome selection.Start small and build in more patient involvement over time. For example, begin with trial optimization as the first project that patients are involved in and in subsequent projects “back the truck up” to get patients involved earlier in the drug development process, as mutual trust and success build up.
      Resistance to change on the part of drug developers, researchers, and clinicians.Train the drug-developing and medical communities to change their way of thinking when it comes to patient perspective. Teach them the value of including patients and lead by example. When it comes to pharmaceutical companies, the change needs to come from the top down and be fully supported throughout the organization.
      Negative perceptions about patients’ ability to participatePatients require careful induction and onboarding.Develop an intake interview so that patients can meet with someone who will be involved in the rest of their participation to outline expectations and offer information tailored to areas in which they will be participating and not just the whole program of work.
      Low population health literacy/lack of knowledge or understanding of the intricacies of research design and drug development processes.Careful selection, mentoring, and patient education programs in advance of involvement activities but also investigator education in communication. Nevertheless, just because patients may not know the details of drug development or research processes does not preclude them from being helpful.
      Patients may not always know how to answer technically complex questions, but it should be more about finding a way to listen to them share their own stories and experiences.
      Patients themselves are unavailable because of consent or cognitive capacity issues.Involve caregivers or patient advocates on their behalf; recruit early-stage or high-functioning patients when possible.
      Language/cultural issues.Use extra resources for translation and cultural sensitivity training.
      Patients move or are lost to follow-up.Maintain strong bonds within the community to maintain contact; use multiple channels for working with patients (e.g., in person meetings, teleconferences, and electronic communications).
      Patients might not be capable of being “objective” or representative of the patient experience beyond their own.Involve more than one patient in the various parts of this process to ensure that you can obtain more than one opinion/experience. Patient experiences may vary, but after talking to a group of patients, patterns and themes will begin to emerge.
      Acknowledge that nobody at the table now is truly objective; the industry wants profit, researchers want results. Furthermore, patient bias toward their needs is not bias: it is a finding. Learning about the experience of individual patients is an important part of understanding the overall patient experience and unmet needs of a specific disease community.
      Contextual factors (e.g., work, culture, and religion) inhibit participation of certain group members.Use multichannel interaction to account for individual constraints and adopt culturally sensitive facilitation practices.
      Table 5A potential approach to including patients in pharmaceutical companies inspired by PatientsIncluded (note that all criteria must be satisfied)
      CriteriaExisting PatientsIncluded criteria for medical conferences

      Patients Included. Patients Included: a charter for conferences. Available from: http://patientsincluded.org/. [Accessed April 12, 2016].

      Existing PatientsIncluded criteria for medical journals

      Patients Included. Patients Included: a charter for conferences. Available from: http://patientsincluded.org/. [Accessed April 12, 2016].

      Potential equivalents for pharmaceutical companies
      1Patients or caregivers with experience relevant to the conference’s central theme actively participate in the design and planning of the event, including the selection of themes, topics, and speakers.At least two patients sit on the editorial board of the journal.All members of the CEO’s leadership team are accountable for integrating patient views into decision making for their respective functional areas. These are captured in company and functional scorecards.
      2Patients or caregivers with experience of the issues addressed by the event participate in its delivery and appear in its physical audience.Patients routinely publish content in the journal as authors of editorials, reviews, or research articles.Company creates a “patient council” composed of patients experienced with relevant therapeutic areas, which reports to the board and is accountable for the progress of patient centricity through key metrics.
      3Travel and accommodation expenses for patients or caregivers participating in the advertised program are paid in full in advance. Scholarships are provided by the conference organizers to allow patients or caregivers affected by the relevant issues to attend as delegates.Patients serve as peer reviewers of submissions to the journal.The patient council creates standard operating procedures to incorporate patient and caregiver input into relevant internal decision-making bodies to provide their perspective at the point of decision making (e.g., final protocol approval and patient service program approval).
      4The disability requirements of participants are accommodated. All applicable sessions, breakouts, ancillary meetings, and other program elements are open to patient delegates.The journal is an open access publication, with no barriers to access full- text content.The patient council has appropriate internal resources in place to allow internal teams to appropriately access patient and caregiver perspectives to generate patient insight and cocreate patient solutions with patients.
      5Access for virtual participants is facilitated, with free streaming video provided online whenever possible.The company’s approach to integrating patients as a part of their team is detailed in the company’s scorecard, key metrics, and each year in the company’s annual report to shareholders.
      CEO, chief executive officer.
      Although patient involvement is a valuable resource during many stages of evidence generation, it may not always be practical to include it in all decisions. For example, patients may not be needed for determining targets for “technical” attributes such as biomarkers or surrogate markers. Nevertheless, a mutual understanding of the technical aspects of the product development process that cannot be altered, such as the delivery mechanism of a medication or clinical trial end points established by regulators, and why these cannot be altered, is essential to the creation of an engagement process that produces meaningful feedback.
      The European Patients’ Academy on Therapeutic Innovation has been established to help address such gaps in knowledge or understanding. By partnering a number of nonprofit, academic, and patient organizations with a number of European pharmaceutical companies, the European Patients’ Academy on Therapeutic Innovation seeks to train and educate patients and provide the support and resources needed so that they can be more directly involved in the drug development process [

      European Patients’ Academy on Therapeutic Innovation [homepage on the internet]. Available from: http://www.patientsacademy.eu/index.php/en/. [Accessed November 8, 2015].

      ]. Recognizing that there is no equivalent organization in the United States at present, one way to overcome such challenges is for drug developers to partner with patient advocacy organizations and interest groups. These entities have a great deal of experience in working with patients and may be best suited to connect drug developers with patients who are ready and willing to play a larger role. One such organization, the Parkinson’s Disease Foundation, offers specialized training programs to provide patients the skills and knowledge they need to take a more active role in research [

      Parkinson’s Disease Foundation. Our work. [Accessed 8 November 2015]. Available from: http://www.pdf.org/en/mission

      ].
      The Parkinson’s Disease Foundation also provides a framework for how patients can be involved in the various stages of drug development [

      Parkinson’s Disease Foundation. Our work. [Accessed 8 November 2015]. Available from: http://www.pdf.org/en/mission

      ]. Taking what was learned from our interviewees, this framework has been adapted and is presented in Figure 1. Patients can and should be involved in drug development from the very beginning. Our patient thought leaders stressed that it is not just about finding a drug that is safe and effective, but rather finding one that truly meets the needs of patients. Without including patients in this conversation early on, it will be difficult to fully understand those needs and the trade-offs that patients are willing to make. Patients’ perspectives on disease burden, treatment experience, risk-benefit assessments, and unmet needs may be incorporated early, informing the drug discovery phase or during the shaping of the target product profile (TPP). The TPP is a strategic guidance used by pharmaceutical sponsors to facilitate discussions and solicit feedback from regulators on the overall drug development program for an investigational product [

      US Department of Health and Human Services, Food and Drug Administration. Guidance for industry and review staff: target product profile—a strategic development process tool. [Accessed 17 December 2015]. Available from: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm080593.pdf.

      ]. Among other things in a TPP, the patient voice can inform product attributes such as the route of administration, dosing, efficacy, acceptable levels of adverse events, and possibly even willingness to pay. Such an approach will lead to the development of a patient-centric TPP that reflects patients’ burden of disease, perspective on disease severity, and experience with existing treatment options. Companies should seek patient input in developing the TPP and continually engage patients to update this throughout the remainder of the drug development process. This will help the organization in identifying suitable criteria and metrics in shaping their products, which, in turn, will steer drug development toward medications that address how patients function and feel, including their quality of life and unmet medical needs. We believe that this investment will lead not only to a drug profile that resonates with unmet patient needs but also to an increased likelihood of favorable reimbursement decisions.
      Fig. 1
      Fig. 1Potential areas of patient involvement throughout the drug development cycle. Adapted with permission from the Parkinson’s Disease Foundation.
      Beyond the TPP, patients could be involved in activities related to clinical trials such as study conception by outlining their needs and priorities; protocol advisement through consultation on the logistics of study design, the appropriateness of inclusion/exclusion criteria, and patient willingness to adhere; advisement on the selection of devices used in trials (if applicable); and consultation on informed consent and whether it is clear enough.
      As with any research, the approach described here has some limitations. It is important to recognize the relatively small number of interviews conducted and that our samples for each cohort are not representative of all health care or patient thought leaders, which could mean that not all the barriers to increasing patient involvement were identified. Furthermore, we do not have specific evidence to support the effectiveness of the recommendations presented. More evidence is needed to support the theorized positive return on investment in increasing patient involvement in drug development. Further research should focus on evaluating the impact and effectiveness of these recommendations or any other efforts to better involve patients in drug development. This evidence will provide the insight needed to take the next step toward establishing industry-wide best practices. Although we recognize that additional work will need to be done to build on the recommendations outlined here and develop a concrete and consistent methodology that can be used by all drug developers, we hope that these proposals can facilitate and encourage such efforts.

      Conclusions

      Along with widespread efforts to curb health care spending, the advent of formal HTAs and payer evaluations for formulary and reimbursement positioning has created the need for drug developers to demonstrate value to obtain reimbursement for their products. Because the cost and benefit of a treatment are ultimately, either directly or indirectly, realized by patients, their input is essential to develop medications that encompass value.
      The results of our interviews highlighted a common interest in increasing patient involvement in drug development activities, but made it clear that there is work to do before this becomes a reality. If the pharmaceutical industry is to truly partner with patients, a number of key cultural and logistical barriers within organizations will have to be overcome. Leadership within pharmaceutical companies must recognize the value of patient engagement across the entire product life cycle and work to transform present perceptions throughout their organizations. Because this industry has a history of being financially successful, it might be considered “safe” to point to present practices as sufficient to maintain their viability. Just because shareholders are doing well does not mean that it has been truly successful or has done right by patients. It is time to redefine what it means to succeed in the drug development industry and how to create products of value.

      Acknowledgments

      We thank the interviewees and patients for their time and leadership in helping us better understand how to incorporate the patient perspective in the development process for new medications.
      Source of financial support: This work was funded by Novartis Pharmaceuticals. No restrictions were placed on the design, analysis, or interpretation of the research or on the writing and submission of the manuscript. The views expressed in this publication are those of the authors.

      Supplemental Materials

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