Patients As Critical Partners in Rare Disease Drug Development

Draft Framework

Patients as Critical Partners in Rare Disease Drug Development:

Establishing Disease Burden, Disease Measurement, and Benefit-Risk Assessments as Part of Rare Disease Drug Development

Broadening the Role for Patients

Drug development is an inherentlyriskyand time-intensive process that may fail to obtain an approval for treatments that address the needs of patients despite reasonable efforts. In the rare disease field in particular, the lack of critical quantitative understanding of the burden of disease for patients and the impacts and progression of disease symptoms greatly complicates the ability to conduct effective drug development.

Effective rare disease drug development could greatly benefit from increased patient engagement and input. Patients could provide additionalimportantinformation throughout this processto enhance understanding of the most critical impacts of a disease, possible ways to measure disease impact, and what the benefit-risk perspective is for possible therapies. An improved patient engagement process should result in a variety of benefits including: higher success rates in the drug development process, additional therapy options, and potentially improved health outcomes.

Although most rare disease drug developers engage patients at some level, a more systematic, rigorous and consistent pattern of engagement that has sufficient regulatory rigor would be a significant advance toward a more efficient and effective drug development process. Here, we provide a proposed framework that outlinesthree opportunities for patient engagement at the pre-IND (submittal of an Investigational New Drug application), mid-stage and late stage development that we believe provide the right time and type of information to enhance the development process.

Selecting Methodologies

Valid and scientifically objective patient engagement requires proven methodologies to elicit patient input in a comprehensive and accurate manner. There are a wide variety of sampling options available to researchers, some of which are outlinedinthe Draft Guidance[1] recently released by the Food and Drug Administration (FDA). Several useful guidelines within the Draft Guidance identify some of the essential qualities that patient-input data should meet. In short, data collection must utilize methods that accurately capture information without bias in order to constitute valid evidence. Key to ensuring this validity is effective communication of risk to the patient to minimize various biases and ensure that patients are informed to fullest extent possible.

Revealing a More Comprehensive Picture ofDisease Burden

Time point: Pre-IND

Early in the development of a rare disease therapeutic, there is often little information in medical literature, few formal studies of the disease outside of clinical surveys from single clinics and few, if any, establishedquantitative clinical measures. Commonly, the medical literature may have significant misconceptions about what affects patients at different stages of a disease and in our own experience, we find that one or more assumed clinical facts about a disease are likely wrong.

It is critical to breakthrough prior misconceptions and overcome the limitations of minimal data to establish a deeper and more quantitative understanding of the disease. Researchers and clinicians must work directly with patients to gain a better understanding of the daily challenges that come with disease, which can be well beyond traditional clinical measures.

A comprehensive patient disease burden survey based on interviews of some patients and prior medical literature is a reasonable starting place. The study should generate a body of information to help construct potential patient reported outcomes (PRO’s) or clinician reported outcomes (Clin-RO’s) later. To obtain the most comprehensive data, access to the study should be as easy as possible and be multicenter. Internet-based work can be useful with a third party Contract Research Organization (CRO) and patient group participation in the development of a comprehensive tool that is still easy to administer. Establishing as broad a sample as possible and an estimate of bias in sampling is important. The survey can be not only questionnaire-based, but may have a physical measurement component with a clinical protocol conducted at clinical sites.

Although natural history studies are always desirable, very often there are not the years of time needed for longitudinal follow-up.In these instances, an extensive cross-sectional survey with retrospective data can provide a broader dataset to work from early on in the program. This engagement should occur early in the drug development process, preferably before a product IND application is filed or certainly well before Phase 2.

Establishing Disease Endpoints: Enhancing Trial Design & Measuring Disease by Physical Function and Patient-Reported Instruments

Time point: Mid-stage from Pre-Phase 2 to Pre-Phase 3

Patient engagement at this stage is critical to developing or identifying a more comprehensive suite of quantitative disease measures (i.e. endpoints) beyond established clinical endpoint measures, as well as understanding which patients are potential candidates for study. From the disease burden and cross-section clinical survey work, as well as some ideas on the potential benefits of a drug, a set of possible endpoints can be constructed for study in Phase 2 and, if successful, used in Phase 3. Depending on the disease, some exploratory work in Phase 2 might be needed in order to refine the endpoints for Phase 3. During Phase 1 and cross-sectional clinical survey work, some insight into the types of possible measures can be found and compared with an existing menu of measures for concordance or reasonable context of use. If no existing measures make sense, then development of new measures might be needed, and would require additional clinical survey studies or phase 2 “learn” studies in which a variety of endpoints are explored in context of a treatment. Two types of efforts should be considered. First is the establishment of quantitative direct measures of disease that might be acceptable as clinical endpoints based on the patients function. Secondly, the assessment of patient-reported or clinician-reported outcome tools should be assessed either in clinical surveys or “learn” Phase 2 studies. For rare diseases, commonly used PRO’s often do not relate specifically enough to the disease and will have dilution of relevant measurementsfrom data in irrelevant or non-applicable questions. Adapting and validating existing tools to be more specific to a rare disease is desirable but arduous in terms of time and investment, especially to meet the established Study Endpoints and Labeling Development (SEALD) process established in regulatory guidance.[2] However this specialization and development of the PRO/Clin-RO tools can be critical to their effective use.

Assessing Benefit-Risk: Evaluating Therapy Impact on Patients

Time point: Post-Phase 2 & Phase 3

At this stage in drug development, sufficient data is available to understand the disease burden and impacts, the preliminary efficacy of a drug, and the potential for adverse events. The product profile possibilities can be presented in a comprehensible manner to patients to assess what their reasonable goals of therapy might be relative to risks to help in designing the critical endpoints and length of studies used to determine safety and efficacy.

The impact of therapy may lie along a spectrum of outcomes ranging from adverse impact, no impact, halting of disease progression, and improvement toward normal function. For example, if the survey demonstrates from the prior work and current data that stabilization is the only achievable step rather than improvement, an assessment of the value of stabilization should be included. The time frame of a study for stabilization could be longer since the decline of untreated patients would need to be demonstrated in Phase 3. Furthermore, clinicians must take into account the impact of therapy and disease on multiple body systems, which may go beyond traditional single domain measures. The total patient outcome is likely the integration of impacts on different domains, but the traditional single primary endpoint design of clinical programs often fails to capture this total impact of treatment well. Understanding the effect of the integration of impacts are important in achieving an accurate assessment of benefit-risk.

Evaluation of risk tolerance in this process can occur at almost any point with hypothetical efficacy, but potentially most effective when real efficacy data are available. There may be a substantial gap in the perception of risk tolerance between patients and other parties engaged in the drug development process. Rare disease patients and those facing acute, life-threatening diseases may display significantly higher risk tolerance for novel therapies given the lack of alternatives for treatment than developers or regulators might consider acceptable.Further, many rare disease patients must also weigh the risk of unchecked disease progression should they opt out of a trial.[3]

Patient perception and tolerance of risk may be in sharp contrast to drug developers and regulators who are charged with maintaining the highest possible degrees of safety and efficacy. Decision-makers must take patient risk tolerance into account, and in some cases, could be key factor in the approval process. These benefit-risk data should be considered when making approval decisions, but should be viewed as one of several important datasetsfor the regulators review and not the sole basis for approval.

Conclusions

Throughout the drug development process, there are a variety of opportunities for enhanced patient engagement including measuring disease burden, determining treatment and trial design, evaluating treatment impact. What we offer here is a proposed starting-point and framework of three specific steps for adding rigor and systemization to patient engagement. When scientifically valid and sound methodologies are applied, this enhanced engagement could dramatically improve efficiency as well as health outcomes. This is of particular importance to rare disease patients, the vast majority of whom lack any FDA-approved treatments.

Patients are ready and waiting to play a larger role in drug development. It is now up to regulators and drug developers to fully engage patients and in doing so improve the efficiency and effectiveness of development for the next generation of rare disease therapies.

[1]U.S. Food & Drug Administration (FDA), “Patient Preference Information – Submission, Review in PMAs, HDE Applications, and De Novo Requests and Inclusion in Device Labeling, Draft Guidance for Industry, Food & Drug Administration Staff, and Other Stakeholders.” May 18, 2015. (page 26).

[2] US Food & Drug Administration. “Study Endpoints and Labeling Development (SEALD) Review.” September 30, 2013.

[3]Franson, TR, Peay H. Parent Project Muscular Dystrophy. “Benefit-Risk Assessments in Rare Disorders, the Case for Therapeautic Development in Duchenne Muscular Dystrophy as the Prototype for New Approaches.” (page 11).