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 inherently risky and 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 additional important information throughout this process to 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 outlines three 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 outlined in the Draft Guidance1 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 Several useful guidelines within the Draft Guidance identify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.
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.
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM446680.pdf
(page 26).
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Revealing a More Comprehensive Picture of Disease 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, established quantitative 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 measurements from data in irrelevant or nonapplicable 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
US Food & Drug Administration. “Study Endpoints and Labeling Development (SEALD) Review.” September 30, 2013.
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/UCM3
86244.pdf
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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. Decisionmakers 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 datasets for 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.
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.”
http://www.parentprojectmd.org/site/DocServer/br_paper_v11__2_.pdf;jsessionid=2C381495CB3753608053FD8DD624B
686.app247d?docID=14503 (page 11).
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