Services

Clinical outcome assessments (COAs) have become indispensable across a wide array of therapeutic areas. When there are limited to no biomarkers or objective measures of relevance to persons living with disease, COAs are employed to measure the appropriate outcomes. Most COAs consist of patient-reported outcomes (PROs). We develop COAs with the intended purpose of evaluating efficacy endpoints and, when appropriate, supporting labeling claims. We provide the following COA development services:

• Development of relevant study documents and protocols
• Institutional Review Board submissions
• Recruitment site training and management
• Face to face concept elicitation interviews and focus groups with patients and caregivers
• Key opinion leader and clinician interviews, as well as Delphi panels
• Face to face cognitive interviews with patients and caregivers
• Transcription of interview data
• Coding and analysis of transcripts
• Reporting of results, including associated recommendations

Before a clinical outcome assessment (COA), such as a patient-reported outcome (PRO), can be disseminated to patient populations or employed as an endpoint in randomized clinical trials (RCTs), fundamental properties of the PRO must be examined to confirm that the:

• PRO coherently measures the domain(s) of relevance
• PRO is reliable
• PRO is valid
• PRO is responsive

The psychometrician at Endpoint Outcomes designs client-specific analyses to assess these fundamental properties of PROs in the context of either observational/stand-alone studies or in-trial validation studies. The Endpoint Outcomes team ensures that the analyses fit within current best psychometric and statistic practices, regulatory guidance on PROs, and FDA division-specific standards for endpoints. Our psychometric evaluations of PROs:

• Employ multiple imputation techniques for non-informative missing data and pattern-mixture models for informative missing data
• Use exploratory factor analyses (EFAs) to ascertain domain structures in PROs
• Apply item response theory (IRT) models to assess item properties and optimal scale composition
  • IRT models include the application of both Rasch and more general IRT frameworks where appropriate
• Construct optimized PRO scores, using both classic test theory (CTT) and IRT approaches
• Evaluate internal consistency of optimized PRO scores, using both CTT (e.g., coefficient α) and IRT (marginal reliability) methods
• Examine test-retest reliability to ascertain temporal reproducibility/stability of PRO scores
• Explore validity of optimized PRO scores, using a variety of techniques such as concurrent and known-groups validity estimates
• Quantify distribution-based and anchor-based minimal clinically important difference (MCID) estimates for definitions of responsiveness
• Assess statistical power of endpoints based on MCID definitions
• Conduct statistical simulations for projecting detectability of effects in future RCTs in which the developed PRO will be fielded
  • These last two steps facilitate the construction of RCTs that maximize PRO-based efficacy detection

Regulatory strategy is the most challenging area when working with endpoints for clinical trials. There are multiple methods for communication with regulatory bodies, differing time points for appropriate communication with regulatory authorities, and some variability in how reviewers examine endpoint data. We will help you navigate this environment from start to finish of a program. We provide the following services related to regulatory strategies:

• When and how to correspond with the FDA, including navigating the Drug Development Tool (DDT) qualification process and Critical Path Innovation Meetings (CPIM)
• Writing relevant sections of meeting requests and briefing books
• Dossier preparation (FDA and EMA)
• Attendance at mock FDA meetings
• Attendance at FDA meetings

Conducting a literature review prior to embarking on clinical outcome assessment (COA) development is useful to identify existing COAs that are suitable as is or could potentially be modified for use to evaluate efficacy endpoints and support labeling claims. In addition, literature reviews can inform the development of a preliminary hypothesized conceptual framework, which is one of the foundational steps when developing a COA. A search strategy, including target sources (e.g., MEDLINE®, relevant conference proceedings), is designed to identify information that will allow us to:

• Identify key disease concepts to develop a preliminary hypothesized conceptual framework
• Conduct a competitive landscape review to identify how COA measures and endpoints are being used by competitors
• Understand existing regulatory guidance related to disease measurement
• Determine if a COA exists that measures the concept(s) of interest
• Evaluate existing COAs to determine if they may be appropriate for the intended context of use
• Document the (available) development and validation history of existing COAs

The development of an endpoint strategy is not just about doing what someone else did; it is about doing what is best for your specific situation.  Effective endpoint strategy requires keeping up with changes in the field and the tendency of regulatory authorities to continually refine or change their recommendations.  Our endpoint strategies start with an in-depth discussion with sponsors and are focused on:

• Identifying or developing responsive measures that separate from a placebo arm in a clinical trial
• Meeting regulatory requirements for labeling/promotion (if a claim is desired)
• Identifying an appropriate hierarchy of endpoints for clinical trials
• Establishing a robust communication strategy for the endpoint
• Developing a product differentiation strategy
  • Benchmarking relevant competitor activities
  • Considering product launch schedule

The Delphi method has been used across fields of research as a systematic process to gain consensus in an area that lacks expert agreement. Delphi panels excel in being able to obtain expert agreement efficiently when there is a clear research question that needs to be answered. Endpoint Outcomes has used Delphi panels to assist with drafting and selecting items for patient-reported outcome (PRO) instruments, developing screening tools, and recommending new treatment paradigms. This method has been utilized by Endpoint Outcomes in many different therapeutic areas, including ophthalmology, women’s health, and neurology.

We facilitate the Delphi panel by guiding 8-10 clinical experts to answer questions and provide feedback through a multi-round voting process, where consensus is typically reached in 2-3 rounds. The experts’ responses from each round are analyzed and provided to respondents in an anonymized summary of the results. Delphi panels can be conducted via online survey, paper questionnaires, face-to-face meetings, video conference, or by a combination of these methods of administration. The results of the Delphi panel can then be published or used to assist in the early stages of the PRO development process.

Exit interviews can be an important component in the drug research and development process.  Exit interviews, particularly if done in early phases of development (e.g., phase 2a) can be a valuable source of information for clinical trial design.  Exit interviews, if done correctly, are conducted with no preconceived notions of treatment benefits and risks experienced by patients during the course of a trial. Exit interviews can help identify existing assessments in trials that are not sensitive or responsive and provide patient-level data to help refine a measurement strategy to successfully document treatment benefits.

Endpoint Outcomes conducts exit interviews to refine or develop clinical outcome assessments (COAs) in order to improve measurement precision in trials, to assist in the development of an endpoint strategy in trials, and to provide potential post-hoc justification of decisions made in the design of existing trials.

Survey research can be a cost-effective way to collect information from patients, caregivers, health care providers and key opinion leaders.  Surveys may consist of closed-ended or open-ended questions or some combination of both.  Surveys may be analyzed using descriptive and inferential statistics, as well as qualitative methods (e.g., coding) for open-ended responses.  Endpoint Outcomes has conducted both paper-and-pen and online, web-based surveys as part of exit interviews, natural history studies, validation studies and Delphi panels.

Natural history studies are often conducted early in the drug development process and examine the course of a disease from its inception through all of its clinical stages.  The studies look at demographic characteristics, genetic and environmental factors, and health-related quality of life associated with a disease in the absence of a treatment. In rare diseases, natural history studies can form the scientific foundation of clinical trial design, including outcomes selection and endpoint development.  The studies are critical when there is little or no previous clinical precedence in a disease area and, if properly planned, may contribute data to form a historic control.

When survey methodology is employed, we work with clients to conduct longitudinal, epidemiological natural history studies so that we are able to help elucidate the incidence, prevalence, homogeneity, and severity of symptom profiles. The results of these studies can provide insight into clinical outcome assessment (COA) construction based on the pattern, relevance, and severity of naturally occurring symptom variation in a given disease. For these types of projects, we employ:

• Mixture models for assessing heterogeneity in symptom profiles
• Generalized linear models for incidence and prevalence
• Generalized mixed models for modeling variation in prevalence and severity

In addition to survey research, Endpoint Outcomes conducts natural history studies by way of interviews with a specialization in capturing information from patients and/or their caregivers to ensure appropriate patient-centered measures are included as endpoints in clinical trials.

The components necessary for electronic clinical outcome assessment (eCOA) equivalency testing are dependent upon the type of changes made in the transition to an electronic format. We offer the following eCOA testing services:

• Cognitive interviews to establish equivalency
• eCOA device usability testing
• Psychometric testing (only required in rare cases when the migration to electronic format required substantial changes)
• Reporting of results

A well thought out communication strategy is essential for ensuring regulatory and reimbursement success.  The communication strategy should be planned at the beginning of an outcomes study rather than at the end to ensure that the messages are tailored to the right audience and are appropriate to secure labeling claims and enhanced market access positioning.  We provide the following services related to communication strategies:

• Manuscript writing
• Abstract and poster production
• FDA and EMA dossiers
• Meeting requests and briefing books
• Letters of intent
• Scoping documents
• Assistance in drafting responses to regulatory correspondence

Often the starting point of endpoint development is to conduct a gap analysis of the current landscape compared to what is needed in the future. Our gap analyses are geared toward identifying what competitors are doing in terms of communication, promotion and labeling around clinical outcome assessment (COA) endpoints, and identifying a strategy to successfully launch a product based on patient-centric data.  We provide the following services related to gap analyses:

• Review of FDA guidances, workshops, advisory committee and other meetings, medical and statistical reviews for approved products
• Review of academic literature and conference proceedings
• Review of existing COAs to support a publication strategy, labeling and/or promotion
• Review of clinical guidelines
• Review of planned and current clinical trials of competitors
• Review of current labeling claims in the US and Europe
• Clinician and patient interviews