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Call for Abstracts for Special Supplement to the Journal of General Internal Medicine

Topic: Research Methods for Evaluating Patient Health Outcomes in Rare Diseases

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The Agency for Healthcare Research and Quality (AHRQ), through its Effective Health Care Program, will sponsor a special journal supplement on research methods for evaluating health outcomes in rare diseases. This announcement invites authors to submit abstracts for manuscripts that describe original research or systematic reviews on methodologies for studying patient-centered health outcomes. Submissions must be original and show how the approach applies to one or more problems in the design, analysis, or conduct of rare diseases research. However, manuscripts may derive from studies examining either rare or common diseases. Authors with abstracts that are highly rated by an expert panel will be invited to submit a manuscript for peer-review and potential publication in a 2014 supplement to the Journal of General Internal Medicine (JGIM). JGIM is a leading peer-reviewed and widely indexed journal with an international audience among practicing clinicians and general medical researchers. Previous AHRQ-sponsored journal supplements on comparative effectiveness and patient-centered outcomes research (see examples from 2007, 2010, and 2012) have garnered high-impact contributions from internationally recognized experts.

Submissions are encouraged from authors with expertise in a broad range of study designs and from across multiple scientific disciplines. This includes authors with methodological expertise in clinical trials, health outcomes studies, health services research, health policy, biostatistics, epidemiology, and qualitative research. Preference will be given to original investigations with new methodological approaches or with methods derived from other disciplines or based on advances from existing methods. The editorial team is also interested in broader policy considerations related to rare disease outcomes research methods, such as the ethical ramifications of innovative clinical trial designs; legal structures to incentivize investment in these areas; use of practice-based research networks and e-support groups to connect patients, primary care physicians, and specialists; and balancing data transparency with the need for patient confidentiality.

We invite you to participate in this journal supplement by submitting a brief abstract to More detailed information about the topic areas and the abstract submission process as well as a submission form are available in the next sections.

Key dates:

  • Abstract submission forms are due by May 31, 2013.
  • Abstract authors who are selected to write a full manuscript will be notified by June 26, 2013.
  • Complete manuscripts from authors of selected abstracts are due by November 22, 2013.

For questions, please contact:


Supplement Overview

The US government has defined an orphan disease as one with a prevalence of fewer than 200,000 patients each year in the US. Approximately 6,000 different diseases qualify as orphan conditions, affecting about 6-8% of the population, or approximately 25 million people in the US alone. Developing therapeutics for these conditions requires detailed understanding of the biological basis and natural history of the disease, the right tools to make the diagnosis, and a strategic approach to translational research and clinical trials. Obstacles exist at every step in the development of these so-called “orphan” drugs and biological products, as well as for devices intended to treat limited populations. For example, studying experimental therapeutic agents in small trials risks under-powering, there may be limited opportunity for replication of study results, and poorly understood diseases and outcomes make the design of trials difficult. In the post-approval setting, observational research to determine a drug or device’s effectiveness may be limited by small numbers of patients and lack of consensus on meaningful outcomes.

These hurdles necessitate innovative approaches to research, which was the motivation for this AHRQ-sponsored journal supplement. The focus of the supplement will be on novel ways of evaluating patient health outcomes in rare diseases. For example, in the pre-approval period, adaptive trial designs, enrichment strategies, and n-of-1 trials have been proposed as mechanisms for addressing the problem of a limited pool of trial participants. But these techniques may result in patient experiences that differ at the individual level in the dose of the drug or course of therapy. What are the guiding principles for these trial designs and any pragmatic aspects of trials in rare disease populations that will inform key decision makers? Also, what are the proper health outcomes that such studies should address? How should such studies integrate novel tools and resources such as biospecimens, and what are the parameters available for surrogate marker development and validation?

After an orphan drug or device is approved, assessments of its effectiveness may require linking of electronic health records or building disease-specific registries. Yet there specific analytic issues, including missing information and mistimed information (e.g., patient-reported outcomes) and numerous logistical and operational challenges to building and aggregating large data repositories, including identifying the proper health outcomes that should be charted, data sharing issues, lack of common data formats, and data privacy concerns. We invite experts in registry building to share evidence-based best practices, and experts in observational research to test rigorous methods for analyzing rare disease outcomes in patient registry data and other secondary data sources, including how to account for bias, measurement issues, missing data, and identification of signals of safety and effectiveness. How can evidence generation be expedited, particularly during the transitioning from pre-marketing clinical research to post-marketing use? While many of the issues are applicable to all therapeutics, they have specific manifestations and implications in treatments for orphan diseases.

This supplement will focus on patient health outcomes in both the pre- and post-market settings. Patient, caregiver and other stakeholder involvement has been recommended as a means of improving the usefulness of clinical research. This will include qualitative research to determine the health outcomes that rare disease patients view as most important, and we invite patient-reported outcomes experts to discuss the applicability of quality of life and other patient-centered outcomes in both pre- and post-marketing studies of rare diseases. Post-approval observational treatment crossover studies and studies of treatment effect heterogeneity as tools for individualized treatment optimization with specific applications to rare conditions.

Finally, our focus on rare disease patient health outcomes raises a number of related policy questions that also need to be addressed. These may be economic, ethical, legal, or social. For example, how can the success in improving some rare disease outcomes (such as in cystic fibrosis or some rare oncologic conditions) be duplicated in other rare disease fields with limited financial resources for infrastructure needs such as the coordination of geographically dispersed patients? These could involve value of information analyses. Do the high costs of orphan drugs limit their impact on patient health outcomes? How should we manage informed consent or other ethical implications of recruiting rare disease patients into innovative clinical trial designs with which researchers have limited experience?; Can rare disease research hurdles be addressed through crowdsourcing, telemedicine, or other emerging social media tools?

In addressing these issues, experts are encouraged to test candidate methods from other fields in medicine, public health, psychology, and education that have not been previously applied to rare diseases. These research methods may apply to certain subsets of rare diseases—i.e., very low prevalence diseases or rare genetic diseases—or may apply to rare diseases more broadly.They may relate identification, diagnosis, or treatment of rare diseases with drugs, devices, invasive or non-invasive procedures, health systems improvement, or other modalities.

The topic areas discussed here (and below) are those that AHRQ aims to cover, although they are neither comprehensive nor final. Abstracts are due May 31, 2013. Submission of an abstract implies that the authors will commit to write a full manuscript by November 22, 2013 and submit that article for consideration exclusively in the AHRQ-sponsored supplement in the Journal of General Internal Medicine. Abstracts will be vetted through a blinded, independent process by members of the Scientific Planning Committee with advice from appropriate consultants identified by the Committee as necessary. Abstract authors who are selected to write a full manuscript will be notified by June 26, 2013. Final article publication is contingent on the manuscript passing the Journal of General Internal Medicine’s standard editorial and peer review process.

Journal information:

The Journal of General Internal Medicine is the official journal of the Society of General Internal Medicine, a national medical society encompassing the internal medicine faculty of every medical school and major teaching hospital in the US. It also has a large international readership, and new articles are rapidly indexed on Medline and all other major scientific search engines. Every effort will be made to ensure that the supplement will be high profile. We will make all manuscripts open access from the date of supplement publication, and editorialists will highlight the importance of your work in the overall challenge of developing treatments for rare diseases. AHRQ, Brigham and Women’s Hospital, and other organizations supporting this effort (such as the National Organization for Rare Disorders) will also engage their media consultants to promote the supplement widely to patients, physicians, scientists, and policymakers.

Scientific Planning Committee:

Aaron S. Kesselheim, M.D., J.D. (co-Chair, Brigham & Women’s Hospital)
Scott R. Smith, Ph.D., M.S.P.H. (co-Chair, AHRQ)

Ethan Basch, M.D. (University of North Carolina-Chapel Hill)
Shein-Chung Chow, Ph.D. (Duke University)
Joshua J. Gagne, Pharm.D., Sc.D. (Brigham & Women’s Hospital)
Richard Gliklich, M.D. (Quintiles Outcome)
Robert Griggs, M.D. (University of Rochester)
David Hickam, M.D., M.P.H. (Patient Centered Outcomes Research Institute)
David Meeker, M.D. (Genzyme)
Katherine Needleman, Ph.D. (FDA Office of Orphan Products Development)
Parivash Nourjah, Ph.D. (AHRQ)
Anne R. Pariser, M.D. (FDA Office of New Drugs)
Yaffa Rubinstein, Ph.D. (NIH Office of Rare Diseases Research)
Peter Saltonstall (National Organization for Rare Disorder)


High-Interest Topics

1. Rare disease patients’ health outcomes in clinical trials

What patient health outcomes should be evaluated in the study of drugs, devices, and other therapies in patients with rare diseases, and how should researchers evaluate them? Small pools of patients make accruing patients difficult, and the geographic spread of patients who might qualify raises the costs and complexity of such trials. In response, some researchers have suggested novel trial designs, such as adaptive clinical trials, which are randomized trials with design and analysis features that may change during the conduct of the trial based on interim analyses, or n-of-1 trials, which are cross-over trials in which a single patient receives a treatment or control or multiple treatments at randomly determined times.

We are interested in creative solutions to evidence generation or surrogate marker development and testing for rare disease treatment, other tools or approaches that might be applied to address the unique features of studying treatments in rare diseases, and the implications of these non-traditional clinical trial methods for rare diseases patients. We are particularly interested in studies showing how these innovative approaches are applied, how their limitations may be overcome, and how their results may be used by key stakeholders, including patients, caregivers, clinicians, and regulators. For example, we would like to see proposals regarding methods used to demonstrate that outcomes are meaningful to patients in the target population.

We specifically invite experts who have experience identifying and studying rare outcomes in other fields (psychology, education, public health, sociology, etc.) to demonstrate how their methods may apply to the study of rare diseases.

2. Emerging data sources for observational research on rare disease patients’ health outcomes

Creative approaches to performing clinical trials of orphan therapeutics put additional pressure on observational research tools used to study effectiveness and safety. We are interested in abstracts that address the construction and use of new data sources for evaluating patient health outcomes in rare diseases.

For example, there has been superb work done recently by rare disease patients, their advocacy groups, and their physicians to build registries of important rare disease patient health outcomes. There are also many existing and nascent networks of electronic healthcare databases that bring together data on large numbers of patients and that could be used to study outcomes in rare diseases. Thus, we are interested in the process of data aggregation and building federated data networks, as well as meta-analytic and linking approaches to bring together individual patient experiences into larger sample sizes that might shed light on the safety or effectiveness of orphan products.

We specifically invite abstracts that apply evidence-based methods for linking registry data and other secondary data sources for studying rare diseases.

3. Novel analytic methods for observational research on rare disease patients’ health outcomes

Studies in patients with rare diseases face important methodological challenges given the usually small numbers of patients and outcomes and the difficulty in choosing an appropriate comparison group. As such, we are interested in research that seeks to examine novel applications of observational methods to rare diseases and orphan products, and help define best practices in these areas that might be used by industry or academic stakeholders as well as regulators focused on postmarket assessments.

We are specifically interested in abstracts that apply the evolving knowledge of prospective observational monitoring to rare disease issues, and those that apply evidence-based methods for analyzing patient health outcomes with registry data.

4. Integrating stakeholder involvement in assessing rare disease patient health outcomes

Involvement of patients and their caregivers offers the promise of identifying and prioritizing for study those outcomes of greatest interest related to rare diseases. Engaging such stakeholders in the research process can generate evidence that helps patients make decisions that reflect their preferred health outcomes. But few consensus methods exist for engaging stakeholders in the research process and it is unclear whether research into patient-centered health outcomes for patients with rare diseases should have different considerations than those for non-rare conditions.

We invite experimental and normative research on the incorporation of stakeholder perspectives in health outcomes research in rare diseases.

We are specifically interested in studies that describe or test how patient-centered health outcomes can be applied to enhance the development or evaluation of therapeutics for rare diseases.

5. Economic, regulatory, ethical, legal, and social issues related to the study of rare disease health outcomes

Considering innovative approaches to rare disease health outcomes raises a number of associated issues of interest to patients, physicians, and policymakers. These include:

  • What economics barriers exist for access to rare disease therapeutics that might affect patient health outcomes?
  • What is the regulatory environment for the approval of therapeutics for rare diseases, and how do regulatory approaches affect research choices? What possibilities are there for international harmonization?
  • How should regulators or prescribing physicians manage data heterogeneity that may emerge from trials of experimental rare disease therapeutics when considering whether to (a) approve the product or (b) prescribe it for an individual patient?
  • How should IRBs handle proposals for novel experimental trial approaches related to rare diseases?
  • How can social media outlets be harnessed to improve research methods into rare disease patient health outcomes?

We are interested in abstracts from experts in these fields who seek to address these questions, or other similar questions we may not have considered. Authors may seek to collaborate in developing consensus statements outlining basic principles in these areas.

We look forward to abstracts with empirical data addressing key economic, ethical, legal, or social implications of innovations in studying rare disease patient outcomes.


Instructions for Submission of Abstracts

Please download the abstract submission form to provide the following information:

Page 1

  1. Title of proposed article and manuscript type (original research or review);
  2. Lead author, as well as co-authors of the paper including their work or academic institutional affiliations and contact information (author and co-author names will not be included for blinded peer review);
  3. Brief conflict of interest disclosure for lead author and co-authors.

Page 2

  1. Title of proposed article (this will allow matching with author names after blinded review);
  2. A description of your proposed article in 250 to 500 words;
  3. Research topic(s) or area(s) of interest; and
  4. The stage of your research (i.e., already completed or will be completed by November).

If you propose more than one submission, please send a separate form for each submission.

Please send the completed abstract submission form to:

The submission deadline is May 31, 2013.

For questions, please contact:

On behalf of AHRQ’s Effective Health Care Program and the Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) Network, we welcome your participation and thank you for your interest.