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McPheeters ML, Lindegren ML, Sathe N, et al. Adjuvant Treatment for Phenylketonuria: Future Research Needs: Identification of Future Research Needs From Comparative Effectiveness Review No. 56 [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Sep. (Future Research Needs Papers, No. 21.)

Cover of Adjuvant Treatment for Phenylketonuria: Future Research Needs

Adjuvant Treatment for Phenylketonuria: Future Research Needs: Identification of Future Research Needs From Comparative Effectiveness Review No. 56 [Internet].

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Table 2 outlines the methods we used to identify and prioritize research needs. We expand on the table’s brief description in each of the following sections.

Table 2. Methods for developing future research needs related to adjuvant therapies for PKU.

Table 2

Methods for developing future research needs related to adjuvant therapies for PKU.

Identification of Evidence Gaps

We identified evidence gaps that limited conclusions that could be drawn about each Key Question from primarily the Discussion and Future Research sections of the report. One investigator extracted research gaps from the review. A senior investigator then reviewed the list for accuracy and completeness and added gaps as appropriate. We augmented this preliminary list of gaps as identified in the review with gaps/needs discussed at the National Institute of Child Health & Human Development PKU Scientific Review Conference: State of the Science and Future Research Needs held on February 22–23, 2012.

We framed gaps as Population-Intervention-Comparators-Outcomes-Timing-Setting (PICOTS) questions by CER Key Question or as nonresearch issues for which greater understanding would benefit PKU treatment (Appendix A). We also indicated where ongoing research may begin to address questions.

Identification of Ongoing Research

We searched clinical research repositories and research-related sites including, AHRQ’s Grants Online database, CenterWatch, NIH Reporter, the Canadian Institute for Health Research, OrphaNet, the UK Medical Research Council, Wellcome Trust, the World Health Organization Clinical Trials Registry, Current Controlled Trials, and the European Union Clinical Trials Register. We also searched the Web sites of relevant advocacy organizations including the Children’s PKU Network, the National PKU Alliance, National Society for PKU, Canadian Association for Rare Disorders, Children Living with Inherited Metabolic Diseases organization, Canadian PKU and Allied Health Disorder Organization, National Organization for Rare Disorders, Genetic Metabolic Dieticians International, Eurordis, Society for the Study of Inborn Errors of Metabolism, British Inherited Metabolic Disease Group, Society for Inherited Metabolic Disorders, International Rare Diseases Research Consortium, and the March of Dimes. Appendix B includes a summary of findings from these searches.

Engagement of Stakeholders, Researchers, and Funders

We then convened a group of stakeholders broadly representative of research, clinical care, patient/consumer, and funder perspectives to provide input on the list and add additional questions as necessary. We generated lists of potential stakeholders via a review of potential Technical Expert Panel members and key informants for the CER, review of investigators in studies included in the CER, review of advocacy and other agencies relevant to PKU, and through consultation with our Task Order Officer (TOO). We reviewed potential stakeholder candidates with the TOO to determine a final set of invitees. Stakeholders completed conflict of interest forms, and none was deemed by the AHRQ TOO to have conflicts that would preclude their participation.

We engaged stakeholders agreeing to participate in the project via an initial conference call to introduce the project and to add to the list of gaps identified from the report. This call was followed by an email message including the revised list of gaps and inviting stakeholders to edit or add questions as necessary.

Criteria for Prioritization

Round One Prioritization

We presented the expanded list of questions to stakeholders via a Web-based survey implemented in the RTI-UNC EPC Prioritization Software.25 The survey asked stakeholders to allot a number of votes to each question to indicate priority. We asked stakeholders to keep in mind EHC prioritization criteria when considering importance but did not require “votes” by each specific criterion at this phase. Based on processes used in prior future research needs projects,3 we limited the number of votes available to roughly two-thirds of the number of questions identified to ensure that stakeholders selected high-priority issues. We then compiled votes across stakeholders and questions. We a priori considered those questions receiving at least 5 points to comprise the top tier of research needs for further prioritization.

Round Two Prioritization

We sent a second Web-based survey (created using RedCap survey software26) to stakeholders asking them to further prioritize the high-priority needs using modified EHC program selection criteria (Table 3) as described in AHRQ EHC methodologic guidance4). Stakeholders ranked each question on each criterion below using a 1 (low) to 5 (high) point scale (Appendix C). Questions were divided by broad category of focus (treatment or methodologic/other).

Table 3. EHC criteria used to prioritize top-tier research needs.

Table 3

EHC criteria used to prioritize top-tier research needs.

We tallied the number of points for each question across all criteria in each category and present questions by tier of priority (top, middle, lower). Appendix D outlines the highest scoring questions on each criterion.

Research Question Development and Research Considerations

Once we had determined the top-tier questions/needs, the core project team discussed potential research designs and considerations relevant to each top tier treatment-related question. This discussion was informed by AHRQ guidance and input received from stakeholders during prior calls. We considered factors including the following:

  • Ethical, legal, and social considerations
  • Resource utilization
  • Availability of relevant datasets
  • Alignment with the system of care for PKU
  • Challenges in assessing outcomes
  • Recruitment issues in rare diseases


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