3.1. Objectives

To perform an updated systematic review of the beneficial and harmful effects of sapropterin dihydrochloride (dose: 5 to 20 mg/kg/day), when used in conjunction with a Phe-restrictive diet, to reduce blood Phe levels in patients with HPA due to BH₄-responsive phenylketonuria.

3.2. Methods

All manufacturer-provided trials considered pivotal by Health Canada were included in the systematic review. Phase 3 studies were selected for inclusion based on the selection criteria presented in Table 2.

Table 2

Inclusion Criteria for the Systematic Review.

The review protocol for the resubmission is largely unchanged from that of the original Kuvan submission. The only differences are the addition of the outcomes of health care resource utilization and proportion of responders to better inform the review. As well, examples of neurophysiologic and neurocognitive effects have been added to clarify this outcome. Any studies included in the previous CDR review were excluded from the current review.

The literature search was performed by an information specialist using a peer-reviewed search strategy. Published literature was identified by searching the following bibliographic databases: MEDLINE (1946—) with in-process records and daily updates via Ovid; Embase (1974—) via Ovid; and PubMed. The search strategy consisted of both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Kuvan (sapropterin dihydrochloride) and phenylketonuria.

No methodological filters were applied to limit retrieval. Where possible, retrieval was limited to the human population. Retrieval was limited by publication year (2011 to 2016 to update a previous Kuvan submission from 2011), but not by language. Conference abstracts were excluded from the search results. See Appendix 2 for the detailed search strategies.

The updated search was completed on March 1, 2016. Regular alerts were established to update the search until the meeting of the CADTH Canadian Drug Expert Committee (CDEC) on July 20, 2016. Regular search updates were performed on databases that do not provide alert services.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the following sections of the Grey Matters checklist (www.cadth.ca/grey-matters):

• Health Technology Assessment Agencies
• Health Economics
• Clinical Practice Guidelines
• Drug and Device Regulatory Approvals
• Advisories and Warnings
• Drug Class Reviews
• Databases (free)
• Internet Search.

Google and other Internet search engines were used to search for additional Web-based materials. These searches were supplemented by reviewing the bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

Two CDR clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least one reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion. Included studies are presented in Table 3; excluded studies (with reasons) are presented in Appendix 3.