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Ratko TA, Marbella A, Godfrey S, et al. Enzyme-Replacement Therapies for Lysosomal Storage Diseases [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Jan. (Technical Briefs, No. 12.)

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Enzyme-Replacement Therapies for Lysosomal Storage Diseases [Internet].

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Several sources were used to inform this Technical Brief. Information was collected in a review of published medical literature, narrative review articles, a search of the grey literature, and discussions with Key Informants.

Guiding Questions 1 and 2 relied on information from published narrative reviews and information in the grey literature. The latter may include information culled from Web sites of pharmaceutical companies, patient advocacy groups, and other sources such as the FDA-approved prescribing information for each ERT product.

Guiding Question 3 was addressed through a systematic scan and description that enumerates select study elements of interest (e.g., study design, sample size) to provide an overview of the published literature including primary and secondary (narrative and systematic reviews) articles. Key Informants provided guidance on the potential clinical outcomes of interest and the potential benefits and harms of ERT as the review was conducted.

Guiding Question 4 relied on integrating information from Key Informants, grey literature, published primary studies and narrative reviews.

Data Sources

Discussions With Key Informants

The Key Informants comprised a group of physician specialists in metabolic diseases, lysosomal storage diseases, and rare diseases. In addition, one payer representative was part of the Key Informant group. Unless otherwise specified, the views presented in this report are those of the authors.

Two Key Informant group conference calls were conducted that included the clinicians mentioned in the preceding paragraph. The Key Informants provided input on the literature review, for example, years to include in the search and potential clinical outcomes. As a follow-up to the group conference calls, the Key Informants were interviewed individually by telephone, using a semi-structured interview outline that provided opportunity to share their clinical experiences with patients with lysosomal storage diseases, their experience with ERT, and their opinions on unresolved or controversial issues relating to ERT. The seven questions we asked in the interviews follow:

  1. Have you seen patients in your practice with any of the six diseases covered in this report (MPS I, MPS II, MPS VI, Gaucher, Fabry, Pompe)?
  2. What challenges, successes, and failures have you experienced in treating these patients?
  3. What factors do you consider before starting ERT with your patients?
  4. What outcomes, beneficial and harmful, have you seen in your patients treated with ERT?
  5. What do you believe are unresolved issues surrounding ERT?
  6. In your view, what needs to be done to resolve these issues, for example by pharmaceutical companies, researchers, or practitioners?
  7. Are you aware of any new ERT products or developments in the development or testing phase that are not common knowledge?

Discussions With Patient Advocates

One call with the patient advocates was conducted. Many patients with an LSD are children, but many are surviving well into adulthood. Patients with late-onset disease are often not diagnosed until the 3rd, 4rd, 5th, or even 6th, decade of life. Therefore, one adult patient and one parent of a child patient were consulted. The adult patient and the parent were asked about their experiences with the disorder prior to ERT and subsequent to ERT. They were asked to describe symptoms, clinical outcomes of importance to them, and factors involved in the decision to begin treatment with ERT. We recognize that the report deals with six unique diseases; however, we primarily sought a broad perspective on the challenges that caregivers and LSD patients face.

Grey Literature Search

The U.S. Food and Drug Administration (FDA) Web site concerning the nine commercially available ERT treatments was accessed. Information was gathered to inform Guiding Questions 1 and 2.

ERT manufacturers provided scientific information packages (SIPs) that contained product information, unpublished data, and a bibliography. Their Web sites were accessed to inform Guiding Questions 1 and 2, using the following Web links:

Registries and patient advocate Web sites for each of the six LSDs were accessed. Examples included:

Current clinical studies involving ERT were identified by searching

Published Literature Search

We searched the published medical literature in MEDLINE®, Embase®, the Cochrane Database, and the Health Technology Assessment Database to address Guiding Question 3. Based on input from the Key Informants, the initial searches encompassed the years 1990 through September 16, 2011, as outlined in Appendix A. Initiation in 1991 corresponds to the year the first ERT product (alglucerase, no longer marketed) received FDA marketing approval. The search was updated on April 24, 2012, while the draft was under peer review.

The DistillerSR® Systematic Review Tool was utilized to facilitate the screening and study selection process. Titles and abstracts were examined using Distiller® to identify articles for potential inclusion. We retrieved selected narrative or systematic review articles on ERT for the pertinent LSDs to provide background materials.

Preclinical studies, meeting abstracts, foreign-language articles, editorials, comments, and letters to the editor were excluded in the first-level title and abstract screen. Reports were eligible for full-text screening if the abstract provided clinical outcomes in patients who received an FDA-approved ERT product; if an abstract wasn’t available but the title was deemed potentially relevant, we retrieved the full text article for further examination. The search was limited to English-language reports based on evidence that suggests language restrictions do not change results of systematic review for conventional medical interventions.31

In the second-level screen, full-text clinical studies were retrieved and screened for inclusion or exclusion in the literature compilations. We sought all randomized controlled trials (RCTs), in particular the pivotal trial or study submitted by the manufacturer for FDA approval for each ERT product. To alert readers and avoid oversampling, if more than one study was available with the same (or nearly same) study population, as in an extension study, we cross-indexed the trials in the tables. We also sought prospective phase I or II nonrandomized studies that included patient subgroups with specific disease manifestations not well represented in RCTs, or treatment protocols or settings that were not reported in RCTs. If higher-level studies (RCTs, prospective phase I and II) were not available, case series (single-arm studies), case-control studies, case reports, and prospective registry studies were eligible for the main evidence compilations.

We also sought registry reports to ascertain whether clinical outcomes reported in that type of publication were consistent with outcomes reported in clinical studies. Reference lists of the included studies and recent review articles were examined to identify other relevant articles. A resource bibliography that lists all the citations we examined in the second-level literature screen is available in Appendix E. We did not assess study quality or the overall strength of the evidence.

Data Organization and Presentation

Information Management

Three main sources of information were consulted for this Technical Brief: published literature, grey literature, and Key Informants. Data from studies published in the medical literature were abstracted into Microsoft Word® tables (Appendix B). Data collected include: study design, number of study subjects, subject age, severity of disease, ERT dosing and administration details, length of follow-up, and type of clinical outcome measures.

Information about clinical indications, ERT dosing, and administration, abstracted from review articles and from the FDA-approved prescribing information for each ERT product, was organized in tables. Information from Key Informants and patient advocates was managed in a Microsoft Word® document.

Data Presentation

Summary tables present selected published studies for each disease, and include the following information: study design, patient population, interventions, dose regimen, follow-up duration, and clinical outcomes that were measured. A narrative summary integrates information gathered from the medical literature, FDA-approved documentation, the grey literature, and the Key Informants, to describe the current state of ERT treatment, clinical indications, dosing and administration details, and a discussion of the key unresolved or controversial issues regarding the treatment.

Peer Review

A draft of this Technical Brief was posted to the AHRQ Web site for four weeks, during which invited peer reviewers, the Key Informants, and the general public were invited to comment on it. All comments received were compiled by AHRQ and provided to the authors for reconciliation. The disposition of comments was posted to the public AHRQ Web site.

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