Pompe Disease Evidence Evaluation Michael Watson, PhD, on behalf of Piero Rinaldo, MD, PhD, and the Decision-Making Workgroup October 1, 2008

Key Question 1 Is there direct evidence that screening for Pompe disease at birth leads to improved health outcomes? –No studies of the overarching question

Key Question 2 What is known about the condition? – broken down as follows: –Is the condition well-defined and important? –What is the incidence of the condition in the US? –What is the spectrum of disease for the condition? –What is the natural history of the condition, including the impact of recognition and treatment?

Key Question 2 Evidence is adequate –Infantile Pompe is well-defined, and classic vs. non- classic does not interfere with the importance of the condition nor raise many concerns about the spectrum of disease –Late-onset raises issues, and the body of evidence regarding detection and treatment seems less robust –Variation in prevalence with wide confidence intervals, as is expected with rare conditions –The largest prevalence studies are not in the US

Key Question 3 Is there a test for the condition with sufficient analytic utility and validity? –Gap that needs to be filled –Variation in how screening is done (e.g., immunofluorescense, MS/MS, immuno capture) –Only one type of test has been tested prospectively in a large-scale population study

Key Question 4 Does the test accurately and reliably detect the condition and clinical disease? –Evidence is adequate that available tests are able to discriminate between those with and without the condition, but at the cost of a high false-positive rate. In the Taiwan study, nearly all (97%) of cases who tested abnormal twice had a false positive outcome –There is some question about separating out late- onset disease and related phenotype. The data supporting early detection and early treatment of late- onset disease is insufficient

132,538 Newborns tested 121 Newborns recalled 1,101 Newborns retested (2 nd sample) 4 True positives (no false negatives) Newborn Screening for Pompe Disease Pilot Study in Taiwan

A FPR 0.83% in a Real Life Scenario State Illinois Indiana Kentucky Michigan Minnesota Ohio Wisconsin Births/ Year 177,417 87,942 54, ,585 70, ,481 69,014 FP/WEEK 0.83% 0.4% FPR PPV

Key Question 5 Are their available treatments for the condition that improve important health outcomes? – broken down as follows: –Does treatment of the condition detected through NBS improve health outcomes when compared with waiting until clinical detection? –Are there subsets of affected children more likely to benefit from treatment that can be identified through testing or clinical findings? –Are the treatments for affected children standardized, widely available, and, if appropriate, FDA approved?

Key Question 5 Adequate evidence that rhGAA improves important health outcomes based on a sample of 18 affected infants Evidence of benefit is specific to infantile-onset Pompe disease compared to natural history, and lasts at least 52 weeks. No long-term health outcomes beyond 52 weeks of treatment or 18 months of age Small body of evidence suggesting that CRIM- cases will not respond or not respond as well to rhGAA. However, it is insufficient to conclude that cases should not be treated.

Key Question 5 No description in the Evidence Review about how these 18 cases were detected. After conferring with the research team, only 2 cases were detected by screening at birth in families where there were other affected children. The other 16 were detected clinically based after a respiratory or cardiac adverse event

Key Question 5 Treatment started prior to 27 weeks of life is effective Gaps –Outcomes of treatment prior to 27 weeks of life –Age at which treatment benefit decreases –The proportion of cases of infantile Pompe disease that could be detected clinically vs. only through screening

Key Question 5 The evidence supporting early treatment of late-onset Pompe disease detected through screening is inadequate

Key Questions 6 and 7 Are there harms or risks identified for the identification and/or treatment of affected children? –No studies reporting harms of screening, including anxiety associated with the need for second screens or diagnostic testing –Diagnostic testing for screen-positive infants seems to carry little risk of harm –Harms of treatment involve immune reactions to rhGAA. These harms relative to the benefits are small.

Key Question 8 What is the estimated cost-effectiveness of testing? –No studies or published models –The magnitude of net benefit (benefit-harms) of treatment, at least up to 18-months is significant for infantile Pompe disease

Overall Adequacy of Evidence If one feels that the lack of evidence regarding how newborn screening might better translate to treatment initiation prior to 27 weeks of life is a critical gap, the evidence, even for infantile Pompe, would be assessed as inadequate. If not, then one could conclude there is adequate evidence. This assumes that screening and diagnosis will indeed discriminate between infantile and late onset Pompe.

Certainty of net benefit Again, certainty (sufficient vs. insufficient) here depends on the level of confidence that treatment benefits require screening for timely case detection and that clinical detection leads to much less benefit in terms of health outcome is important.

Contextual issues While the evidence of follow up for treatment is short, treatment translates to survival and ventilator independence. This is a compelling potential net benefit.

Summary Based on what is presented in the report of the ERW, there are significant concerns with –testing specificity –the comparative effectiveness of alternative testing algorithms (repeat specimen vs. 2nd tier tests) –the potential applicability of prognostic tools.

Summary The dramatic effectiveness of available treatment in infantile Pompe cases has been noted. However, better evidence is needed regarding –the ability for screening to distinguish between infantile and late onset disease –the efficacy of treatment in either pre- symptomatic or symptomatic cases