Factors contributing to the efficacy-effectiveness gap in the case of orphan drugs for metabolic diseases
Y Schuller, CEM Hollak, CC Gispen-de Wied, V Stoyanova-Beninska, M Biegstraaten
Drugs
Correspondence to:
Mrs. Y. Schuller
Academic Medical Center, University of Amsterdam
Dept. of Endocrinology and Metabolism, F5-165
P.O. Box 22660, 1100 DD Amsterdam, The Netherlands
Tel: +31 20 56 67672, Fax: +31 20 69 17682, e-mail:
Supplementary Table2: EMA considerations and post-marketing obligations
miglustat / 1. Gaucher disease / 3 / Size of effect of miglustat is difficult to estimate because of heterogeneity of disease, small number of evaluable patients and lack of a placebo arm for comparison. The lack of data on bone disease is a clear deficiency. However, significant reduction in spleen and liver volumes and biochemical and haematological parameters (from baseline) was seen, as were clinically significant improvements from baseline in QoL parameters. / Randomized, open label, case-controlled study of effectiveness and safety of miglustat versus ERT. Natural history observational study.
2. Niemann-Pick C / 1 / Efficacy analyses are only explorative and due to study design it is difficult to draw any conclusions concerning long term effectiveness. / Niemann-Pick C registry including data on effectiveness parameters, characteristics of ''responders'' / ''non responders'', long-term effectiveness results.
velaglucerase alfa / Gaucher disease / 2 / Interpretation of the results is limited by low number of patients investigated and by study design. / Post-authorization registry (Gaucher observational study).
eliglustat / Gaucher disease / 2 / Endpoints used are considered clinically relevant. Open-label design is acceptable. / Investigate long-term safety in patients by a sub-registry to the International Collaborative Gaucher Group Gaucher Registry.
agalsidase beta / Fabry disease / 1 / Variability of clinical presentation makes it difficult to demonstrate clinical benefits in short term. Longer follow-up is needed and special patient groups need to be studied for an accurate assessment of the clinical benefit. / Antibody-formation, long-term safety and effectiveness, maintenance dosing regimens after clearance of sphingolipids.
agalsidase alfa / Fabry disease / 3 / Neuropathic pain in Fabry disease is reduced but not abolished by agalsidase alfa. However, the exact magnitude of pain reduction is difficult to estimate due to methodological limitations. The overall conclusion that can be drawn is that all the chosen endpoints consistently show improvement when compared with placebo. Potential surrogate markers for the assessment of progression of disease should be explored further and validated. / Phase IV clinical study, identifying optimal dose and dosing interval. Infusion reactions and antibody-formation.
alglucosidase alfa / Pompe disease (infants)
/ 3 / The pivotal study showed that treatment with alglucosidase alfa of patients with infantile-onset Pompe disease aged less than 6 months significantly prolonged survival and ventilator-free survival at 18-months of age compared to a historical control subgroup. Studies included only infantile-onset Pompe disease patients. Extrapolating data obtained in infantile-onset Pompe disease patients to late-onset disease patients is not a valid approach. / Randomized, double-blind, placebo-controlled study in late-onset Pompe disease patients with mild to moderate disease.
Pompe disease (adults) / 1 / Study suggests a positive effect of Myozyme in late-onset Pompe disease, but more probably in mild or moderate stages of the disease. / Evaluation of long-term effectiveness and safety through Pompe registry.
laronidase / MPS 1 (Hurler disease) / 1 / Experts consider that the endpoints studied are appropriate and that, although small, the demonstrated efficacy is clinically relevant, especially in the light of the absence of alternative therapies. / Clinical study on alternative dosing regimens. Long-term safety and effectiveness through MPS I registry program.
idursulfase / MPS 2 (Hunter disease) / 2 / Idursulfase does not cross the blood brain barrier and therefore is not expected to have any effect on CNS disease. / Establishment of Hunter Outcome Survey with a commitment to continue to analyze data for at least the first 10 years, to gather long-term data on relevant clinical end-points. Studies in patients <5years.
elosulfase alfa / MPS 4a (Morquio disease) / 1 / Study design and inclusion and exclusion criteria are acceptable. No other single endpoint (than 6-MWT) that would be more sensitive could be identified at the present time. / Set-up of disease-specific registry.
galsulfase / MPS 6 (Maroteaux-Lamy Syndrome) / 1 / Disease in relatively avascular tissues appears unaffected by ERT. Improvements demonstrated in the clinical studies appear to represent clinical benefits. / Studies in pregnant women. Ongoing, observational database on clinical and safety outcomes.
sebelipase alfa / Lysosomal acid lipase-deficiency / 3 / Results observed in the pivotal trials were positive, with significant improvements in survival, molecular markers, liver histology, liver size, growth and QOL. Study design (combined phase 2/3 open-label trial without a comparison arm) is acceptable as the disease is lethal and there is no effective treatment available. / Clinical trial on long-term effectiveness. Registry.
sapropterin / Phenylketonuria (PKU) / 3 / A statistically significant dose related effect was shown in Phe levels in both pivotal studies. Product does not work in all patients with PKU but only in those who have shown a definite effect. / Studies in pregnant women, children <4 yrs, elderly patients with renal of hepatic insufficiency. Long-term safety and effectiveness.
betaine / Homocystinuria / 3 / Since no patient has been treated with betaine alone, it is difficult to distinguish the clinical benefits attributable to betaine from those attributable to other treatments(diet, supportive). Homocysteine plasma concentrations are generally accepted as a surrogate endpoint for the severity of disease. Therefore, it can be considered that betaine offers benefit to patients with homocystinuria. / Patient registry to gather data on demographics, drug utilization and safety profile.
mercaptamine / Cystinosis / 2 / The primary endpoint WBC cystine level is generally accepted as surrogate endpoint for treatment effect. / Not reported.
nitisinone / Hereditary tyrosinemia type 1 (HT-1) / 3 / Nitisinone seems to be an effective treatment for HT-1, particularly if started early before there is irreversible liver damage.The risk for death, the need for liver transplantation due to liver failure, the risk of hepatocellular carcinoma and the risk of life-threatening porphyria-like crises appear to be small in patients in whom nitisinone treatment is started before six months of age. / Long-term safety data through a post-marketing surveillance program.
alipogene tiparvovec / Lipoprotein lipase deficiency / 3 / The evidence generated by overall efficacy data, although hampered by statistical limitations, suggested that Glybera leads to a clinically relevant reduction of pancreatitis risk only in patients with severe or multiple pancreatitis attacks. This is a subgroup of severely affected patients with a high unmet medical need. / Assess postprandial chylomicron metabolism as surrogate marker of successful LPLD treatment. Set-up of a disease registry / surveillance program.
carglumic acid / 1. Hyperammonemia (due to NAGS deficiency) / 3 / NAGS-deficiency: Given the rarity of the disease, one cannot expect to prove efficacy through controlled clinical trials. However, it has been shown that carglumic acid has an important effect size in terms of mortality, growth and psychomotor development compared to no treatment or conventional therapy. / Systematic follow-up of all NAGS deficient patients treated with carglumic acid.
2. Hyperammonemia (due to organic acidurias PA, MMA and IVA) / 1 / PA, MMA, or IVA: Given the rareness of the conditions, comparison of treatment between carglumic acid and NH3 scavengers was based on paired retrospective comparison and yields very low quality or strength. The study showed that treatment with carglumic acid on its own or in combination with sodium benzoate induced a rapid decrease in ammonia levels in all age groups, reducing the risk of neurological complications in patients with PA, MMA, and IVA. / Not reported.
zinc / Wilson’s disease / 3 / There is clear evidence that zinc is effective in patients with Wilson’s disease; Reduction of urine copper, decrease in non ceruloplasmin plasma copper, stabilization or improvement of clinical symptoms and liver function tests, prevention of the occurrence of clinical symptoms in presymptomatic patients. / Not reported.
cholic acid (Kolbam) / Inborn errors in primary bile acid synthesis / 2 / Inability to collect comprehensive information because it would be contrary to medical ethics principles. / Monitor long term effectiveness in patients treated with Kolbam from a patient registry.
cholic acid (Orphacol) / Inborn errors in primary bile acid synthesis / 3 / Effectiveness based on literature data (‘well-established use’ application). Disease rarity made controlled clinical studies impossible. Reporting and publication bias are potential concerns.Overall, cholic acid treatment results for 38 patients with 3β-Hydroxy-Δ5 -C27-steroid oxidoreductase deficiency and seven patients with Δ4 -3-Oxosteroid-5β-reductase deficiency are reported in literature. Cholic acid therapy has been shown to: postpone or obviate the need for liver transplantation, restore normal laboratory parameters, improve histological lesions of the liver, and significantly improve all of the patient’s symptoms. / Monitor safety and effectiveness in patients treated with Orphacol from a patient surveillance database.
hydrocortisone / Adrenal insufficiency / 1 / Efficacy data concerning tolerability and well-being should be interpreted with caution due to the open-label design of the studies. / Prospective multicenter, European registry of patients with chronic adrenal insufficiency. Swedish retrospective study, evaluating the pattern of Plenadren use from Swedish quality registries.
pasireotide / 1. Cushing’s disease / 1 / High drop-out rate (unsatisfactory therapeutic effect and adverse events) should be taken into account for the efficacy and safety profile of pasireotide. / Post-marketing surveillance study to document safety and effectiveness.
2. Acromegaly / 1 / Study design and inclusion and exclusion criteria are considered adequate. / Study on long-term safety and effectiveness.
ketoconazole / Cushing’s syndrome / 1 / Effectiveness based on literature data (‘well-established use’ application). Patient population described is considered appropriate. / Post authorisation safety study.
pegvisomant / Acromegaly / 2 / Submitted documentation does not allow a conclusion on the efficacy of pegvisomant versus somatostatin analogues. Although statistically significant improvements in total signs and symptoms score compared with the placebo group were shown, treatment withpegvisomant does not reduce tumor size. / Long-term study of tumor volume in patients treated with pegvisomant. Clinical study on combination treatment using somatostatin analogues with pegvisomant.
glycerol phenylbutyrate / Urea cycle disorders / 2 / Efficacy was demonstrated in the reduction of both blood ammonia and glutamine. No significant differences between treatment groups (glycerol phenylbutyrate vs sodium phenylbutyrate). However, it is acknowledged that the sustained release characteristics provided a better control during the day. / Document long-term safety and clinical outcomes in a non-interventional post-authorisation safety study.
asfotase alfa / Hypophosphatasia / 2 / Patient population studied is acceptable.During the course of clinical studies, the main objectives were variously changed with regard to the primary endpoint. In addition, based on the basis of emerging data, changes were made to the dosage of study drug and the inclusion / exclusion criteria of study subjects. For these reasons, cautious interpretation of data is required. Based on 1) the improvement in x-ray appearance, 2) the histological appearance of bone biopsy material and 3) the apparent catch-up height-gain demonstrated in some patients, CHMP considered, although the data is very limited, that the totality of evidence submitted supports a specific and limited claim for clinical efficacy. / Observational, longitudinal, prospective, long-term registry of patients with HPP to collect information on the epidemiology, clinical outcomes, quality of life and safety.
afamelanotide / Erythropoietic protoporphyria / 2 / The magnitude of the effect size is considered small.The studies had to be regarded as insufficiently blinded due to the pharmacodynamic effect (increase in pigmentation) of afamelanotide. Despite this, the pivotal studies show a beneficial effect. Treatment with afamelanotide led to a small increase in sun exposure. The results of the secondary endpoints numerically favour the afamelanotide group. / Disease registry and long-term safety study.
1 Notes are copied from EPARs, available at
6-MWT = 6-minute walk test; BH4 = tetrahydrobiopterin; CNS = central nervous system; ERT = enzyme replacement therapy; HT-1 = Hereditary tyrosinemia type 1;IVA = isovaleric acidemia; LPLD = lipoprotein lipase deficiency;MMA = methylmalonic acidemia; MPS = mucopolysaccharidosis; NAGS = N-acetylglutamate synthase; PA = propionic acidemia; Phe = phenylalanine; PKU = phenylketonuria; WBC = white blood cell