Table 3.

Characteristics of pivotal studies (n = 40)

Drug	Study	Study phase	Multicentre	Multinational	Endpoint	Control	Randomized	Blinding	Study population representative	Duration	No. of patients	QoL-end point
Miglustat (Gaucher)	OGT 918-001	I/II	Yes	Yes	Surrogatea	No	No	n/a	Yes	12 months	28	No
Miglustat (NPC)	OGT 918-007	II	Yes	Yes	FOM	St. of care	Yes	No	Yes	12 months	31	Yes
Velaglucerase alfa	HGT-GCB-039	III	Yes	Yes	Surrogatea	Active comp.	Yes	Yes	Yes	9 months	35	No
Eliglustat	GZD02507	III	Yes	Yes	Surrogatea	Placebo	Yes	Yes	Yes	39 weeks	40	Yes
	GZGD02607	III	Yes	Yes	Surrogatea	Active comp.	Yes	No, but justified	Yes	52 weeks	160	No
Agalsidase beta	AGAL-1-002-98	III	Yes	Yes	Biomarker	Placebo	Yes	Yes	No	20 weeks	58	Yes
Agalsidase alfa	TKT-003	II	No	No	Clinical	Placebo	Yes	Yes	No	6 months	26	Yes
	TKT-005	II	No	No	Biomarker	Placebo	Yes	Yes	Yes	6 months	15	No
Alglucosidase alfa	AGLU01602	II/III	Yes	Yes	Clinical	Diff. dose	Yes	No	Yes	52 weeks	18	No
	AGLU01702	II	Yes	Yes	Clinical	Hist. control	No	n/a	Yes	120 weeks	21	No
	AGLU02704	NR	Yes	Yes	FOM	Placebo	Yes	Yes	Yes	78 weeks	90	Yes
Laronidase	ALID-003-99	III	Yes	Yes	FOM	Placebo	Yes	Yes	No	12 months	45	Yes
Idursulfase	TKT024	II/III	Yes	Yes	FOM	Placebo	Yes	Yes	No	12 months	96	No
Elosulfase alfa	MOR-004	III	Yes	Yes	FOM	Placebo	Yes	Yes	No	24 weeks	176	Yes
Galsulfase	ASB-03-05	III	Yes	Yes	FOM	Placebo	Yes	Yes	No	24 weeks	39	No
Sebelipase alfa	LAL-CL02	III	Yes	NR	Biomarker	Placebo	Yes	Yes	Yes	20 weeks	66	Yes
	LAL-CL03	NR	Yes	Yes	Clinical	No	No	n/a	Yes	Up to 208 weeks	9	No
Sapropterin	PKU-003	III	Yes	Yes	Surrogatea	Placebo	Yes	Yes	Yes	6 weeks	88	No
	PKU-006	III	Yes	Yes	Surrogatea	Placebo	Yes	Yes	Yes	10 weeks	45	No
Betaine	Case reports	n/a	n/a	n/a	Biomarker	n/a	n/a	n/a	Yes	n/a	±140	No
Mercaptamine	RP103-03	III	Yes	Yes	Surrogate	Active comp.	Yes	No, but justified	Yes	8 weeks	43	Yes
Nitisinone	NTBC study	NR	Yes	Yes	Clinical	No	No	n/a	Yes	NR	207	No
Alipogene	AMT-011-01	NR	No	No	Biomarker	No	No	n/a	Yes	12 weeks	14	No
Tiparvovec	AMT-011-02	NR	Yes	No	Biomarker	No	No	n/a	Yes	18 weeks	5	Yes
	AMT-010-01	NR	Yes	Yes	Biomarker	No	No	n/a	Yes	3 months	8	No
Carglumic acid (organic acidurias)	OE-CGA001-OA2009	IIIb	Yes	Yes	Biomarker	No	No	n/a	Yes	15 days	77	No
Carglumic acid (NAGS deficiency)	Case reports	n/a	n/a	n/a	Biomarker	n/a	n/a	n/a	Yes	n/a	20	No
Zinc	Existing literature	NR	No	No	Biomarker	No	No	n/a	Yes	±3 years	148	No
Cholic acid (Kolbam)	CAC-91-10-10	III	No	No	Biomarker	No	No	n/a	Yes	Up to 17 years	52	No
Cholic acid (Orphacol)	Case reports	n/a	n/a	n/a	Biomarker	n/a	n/a	n/a	Yes	n/a	49	No
Hydrocortisone	DC 06/02	II/III	Yes	No	Biomarker	Active comp.	Yes	No, but justified	Yes	24 weeks	64	Yes
Pasireotide (Cushing)	B2305	III	Yes	NR	Biomarker	Diff. dose	Yes	Yes	Yes	12 months	162	Yes
Pasireotide	C2305	III	Yes	Yes	Biomarker	Active comp.	Yes	Yes	Yes	12 months	358	Yes
(Acromegaly)	C2402	III	Yes	Yes	Biomarker	Active comp.	Yes	Yes	Yes	24 weeks	198	Yes
Ketoconazole	Literature data	n/a	n/a	n/a	Biomarker	n/a	n/a	n/a	Yes	n/a	>800	n/a
Pegvisomant	SEN-3614	III	Yes	Yes	Biomarker	Placebo	Yes	Yes	Yes	12 weeks	112	Yes
Glycerol phenylbutyrate	HPN-100-006	III	NR	NR	Biomarker	Active comp.	Yes	Yes	Yes	4 weeks	44	No
Asfotase alfa	ENB-006-09	II	Yes	Yes	Clinical	Hist. control + diff. dose	Yes	No	Yes	24 weeks	13	Yes
	ENB-008-10	II	Yes	Yes	Clinical	Hist. control + diff. dose	Yes	No	Yes	Ongoing (extension)	12	Yes
Afamelanotide	CUV039	III	Yes	No	Clinical	Placebo	Yes	Yes	Yes	6 months	93	Yes

FOM functional outcome measure, n/a not applicable, NR not reported, NPC Niemann-Pick C

^aEndpoint is either (1) validated as a surrogate endpoint in scientific studies, or (2) widely accepted by clinical experts as a valid surrogate for a clinical endpoint