International comparison of availability for orphan drugs: focused on approved orphan drugs in South Korea

Figures & data

Table 1. Criteria and incentives for orphan drug in South Korea and three major jurisdictions.

Terms		South Korea	USA	EU	Japan
Legal basis		The 1998 Regulation on Orphan Drug Designation Notification	The 1983 Orphan Drug Act and amendments	Regulation (EC) No 141/2000	Pharmaceutical Affairs Law
Prevalence of rare disease		< 20,000 patients	< 200,000 patients	< 5 in 10,000 patients	< 50,000 patients
Orphan drug designation authority		MFDS	OOPD (FDA)	COMP (EMA)	MLHW – PMDA – NIBIO
Incentives for orphan drug development	Research grants	✓	✓	✓	✓
	Tax incentives	✓	✓ (Tax credits for qualified clinical trials)	✓ (Incentives in Meer States)	✓ (12% of study expenses for orphan drug incurred during the NIBIO subsidy payment period can be reported as a tax credit)
	Fee waivers and reductions	✓ (Reduction of fee such as approval, priority review, and permission application)	✓ (There is no fee for human drug applications unless they include an indication other than a rare disease or condition)	✓ (Reduced fees for protocol assistance, marketing-authorisation applications, inspections before authorisation, applications for changes to marketing authorisations made after approval, and reduced annual fees)	✓ (PMDA provides a priority consultation system for designated orphan drug. Lower user fee categories for PMDA’s consultation are applicable to designated orphan drugs)
	Exclusivity	✓ 4–10 years market exclusivity	✓ Potential for 7 years of market exclusivity after approval	✓ 10 years market exclusivity	✓ The re-examination period for the drugs will be extended up to 10 years for drugs
	Expedited review process	Priority Review Partial exemption from approval submission data	Priority review Breakthrough therapy designation Accelerated approval Fast track designation	Accelerated assessment Conditional marketing authorisation Authorisation under exceptional circumstances	Priority review

Note: EC: European Commission; MFDS: Ministry of Food and Drug Safety; OOPD: Office of Orphan Products Development; COMP: Committee for Orphan Medicinal Products; MLHW: Ministry of Health, Labour, and Welfare of Japan; PMDA: Pharmaceuticals and Medical Devices Agency; NIBIO: National Institute of Biomedical Innovation

Table 2. Designation and approval status of orphan drugs in South Korea and three major jurisdictions countries (2012–2021).

Jurisdiction	Year/Classification	2012	2013	2014	2015	2016	2017	2018	2019	2020	2021	Total
South Korea	Designated Products^a	10	13	16	27	18	3	16	21	19	26	169
	Approved Products^b	10	11	15	21	15	3	14	14	13	0	116
	Approval Rate (%)	100.00	84.62	93.75	77.78	83.33	100.00	87.50	66.67	68.42	0.00	68.64
USA	Designated Products	207	278	302	367	353	492	343	340	476	363	3521
	Approved Products	56	73	48	53	60	54	23	15	12	1	395
	Approval Rate (%)	27.05	26.26	15.89	14.44	17.00	10.98	6.71	4.41	2.52	0.28	11.22
EU	Designated Products	89	87	152	134	167	129	144	98	137	163	1300
	Approved Products	17	11	15	10	7	9	10	2	1	0	82
	Approval Rate (%)	19.10	12.64	9.87	7.46	4.19	6.98	6.94	2.04	0.73	0.00	6.31
Japan	Designated Products	31	32	30	32	22	16	34	36	53	29	315
	Approved Products	26	26	25	27	20	14	27	26	22	1	214
	Approval Rate (%)	83.87	81.25	83.33	84.38	90.91	87.50	79.41	72.22	41.51	3.45	67.94

^a Designated products are the number of products designated as orphan drugs each year from 2012 to 2021.

^b Approved products are the number of approvals for products designated as orphan drugs when checked on December 31, 2021 (reference date). The current approval rate is low because it takes time to obtain approval after designation as an orphan drug.

Figure 1. Approval time, lag time, and designation gap of orphan drugs approved in each jurisdiction.

Note: Based on 169 products designated as orphan drugs in South Korea from 2012 to 2021. We compared the demand time, lag time, and designation gap by country for the products approved in each country. (A) Approval time: South Korea vs. USA, EU, and Japan (P < 0.001). (B) Lag time: South Korea vs. USA and EU (P < 0.001), and South Korea vs. Japan (P < 0.299). (C) Designation gap: South Korea vs. USA, EU (P < 0.001), and South Korea vs. Japan (P = 0.003). (We marked n.s.: not significant, *P < 0.05, **P < 0.01, and ***P < 0.001).

Table 3. Approval time, lag time, and designation gap of orphan drugs approved in each jurisdiction.

Jurisdiction	Designated products (N)	Approved products (N)	Approval rate (%)	First designated products (N)	First approved products (N)	Approval time			Lag time			Designation gap
						Mean	Median	P value	Mean	Median	P value	Mean	Median	P value
South Korea	169	116	68.64	15	21	11.67	9.70	–	32.36	17.23	–	73.34	59.34	–
USA	130	120	92.31	92	87	60.97	54.55	<0.001	9.73	0.00	<0.001	7.55	0.00	<0.001
EU	102	87	85.29	25	27	64.14	59.00	<0.001	9.86	5.00	<0.001	14.74	4.64	<0.001
Japan	90	80	88.89	17	22	30.16	21.65	<0.001	22.69	11.04	0.299	46.54	34.00	0.003

Note: Based on 169 products designated as orphan drugs in South Korea from 2012 to 2021. Approval time: Period (months) from designation to approval of drugs by country for products approved in each country. Lag time: Period (months) from the first country of approval to the approval of drugs by each country for products approved in each country. Designation gap: Period (months) from the first country of designation to the designation of drugs by country for products approved in each country. First approved and designated products: If the product was first approved or designated in the country, the drug lag and designation gap were set to zero. N: Number of designated (approved) products in each country. P Value: Compared with South Korea.

Figure 2. Lag time and designation gap of orphan drugs in each jurisdiction, excluding the first approved and designated product.

Note: Based on 169 products designated as orphan drugs in South Korea from 2012 to 2021. We compared the lag time and designation gap by country for products approved in each country, excluding the first-approved and designated products. (A) Lag time: South Korea vs. USA (P = 0.503), the EU (P < 0.001), and Japan (P = 0.903). (B) Designation gap: South Korea vs. USA, EU (P < 0.001), and South Korea vs. Japan (P = 0.011). (We marked n.s.: not significant, *P < 0.05, **P < 0.01, and ***P < 0.001).

Table 4. Lag time and designation gap of orphan drugs in each jurisdiction, excluding the first approved and designated product.

	Jurisdiction	N	Mean	SD	Median	Min – Max	P value
Lag time	South Korea	95	39.51	57.62	19.96	0.46–324.04	–
	USA	33	35.37	40.69	20.23	0.10–140.46	0.503
	EU	60	14.29	24.17	7.97	0.66–153.90	<0.001
	Japan	58	31.30	29.57	25.13	1.71–152.26	0.903
Designation gap	South Korea	101	84.23	64.36	70.53	0.26–369.45	–
	USA	28	32.35	34.37	16.18	0.66–124.64	<0.001
	EU	62	20.68	29.59	9.75	0.20–150.19	<0.001
	Japan	63	59.09	42.78	47.97	0.52–183.82	0.011

Note: Based on 169 products designated as orphan drugs in South Korea from 2012 to 2021. First, products approved in lag time and first designated products in the designation gap are excluded. Lag time: Period (months) from the first country of approval to the approval of drugs by each country for products approved in each country. Designation Gap: Period (months) from the first country of designation to the designation of drugs by country for products approved in each country. N: Number of designated (or approved) products in each country; SD: Standard Deviation. P value: Compared with South Korea.

Figure 3. Approval time, lag time, and designation gap of orphan drugs approved in all jurisdictions.

Note: Based on 169 products designated as orphan drugs in South Korea from 2012 to 2021. We compared the demand time, lag time, and designation gap by country for 45 products approved in all countries. (A) Approval time: South Korea vs. USA, EU, and Japan (P < 0.001). (B) Lag time: South Korea vs. USA and EU (P < 0.001), and South Korea vs. Japan (P = 0.812). (C) Designation gap: South Korea vs. USA, EU (P < 0.001), and South Korea vs. Japan (P = 0.048). (We marked n.s.: not significant, *P < 0.05, **P < 0.01, and ***P < 0.001).

Table 5. Approval time, lag time, and designation gap of orphan drugs approved in all jurisdictions.

Country	Approved products (N)	Approval time			Lag time			Designation gap
		Mean	Median	P value	Mean	Median	P value	Mean	Median	P value
South Korea	45	11.38	9.70	–	31.48	17.82	–	83.21	73.65	–
USA		64.75	54.70	<0.001	10.22	0.00	<0.001	8.59	0.00	<0.001
EU		56.37	49.20	<0.001	6.18	5.19	<0.001	12.92	4.49	<0.001
Japan		28.71	21.20	<0.001	30.61	22.04	0.812	65.01	58.37	0.048

Note: Based on 169 products designated as orphan drugs in South Korea from 2012 to 2021. Approval time (months): Period from designation to approval of drugs by country for the 45 products approved in all countries. Lag time (months): Period from the first country of approval to approval of drugs by country for the 45 products approved in all countries. Designation gap (months): Period from the first country of designation to the designation of drugs by country for the 45 products approved in all countries. N: Number of approved products in all countries P value: Compared with South Korea.

Data availability statement

The datasets analysed in the current study are available from the corresponding author upon request.