[Federal Register Volume 85, Number 136 (Wednesday, July 15, 2020)]
[Notices]
[Pages 42868-42871]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-15253]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2008-N-0567]


Notice of Decision Not To Designate Clonorchiasis as an Addition 
to the Current List of Tropical Diseases in the Federal Food, Drug, and 
Cosmetic Act

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or Agency), in response 
to suggestions submitted to the public docket FDA-2008-N-0567, between 
June 20, 2018, and November 21, 2018, has analyzed whether the 
foodborne trematode infection clonorchiasis meets the statutory 
criteria for designation as a ``tropical disease'' for the purposes of 
obtaining a priority review voucher (PRV) under the Federal Food, Drug, 
and Cosmetic Act (FD&C Act), namely whether it primarily affects poor 
and marginalized populations and whether there is ``no significant 
market'' for drugs that prevent or treat clonorchiasis in developed 
countries. The Agency has determined at this time that clonorchiasis 
does not meet the statutory criteria for addition to the tropical 
diseases list under the FD&C Act. Although clonorchiasis 
disproportionately affects poor and marginalized populations, it is an 
infectious disease for which there is a significant market in developed 
nations; therefore, FDA declines to add it to the list of tropical 
diseases.

DATES: July 15, 2020.

ADDRESSES: Submit electronic comments on additional diseases suggested 
for designation to https://www.regulations.gov. Submit written comments 
on additional diseases suggested for designation to the Dockets 
Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified 
with the docket number found in brackets in the heading of this 
document.

FOR FURTHER INFORMATION CONTACT: Katherine Schumann, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, Rm. 6242, Silver Spring, MD 20993-0002, 301-
796-1300, [email protected]; or Stephen Ripley, Center for 
Biologics Evaluation and Research, Food and Drug Administration, 10903 
New Hampshire Ave., Rm. 7301, Silver Spring, MD 20993-0002, 240-402-
7911.

[[Page 42869]]


SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background: Priority Review Voucher Program
II. Decision Not To Designate Clonorchiasis
    A. Clonorchiasis
    B. FDA Determination
III. Process for Requesting Additional Diseases To Be Added to the 
List
IV. Paperwork Reduction Act
V. References

I. Background: Priority Review Voucher Program

    Section 524 of the FD&C Act (21 U.S.C. 360n), which was added by 
section 1102 of the Food and Drug Administration Amendments Act of 2007 
(Pub. L. 110-85), uses a PRV incentive to encourage the development of 
new drugs, including biological products, for prevention and treatment 
of certain diseases that, in the aggregate, affect millions of people 
throughout the world. Further information about the tropical disease 
PRV program can be found in the October 6, 2016 (81 FR 69537) guidance 
for industry ``Tropical Disease Priority Review Vouchers,'' available 
at https://www.fda.gov/media/72569/download. Additions to the statutory 
list of tropical diseases by an FDA final order published in the 
Federal Register can be accessed at https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/tropical-disease-priority-review-voucher-program.
    On August 20, 2015, FDA published a final order (80 FR 50559) 
(August 2015 final order) designating Chagas disease and 
neurocysticercosis as additions to the list of tropical diseases under 
section 524 of the FD&C Act. The August 2015 final order also set forth 
FDA's interpretation of the statutory criteria for designating 
additions to the section 524 list of tropical diseases and expands the 
list of tropical diseases under section 524(a)(3)(R) of the FD&C Act. 
That section, later redesignated as section 524(a)(3)(S) of the FD&C 
Act, authorizes FDA to designate by order ``[a]ny other infectious 
disease for which there is no significant market in developed nations 
and that disproportionately affects poor and marginalized populations'' 
as a tropical disease for which approved drug applications may be 
eligible for a PRV.
    FDA has applied its criteria as set forth in the August 2015 final 
order to analyze whether clonorchiasis meets the statutory criteria for 
addition to the tropical diseases list. As discussed below, the Agency 
has determined that clonorchiasis does not meet the statutory criteria 
for designation as a PRV-eligible ``tropical disease'' under section 
524 of the FD&C Act; thus, FDA will not add it to the list of tropical 
diseases whose applications may be eligible for a priority review 
voucher.

II. Decision Not To Designate Clonorchiasis

    FDA has considered all disease suggestions submitted to the public 
docket (FDA-2008-N-0567) between June 20, 2018, and November 21, 2018, 
as potential additions to the list of tropical diseases under section 
524 of the FD&C Act, under the docket review process explained on the 
Agency's web page at https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm534162.htm. Based on an 
assessment of currently available information, and using the criteria 
from its August 2015 final order, FDA has determined that clonorchiasis 
will not be designated as a ``tropical disease'' for purposes of the 
tropical disease PRV program under section 524 of the FD&C Act.

A. Clonorchiasis

    Clonorchiasis is caused by Clonorchis sinensis, trematodes 
(parasitic flatworms), also known as flukes, which are acquired by 
humans through the consumption of raw or undercooked fish (Ref. 1). The 
natural final hosts of C. sinensis are dogs and other fish-eating 
carnivores (Ref. 2). C. sinensis are reported in the Democratic 
People's Republic of Korea (North Korea), the Republic of Korea (South 
Korea), China, Taiwan, Vietnam, Japan, and the Russian Far East (Ref. 
1).
    The final location of adult C. sinensis is the smaller bile ducts 
of the liver (Ref. 2). The symptoms of clonorchiasis are related to 
inflammation and fibrosis of the tissues adjacent to bile ducts. While 
the majority of infected individuals are asymptomatic, patients may 
develop cholangitis, intrahepatic calculi, or cholangiohepatitis (Ref. 
2). Chronic infection is also associated with the development of 
cholangiocarcinoma, a severe and fatal form of bile duct cancer, and C. 
sinensis is recognized by the International Agency for Research on 
Cancer (IARC) as Group 1, which means that the agent is classified as 
carcinogenic to humans (Refs. 3 and 4).
    There is one FDA approved treatment for clonorchiasis, 
praziquantel, approved in 1982 and indicated for the treatment of 
infections due to all species of schistosoma and infections due to the 
liver flukes C. sinensis and Opisthorchis viverrini (Ref. 5).
1. Significant Market in Developed Nations
    FDA was unable to make the determination that no significant market 
exists for the treatment or prevention of clonorchiasis in developed 
nations, as the most recent data shows significant prevalence of 
clonorchiasis in a developed nation. As stated above, clonorchiasis 
occurs as a result of infection by C. sinensis, which has been reported 
in North Korea, South Korea, China, Taiwan, Vietnam, Japan, and the 
Russian Far East. The limited range of C. sinensis means that 
individuals are infected only in those countries noted, and infections 
in other countries only occur from the movement of infected persons. 
North Korea, China, Vietnam, and the Russian Federation (Russia) are 
not on the World Bank's list of high-income countries (Ref. 6). 
However, South Korea, Japan, and Taiwan are high-income economies, 
based on World Bank's list of high-income countries, and therefore are 
considered developed countries for purposes of this order (Ref. 6).
    In the developed countries where C. sinensis is found, 
clonorchiasis rates are typically low. C. sinensis was endemic in Japan 
throughout the 1950s; however, improved hygiene associated with 
modernization and industrialization has reduced its incidence in humans 
in the country to a negligible level (Ref. 7). Likewise, in Taiwan, C. 
sinensis has been nearly eliminated from all but a small number of poor 
rural areas (Refs. 8 and 9). However, as of 2008, South Korea had an 
estimated 1.4 million people infected with C. sinensis. Based on data 
from 1981, the egg-positive proportion of people living near 7 major 
rivers was 22 percent among 13,373 examined, varying from 0.6 percent 
to 45.5 percent (Ref. 10). The persistence of C. sinensis infection is 
thought to be primarily due to difficulties in changing the traditional 
habit of eating raw freshwater fish (Refs. 10 and 11). The 2017 South 
Korean population was 51.42 million, and using the most recent estimate 
of 1.4 million people infected with C. sinensis, the estimated 
prevalence of C. sinensis infection in South Korea is over 2 percent of 
the population (Ref. 12). This prevalence is higher than 0.1 percent of 
the population of South Korea. The 0.1 percent of the population was 
discussed in FDA's order of 2015 as a factor for aiding in the 
determination of whether a significant market may exist for a disease's 
treatment. FDA worked to find a more recent prevalence rate for 
clonorchiasis infections in South Korea but was unsuccessful. If more 
recent

[[Page 42870]]

prevalence information is publicly accessible, please provide this 
information to the Dockets Management Staff for Docket No. FDA-2008-N-
0567 (see ADDRESSES) and the Agency will reevaluate our findings.
    There is currently no estimate of the number of individuals with 
clonorchiasis in the United States. Of the infections that do occur in 
the United States, foodborne trematode infections occur predominantly 
in immigrants and travelers from endemic regions (Refs. 13 and 14). For 
example, in a retrospective study in one U.S. travel medicine clinic 
over 6 years, only 17 cases of Opisthorchis spp. and Clonorchis spp. 
were identified through the review of ova and parasite records (Ref. 
15). All patients with identified cases were migrants from Laos, 
Cambodia, Thailand, Vietnam, the former Soviet Union, and Ecuador (Ref. 
15).
    There is evidence that U.S. military personnel were exposed to 
Opisthorchis spp. and Clonorchis spp. during their service in the 
Vietnam War (Ref. 16). In one study, there was evidence that veterans 
were likely previously infected, but patients in the study did not have 
evidence of ongoing infection given negative stool exams and negative 
imaging studies, and therefore would not have ongoing infections 
requiring treatment now (Ref. 16).
    As illustrated above, clonorchiasis occurs rarely in most developed 
nations. However, in South Korea, the prevalence was 1.4 million people 
infected as of 2008, which may offer an incentive to drive development 
of new drug products to treat or prevent clonorchiasis.
2. Clonorchiasis Disproportionately Affects Poor and Marginalized 
Populations
    Clonorchiasis disproportionately affects poor and marginalized 
populations around the world. As areas where clonorchiasis occurs 
develop economically, the epidemiology of clonorchiasis changes, and 
fewer cases of clonorchiasis occur. This is supported by data in Japan 
and Taiwan where incidences of clonorchiasis have fallen rapidly with 
improved hygiene as the countries have developed (Refs. 7 and 8).
    Transmission of foodborne trematodes within countries is typically 
restricted to limited areas and reflects behavioral and ecological 
patterns that are related to socioeconomic status. This includes 
people's food habits, methods of food production and preparation, and 
the distribution of intermediate hosts. For example, food can be 
contaminated through unhygienic preparation and storage. Furthermore, 
the consumption of raw fish and crustaceans is a main risk factor for 
contracting these parasites. The parasite's life cycle is closely 
linked with water and sanitation. In populations without access to 
toilets, or without sewage system infrastructure, unprocessed human and 
animal fecal waste may be found near water or used as manure or fish 
feed. This can contaminate drinking water and aquatic vegetables, 
leading to a continuous cycle of infections.
    Clonorchiasis is included in the World Health Organization (WHO) 
List of Neglected Tropical Diseases (Ref. 17). The WHO Foodborne 
Disease Burden Epidemiology Reference Group identified clonorchiasis as 
an important cause of disability, with an estimated annual incidence of 
over 31,620 infections and 5,770 deaths, resulting in global disability 
adjusted life years, which is calculated by adding the number of years 
of life lost to mortality and the number of years lived with disability 
due to morbidity due to the illness, of 522,863 (Ref. 18). Given the 
above information, it is reasonable to conclude that clonorchiasis 
disproportionately affects poor and marginalized populations.

B. FDA Determination

    In sum, although clonorchiasis disproportionately affects poor and 
marginalized populations, it is an infectious disease that fails to 
meet the statutory criterion for ``no significant market in developed 
nations.'' FDA has determined that, at this time, the available 
information does not support a determination that clonorchiasis meets 
the statutory criteria in section 524 of the FD&C Act for addition to 
the list of tropical diseases.

III. Process for Requesting Additional Diseases To Be Added to the List

    FDA's current determination regarding clonorchiasis does not 
preclude interested persons from requesting its consideration in the 
future. To facilitate the consideration of future additions to the 
list, FDA established a public docket (see https://www.regulations.gov, 
Docket No. FDA-2008-N-0567) through which interested persons may submit 
requests for additional diseases to be added to the list. Such requests 
should be accompanied by information to document that the disease meets 
the criteria set forth in section 524(a)(3)(S) of the FD&C Act. FDA 
will periodically review these requests, and, when appropriate, expand 
the list. For further information, see FDA's Tropical Disease Priority 
Review Voucher Program web page at https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/tropical-disease-priority-review-voucher-program.

IV. Paperwork Reduction Act

    This notice reiterates the ``open'' status of the previously 
established public docket through which interested persons may submit 
requests for additional diseases to be added to the list of tropical 
diseases that FDA has found to meet the criteria in section 
524(a)(3)(S) of the FD&C Act. Such a request for information is exempt 
from Office of Management and Budget review under 5 CFR 1320.3(h)(4) of 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3521). 
Specifically, ``[f]acts or opinions submitted in response to general 
solicitations of comments from the public, published in the Federal 
Register or other publications, regardless of the form or format 
thereof'' are exempt, ``provided that no person is required to supply 
specific information pertaining to the commenter, other than that 
necessary for self-identification, as a condition of the full 
consideration of the comment.''

V. References

    The following references marked with an asterisk (*) are on display 
at the Dockets Management Staff (see ADDRESSES) and are available for 
viewing by interested persons between 9 a.m. and 4 p.m., Monday through 
Friday; they also are available electronically at https://www.regulations.gov. References without asterisks are not on public 
display at https://www.regulations.gov because they have copyright 
restriction. Some may be available at the website address, if listed. 
References without asterisks are available for viewing only at the 
Dockets Management Staff. FDA has verified the website addresses, as of 
the date this document publishes in the Federal Register, but websites 
are subject to change over time.

1. *U.S. Centers for Disease Control and Prevention, 2018, 
``Parasites--Clonorchis: Epidemiology & Risk Factors,'' accessed 
October 24, 2019, https://www.cdc.gov/parasites/clonorchis/epi.html.
2. *WHO, 2018, ``Fact Sheet on Foodborne Trematodiases,'' accessed 
October 23, 2019, https://www.who.int/news-room/fact-sheets/detail/foodborne-trematodiases.
3. *WHO, IARC, 2019, ``IARC Monographs on the Identification of 
Carcinogenic Hazards to Humans, Agents Classified by the IARC 
Monographs,'' Vols. 1-125, accessed October 23, 2019, https://
monographs.iarc.fr/agents-classified-by-

[[Page 42871]]

the-iarc/.
4. *WHO, IARC, 2012, ``IARC Monographs on the Evaluation of 
Carcinogenic Risks in Humans, Opisthorchis Viverrini and Clonorchis 
Sinensis,'' Vol. 100B, 341-370, accessed October 23, 2019, https://monographs.iarc.fr/wp-content/uploads/2018/06/mono100B-13.pdf.
5. U.S. National Library of Medicine, 2015, ``Label: Biltricide-
Praziquantel Tablet, Film Coated,'' DailyMed.
6. The World Bank, ``World Bank Country and Lending Groups,'' 
accessed December 12, 2018, https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-world-bank-country-and-lending-groups.
7. Nakamura-Uchiyama, F., K. Hiromatsu, K. Ishiwata, et al., 2003, 
``The Current Status of Parasitic Diseases in Japan,'' Internal 
Medicine, 42(3):222-236.
8. Lo, T.C., J.H. Chang, H.H. Lee, et al., 2013, ``Risk Factors for 
and Prevalence of Clonorchiasis in Miaoli County, Taiwan,'' 
Southeast Asian Journal of Tropical Medicine and Public Health, 
44(6):950-958.
9. Yeh, T.C., P.R. Lin, E.R. Chen, et al., 2001, ``Current Status of 
Human Parasitic Infections in Taiwan,'' Journal of Microbiology, 
Immunology, and Infection, 34(3):155-160.
10. Seo, B.S., S.H. Lee, S.Y. Cho, et al., 1981, ``An Epidemiologic 
Study on Clonorchiasis and Metagonimiasis in Riverside Areas in 
Korea,'' Kisaengchunghak Chapchi, 19(2):137-150.
11. Shin, E.H., S.M. Guk, H.J. Kim, et al., 2008, ``Trends in 
Parasitic Diseases in the Republic of Korea,'' Trends in 
Parasitology, epub ahead of print February 5, 2008, doi: 10.1016/
j.pt.2007.12.003.
12. Statistics Korea, 2018, ``2017 Population and Housing Census,'' 
accessed October 24, 2019, http://kostat.go.kr/portal/eng/pressReleases/8/7/index.board.
13. Furst, T., U. Duthaler, B. Sripa, et al., 2012, ``Trematode 
Infections: Liver and Lung Flukes,'' Infectious Disease Clinics of 
North America, 26(2):399-419.
14. Qian, M.-B., Y.-D. Chen, S. Liang, et al., 2012, ``The Global 
Epidemiology of Clonorchiasis and its Relation with 
Cholangiocarcinoma,'' Infectious Diseases of Poverty, epub ahead of 
print October 25, 2012, doi: 10.1186/2049-9957-1-4.
15. Stauffer, W.M., J.S. Sellman, and P.F. Walker, 2004, ``Biliary 
Liver Flukes (Opisthorchiasis and Clonorchiasis) in Immigrants in 
the United States: Often Subtle and Diagnosed Years After Arrival,'' 
Journal of Travel Medicine, 11(3):157-159.
16. Psevdos, G., F.M. Ford, and S.T. Hong, 2018, ``Screening US 
Vietnam Veterans for Liver Fluke Exposure 5 Decades After the End of 
the War,'' Infectious Diseases in Clinical Practice, epub ahead of 
print January 16, 2018, doi: 0.1097/IPC.0000000000000611.
17. *WHO, 2018, ``Neglected Tropical Diseases,'' accessed October 
24, 2019, https://www.who.int/neglected_diseases/diseases/en/.
18. *WHO, Foodborne Disease Burden Epidemiology Reference Group, 
2015, ``WHO Estimates of the Global Burden of Foodborne Diseases 
2007-2015,'' accessed October 24, 2019, https://www.who.int/foodsafety/publications/foodborne_disease/fergreport/en/.

    Dated: July 8, 2020.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2020-15253 Filed 7-14-20; 8:45 am]
BILLING CODE 4164-01-P