[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