[Federal Register Volume 85, Number 136 (Wednesday, July 15, 2020)]
[Notices]
[Pages 42860-42863]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-15254]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

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


Designating Additions to the Current List of Tropical Diseases in 
the Federal Food, Drug, and Cosmetic Act

AGENCY: Food and Drug Administration, HHS.

ACTION: Final amendment; final order.

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SUMMARY: The Federal Food, Drug, and Cosmetic Act (FD&C Act) authorizes 
the Food and Drug Administration (FDA or Agency) to award priority 
review vouchers (PRVs) to tropical disease product applicants when the 
applications meet certain criteria. The FD&C Act lists the diseases 
that are considered tropical diseases for purposes of obtaining PRVs 
and provides for Agency expansion of that list to include other 
diseases that satisfy the definition of ``tropical diseases'' as set 
forth in the FD&C Act. The Agency has determined that brucellosis 
satisfies this definition and is therefore adding it to the list of 
designated tropical diseases whose product applications may result in 
the award of PRVs. Sponsors submitting certain drug or biological 
product applications for the prevention or treatment of brucellosis may 
be eligible to receive a PRV if such applications are approved by FDA.

DATES: This order is issued on 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, Katherine.Schumann@fda.hhs.gov; or Stephen Ripley, Center for 
Biologics Evaluation and Research, Food and Drug Administration, 10903 
New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002, 
240-402-7911.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background: Priority Review Voucher Program
II. Disease Being Designated
    A. No Significant Market in Developed Nations
    B. Disproportionately Affects Poor and Marginalized Populations
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 for prevention and treatment of certain diseases that, in the 
aggregate, affect millions of people throughout the world. To be 
eligible to receive a tropical disease PRV, a drug must be for a 
``tropical disease'' as listed under section 524(a)(3) of the FD&C Act. 
This list can be expanded by the Agency under section 524(a)(3)(S) of 
the FD&C Act, which 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 an addition to the tropical disease list. 
Further information about the tropical disease PRV program can be found 
in the guidance for industry ``Tropical Disease Priority Review 
Vouchers,'' available at https://www.fda.gov/media/72569/download.
    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 
eligible for PRV consideration. This final order also set forth FDA's 
interpretation of the statutory criteria for tropical disease 
designation and expands the list of tropical diseases under section 
524(a)(3)(S) of the FD&C Act. Additions by order to the statutory list 
of tropical diseases 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.
    In this document, FDA has applied its August 2015 criteria as set 
forth in the final order for analyzing whether the zoonotic infection 
brucellosis meets the statutory criteria for addition to the tropical 
disease list.

II. Disease Being Designated

    FDA has considered all diseases submitted to the public docket 
(FDA-2008-N-0567) between October 1, 2018, and June 30, 2019, as 
potential additions to the list of tropical diseases under section 524 
of the FD&C Act, pursuant to the docket review process explained on the 
Agency's website at https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/tropical-disease-priority-review-voucher-program. Based on an assessment using the criteria from its August 2015 
final order, FDA has determined that brucellosis will be designated as 
an addition to the list of ``tropical diseases'' under section 524 of 
the FD&C Act.
    Brucellosis is one of the most common zoonotic infections, meaning 
it is transmissible from animals to humans. The species most commonly 
associated with human disease are B. abortus, B. melitensis, B. suis, 
and, rarely, B. canis. Brucellosis occurs in greater than 500,000 
individuals worldwide annually through contact with fluids or 
inhalation of aerosols from infected wild or domestic animals 
(including sheep, cattle, goats, pigs and other animals) or ingestion 
of food products derived from infected animals, such as undercooked 
meat or unpasteurized milk and cheese (Refs. 1 and 2). Brucellosis can 
cause significant morbidity in both humans and animals. FDA's rationale 
for adding this disease to the list is discussed in the analyses that 
follow.
    Efforts to control infections caused by Brucella spp. in livestock 
in high-income countries have led to a notable drop in human infections 
but brucellosis continues to cause a significant burden of disease in 
developing countries (Ref. 3). Severity of disease can vary widely, 
from asymptomatic disease to moderate illness with acute fever, 
malaise, and weight loss, to more severe illnesses including 
meningitis, endocarditis, osteomyelitis, and pneumonitis (Refs. 4 and 
5). With appropriate therapy, brucellosis rarely causes death. Chronic 
infections with Brucella spp. cause granulomatous disease that can 
affect any organ, leading to chronic debilitating symptoms including 
arthritis, uveitis, and neuropsychiatric abnormalities (Ref. 6). In 
pregnant women, Brucella spp. infections are associated with a high 
risk of spontaneous abortion, miscarriage, and fetal death (Ref. 1). 
The incubation

[[Page 42861]]

period is highly variable, usually 1 to 4 weeks, but may be as long as 
6 months.
    The treatment regimens for adults with uncomplicated brucellosis 
have changed little in 30 years. There are currently three FDA approved 
treatments for brucellosis: Doxycycline, streptomycin, and tetracycline 
(Refs. 7, 8, and 25). Prolonged treatment (greater than 6 weeks) with 
two or more antimicrobials are generally required, and relapses occur 
in 5 to 15 percent of patients (Refs. 9 and 10). While an effective 
vaccine exists for brucellosis in livestock (Ref. 11), there are no 
vaccines licensed in the United States for human use.

A. No Significant Market in Developed Nations

    No significant direct market exists for the prevention or treatment 
of brucellosis in developed nations. In high-income countries, the 
direct market for products to prevent brucellosis in humans is small 
due to the success of strategies to decrease human exposure through 
control efforts in livestock and food. The incidence in the United 
States is 0.4 cases per million with approximately 100 cases of 
brucellosis in humans reported annually (Ref. 12). Three-quarters of 
these cases are due to B. melitensis or B. abortus associated with 
ingestion of unpasteurized dairy products from countries where the 
disease remains endemic (Ref. 1). Brucellosis has been significantly 
reduced or eliminated in Northern Europe. For example, in Germany, 22 
to 47 annual cases were reported between 2010 and 2015, with most cases 
occurring following travel or consumption of contaminated imported 
products (Ref. 13).
    Brucellosis is considered endemic in some Mediterranean countries 
that are designated as high income by the World Bank; presence on the 
World Bank's list, FDA determined in the August 2015 final order, will 
be used as evidence that such a country should be considered a 
``developed nation'' for tropical disease determination (Ref. 14). 
These high-income countries include Greece (20.9 cases per million of 
population per year), Spain (15.1), and Portugal (13.9). However, the 
annual incidence of brucellosis in these countries is considerably 
lower than in Turkey (262.2) and the Republic of North Macedonia (148), 
which are not on the World Bank list of high-income economies (Ref. 
15). Saudi Arabia, classified by the Word Bank as high-income, has a 
reported annual incidence of brucellosis of 214.4 per million of 
population (Ref. 15). Within Latin America, Mexico is a prominent 
reservoir of human brucellosis, with an annual incidence of 28.7 cases 
per million of population, while Panama and Argentina, both on the 
World Bank list of high-income countries, have a lower rate of disease 
at 10.1 and 8.4 cases per million of population per year, respectively 
(Ref. 15).
    The characteristics of specific diseases under consideration may 
affect the measures of occurrence used to estimate the likely market 
for interventions. As described in the August 2015 final order, FDA has 
used a disease prevalence rate of 0.1 percent of the population in 
developed countries for aiding in the determination of whether a 
``significant market'' may exist for treatment of a disease. In this 
order, incidence rather than prevalence was considered to provide a 
better estimate of market size. Incidence measures new cases that are 
diagnosed in a population in a given time period. In an acute disease 
such as brucella, that can be resolved through treatment, incidence 
represents a reasonable indicator for the number of cases that would be 
treated in a given year and provides a better estimate of market size. 
As noted in the August 2015 final order, ``[t]he market for many FDA-
approved products includes situations in which individuals (often 
reimbursed by their insurers) purchase the products for use by a 
specific patient. This reflects what we will refer to as the `direct' 
market, and the direct market for a drug in a developed country can 
often by estimated by assessing the occurrence of a particular disease 
in that country.'' Even in countries designated by the World Bank as 
high-income where the disease is considered endemic, the incidence is 
well below 0.1 percent of the population; therefore, the direct market 
for products to prevent or treat brucellosis in humans would be small. 
These markets are unlikely to provide sufficient incentive to encourage 
development of products to treat or prevent brucellosis.
    No significant indirect market exists for the treatment or 
prevention of brucellosis in developed nations. The U.S. Centers for 
Disease Control and Prevention (CDC) has designated Brucella spp. B. 
suis, B. melitensis, and B. abortus as select agents, a subset of 
biological agents and toxins that may pose a severe threat to public 
health, due to the ease of aerosolization, low infectious dose, and 
difficulty in diagnosis; and the CDC, U.S. Department of Agriculture, 
and U.S. Department of the Interior, have identified brucellosis as one 
of eight diseases of greatest national concern that should be addressed 
jointly by Federal zoonotic disease programs (Refs. 1 and 16). Despite 
these designations, at present FDA is unaware of any significant 
funding for drug development targeting treatment or prophylaxis of 
brucellosis by U.S. government sources. Further, Brucella spp. are not 
listed as a high priority threat in the 2017-2018 Public Health 
Emergency Medical Countermeasures Enterprise (PHEMCE) Strategy and 
Implementation Plan (Ref. 17).
    Given the above information, it is reasonable to conclude that no 
significant market exists in developed nations for the prevention or 
treatment of brucellosis in humans.

B. Disproportionately Affects Poor and Marginalized Populations

    While brucellosis is not currently designated by the World Health 
Organization (WHO) as a neglected tropical disease, WHO has identified 
it as a neglected zoonotic disease (Ref. 18). Successful animal 
vaccination programs for brucellosis require sustained implementation 
over several years. Largely eliminated in developed nations, 
brucellosis disproportionally affects poor and marginalized populations 
in endemic countries where inadequate control measures maintain an 
ongoing reservoir of disease in animals. Brucellosis remains 
significant in many parts of the world, including some countries in the 
Mediterranean Basin, Africa, the Middle East, Asia, and Central and 
South America (Refs. 1 and 19). The reemergence of brucellosis in the 
Balkans and, more recently, some parts of the Middle East suggests that 
geopolitical factors could be important drivers of the disease (Refs. 
20 and 21).
    Illnesses caused by Brucella spp. result in significant morbidity 
with disproportionate impact on marginalized populations. Transmission 
of brucellosis to humans occurs most frequently in individuals who 
consume infected meat or unpasteurized dairy products, exposures that 
occur more commonly in resource-poor regions. Efforts to control 
Brucella spp. in humans in low-income countries using methods employed 
in high income nations, such as vaccination of livestock, have had 
limited success due to insufficient veterinary resources and high 
infection rates in wild animal populations (Ref. 22). In addition, 
routine pasteurization of dairy products tends to be less common in 
developing countries (Ref. 3).
    Human infection with Brucella spp. results in significant losses in 
work days, lowering income and often the socioeconomic status of 
affected

[[Page 42862]]

individuals and their families (Ref. 3). A Disability-Adjusted Life 
Years (DALY) weighting for acute brucellosis is similar to an episode 
of malaria (Refs. 6 and 23). DALY burdens for brucellosis have not been 
calculated, however, in part due to the difficulty in obtaining 
accurate surveillance data in affected low-income countries (Ref. 22).
    As mentioned above, prolonged treatment courses of greater than 6 
weeks with two or more antimicrobials are generally required. These 
recommended treatment regimens pose special challenges for resource-
poor countries (Ref. 24).
    The above information demonstrates it is reasonable to conclude 
that brucellosis disproportionately affects poor and marginalized 
populations.
    Given the factors described above, FDA has determined that 
brucellosis meets both the statutory criteria of ``no significant 
market in developed nations'' and ``disproportionately affects poor and 
marginalized populations.'' Therefore, FDA is designating brucellosis 
as an addition to the tropical disease list under section 524 of the 
FD&C Act.

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

    The purpose of this order is to add brucella 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. By expanding the list to include 
brucellosis with this order, FDA does not mean to preclude the addition 
of other diseases to this list in the future. Interested persons may 
submit requests for additional diseases to be added to the list to the 
public docket established by FDA for this purpose (see https://www.regulations.gov, Docket No. FDA-2008-N-0567). 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 final order 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 agency's 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 are also 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 (CDC), 2017, 
``Brucellosis Reference Guide: Exposures, Testing, and Prevention,'' 
accessed January 11, 2020, https://www.cdc.gov/brucellosis/pdf/brucellosi-reference-guide.pdf.
2. Kimberlin, D.W., M.T. Brady, M.A. Jackson, and the American 
Academy of Pediatrics, 2018, ``Brucellosis,'' Red Book (2018-2021): 
Report of the Committee on Infectious Diseases, 31st Ed., pp. 255-
257.
3. Franc, K.A., R.C. Krecek, B.N. H[auml]sler, and A.M. Arenas-
Gamboa, 2018, ``Brucellosis Remains a Neglected Disease in the 
Developing World: A Call for Interdisciplinary Action,'' BioMed 
Central Public Health, 18(1):125.
4. Colmenero, J.D., J.M. Reguera, F. Martos, et al., 1996, 
``Complications Associated With Brucella Melitensis Infection: A 
Study of 530 Cases,'' Medicine, 75(4):195-211.
5. Buzgan, T., M.K. Karahocagil, H. Irmak, et al., 2010, ``Clinical 
Manifestations and Complications in 1028 Cases of Brucellosis: A 
Retrospective Evaluation and Review of the Literature,'' 
International Journal of Infectious Diseases, epub ahead of print 
November 11, 2009, doi: 10.1016/j.ijid.2009.06.031.
6. Dean, A.S., L. Crump, H. Greter, et al., 2012, ``Clinical 
Manifestations of Human Brucellosis: A Systematic Review and Meta-
Analysis,'' PLoS Neglected Tropical Diseases, epub ahead of print 
December 6, 2012, doi: 10.1371/journal.pntd.0001929.
7. * U.S. Food and Drug Administration (FDA), Acticlate (doxycycline 
hyclate) label, accessed June 25, 2019, https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205931s003,208253s001lbl.pdf.
8. * FDA, Streptomycin for Injection label, cited June 25, 2019, 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/064210s009lbl.pdf.
9. Ariza, J., M. Bosilkovski, A. Cascio, et al., 2007, 
``Perspectives for the Treatment of Brucellosis in the 21st Century: 
The Ioannina Recommendations,'' PLoS Medicine, 4(12):e317.
10. CDC, 2017, ``Brucellosis Reference Guide: Exposures, Testing, 
and Prevention,'' accessed January 11, 2020, https://www.cdc.gov/brucellosis/pdf/brucellosi-reference-guide.pdf.
11. * U. S. Department of Agriculture, Animal and Plant Health 
Inspection Service, ``Facts About Brucellosis,'' cited June 19, 
2019, https://www.aphis.usda.gov/animal_health/animal_diseases/brucellosis/downloads/bruc-facts.pdf.
12. * CDC, 2012, ``Brucellosis Surveillance,'' cited July 12, 2019, 
https://www.cdc.gov/brucellosis/resources/surveillance.html.
13. Norman, F.F., B. Monge-Maillo, S. Chamorro-Tojeiro, et al., 
2016, ``Imported Brucellosis: A Case Series and Literature Review,'' 
Travel Medicine and Infectious Diseases, epub ahead of print May 13, 
2016, doi: 10.1016/j.tmaid.2016.05.005.
14. The World Bank, 2018, ``World Bank Country and Lending Groups,'' 
cited April 29, 2019, https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-world-bank-country-and-lending-groups.
15. Pappas, G., P. Papadimitriou, N. Akritidis, et al., 2006, ``The 
New Global Map of Human Brucellosis,'' The Lancet. Infectious 
Diseases, 6(2):91-99.
16. * CDC, 2019, ``Prioritizing Zoonotic Diseases for 
Multisectional, One Health Collaboration in the United States--
Workshop Summary,'' cited July 12, 2019, https://www.cdc.gov/onehealth/pdfs/us-ohzdp-report-508.pdf.
17. * Department of Health and Human Services, 2017, ``2017-2018 
Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) 
Strategy and Implementation Plan,'' accessed January 13, 2020, 
https://www.phe.gov/Preparedness/mcm/phemce/Documents/2017-phemce-sip.pdf.
18. * World Health Organization (WHO), Department of Control of 
Neglected Tropical Diseases, 2014, ``The Control of Neglected 
Zoonotic Diseases: From Advocacy to Action. Report of the Fourth 
International Meeting Held at WHO Headquarters, Geneva, Switzerland, 
19-20 November 2014,'' accessed January 13, 2020, https://www.who.int/neglected_diseases/ISBN9789241508568_ok.pdf.

[[Page 42863]]

19. * WHO, Corbel, M.J., 2006, ``Brucellosis in Humans and 
Animals,'' accessed January 10, 2020, https://www.who.int/csr/resources/publications/Brucellosis.pdf.
20. Pappas, G., 2010, ``The Changing Brucella Ecology: Novel 
Reservoirs, New Threats,'' International Journal of Antimicrobial 
Agents, 36(Suppl 1):8S-11S, epub ahead of print August 8, 2010, doi: 
10.1016/j.ijantimicag.2010.06.013.
21. Dean, A.S., L. Crump, H. Greter, et al., 2012, ``Global Burden 
of Human Brucellosis: A Systematic Review of Disease Frequency,'' 
PLoS Neglected Tropical Diseases, epub October 25, 2012, doi: 
10.1371/journal.pntd.0001865.
22. McDermott, J., D. Grace, and J. Zinsstag, 2013, ``Economics of 
Brucellosis Impact and Control in Low-Income Countries,'' Revue 
Scientifique et Technique, 32(1):249-261.
23. * WHO, 2008, ``The Global Burden of Disease: 2004 Update,'' 
accessed January 14, 2020, https://www.who.int/healthinfo/global_burden_disease/2004_report_update/en/.
24. Gray, A. and H.R. Manasse, Jr., 2012, ``Shortages of Medicines: 
A Complex Global Challenge,'' Bulletin of the World Health 
Organization, 90(3):158-158A.
25. FDA, tetracycline hydrochloride capsule label, accessed June 29, 
2020, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6f363d06-2400-43be-8fe5-69246c0fdc49.

    Dated: July 8, 2020.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2020-15254 Filed 7-14-20; 8:45 am]
BILLING CODE 4164-01-P


