Designating Additions to the Current List of Tropical Diseases in the Federal Food, Drug, and Cosmetic Act
| Published date | 15 July 2020 |
| Record Number | 2020-15254 |
| Section | Notices |
| Court | Food And Drug Administration,Health And Human Services Department |
Federal Register, Volume 85 Issue 136 (Wednesday, July 15, 2020)
[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, [email protected]; 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
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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
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6. Dean, A.S., L. Crump, H. Greter, et al., 2012, ``Clinical
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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:
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10. CDC, 2017, ``Brucellosis Reference Guide: Exposures, Testing,
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11. * U. S. Department of Agriculture, Animal and Plant Health
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13. Norman, F.F., B. Monge-Maillo, S. Chamorro-Tojeiro, et al.,
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New Global Map of Human Brucellosis,'' The Lancet. Infectious
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16. * CDC, 2019, ``Prioritizing Zoonotic Diseases for
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17. * Department of Health and Human Services, 2017, ``2017-2018
Public Health Emergency Medical Countermeasures Enterprise (PHEMCE)
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18. * World Health Organization (WHO), Department of Control of
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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
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20. Pappas, G., 2010, ``The Changing Brucella Ecology: Novel
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21. Dean, A.S., L. Crump, H. Greter, et al., 2012, ``Global Burden
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22. McDermott, J., D. Grace, and J. Zinsstag, 2013, ``Economics of
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24. Gray, A. and H.R. Manasse, Jr., 2012, ``Shortages of Medicines:
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25. FDA, tetracycline hydrochloride capsule label, accessed June 29,
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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
