[Federal Register Volume 83, Number 165 (Friday, August 24, 2018)]
[Notices]
[Pages 42904-42910]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-18314]


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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 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 chikungunya virus 
disease, Lassa fever, rabies, and cryptococcal meningitis satisfy this 
definition and is therefore adding them 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 chikungunya virus 
disease, Lassa fever, rabies, and cryptococcal meningitis may be 
eligible to receive a PRV if such applications are approved by FDA.

DATES: This order is effective August 24, 2018.

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, <a href="/cdn-cgi/l/email-protection#0e456f7a666b7c67606b205d6d667b636f60604e686a6f2066667d20696178"><span class="__cf_email__" data-cfemail="400b2134282532292e256e132328352d212e2e002624216e2828336e272f36">[email protected]</span></a>; or Office of Communication, 
Outreach and Development (OCOD), Center for Biologics Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Silver Spring, MD 20993-0002, 1-800-835-4709 or 240-402-8010, 
<a href="/cdn-cgi/l/email-protection#98f7fbf7fcd8fefcf9b6f0f0ebb6fff7ee"><span class="__cf_email__" data-cfemail="6a0509050e2a0c0e0b44020219440d051c">[email protected]</span></a>.

SUPPLEMENTARY INFORMATION: 

Table of Contents

I. Background: Priority Review Voucher Program
II. Diseases Being Designated
    A. Chikungunya Virus Disease
    B. Lassa Fever
    C. Rabies
    D. Cryptococcal Meningitis
III. Process for Requesting Additional Diseases To Be Added to the 
List
IV. Paperwork Reduction Act
V. References

[[Page 42905]]

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, 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. Further 
information about the tropical disease PRV program can be found in 
guidance for industry ``Tropical Disease Priority Review Vouchers'' (81 
FR 69537, October 6, 2016, available at https://www.federalregister.gov/documents/2015/08/20/2015-20554/designating-additions-to-the-current-list-of-tropical-diseases-in-the-federal-food-drug-and-cosmetic). Additions to the statutory list of tropical 
diseases published in the Federal Register can be accessed at https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm534162.htm.
    On August 20, 2015, FDA published a final order (80 FR 50559) 
(final order) designating Chagas disease and neurocysticercosis as 
tropical diseases. That final order also sets 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, 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 a tropical disease.
    In this document, FDA has applied its August 2015 criteria as set 
forth in the final order to analyze whether Chikungunya virus disease, 
Lassa fever, rabies, and cryptococcal meningitis meet the statutory 
criteria for addition to the tropical disease list.

II. Diseases Being Designated

    FDA has considered all diseases submitted to the public docket 
(FDA-2008-N-0567) between August 20, 2015, and June 20, 2018, 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 (see https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm534162.htm). Based on an 
assessment using the criteria from its August 20, 2015, final order, 
FDA has determined that the following additional diseases will be 
designated as ``tropical diseases'' under section 524 of the FD&C Act:

<bullet> Chikungunya virus disease
<bullet> Lassa fever
<bullet> Rabies
<bullet> Cryptococcal meningitis

    FDA's rationale for adding these diseases to the list is discussed 
in the analyses that follow.

A. Chikungunya Virus Disease

    Chikungunya virus (CHIKV) is an arbovirus transmitted by Aedes 
mosquitoes in tropical climates in Africa, Asia, islands in the Indian 
and Pacific Oceans, Europe, and, since 2013, the Americas (Ref. 1). 
Although CHIKV mortality is relatively low (0.01 to 0.1 percent), 
attack rates are very high (33 to 66 percent) and most infections are 
symptomatic (Refs. 2 and 3). Many infected individuals experience 
painful arthralgia, which can persist for months and even years (Ref. 
4). Life-threatening manifestations of CHIKV, including organ failure, 
meningoencephalitis, hemorrhagic symptoms, and myocardial disease, and 
death occur in neonates, the elderly, and individuals with chronic 
comorbidities (Ref. 3).
    There is no approved antiviral treatment for CHIKV in the United 
States or anywhere else in the world (Refs. 5 and 6). Therapeutic 
management largely aims to relieve pain and inflammation and limit the 
loss of mobility and physical fitness through the use of analgesic and 
non-steroidal anti-inflammatory drugs. There is no approved CHIKV 
vaccine (Ref. 6).
1. No Significant Market in Developed Nations
    CHIKV disease occurs rarely in developed nations (Ref. 1). 
Outbreaks of CHIKV primarily occur in poor tropical regions where 
uncontrolled breeding of Aedes aegypti and Aedes albopictus mosquitoes 
occurs in close proximity to humans due to inadequate sanitation and 
poor living conditions (Ref. 7). For example, in 2015, more than 
700,000 suspected or confirmed cases of CHIKV were reported in the 
Americas; however, only 1,185 of those cases occurred in the United 
States (excluding territories) and Canada, all of which were imported 
(Refs. 8 and 9). The U.S. territories of Puerto Rico and the U.S. 
Virgin Islands reported 202 cases, all of which were transmitted 
locally (Ref. 8). There were no locally transmitted cases of CHIKV 
reported in Europe, Japan, Australia, or New Zealand in 2015 (Ref. 10). 
Even among U.S. military and military dependents, who are sometimes 
deployed to outbreak areas, CHIKV infection is rare; there were only 
121 CHIKV cases among U.S. Department of Defense healthcare 
beneficiaries between January 2014 and February 2015 (Ref. 11).
    Based on the epidemiology of reported CHIKV cases, the market for 
vaccines in developed nations such as the United States would largely 
comprise travelers at risk of CHIKV infection and military populations. 
These markets are unlikely to provide sufficient incentive to encourage 
development of products to treat or prevent CHIKV infection. Although a 
limited number of locally transmitted cases have recently been reported 
in U.S. territories, the disease is not currently considered endemic in 
those areas. Whether those populations could broaden the market for 
products to treat or prevent CHIKV infection in the future is unknown. 
CHIKV drug development is not significantly funded by U.S. Government 
sources, and CHIKV is not among the Centers for Disease Control and 
Prevention's (CDC) list of potential bioterrorism agents.
2. Disproportionately Affects Poor and Marginalized Populations
    Poor populations in tropical environments experience the primary 
burden of CHIKV disease because they are disproportionally exposed to 
its mosquito vectors (Ref. 7). Arboviral diseases disproportionally 
affect low-income urban and rural populations through increased 
mosquito exposure due to poor housing, lack of sanitation 
infrastructure, and outdoor occupations such as animal husbandry (Refs. 
7 and 12). Large-scale and systematic insecticide mosquito control 
programs, once considered a public health priority throughout the world 
due to yellow fever virus, were largely dismantled due to diminishing 
resources and are therefore not available in most developing nations 
(Ref. 13).
    Although CHIKV infection is rarely fatal, CHIKV sequelae have a 
major impact on productivity and economics in developing nations (Ref. 
7). CHIKV outbreaks are often explosively large, with high attack rates 
and high rates of symptomatic disease (Refs. 1 and 3). An outbreak in 
India in 2006 involved more than 1.3 million suspected cases and was 
associated with more than 25,000 Disability Adjusted Life Years (DALYs) 
lost (Ref. 14). A meta-analysis of 38 published studies confined to 
cases occurring in 2005 estimated that CHIKV led to up to 1 million 
years of healthy life lost and 1.5 million DALYs lost (Ref. 15).
    Neonates are particularly vulnerable to serious complications of 
CHIKV infection. Among neonates born 1 day

[[Page 42906]]

before or within 5 days following the onset of their infected mothers' 
symptoms, 50 percent are born with CHIKV infection (Ref. 3). Neonates 
are also highly vulnerable to direct inoculation of CHIKV through 
mosquito bites. Infected neonates present with fever, breastfeeding 
difficulties, thrombocytopenia, lymphopenia, and moderate hepatic 
cytolysis. One in four develops one or more serious complications, such 
as encephalopathy with progressive cerebral edema, sepsis, coagulopathy 
with hemorrhage, and cardiomyopathy (Ref. 3).
    The elderly and individuals with chronic comorbid conditions are 
also susceptible to life-threatening CHIKV disease (Refs. 3 and 16). A 
case series of 65 patients admitted to intensive care units with 
confirmed CHIKV in Martinique and Guadeloupe found that most patients 
were older than 50, and 83 percent of patients had preexisting 
comorbidities such as hypertension, diabetes, heart failure, and 
chronic kidney disease (Ref. 16). Upon admission, 57 percent required 
mechanical ventilation, 46 percent had shock requiring vasoactive 
drugs, 31 percent required renal replacement therapy, and 27 percent 
died (Ref. 16).
    The World Health Organization (WHO) has designated Chikungunya as a 
Neglected Tropical Disease (Ref. 17).
    Given the factors described above, FDA has determined that CHIKV 
disease meets both statutory criteria of ``no significant market in 
developed nations'' and ``disproportionately affects poor and 
marginalized populations.'' Therefore, FDA is designating CHIKV disease 
as a tropical disease under section 524 of the FD&C Act.

B. Lassa Fever

    Lassa fever (LF) is an acute viral infection caused by Lassa virus, 
a single-stranded ribonucleic acid virus belonging to the arenavirus 
family. LF is endemic in parts of West Africa (Benin, Ghana, Guinea, 
Liberia, Mali, Sierra Leone, and Nigeria), but probably exists in other 
West African countries where the animal vector for Lassa virus is 
distributed. Most Lassa virus infections (~80 percent) are mild or 
asymptomatic. In the remaining 20 percent of Lassa virus infections, 
the disease may progress to more severe symptoms that include 
respiratory distress, bleeding, shock, multiorgan system failure, and 
death. Involvement of the central nervous system may also occur with 
tremors, encephalitis, or hearing loss (Ref. 18).
    The overall mortality rate of all Lassa virus infections is 
approximately 1 percent. However, the mortality rate in hospitalized 
patients is about 15 to 20 percent (Ref. 19). The most common 
complication of Lassa virus infection is sensorineural hearing loss. 
About one-third of hospitalized patients develop hearing loss; in most 
of these patients, hearing loss is permanent. Sensorineural hearing 
loss may also occur in patients with mild or asymptomatic disease (Ref. 
20).
    Currently, there are no FDA-approved drugs for prophylaxis or 
treatment of LF. In the absence of vaccine that protects against LF, 
disease prevention relies on good community hygiene to avert rodents 
from entering homes.
1. No Significant Market in Developed Nations
    LF does not occur in developed countries, except for a few imported 
cases. Characteristically, since 1969, only six cases of LF have been 
documented in travelers returning to the United States (not including 
convalescent patients) (Ref. 21). Thus, LF appears to meet the criteria 
of not having a significant direct market in developed countries.
    FDA is also unaware of evidence of a significant indirect market 
for LF products. Lassa virus, like other hemorrhagic viruses, has been 
categorized as a Category A pathogen by CDC (Refs. 22 to 24). Category 
A pathogens are considered a threat to public health and are viewed as 
potential biological weapons threat agents. Therefore, if a drug 
against a Category A pathogen is developed, it could have an indirect 
market if stockpiled as a medical countermeasure for the U.S. 
Government. At present, however, FDA is unaware of any significant 
funding by the military, the Biomedical Advanced Research and 
Development Authority, or any other U.S. Government sources for drug 
development targeting treatment or prophylaxis against LF. Further, 
Lassa virus is not listed as a high-priority threat in the 2017 Public 
Health Emergency Medical Countermeasures Enterprise (PHEMCE) Strategy 
and Implementation Plan (Ref. 25).
2. Disproportionately Affects Poor and Marginalized Populations
    LF is exclusively endemic in some West African countries. LF cases 
identified in areas where LF is not endemic have occurred rarely and 
are usually imported by persons returning from West Africa. Every year, 
Lassa virus is estimated to cause 100,000 to 300,000 infections in West 
Africa, with approximately 5,000 deaths (Refs. 19 and 21). All 
countries where LF is known to be endemic (Benin, Ghana, Guinea, 
Liberia, Mali, Sierra Leone, and Nigeria) are classified by the World 
Bank as either low income (gross national income per capita of $1,045 
or less) or lower-middle income (gross national income per capita of 
$1,046-$4,125). Further, the incidence of LF in endemic countries is 
much higher among the poorest rural populations (Ref. 26). The 
characteristics of the disease (high morbidity and mortality) indicate 
a potentially significant DALY impact, although a comprehensive 
literature search failed to identify any DALY data.
    LF causes serious disease and death in both sexes and in all age 
groups, including children. The mortality rate is much higher for women 
in their third trimester of pregnancy. Spontaneous abortion is also a 
serious complication of Lassa virus infection, with a 95 percent 
mortality in fetuses of pregnant women (Refs. 21 and 26).
    LF has not been designated by WHO as a neglected tropical disease. 
However, a panel of scientists and public health experts convened by 
WHO met in Geneva on December 8 and 9, 2015, to prioritize the top 5 to 
10 emerging pathogens likely to cause severe outbreaks in the near 
future and for which few or no medical countermeasures exist. LF was 
one out of the nine diseases included in the initial list that need 
research and development preparedness to help control future outbreaks 
(Refs. 26 and 27).
    Given the factors described above, FDA has determined that LF meets 
both statutory criteria of ``no significant market in developed 
nations'' and ``disproportionately affects poor and marginalized 
populations.'' Therefore, FDA is designating Lassa fever as a tropical 
disease under section 524 of the FD&C Act.

C. Rabies

    Human rabies infection is caused by the rabies virus, which 
typically enters the body through animal bite wounds or by direct 
contact of the virus with the body's mucosal or respiratory surfaces. 
Virtually all patients with human rabies infection ultimately progress 
to coma followed by death, although rare recoveries have been reported 
(Ref. 28).
    As rabies is almost always fatal, post-exposure prophylaxis is 
recommended after suspected or proven exposure to rabies virus. Post-
exposure rabies prophylaxis (PEP) should include wound cleansing, 
infiltration of rabies immunoglobulin into and around the wound, and 
vaccination with cell culture rabies vaccines (Ref. 29). Pre-exposure 
prophylaxis, consisting of

[[Page 42907]]

administration of a rabies vaccine course, is recommended for anyone 
who is at continual, frequent, or increased risk for exposure to the 
rabies virus (Ref. 30). Rabies vaccines licensed for human use in the 
United States include human diploid cell vaccine (IMOVAX) and purified 
chick embryo cell vaccine (RabAvert). WHO has recommended 
discontinuation of nerve tissue vaccines, which are associated with 
more severe adverse reactions and are less immunogenic than cell-
culture and embryonated egg-based rabies vaccines, since 1984; however, 
these vaccines remain in use in some developing nations (Ref. 31). Two 
rabies immunoglobulin products are licensed in the United States: 
IMOGAM and HyperRab. There are no approved treatments for symptomatic 
human rabies infection.
1. No Significant Market in Developed Nations
    In developed nations, wild animals (e.g., raccoons, bats, skunks, 
foxes), rather than domesticated animals, account for the vast majority 
of reported rabies cases. Successful rabies vaccination programs have 
eliminated canine rabies in developed nations (including the United 
States), except for cases contracted while living in or travelling to 
rabies-endemic areas (Ref. 31). WHO categorizes Europe and North 
America as low-risk areas for humans contracting rabies (Ref. 32). 
Specific rabies prevalence information in the U.S. animal population 
was not identified in review of CDC rabies surveillance data; however, 
in 2014, a total of 6,033 animals were reported to be rabid in the 
United States, over 90 percent occurring in wild animals (Ref. 33).
    Using pre-exposure or post-exposure prophylaxis can prevent human 
rabies infection. Christian, et al. reported an estimated 6,000 to 
7,000 vaccine doses used annually in the United States for pre-exposure 
vaccination of critical personnel engaged in occupational activities 
with a risk for rabies exposure, and a separate survey estimated 6,600 
vaccine doses required each year to vaccinate approximately 2,200 
veterinary students (Ref. 34).
    The United States does not have a national reporting system for use 
of rabies PEP; therefore, the accurate usage information is unknown. 
The CDC states an estimated 40,000 to 50,000 PEP treatments are 
administered annually in the United States, yielding an incidence of 
0.01 to 0.02 percent using 2015 U.S. Census Bureau population estimate 
data (Refs. 35 and 36). Christian, et al. reported that between 2006 
and 2008, the annual U.S. national average PEP use was estimated at 
23,415 courses (range: 10,645-35,845), with an average annual rate of 
PEP administration for 16 states and NYC of 8.46/100,000 persons 
(range: 1.14-18.89/100,000 persons) (Ref. 34). The available data 
regarding pre-exposure and post-exposure rabies prophylaxis in the 
United States suggests that the population for whom rabies vaccines and 
human rabies immunoglobulin products are used is below 0.1 percent of 
the population, supporting the conclusion that there is no significant 
market for preventing human rabies infection in developed nations.
    Between 2006 and 2011, there were 12 human rabies cases reported in 
Europe, of which 6 were imported (Refs. 37 and 38). In the United 
States and Puerto Rico, 37 persons have been diagnosed with human 
rabies since 2003, including 11 cases (30 percent) with exposure 
occurring outside of the United States and its territories and 5 cases 
(14 percent) acquired from organ or tissue transplantation (Ref. 33). 
Although a specific prevalence is not reported, the rarity of human 
rabies infection in the United States is well below 0.1 percent of the 
population. A direct market for products to treat symptomatic rabies 
would therefore be small.
    The Joint Regulation on Immunizations and Chemoprophylaxis for the 
Prevention of Infectious Diseases Army Regulation 40-562 provides 
general guidance on rabies prevention recommendations for military 
personnel (Army, Navy, Air Force, Marine Corps, Coast Guard) (Ref. 39). 
Nevertheless, FDA is unaware of evidence suggesting any sizable 
government or other indirect market for rabies virus products.
2. Disproportionately Affects Poor and Marginalized Populations
    Although rabies is present in all continents except Antarctica, 
more than 95 percent of human deaths occur in Asia and Africa. WHO has 
designated rabies virus as a Neglected Tropical Disease (Ref. 17). It 
considers rabies a neglected disease of poor and vulnerable populations 
and reports the majority of deaths (84 percent) occur in rural areas 
(Ref. 31). In contrast to rabies epidemiology in developed nations, 
domestic dogs account for 99 percent of human rabies cases globally. 
Children in particular are at risk for human rabies infection: 40 
percent of people bitten by suspected rabid animals are less than 15 
years of age (Ref. 40).
    Human rabies infection is a preventable disease, and the 
overwhelming majority of rabies deaths result from the lack of 
recommended PEP administration following suspected rabies exposure 
(Ref. 39). The annual number of human rabies deaths worldwide estimated 
in 2010 ranged from 26,400 (95 percent confidence interval 15,200-
45,200) to 61,000 (95 percent CI 37,000-86,000) using different 
statistical approaches (Ref. 31). Using these data, DALYs for human 
rabies are estimated at 1.9 million (95 percent CI, 1.3-2.6 million) 
(id.). In developing countries, licensed purified cell culture and 
embryonated egg-based rabies vaccines and immunoglobulin for rabies PEP 
are neither readily available (due to shortages) nor accessible 
(distance to medical centers, affordability) (Refs. 39 and 40). The 
average cost of rabies PEP is reported to be US $40 in Africa and US 
$49 in Asia, which greatly exceeds the average daily income estimated 
at US $1-$2 per person (Ref. 40).
    Given the factors described above, FDA has determined that rabies 
meets both the statutory criteria of ``no significant market in 
developed nations'' and ``disproportionately affects poor and 
marginalized populations.'' Therefore, FDA is designating rabies as a 
tropical disease under section 524 of the FD&C Act.

D. Cryptococcal Meningitis

    Cryptococcus species are encapsulated fungi found in the 
environment throughout the world. The two most prominent species that 
cause human disease are C. neoformans and C. gattii (Ref. 41). The 
majority of cryptococcal meningitis (CM) is caused by C. neoformans 
infection in immunocompromised individuals. The incidence of CM 
increased substantially with the human immunodeficiency virus (HIV)/
acquired immune deficiency syndrome (AIDS) epidemic in the late 20th 
century and remains high in developing countries that lack access to 
effective antiretroviral therapy (Ref. 42).
    Cryptococcal infection typically occurs by inhalation of the fungi 
into the lungs. In immunocompromised individuals, the resulting 
pulmonary infection frequently spreads to the central nervous system, 
causing meningitis (Ref. 43). The primary recommended treatment of CM 
in developed countries includes a 2-week induction phase with 
amphotericin B and oral flucytosine, followed by long-term maintenance 
therapy with oral fluconazole (Ref. 44). In resource-limited nations, 
oral fluconazole is often the only therapeutic option available. Poor 
access to care and limited availability of standard antifungal therapy 
for patients with CM result in

[[Page 42908]]

significantly higher mortality and treatment failure rates in 
developing countries (Ref. 45). Park, et al. (2009) estimated that, 
excluding HIV/AIDS, CM is the fourth leading cause of death in sub-
Saharan Africa, causing more deaths than tuberculosis (Ref. 46).
1. No Significant Market in Developed Nations
    Immunocompromised patients are typically the most vulnerable 
population to develop serious manifestations from infection with 
Cryptococcus, and the prevalence of CM is closely linked to the 
prevalence of untreated and poorly managed HIV/AIDS. There has been a 
reduction in the incidence of CM in the United States and other 
developed nations due to the availability of antiretroviral therapy and 
lower rates of individuals with advanced HIV/AIDS (Ref. 42). Per the 
CDC, national estimates of the incidence of cryptococcosis are 
difficult to establish because it is only reportable in a few states 
(id.). In 2000, a population-based surveillance study in two U.S. 
metropolitan areas estimated that the annual incidence of 
cryptococcosis among persons with AIDS was between 2 and 7 cases per 
1,000, and the overall incidence was 0.4 to 1.3 cases per 100,000 (Ref. 
47). As of 2009, Pyrgos, et al. estimated that approximately 3,400 
annual hospitalizations were associated with CM in the United States 
(Ref. 48). Given that the overwhelming majority of patients diagnosed 
with CM in the United States will initiate therapy in the hospital, FDA 
considers 3,400 annually a rough estimate of the number of cases of CM 
in the United States. Based on the CDC treatment guidelines for CM, FDA 
estimates that most CM patients will receive at least 1 year of 
therapy. Therefore, even if the proportion of CM patients on therapy at 
any given time is 50 times the annual incidence of CM, the prevalence 
of CM in the United States remains below 0.1 percent of the population.
    Clinical practice guidelines for the management of cryptococcal 
disease do not routinely recommend primary antifungal prophylaxis for 
cryptococcosis in HIV-infected patients in the United States and 
Europe. This recommendation is based on the relative infrequency of 
cryptococcal disease, lack of survival benefits, potential for drug-
drug interactions, creation of direct antifungal drug resistance, 
medication compliance, and costs. Routine primary prophylaxis for 
cryptococcosis is also not currently recommended in transplant 
recipients (Ref. 44).
    The emergence of C. gattii in the Pacific Northwest in 2004, 
primarily among immunocompetent individuals, raised concerns about a 
new serious infectious disease risk for people residing in or traveling 
to the Pacific Northwest states. However, there have been only 60 cases 
reported to CDC between 2004 and 2010 (Ref. 49). U.S. cases continue to 
be reported at a relatively low rate, 20-23 cases per year each in 2012 
and 2013 (Ref. 50). The emergence of C. gattii in the United States has 
not resulted in a large number of cases that could potentially warrant 
a significant market for treatment or prevention.
    Therefore, in the United States and other developed countries, 
there does not appear to be a significant market for developing new 
drugs or vaccines for the treatment or prevention of CM. Additionally, 
given the low incidence of CM and the low risk of infection to 
immunocompetent individuals, it is unlikely that antifungal therapies 
specifically directed against CM will become a national stockpiling 
priority in the foreseeable future.
2. Disproportionately Affects Poor and Marginalized Populations
    CM is not currently designated by WHO as a Neglected Tropical 
Disease (Ref. 17). Additionally, no DALY data were found to distinguish 
the disease burden of CM in developing versus developed countries. 
However, the incidence of CM is high in developing countries due to 
limited access to antiretroviral therapy to treat HIV infection (Ref. 
42). Annually, there are approximately 1 million cases of CM worldwide 
in patients with HIV/AIDS and 625,000 deaths (Ref. 46). Approximately 
75 percent of these infections are in sub-Saharan Africa (id.). The 
case fatality rate for CM patients living in sub-Saharan Africa is 35 
to 65 percent, compared to a 10- to 20-percent case fatality rate in 
most developed nations (Ref. 51).
    The HIV epidemic imposes a particular burden on women and children, 
specifically in sub-Saharan Africa where women account for 
approximately 57 percent of all people living with HIV (Ref. 52). In 
2012, there were an estimated 260,000 newly infected children in low- 
and middle-income countries (id.). Children with HIV are more likely to 
face gaps in access to HIV treatment. For example, in 2012, 
approximately 34 percent of children had access to HIV treatment versus 
approximately 64 percent for adults (id.). As CM is most prevalent in 
persons infected with HIV and HIV disproportionately impacts women and 
children, it is reasonable to conclude that CM also disproportionately 
affects these populations.
    Given the factors described above, FDA has determined that CM meets 
both statutory criteria of ``no significant market in developed 
nations'' and ``disproportionately affects poor and marginalized 
populations.'' Therefore, FDA is designating cryptococcal meningitis as 
a tropical disease 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 diseases 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 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 https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm534162.htm.

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. 3501-3520). 
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 are on display at the Dockets Management 
Staff (see ADDRESSES) and are available for

[[Page 42909]]

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. 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.

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    Dated: August 21, 2018.
Leslie Kux, Associate Commissioner for Policy.
[FR Doc. 2018-18314 Filed 8-23-18; 8:45 am]
BILLING CODE 4164-01-P


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