42904 Federal Register / Vol. 83, No. 165 / Friday, August 24, 2018 / Notices 

OPQ staff participating in this 

program will benefit by gaining a better 

understanding of current industry 

practices, processes, and procedures. 

Participating sites will have an 

opportunity to showcase their 

technologies and their actual 

manufacturing and testing facilities. 

Although observation of all aspects of 

drug development and production 

would be beneficial to OPQ staff, OPQ 

has identified a number of areas of 

particular interest to its staff. The 

following list identifies some examples 

of these areas but is not intended to be 

exhaustive, mutually exclusive, or to 

limit industry response: 

• Drug products 

Æ Solutions, suspensions, emulsions, 

and semisolids 

Æ Modified- and immediate-release 

formulations 

Æ Drug-device combination products 

(e.g., inhalation products, transdermal 

systems, implants intended for drug 

delivery, and prefilled syringes) 

• Active pharmaceutical ingredients 

manufactured by 

Æ Chemical synthesis 

Æ Fermentation 

Æ Biotechnology 

• Design, development, manufacturing 

and controls 

Æ Engineering controls for aseptic 

processes 

Æ Novel delivery technologies 

Æ Hot melt extrusion 

Æ Soft-gel encapsulation 

Æ Lyophilization 

Æ Blow-Fill-Seal and isolators 

Æ Spray-drying 

Æ Process analytical technology, 

measurement systems, and real-time 

release testing 

• Emerging technologies 

Æ Continuous manufacturing 

Æ 3-dimensional printing 

Æ Nanotechnology 

III. Site Selection 

Selection of potential facilities will be 

based on the priorities developed for 

OPQ staff training, the facility’s current 

compliance status with FDA, and in 

consultation with the appropriate FDA 

district office. All travel expenses 

associated with this program will be the 

responsibility of OPQ; therefore, 

selection will be based on the 

availability of funds and resources for 

the fiscal year. OPQ will not provide 

financial compensation to the 

pharmaceutical site as part of this 

program. 

IV. Proposals for Participation 

Companies interested in offering a site 

visit or learning more about this site 

visit program should respond by 

submitting a proposal directly to Janet 

Wilson (see DATES and FOR FURTHER

INFORMATION CONTACT sections of this 

document for more information). To aid 

in OPQ’s site selection and planning, 

your proposal should include the 

information below: 

• A contact person, 

• Site visit location(s), 

• Facility Establishment Identifier 

and Data Universal Numbering System 

numbers, as applicable, 

• Maximum number of FDA staff that 

can be accommodated during a site visit 

(maximum of 20), 

• A proposed agenda outlining the 

learning objectives and associated 

activities for the site visit, 

• Maximum number of site visits (no 

more than 2) that your site would be 

willing to host by the close of the 

government fiscal year, September 30, 

2019, and 

• Proposed dates for each site visit 

(i.e. month and week). 

Please note that the requested 

proposed agenda will be reviewed to 

determine the educational benefit to 

OPQ in conducting the visit, and 

selected sites may be asked to refine the 

agenda to maximize the educational 

benefit. After a site is selected, OPQ will 

communicate with the contact person 

for the site to determine the actual dates 

for the visit. 

Proposals submitted without this 

minimum information will not be 

considered. Based on response rate and 

type of responses, OPQ may or may not 

consider alternative pathways to 

meeting our training goals. 

Dated: August 21, 2018. 

Leslie Kux, 

Associate Commissioner for Policy. 

[FR Doc. 2018–18305 Filed 8–23–18; 8:45 am] 

BILLING CODE 4164–01–P 

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. 

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, Katherine.Schumann@

fda.hhs.gov; 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, ocod@fda.hhs.gov. 

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 


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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/designatingadditions-to-the-current-list-of-tropicaldiseases-in-the-federal-food-drug-andcosmetic). Additions to the statutory list 

of tropical diseases published in the 

Federal Register can be accessed at 

https://www.fda.gov/AboutFDA/ 

CentersOffices/OfficeofMedicalProducts

andTobacco/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/Centers

Offices/OfficeofMedicalProducts

andTobacco/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: 

• Chikungunya virus disease 

• Lassa fever 

• Rabies 

• 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 lowincome 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 


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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 onethird 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, postexposure 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). Preexposure prophylaxis, consisting of 


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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 longterm maintenance therapy with oral 

fluconazole (Ref. 44). In resourcelimited 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 


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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 populationbased 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 middleincome 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/Officeof

MedicalProductsandTobacco/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 


daltland on DSKBBV9HB2PROD with NOTICES
Federal Register / Vol. 83, No. 165 / Friday, August 24, 2018 / Notices 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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Hygiene, 76:1189–1193, 2007. 

3. Simon, F., E. Javelle, A. Cabie, et al., 

‘‘French Guidelines for the Management 

of Chikungunya (Acute and Persistent 

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45:243–263, 2015. 

4. Borgherini, G., P. Poubeau, A. Jossaume, et 

al., ‘‘Persistent Arthralgia Associated 

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6. McSweegan, E., S.C. Weaver, M. Lecuit, et 

al., ‘‘The Global Virus Network: 

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7. LaBeaud, A.D., ‘‘Why Arboviruses Can Be 

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13. Marimoutou, C., E. Vivier, M. Oliver, et 

al., ‘‘Morbidity and Impaired Quality of 

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14. Krishnamoorthy, K., K.T. 

Harichandrakumar, A. Krishna Kumari, 

et al., ‘‘Burden of Chikungunya in India: 

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15. Labeaud, A.D., F. Bashir, C.H. King, 

‘‘Measuring the Burden of Arboviral 

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9:1, 2011. 

16. Crosby, L., C. Perreau, B. Madeux, et al., 

‘‘Severe Manifestations of Chikungunya 

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19. CDC, ‘‘Imported Lassa Fever—New 

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20. Cummins, D., J.B. McCormick, D. 

Bennett, et al., ‘‘Acute Sensorineural 

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21. CDC, ‘‘Lassa Fever Confirmed in Death of 

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May 25, 2015; available at https://

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22. Rotz, L.D., A.S. Khan, S.R. Lillibridge, et 

al., ‘‘Public Health Assessment of 

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23. Borio, L., T. Inglesby, C.J. Peters, et al., 

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287:2391–2397, 2002. 

24. Ryan, C.P., ‘‘Zoonoses Likely To Be Used 

in Bioterrorism,’’ Public Health Reports, 

123:276–281; available at https://

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PMC2289981/. 

25. Department of Health and Human 

Services, ‘‘2017–2018 Public Health 

Emergency Medical Countermeasures 

Enterprise (PHEMCE) Strategy and 

Implementation Plan,’’ 2017; available at 

https://www.phe.gov/Preparedness/ 

mcm/phemce/Pages/strategy.aspx. 

26. WHO, ‘‘Essential Medicines and Health 

Products: WHO Publishes List of Top 

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available at http://www.who.int/ 

medicines/ebola-treatment/WHO-list-oftop-emerging-diseases/en/. 

27. WHO, ‘‘2017 Annual Review of Diseases 

Prioritized Under the Research and 

Development Blueprint,’’ February 11, 

2018; available at http://www.who.int/ 

blueprint/what/research-development/ 

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28. Bassin, S.L., C.D. Rupprecht, and T.P. 

Bleck, ‘‘Rhabdoviruses,’’ in: Mandell, 

G.L., J.E. Bennett, R. Dolin, eds., 

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29. Rupprecht, C.E., D. Briggs, C.M. Brown, 

et al., ‘‘Use of a Reduced (4-Dose) 

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in: Morbidity and Mortality Weekly 

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30, 2010. 

30. WHO, ‘‘WHO Guide for Rabies Pre and 

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34. Christian, K.A., J.D. Blanton, M. 

Auslander, et al., ‘‘Epidemiology of 

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27, 2009. 

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‘‘Annual Estimates of the Resident 

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41. Gullo, F.P., S.A. Rossi, J.C. Sardi, et al., 

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et al., ‘‘Clinical Practice Guidelines for 

the Management of Cryptococcal 

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45. Rothe, C., D.J. Sloan, P. Goodson, et al., 

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8(6):e67311, 2013. 

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794, 2003. 

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Cryptococcus Gattii in the United States 

and Canada,’’ Infection and Drug 

Resistance, 8:89–97, May 11, 2015. 

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2013_en.pdf (accessed August 8, 2016). 

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 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Health Resources and Services 

Administration 

Agency Information Collection 

Activities: Submission to OMB for 

Review and Approval; Public Comment 

Request; The Secretary’s Discretionary 

Advisory Committee on Heritable 

Disorders in Newborns and Children’s 

Public Health System Assessment 

Surveys OMB No. 0906–0014—Revised 

AGENCY: Health Resources and Services 

Administration (HRSA), Department of 

Health and Human Services. 

ACTION: Notice. 

SUMMARY: In compliance with of the 

Paperwork Reduction Act of 1995, 

HRSA has submitted an Information 

Collection Request (ICR) to the Office of 

Management and Budget (OMB) for 

review and approval. Comments 

submitted during the first public review 

of this ICR will be provided to OMB. 

OMB will accept further comments from 

the public during the review and 

approval period. 

DATES: Comments on this ICR should be 

received no later than September 24, 

2018. 

ADDRESSES: Submit your comments to 

paperwork@hrsa.gov or mail the HRSA 

Information Collection Clearance 

Officer, Room 14N136B, 5600 Fishers 

Lane, Rockville, MD 20857. 

FOR FURTHER INFORMATION CONTACT: To 

request a copy of the clearance requests 

submitted to OMB for review, email Lisa 

Wright-Solomon, the HRSA Information 

Collection Clearance Officer at 

paperwork@hrsa.gov or call (301) 443– 

1984. 

SUPPLEMENTARY INFORMATION: 

Information Collection Request Title: 

The Secretary’s Discretionary Advisory 

Committee on Heritable Disorders in 

Newborns and Children’s Public Health 

System Assessment Surveys OMB No. 

0906–0014—Revised. 

Abstract: The purpose of the public 

health system assessment surveys is to 

inform the Secretary’s Discretionary 

Advisory Committee on Heritable 

Disorders in Newborns and Children 

(Committee) on the ability to add 

newborn screening for particular 

conditions within a state, including the 

feasibility, readiness and overall 

capacity to screen for a new condition. 

The Committee was established under 

Section 1111 of the Public Health 

Service Act, 42 U.S.C. 300b–10, as 

amended in the Newborn Screening 

Saves Lives Reauthorization Act of 

2014. The Committee is governed by the 

provisions of the Federal Advisory 

Committee Act, as amended (5 U.S.C. 

App.), which sets forth standards for the 

formation and use of advisory 

committees. The purpose of the 

Committee is to provide the Secretary 

with recommendations, advice, and 

technical information regarding the 

most appropriate application of 

technologies, policies, guidelines, and 

standards for: (a) Effectively reducing 

morbidity and mortality in newborns 

and children having, or at risk for, 

heritable disorders; and (b) enhancing 

the ability of state and local health 

agencies to provide for newborn and 

child screening, counseling, and health 

care services for newborns and children 

having, or at risk for, heritable 

disorders. Specifically, the Committee 

makes systematic evidence-based 

recommendations on newborn screening 

for conditions that have the potential to 

change the health outcomes for 

newborns. 

The Committee tasks an external 

workgroup to conduct systematic 

evidence-based reviews for conditions 

being considered for addition to the 

Recommended Uniform Screening 

Panel, and their corresponding newborn 

screening test(s), confirmatory test(s), 

and treatment(s). Reviews also include 

an analysis of the benefits and harms of 

newborn screening for a selected 

condition at a population level and an 

assessment of state public health 

newborn screening programs’ ability to 

implement the screening of a new 

condition. 

Need and Proposed Use of the 

Information: HRSA proposes that the 

data collection surveys be administered 

by the Committee’s external Evidence 

Review Group to all state newborn 

screening programs in the United States 

up to twice a year for two conditions. 

The surveys were developed to capture 

the following: (1) The readiness of state 

public health newborn screening 

programs to expand newborn screening 

to include the target condition; (2) 

specific requirements of screening for 


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