83 FR 42904 - Designating Additions to the Current List of Tropical Diseases in the Federal Food, Drug, and Cosmetic Act
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration Federal Register Volume 83, Issue 165 (August 24, 2018)
Food and Drug Administration
Federal Register Volume 83, Issue 165 (August 24, 2018)
| Page Range | 42904-42910 | |
| FR Document | 2018-18314 |
[Federal Register Volume 83, Number 165 (Friday, August 24, 2018)] [Notices] [Pages 42904-42910] From the Federal Register Online [www.thefederalregister.org] [FR Doc No: 2018-18314] ----------------------------------------------------------------------- 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 [[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: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 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. 1. Petersen, L.R. and A.M. Powers, ``Chikungunya: Epidemiology,'' F1000Research, 5(F1000 Faculty Rev):82, 2016. 2. Sergon, K., A.A. Yahaya, J. Brown, et al., ``Seroprevalence of Chikungunya Virus Infection on Grande Comore Island, Union of the Comoros, 2005,'' American Journal of Tropical Medicine and Hygiene, 76:1189-1193, 2007. 3. Simon, F., E. Javelle, A. Cabie, et al., ``French Guidelines for the Management of Chikungunya (Acute and Persistent Presentations) November 2014,'' Medecine Et Maladies Infectieuses, 45:243-263, 2015. 4. Borgherini, G., P. Poubeau, A. Jossaume, et al., ``Persistent Arthralgia Associated With Chikungunya Virus: A Study of 88 Adult Patients on Reunion Island,'' Clinical Infectious Diseases, 47:469- 475, 2008. 5. Abdelnabi, R., J. Neyts, and L. Delang, ``Towards Antivirals Against Chikungunya Virus,'' Antiviral Research, 121:59-68, 2015. 6. McSweegan, E., S.C. Weaver, M. Lecuit, et al., ``The Global Virus Network: Challenging Chikungunya,'' Antiviral Research, 120:147-152, 2015. 7. LaBeaud, A.D., ``Why Arboviruses Can Be Neglected Tropical Diseases,'' PLOS Neglected Tropical Disease, 2:e247, 2008. 8. CDC, ``Chikungunya: 2015 Final Data for the United States;'' available at https://www.cdc.gov/chikungunya/geo/united-states-2015.html. 9. Pan American Health Organization, Regional Office for the Americans of the World Health Organization, ``Chikungunya;'' available at https://www.paho.org/hq/index.php?option=com_topics&view=article&id=343&Itemid=40931. 10. CDC, ``Chikungunya Virus Geographic Distribution;'' available at https://www.cdc.gov/chikungunya/geo/index.html. 11. Writer, J.V. and L. Hurt, ``Chikungunya Infection in DoD Healthcare Beneficiaries Following the 2013 Introduction of the Virus into the Western Hemisphere, 1 January 2014 to 28 February 2015,'' Medical Surveillance Monthly Report, 22:2-6, 2015. 12. Labeaud, A.D., F. Bashir, and C.H. King, ``Measuring the Burden of Arboviral Diseases: The Spectrum of Morbidity and Mortality from Four Prevalent Infections,'' Population Health Metrics, 9:1, 2011. 13. Marimoutou, C., E. Vivier, M. Oliver, et al., ``Morbidity and Impaired Quality of Life 30 Months After Chikungunya Infection: Comparative Cohort of Infected and Uninfected French Military Policemen in Reunion Island,'' Medicine (Baltimore), 91:212-219, 2012. 14. Krishnamoorthy, K., K.T. Harichandrakumar, A. Krishna Kumari, et al., ``Burden of Chikungunya in India: Estimates of Disability Adjusted Life Years (DALY) Lost in 2006 Epidemic,'' Journal of Vector Borne Diseases, 46:26-35, 2009. 15. Labeaud, A.D., F. Bashir, C.H. King, ``Measuring the Burden of Arboviral Diseases: The Spectrum of Morbidity and Mortality from Four Prevalent Infections,'' Population Health Metrics, 9:1, 2011. 16. Crosby, L., C. Perreau, B. Madeux, et al., ``Severe Manifestations of Chikungunya Virus in Critically Ill Patients During the 2013-2014 Caribbean Outbreak,'' International Journal of Infectious Diseases, 48:78-80, 2016. 17. WHO Neglected Tropical Diseases Program, ``Neglected Tropical Diseases;'' available at http://www.who.int/neglected_diseases/diseases/en/(accessed August 19, 2016). 18. Seregin, A., N. Yun, and S. Paessler, ``Lymphocytic Choriomenengitis, Lassa Fever, and South American Hemorrhagic Fevers (Arenaviruses),'' in: Mandell, G.L., J.E. Bennett, and R. Dolin, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 8th ed. PA: Churchill Livingstone Elsevier; 2031-2037, 2014. 19. CDC, ``Imported Lassa Fever--New Jersey, 2004,'' Morbidity and Mortality Weekly Report, 53:894-897, 2004, available at https://www.ncbi.nlm.nih.gov/pubmed/15457145. 20. Cummins, D., J.B. McCormick, D. Bennett, et al., ``Acute Sensorineural Deafness in Lassa Fever,'' Journal of the American Medical Association, 264:2093-2096, 1990. 21. CDC, ``Lassa Fever Confirmed in Death of U.S. Traveler Returning from Liberia,'' May 25, 2015; available at https://www.cdc.gov/media/releases/2015/p0525-lassa.html. 22. Rotz, L.D., A.S. Khan, S.R. Lillibridge, et al., ``Public Health Assessment of Potential Biological Terrorism Agents,'' Emerging Infectious Disease, 8:225-230, 2002. 23. Borio, L., T. Inglesby, C.J. Peters, et al., ``Hemorrhagic Fever Viruses as Biological Weapons: Medical and Public Health Management,'' Journal of the American Medical Association, 287:2391- 2397, 2002. 24. Ryan, C.P., ``Zoonoses Likely To Be Used in Bioterrorism,'' Public Health Reports, 123:276-281; available at https://www.ncbi.nlm.nih.gov/pmc/articles/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 Emerging Diseases Likely To Cause Major Epidemics,'' December 10, 2015; available at http://www.who.int/medicines/ebola-treatment/WHO-list-of-top-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/2017-Prioritization-Long-Report.pdf. 28. Bassin, S.L., C.D. Rupprecht, and T.P. Bleck, ``Rhabdoviruses,'' in: Mandell, G.L., J.E. Bennett, R. Dolin, eds., Principles and Practice of Infectious Diseases, 7th ed., Philadelphia, PA: Churchill Livingstone; 2249-2258, 2010. 29. Rupprecht, C.E., D. Briggs, C.M. Brown, et al., ``Use of a Reduced (4-Dose) Vaccine Schedule for Postexposure Prophylaxis to Prevent Human Rabies: Recommendations of the Advisory Committee on Immunization Practices,'' Centers for Disease Control and Prevention (CDC), Morbidity and Mortality Weekly Report, Recomm Rep. 59(RR- 2):1-9, March 19, 2010. Erratum in: Morbidity and Mortality Weekly Report, Recomm Rep. 59(16):493, April 30, 2010. 30. WHO, ``WHO Guide for Rabies Pre and Post Exposure Prophylaxis in Humans (updated 2014);'' available at http://www.who.int/rabies/PEP_Prophylaxis_guideline_15_12_2014.pdf (accessed September 7, 2016). 31. WHO, ``WHO Expert Consultation on Rabies, 2nd Report, WHO Technical Report Series 982 Geneva,'' WHO Press, 2013. 32. WHO, ``Distribution of Risk Levels for Humans Contacting Rabies, Worldwide, 2013;'' available at http://www.who.int/rabies/Global_distribution_risk_humans_contracting_rabies_2013.png (accessed August 19, 2016). 33. Monroe, B.P., P. Yager, J. Blanton, et al., ``Rabies Surveillance in the United States During 2014,'' Journal of the American Veterinary Medical Association. 248(7):777-788, April 1, 2016. 34. Christian, K.A., J.D. Blanton, M. Auslander, et al., ``Epidemiology of Rabies Post-Exposure Prophylaxis--United States of America, 2006-2008,'' Vaccine, 27(51):7156-7161, November 27, 2009. 35. U.S. Census Bureau, Population Division, ``Annual Estimates of the Resident Population: April 1, 2010 to July 1, 2015,'' available at https://factfinder.census.gov/faces/nav/jsf/pages/index.xhtml. 36. WHO, ``Rabies Fact Sheet,'' March 2016; available at http://www.who.int/mediacentre/factsheets/fs099/en/ (accessed August 18, 2016). 37. See https://ecdc.europa.eu/en/rabies/facts (accessed January 9, 2017). 38. The European Centre for Disease Prevention and Control, ``Expert Consultation on Rabies Post-Exposure Prophylaxis,'' January 15, 2009; available at https://ecdc.europa.eu/en/publications/ Publications/0906_MER_ [[Page 42910]] Expert_Consultation_on_Rabies_Post-exposure_Prophylaxis.pdf (accessed January 9, 2017). 39. See https://armypubs.army.mil/ProductMaps/PubForm/AR_Details.aspx?ID=0902c85180010355 (accessed May 5, 2017). 40. CDC, ``Cost of Rabies Prevention,'' updated August 3, 2015; available at https://www.cdc.gov/rabies/location/usa/cost.html (accessed February 9, 2017). 41. Gullo, F.P., S.A. Rossi, J.C. Sardi, et al., ``Cryptococcosis: Epidemiology, Fungal Resistance, and New Alternatives for Treatment,'' European Journal of Clinical Microbiology and Infectious Diseases, 32:1377-1391, 2013. 42. CDC, ``C. neoformans Infection Statistics;'' available at https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/statistics.html (accessed August 8, 2016). 43. Makadzange, A.T. and G. McHugh, ``New Approaches to the Diagnosis and Treatment of Cryptococcal Meningitis,'' Seminars in Neurology, 34(1):47-60, 2014. 44. Perfect, J.R., W.E. Dismukes, F. Dromer, et al., ``Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Disease Society of America,'' Clinical Infectious Diseases, 50:291-322, 2010. 45. Rothe, C., D.J. Sloan, P. Goodson, et al., ``A Prospective Longitudinal Study of the Clinical Outcomes from Cryptococcal Meningitis Following Treatment Induction with 800 mg Oral Fluconazole in Blantyre, Malawi,'' PLOS One, 8(6):e67311, 2013. 46. Park, B.J., K.A. Wannemuehler, B.J. Marston, et al., ``Estimation of the Current Global Burden of Cryptococcal Meningitis Among Persons Living with HIV/AIDS,'' AIDS, 23:525-530, 2009. 47. Mirza, S.A., M. Phelan, D. Rimland, et al., ``The Changing Epidemiology of Cryptococcosis: An Update from Population-Based Active Surveillance in 2 Large Metropolitan Areas, 1992-2000,'' Clinical Infectious Diseases, 36(6):789-794, 2003. 48. Pyrgos, V., A.E. Seitz, C.A. Steiner, et al., ``Epidemiology of Cryptococcal Meningitis in the US: 1997-2009,'' PLOS One, 8(2):e56269, 2013. 49. CDC, ``Emergence of Cryptococcus gattii--Pacific Northwest, 2004-2010,'' Morbidity and Mortality Weekly Report, 59(28):865-868, 2010 available at https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5928a1.htm?s_cid=mm5928a1_w. 50. Espinel-Ingroff, A. and S.E. Kidd, ``Current Trends in the Prevalence of Cryptococcus Gattii in the United States and Canada,'' Infection and Drug Resistance, 8:89-97, May 11, 2015. 51. WHO, ``Rapid Advice: Diagnosis, Prevention and Management of Cryptococcal Disease in HIV-Infected Adults, Adolescents and Children,'' December 2011; available at http://www.who.int/hiv/pub/cryptococcal_disease2011/ (accessed August 8, 2016). 52. Joint United Nations Programme on HIV/AIDS (UNAIDS), ``Global Report: UNAIDS Report on the Global AIDS Epidemic 2013;'' available at http://files.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2013/gr2013/UNAIDS_Global_Report_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
![42904 Federal Register / Vol. 83, No. 165 / Friday, August 24, 2018 / Notices
OPQ staff participating in this submitting a proposal directly to Janet applications meet certain criteria. The
program will benefit by gaining a better Wilson (see DATES and FOR FURTHER FD&C Act lists the diseases that are
understanding of current industry INFORMATION CONTACT sections of this considered tropical diseases for
practices, processes, and procedures. document for more information). To aid purposes of obtaining PRVs and
Participating sites will have an in OPQ’s site selection and planning, provides for Agency expansion of that
opportunity to showcase their your proposal should include the list to include other diseases that satisfy
technologies and their actual information below: the definition of ‘‘tropical diseases’’ as
manufacturing and testing facilities. • A contact person, set forth in the FD&C Act. The Agency
Although observation of all aspects of • Site visit location(s), has determined that chikungunya virus
drug development and production • Facility Establishment Identifier disease, Lassa fever, rabies, and
would be beneficial to OPQ staff, OPQ and Data Universal Numbering System cryptococcal meningitis satisfy this
has identified a number of areas of numbers, as applicable, definition and is therefore adding them
particular interest to its staff. The • Maximum number of FDA staff that to the list of designated tropical diseases
following list identifies some examples can be accommodated during a site visit whose product applications may result
of these areas but is not intended to be (maximum of 20), in the award of PRVs. Sponsors
exhaustive, mutually exclusive, or to • A proposed agenda outlining the submitting certain drug or biological
limit industry response: learning objectives and associated
product applications for the prevention
• Drug products activities for the site visit,
or treatment of chikungunya virus
Æ Solutions, suspensions, emulsions, • Maximum number of site visits (no
disease, Lassa fever, rabies, and
and semisolids more than 2) that your site would be
willing to host by the close of the cryptococcal meningitis may be eligible
Æ Modified- and immediate-release
formulations government fiscal year, September 30, to receive a PRV if such applications are
Æ Drug-device combination products 2019, and approved by FDA.
(e.g., inhalation products, transdermal • Proposed dates for each site visit DATES: This order is effective August 24,
systems, implants intended for drug (i.e. month and week). 2018.
delivery, and prefilled syringes) Please note that the requested
• Active pharmaceutical ingredients proposed agenda will be reviewed to ADDRESSES: Submit electronic
manufactured by determine the educational benefit to comments on additional diseases
Æ Chemical synthesis OPQ in conducting the visit, and suggested for designation to https://
Æ Fermentation selected sites may be asked to refine the www.regulations.gov. Submit written
Æ Biotechnology agenda to maximize the educational comments on additional diseases
• Design, development, manufacturing benefit. After a site is selected, OPQ will suggested for designation to the Dockets
and controls communicate with the contact person Management Staff (HFA–305), Food and
Æ Engineering controls for aseptic for the site to determine the actual dates Drug Administration, 5630 Fishers
processes for the visit. Lane, Rm. 1061, Rockville, MD 20852.
Æ Novel delivery technologies Proposals submitted without this All comments should be identified with
Æ Hot melt extrusion minimum information will not be the docket number found in brackets in
Æ Soft-gel encapsulation considered. Based on response rate and the heading of this document.
Æ Lyophilization type of responses, OPQ may or may not
Æ Blow-Fill-Seal and isolators FOR FURTHER INFORMATION CONTACT:
consider alternative pathways to
Æ Spray-drying meeting our training goals. Katherine Schumann, Center for Drug
Æ Process analytical technology, Evaluation and Research, Food and
measurement systems, and real-time Dated: August 21, 2018. Drug Administration, 10903 New
release testing Leslie Kux, Hampshire Ave., Bldg. 22, Rm. 6242,
• Emerging technologies Associate Commissioner for Policy. Silver Spring, MD 20993–0002, 301–
Æ Continuous manufacturing [FR Doc. 2018–18305 Filed 8–23–18; 8:45 am] 796–1300, Katherine.Schumann@
Æ 3-dimensional printing BILLING CODE 4164–01–P fda.hhs.gov; or Office of
Æ Nanotechnology Communication, Outreach and
III. Site Selection Development (OCOD), Center for
DEPARTMENT OF HEALTH AND Biologics Evaluation and Research,
Selection of potential facilities will be HUMAN SERVICES Food and Drug Administration, 10903
based on the priorities developed for New Hampshire Ave., Silver Spring, MD
OPQ staff training, the facility’s current Food and Drug Administration
20993–0002, 1–800–835–4709 or 240–
compliance status with FDA, and in
[Docket No. FDA–2008–N–0567] 402–8010, ocod@fda.hhs.gov.
consultation with the appropriate FDA
district office. All travel expenses Designating Additions to the Current SUPPLEMENTARY INFORMATION:
associated with this program will be the List of Tropical Diseases in the Federal
responsibility of OPQ; therefore, Table of Contents
Food, Drug, and Cosmetic Act
selection will be based on the I. Background: Priority Review Voucher
availability of funds and resources for AGENCY: Food and Drug Administration, Program
the fiscal year. OPQ will not provide HHS. II. Diseases Being Designated
financial compensation to the ACTION: Final order. A. Chikungunya Virus Disease
daltland on DSKBBV9HB2PROD with NOTICES
pharmaceutical site as part of this B. Lassa Fever
program. SUMMARY: The Federal Food, Drug, and C. Rabies
Cosmetic Act (FD&C Act) authorizes the D. Cryptococcal Meningitis
IV. Proposals for Participation Food and Drug Administration (FDA or III. Process for Requesting Additional
Companies interested in offering a site Agency) to award priority review Diseases To Be Added to the List
visit or learning more about this site vouchers (PRVs) to tropical disease IV. Paperwork Reduction Act
visit program should respond by product applicants when the V. References
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![Federal Register / Vol. 83, No. 165 / Friday, August 24, 2018 / Notices 42905
I. Background: Priority Review designated as ‘‘tropical diseases’’ under CHIKV cases among U.S. Department of
Voucher Program section 524 of the FD&C Act: Defense healthcare beneficiaries
Section 524 of the FD&C Act (21 • Chikungunya virus disease between January 2014 and February
U.S.C. 360n), which was added by • Lassa fever 2015 (Ref. 11).
• Rabies Based on the epidemiology of
section 1102 of the Food and Drug reported CHIKV cases, the market for
Administration Amendments Act of • Cryptococcal meningitis
vaccines in developed nations such as
2007, uses a PRV incentive to encourage FDA’s rationale for adding these
the United States would largely
the development of new drugs for diseases to the list is discussed in the comprise travelers at risk of CHIKV
prevention and treatment of certain analyses that follow. infection and military populations.
diseases that, in the aggregate, affect A. Chikungunya Virus Disease These markets are unlikely to provide
millions of people throughout the sufficient incentive to encourage
world. Further information about the Chikungunya virus (CHIKV) is an
development of products to treat or
tropical disease PRV program can be arbovirus transmitted by Aedes
prevent CHIKV infection. Although a
found in guidance for industry mosquitoes in tropical climates in
limited number of locally transmitted
‘‘Tropical Disease Priority Review Africa, Asia, islands in the Indian and
cases have recently been reported in
Vouchers’’ (81 FR 69537, October 6, Pacific Oceans, Europe, and, since 2013,
U.S. territories, the disease is not
2016, available at https:// the Americas (Ref. 1). Although CHIKV
currently considered endemic in those
www.federalregister.gov/documents/ mortality is relatively low (0.01 to 0.1 areas. Whether those populations could
2015/08/20/2015-20554/designating- percent), attack rates are very high (33 broaden the market for products to treat
additions-to-the-current-list-of-tropical- to 66 percent) and most infections are or prevent CHIKV infection in the future
diseases-in-the-federal-food-drug-and- symptomatic (Refs. 2 and 3). Many is unknown. CHIKV drug development
cosmetic). Additions to the statutory list infected individuals experience painful is not significantly funded by U.S.
of tropical diseases published in the arthralgia, which can persist for months Government sources, and CHIKV is not
Federal Register can be accessed at and even years (Ref. 4). Life-threatening among the Centers for Disease Control
https://www.fda.gov/AboutFDA/ manifestations of CHIKV, including and Prevention’s (CDC) list of potential
CentersOffices/OfficeofMedicalProducts organ failure, meningoencephalitis, bioterrorism agents.
andTobacco/CDER/ucm534162.htm. hemorrhagic symptoms, and myocardial
disease, and death occur in neonates, 2. Disproportionately Affects Poor and
On August 20, 2015, FDA published the elderly, and individuals with Marginalized Populations
a final order (80 FR 50559) (final order) chronic comorbidities (Ref. 3).
designating Chagas disease and Poor populations in tropical
There is no approved antiviral environments experience the primary
neurocysticercosis as tropical diseases. treatment for CHIKV in the United
That final order also sets forth FDA’s burden of CHIKV disease because they
States or anywhere else in the world are disproportionally exposed to its
interpretation of the statutory criteria for (Refs. 5 and 6). Therapeutic
tropical disease designation and mosquito vectors (Ref. 7). Arboviral
management largely aims to relieve pain diseases disproportionally affect low-
expands the list of tropical diseases and inflammation and limit the loss of income urban and rural populations
under section 524(a)(3)(S) of the FD&C mobility and physical fitness through through increased mosquito exposure
Act, which authorizes FDA to designate the use of analgesic and non-steroidal due to poor housing, lack of sanitation
by order ‘‘[a]ny other infectious disease anti-inflammatory drugs. There is no infrastructure, and outdoor occupations
for which there is no significant market approved CHIKV vaccine (Ref. 6). such as animal husbandry (Refs. 7 and
in developed nations and that
1. No Significant Market in Developed 12). Large-scale and systematic
disproportionately affects poor and
Nations insecticide mosquito control programs,
marginalized populations’’ as a tropical
once considered a public health priority
disease. CHIKV disease occurs rarely in throughout the world due to yellow
In this document, FDA has applied its developed nations (Ref. 1). Outbreaks of fever virus, were largely dismantled due
August 2015 criteria as set forth in the CHIKV primarily occur in poor tropical to diminishing resources and are
final order to analyze whether regions where uncontrolled breeding of therefore not available in most
Chikungunya virus disease, Lassa fever, Aedes aegypti and Aedes albopictus developing nations (Ref. 13).
rabies, and cryptococcal meningitis mosquitoes occurs in close proximity to Although CHIKV infection is rarely
meet the statutory criteria for addition humans due to inadequate sanitation fatal, CHIKV sequelae have a major
to the tropical disease list. and poor living conditions (Ref. 7). For impact on productivity and economics
II. Diseases Being Designated example, in 2015, more than 700,000 in developing nations (Ref. 7). CHIKV
suspected or confirmed cases of CHIKV outbreaks are often explosively large,
FDA has considered all diseases were reported in the Americas; with high attack rates and high rates of
submitted to the public docket (FDA– however, only 1,185 of those cases symptomatic disease (Refs. 1 and 3). An
2008–N–0567) between August 20, occurred in the United States (excluding outbreak in India in 2006 involved more
2015, and June 20, 2018, as potential territories) and Canada, all of which than 1.3 million suspected cases and
additions to the list of tropical diseases were imported (Refs. 8 and 9). The U.S. was associated with more than 25,000
under section 524 of the FD&C Act, territories of Puerto Rico and the U.S. Disability Adjusted Life Years (DALYs)
pursuant to the docket review process Virgin Islands reported 202 cases, all of lost (Ref. 14). A meta-analysis of 38
explained on the Agency’s website (see which were transmitted locally (Ref. 8). published studies confined to cases
daltland on DSKBBV9HB2PROD with NOTICES
https://www.fda.gov/AboutFDA/Centers There were no locally transmitted cases occurring in 2005 estimated that CHIKV
Offices/OfficeofMedicalProducts of CHIKV reported in Europe, Japan, led to up to 1 million years of healthy
andTobacco/CDER/ucm534162.htm). Australia, or New Zealand in 2015 (Ref. life lost and 1.5 million DALYs lost (Ref.
Based on an assessment using the 10). Even among U.S. military and 15).
criteria from its August 20, 2015, final military dependents, who are sometimes Neonates are particularly vulnerable
order, FDA has determined that the deployed to outbreak areas, CHIKV to serious complications of CHIKV
following additional diseases will be infection is rare; there were only 121 infection. Among neonates born 1 day
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![42908 Federal Register / Vol. 83, No. 165 / Friday, August 24, 2018 / Notices
significantly higher mortality and among immunocompetent individuals, that CM also disproportionately affects
treatment failure rates in developing raised concerns about a new serious these populations.
countries (Ref. 45). Park, et al. (2009) infectious disease risk for people Given the factors described above,
estimated that, excluding HIV/AIDS, residing in or traveling to the Pacific FDA has determined that CM meets
CM is the fourth leading cause of death Northwest states. However, there have both statutory criteria of ‘‘no significant
in sub-Saharan Africa, causing more been only 60 cases reported to CDC market in developed nations’’ and
deaths than tuberculosis (Ref. 46). between 2004 and 2010 (Ref. 49). U.S. ‘‘disproportionately affects poor and
cases continue to be reported at a marginalized populations.’’ Therefore,
1. No Significant Market in Developed FDA is designating cryptococcal
Nations relatively low rate, 20–23 cases per year
each in 2012 and 2013 (Ref. 50). The meningitis as a tropical disease under
Immunocompromised patients are emergence of C. gattii in the United section 524 of the FD&C Act.
typically the most vulnerable States has not resulted in a large number
population to develop serious III. Process for Requesting Additional
of cases that could potentially warrant Diseases To Be Added to the List
manifestations from infection with a significant market for treatment or
Cryptococcus, and the prevalence of CM prevention. The purpose of this order is to add
is closely linked to the prevalence of diseases to the list of tropical diseases
Therefore, in the United States and
untreated and poorly managed HIV/ that FDA has found to meet the criteria
other developed countries, there does
AIDS. There has been a reduction in the in section 524(a)(3)(S) of the FD&C Act.
not appear to be a significant market for
incidence of CM in the United States By expanding the list with this order,
developing new drugs or vaccines for
and other developed nations due to the FDA does not mean to preclude the
the treatment or prevention of CM.
availability of antiretroviral therapy and addition of other diseases to this list in
Additionally, given the low incidence of
lower rates of individuals with the future. Interested persons may
CM and the low risk of infection to
advanced HIV/AIDS (Ref. 42). Per the submit requests for additional diseases
immunocompetent individuals, it is
CDC, national estimates of the incidence to be added to the list to the public
unlikely that antifungal therapies
of cryptococcosis are difficult to docket established by FDA for this
specifically directed against CM will
establish because it is only reportable in purpose (see https://
become a national stockpiling priority
a few states (id.). In 2000, a population- www.regulations.gov, Docket No. FDA–
in the foreseeable future.
based surveillance study in two U.S. 2008–N–0567). Such requests should be
metropolitan areas estimated that the 2. Disproportionately Affects Poor and accompanied by information to
annual incidence of cryptococcosis Marginalized Populations document that the disease meets the
among persons with AIDS was between criteria set forth in section 524(a)(3)(S)
2 and 7 cases per 1,000, and the overall CM is not currently designated by
of the FD&C Act. FDA will periodically
incidence was 0.4 to 1.3 cases per WHO as a Neglected Tropical Disease
review these requests, and, when
100,000 (Ref. 47). As of 2009, Pyrgos, et (Ref. 17). Additionally, no DALY data
appropriate, expand the list. For further
al. estimated that approximately 3,400 were found to distinguish the disease
information, see https://www.fda.gov/
annual hospitalizations were associated burden of CM in developing versus
AboutFDA/CentersOffices/Officeof
with CM in the United States (Ref. 48). developed countries. However, the
MedicalProductsandTobacco/CDER/
Given that the overwhelming majority of incidence of CM is high in developing
ucm534162.htm.
patients diagnosed with CM in the countries due to limited access to
United States will initiate therapy in the antiretroviral therapy to treat HIV IV. Paperwork Reduction Act
hospital, FDA considers 3,400 annually infection (Ref. 42). Annually, there are This final order reiterates the ‘‘open’’
a rough estimate of the number of cases approximately 1 million cases of CM status of the previously established
of CM in the United States. Based on the worldwide in patients with HIV/AIDS public docket through which interested
CDC treatment guidelines for CM, FDA and 625,000 deaths (Ref. 46). persons may submit requests for
estimates that most CM patients will Approximately 75 percent of these additional diseases to be added to the
receive at least 1 year of therapy. infections are in sub-Saharan Africa list of tropical diseases that FDA has
Therefore, even if the proportion of CM (id.). The case fatality rate for CM found to meet the criteria in section
patients on therapy at any given time is patients living in sub-Saharan Africa is 524(a)(3)(S) of the FD&C Act. Such a
50 times the annual incidence of CM, 35 to 65 percent, compared to a 10- to request for information is exempt from
the prevalence of CM in the United 20-percent case fatality rate in most Office of Management and Budget
States remains below 0.1 percent of the developed nations (Ref. 51). review under 5 CFR 1320.3(h)(4) of the
population. The HIV epidemic imposes a Paperwork Reduction Act of 1995 (44
Clinical practice guidelines for the particular burden on women and U.S.C. 3501–3520). Specifically, ‘‘[f]acts
management of cryptococcal disease do children, specifically in sub-Saharan or opinions submitted in response to
not routinely recommend primary Africa where women account for general solicitations of comments from
antifungal prophylaxis for approximately 57 percent of all people the public, published in the Federal
cryptococcosis in HIV-infected patients living with HIV (Ref. 52). In 2012, there Register or other publications,
in the United States and Europe. This were an estimated 260,000 newly regardless of the form or format thereof’’
recommendation is based on the relative infected children in low- and middle- are exempt, ‘‘provided that no person is
infrequency of cryptococcal disease, income countries (id.). Children with required to supply specific information
lack of survival benefits, potential for HIV are more likely to face gaps in pertaining to the commenter, other than
drug-drug interactions, creation of direct access to HIV treatment. For example, in that necessary for self-identification, as
daltland on DSKBBV9HB2PROD with NOTICES
antifungal drug resistance, medication 2012, approximately 34 percent of a condition of the agency’s full
compliance, and costs. Routine primary children had access to HIV treatment consideration of the comment.’’
prophylaxis for cryptococcosis is also versus approximately 64 percent for
not currently recommended in adults (id.). As CM is most prevalent in V. References
transplant recipients (Ref. 44). persons infected with HIV and HIV The following references are on
The emergence of C. gattii in the disproportionately impacts women and display at the Dockets Management Staff
Pacific Northwest in 2004, primarily children, it is reasonable to conclude (see ADDRESSES) and are available for
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![42910 Federal Register / Vol. 83, No. 165 / Friday, August 24, 2018 / Notices
Expert_Consultation_on_Rabies_Post- 52. Joint United Nations Programme on HIV/ Abstract: The purpose of the public
exposure_Prophylaxis.pdf (accessed AIDS (UNAIDS), ‘‘Global Report: health system assessment surveys is to
January 9, 2017). UNAIDS Report on the Global AIDS inform the Secretary’s Discretionary
39. See https://armypubs.army.mil/ Epidemic 2013;’’ available at http:// Advisory Committee on Heritable
ProductMaps/PubForm/AR_ files.unaids.org/en/media/unaids/
Details.aspx?ID=0902c85180010355 contentassets/documents/epidemiology/
Disorders in Newborns and Children
(accessed May 5, 2017). 2013/gr2013/UNAIDS_Global_Report_ (Committee) on the ability to add
40. CDC, ‘‘Cost of Rabies Prevention,’’ 2013_en.pdf (accessed August 8, 2016). newborn screening for particular
updated August 3, 2015; available at conditions within a state, including the
Dated: August 21, 2018.
https://www.cdc.gov/rabies/location/ feasibility, readiness and overall
usa/cost.html (accessed February 9, Leslie Kux, Associate Commissioner for capacity to screen for a new condition.
2017). Policy. The Committee was established under
41. Gullo, F.P., S.A. Rossi, J.C. Sardi, et al., [FR Doc. 2018–18314 Filed 8–23–18; 8:45 am] Section 1111 of the Public Health
‘‘Cryptococcosis: Epidemiology, Fungal BILLING CODE 4164–01–P Service Act, 42 U.S.C. 300b–10, as
Resistance, and New Alternatives for
Treatment,’’ European Journal of Clinical
amended in the Newborn Screening
Microbiology and Infectious Diseases, Saves Lives Reauthorization Act of
DEPARTMENT OF HEALTH AND 2014. The Committee is governed by the
32:1377–1391, 2013.
42. CDC, ‘‘C. neoformans Infection HUMAN SERVICES provisions of the Federal Advisory
Statistics;’’ available at https:// Committee Act, as amended (5 U.S.C.
www.cdc.gov/fungal/diseases/ Health Resources and Services App.), which sets forth standards for the
cryptococcosis-neoformans/ Administration formation and use of advisory
statistics.html (accessed August 8, 2016). committees. The purpose of the
43. Makadzange, A.T. and G. McHugh, ‘‘New Agency Information Collection
Activities: Submission to OMB for Committee is to provide the Secretary
Approaches to the Diagnosis and
Review and Approval; Public Comment with recommendations, advice, and
Treatment of Cryptococcal Meningitis,’’
Seminars in Neurology, 34(1):47–60, Request; The Secretary’s Discretionary technical information regarding the
2014. Advisory Committee on Heritable most appropriate application of
44. Perfect, J.R., W.E. Dismukes, F. Dromer, technologies, policies, guidelines, and
Disorders in Newborns and Children’s
et al., ‘‘Clinical Practice Guidelines for standards for: (a) Effectively reducing
Public Health System Assessment
the Management of Cryptococcal morbidity and mortality in newborns
Surveys OMB No. 0906–0014—Revised
Disease: 2010 Update by the Infectious and children having, or at risk for,
Disease Society of America,’’ Clinical AGENCY: Health Resources and Services heritable disorders; and (b) enhancing
Infectious Diseases, 50:291–322, 2010. the ability of state and local health
Administration (HRSA), Department of
45. Rothe, C., D.J. Sloan, P. Goodson, et al., agencies to provide for newborn and
‘‘A Prospective Longitudinal Study of Health and Human Services.
child screening, counseling, and health
the Clinical Outcomes from Cryptococcal ACTION: Notice.
Meningitis Following Treatment care services for newborns and children
Induction with 800 mg Oral Fluconazole SUMMARY: In compliance with of the having, or at risk for, heritable
in Blantyre, Malawi,’’ PLOS One, Paperwork Reduction Act of 1995, disorders. Specifically, the Committee
8(6):e67311, 2013. HRSA has submitted an Information makes systematic evidence-based
46. Park, B.J., K.A. Wannemuehler, B.J. Collection Request (ICR) to the Office of recommendations on newborn screening
Marston, et al., ‘‘Estimation of the Management and Budget (OMB) for for conditions that have the potential to
Current Global Burden of Cryptococcal change the health outcomes for
Meningitis Among Persons Living with
review and approval. Comments
submitted during the first public review newborns.
HIV/AIDS,’’ AIDS, 23:525–530, 2009. The Committee tasks an external
47. Mirza, S.A., M. Phelan, D. Rimland, et al., of this ICR will be provided to OMB.
OMB will accept further comments from workgroup to conduct systematic
‘‘The Changing Epidemiology of
the public during the review and evidence-based reviews for conditions
Cryptococcosis: An Update from
Population-Based Active Surveillance in being considered for addition to the
approval period.
2 Large Metropolitan Areas, 1992–2000,’’ Recommended Uniform Screening
DATES: Comments on this ICR should be Panel, and their corresponding newborn
Clinical Infectious Diseases, 36(6):789–
794, 2003. received no later than September 24, screening test(s), confirmatory test(s),
48. Pyrgos, V., A.E. Seitz, C.A. Steiner, et al., 2018. and treatment(s). Reviews also include
‘‘Epidemiology of Cryptococcal ADDRESSES: Submit your comments to an analysis of the benefits and harms of
Meningitis in the US: 1997–2009,’’ PLOS newborn screening for a selected
paperwork@hrsa.gov or mail the HRSA
One, 8(2):e56269, 2013. condition at a population level and an
49. CDC, ‘‘Emergence of Cryptococcus Information Collection Clearance
Officer, Room 14N136B, 5600 Fishers assessment of state public health
gattii—Pacific Northwest, 2004–2010,’’
Lane, Rockville, MD 20857. newborn screening programs’ ability to
Morbidity and Mortality Weekly Report,
59(28):865–868, 2010 available at https:// implement the screening of a new
FOR FURTHER INFORMATION CONTACT: To
www.cdc.gov/mmwr/preview/ condition.
request a copy of the clearance requests Need and Proposed Use of the
mmwrhtml/mm5928a1.htm?s_ submitted to OMB for review, email Lisa
cid=mm5928a1_w. Information: HRSA proposes that the
50. Espinel-Ingroff, A. and S.E. Kidd,
Wright-Solomon, the HRSA Information data collection surveys be administered
‘‘Current Trends in the Prevalence of Collection Clearance Officer at by the Committee’s external Evidence
Cryptococcus Gattii in the United States paperwork@hrsa.gov or call (301) 443– Review Group to all state newborn
and Canada,’’ Infection and Drug 1984. screening programs in the United States
daltland on DSKBBV9HB2PROD with NOTICES
Resistance, 8:89–97, May 11, 2015. SUPPLEMENTARY INFORMATION: up to twice a year for two conditions.
51. WHO, ‘‘Rapid Advice: Diagnosis,
Information Collection Request Title: The surveys were developed to capture
Prevention and Management of
Cryptococcal Disease in HIV-Infected The Secretary’s Discretionary Advisory the following: (1) The readiness of state
Adults, Adolescents and Children,’’ Committee on Heritable Disorders in public health newborn screening
December 2011; available at http:// Newborns and Children’s Public Health programs to expand newborn screening
www.who.int/hiv/pub/cryptococcal_ System Assessment Surveys OMB No. to include the target condition; (2)
disease2011/ (accessed August 8, 2016). 0906–0014—Revised. specific requirements of screening for
VerDate Sep<11>2014 19:17 Aug 23, 2018 Jkt 244001 PO 00000 Frm 00052 Fmt 4703 Sfmt 4703 E:\FR\FM\24AUN1.SGM 24AUN1](https://thefederalregister.org/doc/83_FR_43069/page/7.svg)
Document Created: 2018-08-24 04:13:38
Document Modified: 2018-08-24 04:13:38
| Category | Regulatory Information | |
| Collection | Federal Register | |
| sudoc Class | AE 2.7: GS 4.107: AE 2.106: | |
| Publisher | Office of the Federal Register, National Archives and Records Administration | |
| Section | Notices | |
| Action | Final order. | |
| Dates | This order is effective August 24, 2018. | |
| 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 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, [email protected] | |
| FR Citation | 83 FR 42904 |
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