[Federal Register Volume 83, Number 165 (Friday, August 24, 2018)]
[Notices]
[Pages 42896-42899]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-18313]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

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


Notice of Decision Not To Designate Pneumocystis Pneumonia as a 
Tropical Disease

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or Agency), in response 
to suggestions submitted to Docket No. FDA-2008-N-0567, has analyzed 
whether Pneumocystis pneumonia (PCP) meets the statutory criteria for 
designation as a tropical disease for the purposes of obtaining a 
priority review voucher (PRV) under the Federal Food, Drug, and 
Cosmetic Act (FD&C Act), namely whether it primarily affects poor and 
marginalized populations and whether there is ``no significant market'' 
for drugs that prevent or treat PCP in developed countries. The Agency 
has determined that PCP does not meet the statutory criteria for 
designation as a tropical disease and declines to designate it as such.

DATES: 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, [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, 800-835-4709 or 240-402-8010, 
[email protected].

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background: Priority Review Voucher Program
II. Decision Not To Designate Pneumocystis Pneumonia
    A. Significant Market in Developed Nations
    B. Disproportionately Affects Poor and Marginalized Populations
    C. FDA Determination
III. Process for Requesting Additional Diseases To Be Added to the 
List
IV. Paperwork Reduction Act
V. References

I. Background: Priority Review Voucher Program

    Section 524 of the FD&C Act (21 U.S.C. 360n), which was added by 
section 1102 of the Food and Drug Administration Amendments Act of 2007 
(FDAAA), uses a PRV incentive to encourage the development of new 
drugs, including biologics, 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.
    In August 2015, FDA published a final order (80 FR 50559, August 
20, 2015) (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)(R) of the FD&C Act, which authorizes the 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.
    FDA has applied its August 2015 criteria as set forth in the final 
order to analyze whether PCP meets the statutory criteria for addition 
to the tropical disease list. As discussed below, the Agency has 
determined that PCP does not meet the statutory criteria for 
designation as a ``tropical disease'' and thus will not add it to the 
list of tropical diseases whose applications may be eligible for a 
priority review voucher.

II. Decision Not To Designate Pneumocystis Pneumonia

    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, under the docket review process explained on the 
Agency's website (see

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https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm534162.htm). Based on an 
assessment using the criteria from its final order, FDA has determined 
that PCP will not be designated as a ``tropical disease'' under section 
524 of the FD&C Act.
    Pneumocystis species are genetically distinct, host-specific 
opportunistic fungal pathogens widely found in nature. Pneumocystis 
jirovecii, found in humans, causes PCP in immunocompromised patients. 
Human immunodeficiency virus (HIV)-infected patients with a low CD4 
count are at the highest risk of PCP. Others at substantial risk 
include hematopoietic cell and solid organ transplant recipients, those 
with cancer (particularly hematologic malignancies), and those 
receiving glucocorticoids, chemotherapeutic agents, and other 
immunosuppressive medications. Among patients with acquired 
immunodeficiency syndrome (AIDS) and PCP, the mortality rate is 10 to 
20 percent during the initial infection, but the rate increases 
substantially when the patient requires mechanical ventilation. The 
mortality rate among patients with PCP in the absence of AIDS is 30 to 
60 percent, depending on the population at risk, with a greater risk of 
death among patients with cancer than among patients undergoing 
transplantation or those with connective tissue disease (Ref. 1).

A. Significant Market in Developed Nations

    In developed nations, a sizable market exists for PCP prophylaxis 
drugs. The prevalence of stage-3 AIDS by year end 2014 in the United 
States (i.e., with AIDS requiring PCP prophylaxis) was approximately 
530,000 (Ref 2). In addition, approximately 30,000 solid organ 
transplantations (Ref. 3) and 19,000 hematopoietic stem cell 
transplants (Ref. 4) are performed annually in the United States. These 
patients receive PCP prophylaxis for 6 months to one year in the post-
transplantation period. There were also about 6,590 new cases of acute 
lymphocytic leukemia (ALL) eligible for PCP prophylaxis in the United 
States in 2016 (Ref. 5).
    Regarding treatment of PCP, the incidence of PCP has declined 
substantially with widespread use of PCP prophylaxis and anti-
retroviral therapy (ART) (see, e.g., Refs. 6-9). In a prospective 
cohort study of 8070 participants at 12 HIV clinics across the United 
States, the incidence in 2003-2007 was <1 case per 100 person-years 
(Ref. 10). PCP now mainly occurs in individuals who are unaware that 
they are HIV positive, lack access to medical care, or are noncompliant 
with medications.
    In contrast to HIV-positive patients, the incidence of PCP in non-
HIV patients is rising in some areas (see, e.g., Refs. 8, 9, 11); 
however, the number of cases in non-HIV patients is still below the 
number of cases in HIV-positive patients (Ref. 12). In the United 
States, the incidence of PCP is estimated to be 9 percent among 
hospitalized HIV/AIDS patients and 1 percent among solid organ 
transplant recipients (Ref. 13).
    Current clinical guidelines recommend chemoprophylaxis against 
primary PCP for HIV infected persons with a CD4 cell count <200 cells/
[micro]L or a history of oral candidiasis (Ref. 14). As indicated 
above, the prevalence of stage-3 HIV infection (i.e., AIDS requiring 
PCP prophylaxis) by year end 2014 in the United States was 
approximately 530,000 patients, including 18,303 patients diagnosed 
with stage-3 HIV infection in 2015 (Ref. 2). These subjects were 
eligible for PCP prophylaxis.
    In summary, a sizable market in developed nations exists for drugs 
indicated for prevention of PCP. At present, FDA is unaware of any 
significant funding by military, the Biomedical Advanced Research and 
Development Authority (BARDA), or any other United States Government 
sources for drug development targeting treatment of or prophylaxis 
against PCP.

B. Disproportionately Affects Poor and Marginalized Populations

    Although no disability-adjusted life year (DALY) data were found to 
distinguish the disease burden of PCP in developing versus developed 
countries, it is noted that PCP occurs frequently among HIV-infected 
patients in many parts of the developing world. In addition, the 
prevalence of HIV-infected persons with PCP ranges from 24 percent (42/
177) in Mexico (Ref. 15) to 55 percent in Thailand (Ref. 16). A 
Brazilian study found 55 percent (15/27) of HIV-infected persons with 
respiratory symptoms had PCP (Ref. 17).
    Studies estimating the burden of fungal infections in different 
countries suggest low total yearly number of PCP cases in Belgium (n = 
120), in contrast, for example, to 9,600 cases among HIV-infected 
people in Tanzania in 2012 (Refs. 18 and 19). In Uganda, the frequency 
of PCP among HIV-infected patients hospitalized with suspected 
pneumonia who had negative sputum acid-fast bacilli smears and 
underwent bronchoscopy decreased from nearly 40 percent of 
bronchoscopies between 1999 and 2000 to less than ten percent between 
2007 and 2008 (Ref. 20). However, it is estimated that there are 
approximately 800 HIV-positive adults with PCP annually and up to 
42,000 children with PCP annually in Uganda (Ref. 21). In Vietnam, the 
prevalence of PCP was 608 cases in 2012, 1149 cases per year in Senegal 
and 990 cases yearly in Nepal (HIV positive individuals) (Refs. 22, 23, 
24). In Ukraine, 13.5 per 100,000 individuals develop PCP annually 
(Ref. 25).
    High rates of anti-Pneumocystis antibodies among African children 
suggest that exposure to the organism is common, and that Pneumocystis 
jirovecii is a common cause of pneumonia among children in sub-Saharan 
Africa (Ref. 26). Furthermore, limited diagnostic resources and less 
commonly performed induced sputum and bronchoalveolar lavage with 
reliance on empiric therapy may cause underestimation of the true 
incidence of PCP (Ref. 27). Several studies suggest that the incidence 
of PCP is increasing in Africa (Refs. 26, 28, 29).
    PCP has been reported to be a leading cause of death in HIV-
infected infants, responsible for at least one quarter of all pneumonia 
deaths in HIV-infected infants (Ref. 30). A recent review found PCP to 
be one of the factors strongly associated with mortality from acute 
lower respiratory infections in children under five years of age in 
low-income economies, lower-middle-income economies, and upper-middle-
income economies (referred to as low- and middle-income countries 
(LMICs)), with odds ratio of 95 percent confidence interval of 4.79, 
2.67-8.61 (Ref. 31). However, the incidence of PCP in infants and 
children in developed countries has decreased because PCP prophylaxis 
has been initiated in all neonates born to HIV-positive mothers (Refs. 
32 and 33).
    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. 34). In 
2012, there were an estimated 260,000 newly infected children in LMICs 
(id.). Children with HIV are more likely to face gaps in access to HIV 
treatment. In 2012, approximately 34 percent of children had access to 
HIV treatment versus approximately 64 percent for adults (id.). Since 
PCP is the most prevalent in persons infected with HIV (Ref. 1) and HIV 
disproportionately impacts women and children, it is reasonable to 
conclude that PCP also disproportionately affects these populations.

[[Page 42898]]

    PCP has not been designated by the World Health Organization (WHO) 
as a neglected tropical disease (Ref. 35).

C. FDA Determination

    In sum, although PCP disproportionately affects poor and 
marginalized populations, it is an infectious disease for which there 
is a significant market in developed nations for drugs indicated for 
prevention of PCP. Based on the information reviewed, FDA has 
determined that PCP does not meet the statutory criteria for a tropical 
disease in section 524 of the FD&C Act.

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

    FDA's current determination regarding PCP does not preclude 
interested persons from requesting its consideration in the future. To 
facilitate the consideration of future additions to the list, FDA 
established a public docket (see https://www.regulations.gov, Docket 
No. FDA-2008-N-0567) through which interested persons may submit 
requests for additional diseases to be added to the list. 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 notice 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 have been placed on display at the Dockets 
Management Staff (see ADDRESSES). They may be seen by interested 
persons between 9 a.m. and 4 p.m. Monday through Friday and are 
available electronically at https://www.regulations.gov. (FDA has 
verified the website addresses, but FDA is not responsible for any 
subsequent changes to the websites after this document publishes in the 
Federal Register.)

1. Thomas, C.F., Jr. and A.H. Limper, ``Pneumocystis Pneumonia,'' 
The New England Journal of Medicine, 350(24):2487-2498, June 10, 
2004.
2. Centers for Disease Control and Prevention (CDC), ``HIV 
Surveillance Report, 2015,'' vol. 27, November 2016, available at 
https://www.cdc.gov/hiv/library/reports/hiv-surveillance.html, 
accessed January 19, 2017.
3. United Network for Organ Sharing, ``Annual Reports,'' accessed 
December 16, 2016, available at https://www.unos.org/about/annual-report/.
4. The U.S. Health Resources and Services Administration, 
``Transplant Activity Report: Total Transplants by Year,'' accessed 
January 19, 2017, available at https://bloodcell.transplant.hrsa.gov/research/transplant_data/transplant_activity_report/index.html.
5. The American Cancer Society, ``Key Statistics for Acute 
Lymphocytic Leukemia,'' accessed January 19, 2017, available at 
http://www.cancer.org/cancer/leukemia-acutelymphocyticallinadults/detailedguide/leukemia-acute-lymphocytic-key-statistics.
6. Miller, R.F., L. Huang, and P.D. Walzer, ``Pneumocystis Pneumonia 
Associated with Human Immunodeficiency Virus,'' Clinics in Chest 
Medicine, 34(2):229-241, June 2013.
7. Morris, A., J.D. Lundgren, H. Masur, et al., ``Current 
Epidemiology of Pneumocystis Pneumonia,'' Emerging Infectious 
Diseases, 10(10):1713-720, October 2004.
8. Azoulay, E., A. Bergeron, S. Chevret, N. Bele, et al., 
``Polymerase Chain Reaction for Diagnosing Pneumocystis Pneumonia in 
Non-HIV Immunocompromised Patients with Pulmonary Infiltrates,'' 
Chest, 135(3):655-661, March 2009.
9. Gamaletsou, M.N., M. Drogari-Apiranthitou, D.W. Denning, et al., 
``An Estimate of the Burden of Serious Fungal Diseases in Greece,'' 
European Journal of Clinical Microbiology & Infectious Diseases 
(official publication of the European Society of Clinical 
Microbiology), 35(7):1115-1120, July 2016.
10. Buchacz, K., R.K. Baker, F.J. Palella, Jr., et al., ``AIDS-
Defining Opportunistic Illnesses in US patients, 1994-2007: A Cohort 
Study,'' AIDS, 24(10):1549-1559, Jun 19, 2010.
11. Maini, R., K.L. Henderson, E.A. Sheridan, et al., ``Increasing 
Pneumocystis Pneumonia, England, UK, 2000-2010,'' Emerging 
Infectious Diseases, 19(3):386-392, March 2013.
12. Walzer, P.D. and A.G. Smulian, ``Pneumocystis species,'' in: 
Mandell, G.L., Bennett, J.E., Dolin, R., eds. Mandell, Douglas, and 
Bennett's Principles and Practice of Infectious Disease, 7th ed. PA: 
Elsevier; 2010, 3377-90.
13. CDC, Fungal Diseases, ``Pneumocystis Pneumonia,'' February 21, 
2018, available at https://www.cdc.gov/fungal/diseases/pneumocystis-pneumonia, accessed November 21, 2016.
14. Kaplan, J.E., H. Masur, K.K. Holmes, et al., ``USPHS/IDSA 
Guidelines for the Prevention of Opportunistic Infections in Persons 
Infected with Human Immunodeficiency Virus: A Summary,'' USPHS/IDSA 
Prevention of Opportunistic Infections Working Group, Clinical 
Infectious Diseases: An Official Publication of the Infectious 
Diseases Society of America, 21(Suppl 1):S12-31, August 1995.
15. Mohar, A., J. Romo, F. Salido, et al., ``The Spectrum of 
Clinical and Pathological Manifestations of AIDS in a Consecutive 
Series of Autopsied Patients in Mexico,'' AIDS, 6(5):467-473, May 
1992.
16. Wannamethee, S.G., S. Sirivichayakul, A. N. Phillips, et al., 
``Clinical and Immunological Features of Human Immunodeficiency 
Virus Infection in Patients from Bangkok, Thailand,'' International 
Journal of Epidemiology, 27(2):289-295, April 1998.
17. Weinberg, A. and M.I. Duarte, ``Respiratory Complications in 
Brazilian Patients Infected with Human Immunodeficiency Virus,'' 
Revista do Instituto de Medicina Tropical de Sao Paulo, 35(2):129-
139, March-April 1993.
18. Lagrou, K., J. Maertens, E. Van Even, et al., ``Burden of 
Serious Fungal Infections in Belgium,'' Mycoses, 58(Suppl 5):1-5, 
October 2015.
19. Faini, D., W. Maokola, W., H. Furrer, et al., ``Burden of 
Serious Fungal Infections in Tanzania,'' Mycoses, 58(Suppl 5):70-79, 
October 2015.
20. Worodria, W., J.L. Davis, A. Cattamanchi, et al., ``Bronchoscopy 
is Useful for Diagnosing Smear-Negative Tuberculosis in HIV-Infected 
Patients,'' The European Respiratory Journal, 36(2):446-448, August 
2010.
21. Parkes[hyphen]Ratanshi, R., B. Achan, R. Kwizera, et al., 
``Cryptococcal Disease and the Burden of Other Fungal Diseases in 
Uganda; Where are the Knowledge Gaps and How Can We Fill Them?'' 
Mycoses, 58(Suppl 5):85-93, October 2015.
22. Beardsley, J., D.W. Denning, N.V. Chau, et al., ``Estimating the 
Burden of Fungal Disease in Vietnam,'' Mycoses, 58(Suppl 5):101-106, 
October 2015.
23. Badiane, A.S., D. Ndiaye, D.W. Denning, ``Burden of Fungal 
Infections in Senegal,'' Mycoses, 58(Suppl 5):63-69, October 2015.
24. Khwakhali, U.S. and D.W. Denning, ``Burden of Serious Fungal 
Infections in Nepal,'' Mycoses, 58(Suppl 5):45-50, October 2015.

[[Page 42899]]

25. Osmanov, A. and D.W. Denning, ``Burden of Serious Fungal 
Infections in Ukraine,'' Mycoses, 58(Suppl 5): 94-100, October 2015.
26. Morrow, B.M., N.Y. Hsaio, M. Zampoli, et al., ``Pneumocystis 
Pneumonia in South African Children with and Without Human 
Immunodeficiency Virus Infection in the Era of Highly Active 
Antiretroviral Therapy,'' The Pediatric Infectious Disease Journal, 
29(6):535-539, June 2010.
27. Stansell, J.D., D.H. Osmond, E. Charlebois, E., et al., 
``Predictors of Pneumocystis carinii Pneumonia in HIV-Infected 
Persons. Pulmonary Complications of HIV Infection Study Group,'' 
American Journal of Respiratory and Critical Care Medicine, 
155(1):60-66, January 1997.
28. Wasserman, S., M.E. Engel, M. Mendelson, ``Burden of 
Pneumocystis Pneumonia in HIV-Infected Adults in Sub-Saharan Africa: 
Protocol for a Systematic Review,'' Systematic Reviews, 2:112, 
December 12, 2013.
29. Fisk, D.T., S. Meshnick, S., and P.H. Kazanjian, ``Pneumocystis 
carinii Pneumonia in Patients in the Developing World Who Have 
Acquired Immunodeficiency Syndrome,'' Clinical Infectious Diseases: 
An Official Publication of the Infectious Diseases Society of 
America, 36(1):70-78, January 1, 2003.
30. de Boer, M.G., J.W. de Fijter, F.P. Kroon, ``Outbreaks and 
Clustering of Pneumocystis Pneumonia in Kidney Transplant 
Recipients: A Systematic Review,'' Medical Mycology, 49(7):673-680, 
October 2011.
31. Sonego, M., M.C. Pellegrin, G. Becker, et al., ``Risk Factors 
for Mortality from Acute Lower Respiratory Infections (ALRI) in 
Children under Five Years of Age in Low and Middle-Income Countries: 
A Systematic Review and Meta-Analysis of Observational Studies,'' 
PLOS One, 10(1):e0116380, 2015.
32. Morris, A., J.D. Lundgren, H. Masur, et al., ``Current 
Epidemiology of Pneumocystis Pneumonia,'' Emerging Infectious 
Diseases, 10(10):1713-1720, October 2004.
33. Avino, L.J., S.M. Naylor, A.M. Roecker, ``Pneumocystis jirovecii 
Pneumonia in the Non-HIV-Infected Population,'' The Annals of 
Pharmacotherapy, 50(8):673-679, August 2016.
34. Joint United Nations Programme on HIV/AIDS (UNAIDS), ``Global 
Report: UNAIDS Report on the Global AIDS Epidemic 2013,'' accessed 
December 9, 2016, available at http://files.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2013/gr2013/UNAIDS_Global_Report_2013_en.pdf.
35. WHO, ``Neglected Tropical Diseases,'' accessed December 9, 2016, 
available at http://www.who.int/neglected_diseases/diseases/en/.

    Dated: August 21, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-18313 Filed 8-23-18; 8:45 am]
 BILLING CODE 4164-01-P