1. Professor of Medicine-Geriatrics Duke University and Durham VA
4/21/2018
Lessons Learned from an AGS Researcher: Pitfalls and Pay-offs of Changing Policy
Kenneth Schmader, MD
Professor of Medicine-Geriatrics
Duke University and Durham VA
Medical Centers

2. Disclosures
Grant support from Merck & Co.

3. From Bench To Bedside

4. 4/21/2018
Zoster Vaccine
Live, attenuated, cell-free preparation of Oka strain VZV
Contains whole live virus and viral antigen

6. Effect of Zoster Vaccine on Incidence of Herpes Zoster
4/21/2018
Effect of Zoster Vaccine on Incidence of Herpes Zoster
Efficacy (95% CI)
51.3% ( )
63.9% (( ))
37.6% ( ) 14 12 10
11.1
11.5
10.7
Incidence of herpes zoster (per 1000 person years) 8
7.2 6
5.4
The zoster vaccine significantly reduced the overall incidence of herpes zoster by 51.3%. Thus, when extrapolated to the general population, and based on an estimated incidence of 1 million cases per year, vaccination of individuals at risk has the potential to prevent more than 500,000 cases of herpes zoster per year. 4
3.9 2
All Subjects
Age 60–69
≥70 n
19,254
19,247
10,370
10,356
8884
8891
Placebo
Zoster Vaccine Live
Oxman MN et al. N Engl J Med 2005;352:

7. Effect of Zoster Vaccine on Incidence of Postherpetic Neuralgia
4/21/2018
Effect of Zoster Vaccine on Incidence of Postherpetic Neuralgia
Efficacy (95% CI)
66.5% ( )
65.7% ( )
66.8% ( )
2.5
2.0
2.13
1.5
Incidence of PHN (per 1000 person years)
1.38
1.0
Importantly, the zoster vaccine significantly reduced the incidence of PHN by approximately 66% in all subjects, demonstrating a reduction in the severity of the disease. It is important to note that this reduction is in ALL subjects, not just those with HZ who would be at risk of PHN. The PI looked at the PHN data a bit differently and this is shown in the next slide.
0.74
0.71
0.5
0.46
0.26
All Subjects
Age 60–69
≥70 n
19,254
19,247
10,370
10,356
8884
8891
Placebo
Zoster Vaccine Live
Oxman MN et al. N Engl J Med 2005;352:

8. A Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia
Volume 352:
June 2, 2005
Number 22
A Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia
in Older Adults
M.N. Oxman, M.D., M.J. Levin, M.D., G.R. Johnson, M.S., K.E. Schmader, M.D., S.E. Straus, M.D., L.D. Gelb, M.D., R.D. Arbeit, M.D., M.S. Simberkoff, M.D., A.A. Gershon, M.D., L.E. Davis, M.D., A. Weinberg, M.D., K.D. Boardman, R.Ph., H.M. Williams, R.N., M.S.N., J. Hongyuan Zhang, Ph.D., P.N. Peduzzi, Ph.D., C.E. Beisel, Ph.D., V.A. Morrison, M.D., J.C. Guatelli, M.D., P.A. Brooks, M.D., C.A. Kauffman, M.D., C.T. Pachucki, M.D., K.M. Neuzil, M.D., M.P.H., R.F. Betts, M.D., P.F. Wright, M.D., M.R. Griffin, M.D., M.P.H., P. Brunell, M.D., N.E. Soto, M.D., A.R. Marques, M.D., S.K. Keay, M.D., Ph.D., R.P. Goodman, M.D., D.J. Cotton, M.D., M.P.H., J.W. Gnann, Jr., M.D., J. Loutit, M.D., M. Holodniy, M.D., W.A. Keitel, M.D., G.E. Crawford, M.D., S.-S. Yeh, M.D., Ph.D., Z. Lobo, M.D., J.F. Toney, M.D., R.N. Greenberg, M.D., P.M. Keller, Ph.D., R. Harbecke, Ph.D., A.R. Hayward, M.D., Ph.D., M.R. Irwin, M.D., T.C. Kyriakides, Ph.D., C.Y. Chan, M.D., I.S.F. Chan, Ph.D., W.W.B. Wang, Ph.D., P.W. Annunziato, M.D., J.L. Silber, M.D., for the Shingles Prevention Study Group

9. To Policy . . .

10. FDA Licensure for Zoster Vaccine Center for Biologics Evaluation and Research (CBER) (2006)
“Indicated for prevention of herpes zoster (shingles) in individuals 60 years of age and older.”

11. Vaccine Efficacy for Incidence of PHN in Patients with Herpes Zoster
4/21/2018
Vaccine Efficacy for Incidence of PHN in Patients with Herpes Zoster
Efficacy (95% CI) 50
Placebo
Zoster Vaccine Live 40
26% (–69%, 68%) 30
55%
(18%, 76%)
% of Zoster Cases with Postherpetic Neuralgia
39%* (7%, 59%)
25.5 20
5% (–107%, 56%)
17.2
18.9
This slide comes from information from the Zostavax Package Insert. It is here to highlight some of the differences in how the data was interpreted between the SPS and the PI. While the Shingles Prevention Study showed vaccine efficacy for PHN within the entire study population, the FDA recommended the vaccine efficacy for PHN should include only those patients with Herpes Zoster. This brought the overall Vaccine efficacy for incidence of PHN from 66% (SPS) to 39% (PI). This also explains why Zostavax is indicated only for the prevention of HZ, not PHN. 10
12.5
8.6
6.9
7.7
6.6
All Subjects
Age 60–69
70–79
≥80
Number of PHN Cases 80 23 45 12 27 8 7
Number of HZ Cases
642
334
261 47
315
122
156 37
*Age-adjusted estimate based on the age strata at randomization.
Oxman MN et al. N Engl J Med 2005;352:

14. Incidence of herpes zoster (per 1000 person years)
4/21/2018
Effect of Zoster Vaccine on Incidence of Herpes Zoster in Year Old Persons
Efficacy (95% CI)
69.8% ( )
Design: RCT, blinded, zoster vaccine
vs. placebo
Participants: Immunocompetent adults
no prior zoster, years old
Setting: Multicenter international
Measures: Incidence of herpes zoster
Follow-up: 2 years ( ) 10 8
Incidence of herpes zoster (per 1000 person years) 6
6.59
The zoster vaccine significantly reduced the overall incidence of herpes zoster by 51.3%. Thus, when extrapolated to the general population, and based on an estimated incidence of 1 million cases per year, vaccination of individuals at risk has the potential to prevent more than 500,000 cases of herpes zoster per year. 4 2
1.99 n
11,228
11,211
Placebo
Schmader KE et al. Clin Infect Dis 2012;54:922-8
Zoster Vaccine

15. FDA Licensure for Zoster Vaccine Center for Biologics Evaluation and Research (CBER) (2011)
“Indicated for prevention of herpes zoster (shingles) in individuals 50 years of age and older.”

16. ACIP CDC Recommendation Update on Herpes Zoster Vaccine: Licensure for Persons Aged 50 Through 59 Years
“In June 2011, the Advisory Committee on Immunization Practices (ACIP) declined to recommend the vaccine for adults aged 50 through 59 years and reaffirmed its current recommendation that herpes zoster vaccine be routinely recommended for adults aged 60 years and older.”
MMWR November 11, 2011 / 60(44);

17. Recommended Adult Immunization Schedule: United States, 2013

18. Barriers Among Primary Care Physicians to Administering Herpes Zoster Vaccine in the Office
Major Barrier
Somewhat of a Barrier
Cost concerns for my patients 53 30
Reimbursement problems for my practice 52 25
Up-front costs for purchasing the vaccine 43 21
Need to store the vaccine in a freezer in a separate sealed compartment 16 20
More pressing medical issues taking precedence over this vaccine 12 23
Difficulty obtaining the vaccine 13
Hurley LP et al. Ann Intern Med 2010;152:

19. U.S. Adult Vaccine Financing Policy
No uniform financing mechanism for adult vaccines
Medicare Part B pays
Influenza
Pneumococcal vaccine,
Td if injured
Hepatitis B for intermediate to high risk individuals
What to do with other/new vaccines?
CMS uses Medicare Part D instead of Part B

20. Lessons Learned
Policy making agencies may not interpret your data the way you do . . .may come to different decisions that you would
Agency purviews may overlap . . .and they may disagree on policy
Your findings or product may need to generate new policy or it may not fit well in existing policy
Important to know how the policy making agency works at the time you are designing your study
This stuff takes a lot of time