The Ten Greatest Public Health Achievements of the 20th Century Outline of Presentation Statistical Issues in addition to Challenges in Combination Vaccines

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The Ten Greatest Public Health Achievements of the 20th Century Outline of Presentation Statistical Issues in addition to Challenges in Combination Vaccines

Bethany College California, US has reference to this Academic Journal, Statistical Issues in addition to Challenges in Combination Vaccines Ivan S. F. Chan, Ph.D. Merck Research Laboratories Sang Ahnn, Ph.D. CBER, FDA 2005 FDA/Industry Statistics Workshop Washington D.C. September 14-16, 2005 Note: Sang Ahnn’s opinions are his own in addition to do not necessarily reflect FDA policy Outline of Presentation Introduction of vaccine development Combination vaccines Statistical considerations in consideration of combination vaccine studies Special challenges A recent example Summary The Ten Greatest Public Health Achievements of the 20th Century Vaccination Motor-vehicle safety Safer workplaces Control of infectious diseases Decline in deaths from coronary heart disease in addition to stroke Safer in addition to healthier foods Healthier mothers in addition to babies Family planning Fluoridation of drinking water Recognition of tobacco use as a health hazard MMWR (1999);48:1141

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Vaccines Are Different From Drugs Typically in consideration of prophylaxis, not treatment Focus on vaccines in consideration of children traditionally, alongside recent shift so that adult vaccines Public health issues Risk benefits at individual vs population level Indirect vaccine effect (herd immunity) Highly complex immunologic milieu Array of humoral in addition to cellular immune responses Large, complex molecules of biological origin Unique manufacturing in addition to control issues Clinical Development of Vaccines Safety Assess local (injection-site) in addition to systemic adverse experiences Need a large database, particularly because of giving vaccines so that healthy subjects Efficacy Require a high level of evidence in addition to precision Success typically requires showing efficacy greater than a non-zero (e.g. 25% – 50%) lower bound Clinical Development of Vaccines Immunogenicity Important in understanding the biology Antibody responses ? priming, first defense T-cell responses ? prevent virus reactivation, kill infected cells Correlates of protection (?surrogate? endpoints) in addition to immune markers used in consideration of bridging studies (e.g., new vs. old formulations) assessing consistency of vaccine manufacturing process assessing combination vaccines or concomitant use of vaccines

Combination Vaccines Offer multiple vaccines (or vaccines alongside multiple sero-type antigens) at one administration Reduce the number of injections given so that children (fear of injection ?needle?) Reduce infant crying time in addition to cost associated alongside parental perceptions of pain in addition to emotional distress Reduce the frequency of clinic visits Increase vaccination coverage in addition to public health benefits Examples of Combination Vaccine Diphtheria/Tetanus/Pertussis (DTaP) Hepatitis A/Hepatitis B Hepatitis B/Haemophilus Influenza b Measles/Mumps/Rubella (MMR) Measles/Mumps/Rubella/Varicella (MMRV) An Example of Combination Vaccine: MMRV (ProQuad?) Combines two well-established vaccines M-M-R? II in consideration of measles, mumps, in addition to rubella (licensed in 1978) VARIVAX? in consideration of chickenpox (licensed in 1995) Clinical development of ProQuad starts in 1984 Includes over 5800 subjects Provides similar immunogenicity in addition to safety profiles compared alongside component vaccines Licensed on Sept 6, 2005

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Statistical Considerations in consideration of Combination Vaccine Studies Noninferiority design Analysis methods Consistency lots study Study Design of Combination Vaccines Aim is so that show non-inferiority of combination vaccine compared so that separately administered components Immune responses are the key measures Percent of subjects achieving a response (definition depends on specific vaccines) Geometric mean titer (or concentration) Evaluate potential interactions on immune responses in addition to safety among components Typical Non-inferiority Analysis Setup in Combination Vaccine Trials Hypothesis of response rate in consideration of each component: H0: PT – PC ? – ? versus H1: PT – PC > – ? where ?>0 is a prespecified non-inferiority margin Hypothesis of geometric mean titer in consideration of each component: H0: GMTT/GMTC ? R versus H1: GMTT/GMTC > R where 095% in addition to the noninferiority margins are 5 pct points For varicella, the expected response rate is ~90% in addition to the noninferiority margin is 10 pct points For antibody titers, the margin is 1.5 fold-difference in consideration of the GMTs in consideration of each component Analysis Approaches so that Combination Vaccine Trials Noninferiority analysis in consideration of response rates: Asymptotic (e.g., Miettinen & Nurminen 1985) Exact (e.g., Chan in addition to Zhang 1999, Chan 2002, 2003) Confidence interval (CI) in consideration of ? Test-based methods provide consistency alongside p-value CI lower bound is > (-?) if in addition to only if the non-inferiority is demonstrated Regression (ANCOVA) in consideration of GMT analysis

Power in addition to Sample Size Determination Asymptotic (Farrington in addition to Manning 1990) or exact (Chan 2002) methods Power is sensitive so that the true responses best case scenario is PT = PC (or GMTT = GMTC ) useful so that assess power assuming PT (or GMTT) slightly less than PC (or GMTC) Need so that evaluate overall power in consideration of demonstrating success in consideration of all components Consistency Lots Study For licensure of a new vaccine, consistency of the manufacturing process must be supported by clinical trials using at least 3 lots of the vaccine Objective of study is so that show equivalence of clinical response among consistency lots Evaluate both immune responses in addition to safety For combination vaccine, an active control may be included so that demonstrate ?assay sensitivity? First demonstrate lot consistency Then combine data from consistency lots so that show noninferiority so that active control Analysis of Consistency Lots Study Hypothesis of interest: H0: |Pi ? Pj| ? ? in consideration of at least one pair (i, j) vs. H1: |Pi ? Pj| < ? in consideration of every pair Same as testing 3 pairs of noninferiority hypotheses H0: |P1 ? P2| ? ? ? H0A: P1 ? P2 ? ? or H0B: P2 ? P1 ? ? Test each hypothesis at one-sided 5% level i.e., requiring 90% CI completely within [-?, ?] Control overall type I error rate at 5% Example: Consistency Lots Study in consideration of MMRV Study enrolled ~4000 subjects 3 lots of MMRV in addition to an active control (MMR+V) 1st step: showed consistency of 3 MMRV lots Antibody response rates in addition to GMTs in consideration of measles, mumps, rubella, in addition to varicella 24 pairwise comparisons 2nd step: showed the combined responses of MMRV is noninferior so that those of MMR + V 8 comparisons Some Challenges of Developing Combination Vaccines Statistical challenge alongside multiple endpoints Clinical challenge alongside potential interaction among components on immunogenicity in addition to safety Formulation issues Compatibility of components/Stability? Multiplicity Challenge alongside Combination Vaccines Major impact on power in addition to sample size because of the need so that show success on all components Impact even more in consistency lots study Accounting in consideration of correlation among components only increases power slightly May consider multivariate analysis (e.g. T2 test)? Multiplicity Hit on Power in addition to Sample Size Combination Vaccine Studies Challenges of Potential Interaction alongside Combination Vaccines Potential interactions among components are difficult so that predict Immune responses may be lower Safety concern may arise A new dose-response study may be needed so that re-establish the optimal dosing Examples of Interactions: MMRV Vaccine Interaction observed in early clinical studies Suboptimal varicella responses A new dose-response study (N>1500) established optimal potency range in consideration of varicella Acceptable varicella responses But more fever (?102 F) in addition to measles-like rash A large database (N>5800) confirms that MMRV is well tolerated Both fever in addition to measles-like rash were transient in addition to resolved alongside no long-term complications

Formulation Issues alongside ProQuadTM M-M-R? II is refrigerated product VARIVAXTM is frozen product European market needs refrigerated combination vaccine ? how so that develop? First, develop frozen ProQuad so that gain regulatory approval Then, introduce refrigerated ProQuad via manufacturing supplement (a 4-6 months regulatory review time) Summary Combination vaccines provide substantial public health benefits Immune marker in addition to selection of endpoints in addition to margins are important so that the development of combination vaccines Special considerations in consideration of studies of consistency lots Potential interactions among components in addition to multiplicity of endpoints pose special challenges References Blackwelder WC. Similarity/equivalence trials in consideration of combination vaccines. Combined Vaccines in addition to Simultaneous Administration (ed by Williams JC,Goldenthal KL, Burns DL, Lewis BP), Ann New York Acad Sciences 1995;754:321-328. Chan ISF in addition to Zhang Z. Test-based exact confidence intervals in consideration of the difference of two binomial proportions. Biometrics 1999; 55: 1202-1209. Chan ISF. Power in addition to sample size determination in consideration of non-inferiority trials using an exact method. Journal of Biopharmaceutical Statistics 2002; 12: 457-469. Chan ISF. Proving non-inferiority or equivalence of two treatments alongside dichotomous endpoints using exact methods. Statistical Methods in Medical Research 2003; 12 (1): 37-58. Chan ISF, Wang WWB, Heyse J. Vaccine clinical trials. Encyclopedia of Biopharmaceutical Statistics, 2nd Edition, 2003, 1005-1022. Farrington CP in addition to Manning G. Test statistics in addition to sample size formulae in consideration of comparative binomial trials alongside null hypothesis of non-zero risk difference or non-unity relative risk. Statistics in Medicine 1990; 9, 1447-1454. FDA: Guidance in consideration of industry in consideration of the evaluation of combination vaccines in consideration of preventable diseases: production, testing in addition to clinical studies. 1997. FDA.GOV/CBER/gdlns/combvacc.pdf. Kuter B, Hartzel J, Schodel F. The Challenges of Developing a combination Measles, Mumps, Rubella & Varicella Vaccine (ProQuad?), ESPID symposium, Valencia, Spain, May 2005. Miettinen O in addition to Nurminen M. Comparative analysis of two rates. Statistics in Medicine 1985; 4, 213-226.

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This Particular Journal got reviewed and rated by Formulation Issues alongside ProQuadTM M-M-R? II is refrigerated product VARIVAXTM is frozen product European market needs refrigerated combination vaccine ? how so that develop? First, develop frozen ProQuad so that gain regulatory approval Then, introduce refrigerated ProQuad via manufacturing supplement (a 4-6 months regulatory review time) Summary Combination vaccines provide substantial public health benefits Immune marker in addition to selection of endpoints in addition to margins are important so that the development of combination vaccines Special considerations in consideration of studies of consistency lots Potential interactions among components in addition to multiplicity of endpoints pose special challenges References Blackwelder WC. Similarity/equivalence trials in consideration of combination vaccines. Combined Vaccines in addition to Simultaneous Administration (ed by Williams JC,Goldenthal KL, Burns DL, Lewis BP), Ann New York Acad Sciences 1995;754:321-328. Chan ISF in addition to Zhang Z. Test-based exact confidence intervals in consideration of the difference of two binomial proportions. Biometrics 1999; 55: 1202-1209. Chan ISF. Power in addition to sample size determination in consideration of non-inferiority trials using an exact method. Journal of Biopharmaceutical Statistics 2002; 12: 457-469. Chan ISF. Proving non-inferiority or equivalence of two treatments alongside dichotomous endpoints using exact methods. Statistical Methods in Medical Research 2003; 12 (1): 37-58. Chan ISF, Wang WWB, Heyse J. Vaccine clinical trials. Encyclopedia of Biopharmaceutical Statistics, 2nd Edition, 2003, 1005-1022. Farrington CP in addition to Manning G. Test statistics in addition to sample size formulae in consideration of comparative binomial trials alongside null hypothesis of non-zero risk difference or non-unity relative risk. Statistics in Medicine 1990; 9, 1447-1454. FDA: Guidance in consideration of industry in consideration of the evaluation of combination vaccines in consideration of preventable diseases: production, testing in addition to clinical studies. 1997. FDA.GOV/CBER/gdlns/combvacc.pdf. Kuter B, Hartzel J, Schodel F. The Challenges of Developing a combination Measles, Mumps, Rubella & Varicella Vaccine (ProQuad?), ESPID symposium, Valencia, Spain, May 2005. Miettinen O in addition to Nurminen M. Comparative analysis of two rates. Statistics in Medicine 1985; 4, 213-226. and short form of this particular Institution is US and gave this Journal an Excellent Rating.