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Clinical Vaccine Development Introduction


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Basic introduction to clinical vaccine development from a US (CBER) perspective

Clinical Vaccine Development Introduction

  1. 1. Clinical Vaccine Development A Practical US Perspective Robert W Malone, MD, MS
  2. 2. Clinical Vaccine Development A Practical US Perspective • General considerations for advanced vaccine development • Review of key ICH and CBER Guidance • Safety, immunogenicity, route, dosing and boosting • Endpoints and correlates • Multi-component vaccines • Clinical trials and expediting results
  3. 3. General Considerations Why are the pathways for vaccine clinical development and licensure different from other drugs and biologicals? • Indication • Safety • Efficacy • Disease incidence • Disease risk factors • Benefits to individuals and populations • Phases of clinical vaccine development
  4. 4. General Considerations Indication • Licensure is based on – Specific indications – Risk/benefit analysis (for all drugs) • Vaccines are usually indicated for individuals free of the disease for use to prevent the disease – Prophylactic vaccines (typical) – Therapeutic vaccines (the exception, developmental) • Specific populations – Often indicated for administration to pediatric and geriatric populations – Individual recipients may not be competent to consent to procedure • Indications may involve infection, disease or symptoms
  5. 5. General Considerations Safety • When individual risk of disease is low, safety (to the individual) of intervention must be very high • The vaccine is typically administered to large numbers of people, therefore rare adverse events will occur (to individuals) • Vaccines (and vaccine adjuvants) are typically designed to elicit an inflammatory response, which can compromise associated tissues (such as adjacent nerves) • Pathogens may evolve antigens which resemble host antigens (risk of autoimmune disease) • Immune responses to antigens, adjuvants, and pathogens vary between individuals
  6. 6. General Considerations Efficacy/Effectiveness • Efficacy/Effectiveness is a function of many factors – Dose of pathogen (almost any vaccine can be overwhelmed) – Route of exposure (mucosal vs parenteral) – Co-morbidity – Poorly understood environmental factors – Host immune status (ex: Helmenth burden) – Prior exposure to related pathogens (or antigens) • Efficacy/Effectiveness can be measured for the individual or emerge from aspects of the population (herd immunity) • Protection from infection vs. protection from disease
  7. 7. General Considerations Disease Incidence • Risk/benefit analysis for vaccines is strongly influenced by disease incidence and severity – Example Smallpox (vaccinia), pre-eradication vs. biodefense – Example Polio (OPV vs IPV) • Disease incidence often varies due to environmental and geographical factors – Yellow fever (Latin America vs. North America) • Disease incidence often varies over time – Significant challenge when powering clinical efficacy trials
  8. 8. General Considerations Disease Risk Factors • Risk of infection (and disease) for any one random individual is often low – Influenza risk = annually 36/100 in US – Measles risk = 0.15 cases/million (US, 2003) • Morbidity and Mortality may vary • Risk of infection and disease may vary – Regional and seasonal fluctuations (Influenza, Polio, etc.) – Epidemic outbreaks may occur (Yellow Fever) – Environmental, socio-cultural factors or lifestyle • Risk may be voluntarily incurred – Travelers, military vaccines – Scientists working with select agents
  9. 9. General Considerations Benefits to individuals and populations • Risk (safety) of vaccination is primarily at the level of an individual (the vaccine recipient) • Benefit (efficacy) of vaccination conveys both to the individual as well as to the population – Herd immunity often contributes as much or more to the protection afforded (vaccination of the young may help protect the elderly) – Individuals may opt out to avoid individual safety risk, thereby increasing risk to the overall population – ―tragedy of the commons‖ can occur
  10. 10. General Considerations Phases of clinical vaccine development • Phase 1 (safety and immunogenicity) – Initial estimate of safety usually is the primary endpoint – Immunogenicity data is often collected (secondary objective) – Efficacy estimate unlikely unless correlate of protection – Often includes dose ranging with stopping rules – May include repeat dosing (―boosting‖) for initial safety – Typically healthy normal adults, rapid accrual! • Phase 2 (immunogenicity and safety) – Expanded dose ranging – IIa often dose timing (boosting strategy) – Testing in special populations • Phase 3 (efficacy and safety) – Often very large field trials (unless correlate of protection) • Phase 4 (post marketing safety surveillance, efficacy)
  11. 11. Key Guidance (ICH and CBER) • Vaccine approval process • Good Clinical Practices (GCP) • Vaccine-specific guidance • Adverse event recording • Animal Rule • Accelerated approval
  12. 12. Key Guidance (ICH and CBER) Vaccine Approval Process ( • pIND filing – Proof of concept – Manufacturing process (including adventitious agent testing) – Toxicology • IND filing – Full description of vaccine – Method of manufacture – QC for lot release and initial stability data – Safety/Toxicology – Ability to elicit a protective immune response (immunogenicity) in animal testing – Proposed Phase 1 clinical protocol for studies in humans, (summary of initial CDP through end of Phase 2 meeting)
  13. 13. Key Guidance (ICH and CBER) Vaccine Approval Process (continued) • Biologics License Application (BLA) – Requires efficacy and safety information necessary to make a risk/benefit assessment and to recommend or oppose the approval of a vaccine – Proposed manufacturing facility undergoes a pre-approval inspection during which production of the vaccine as it is in progress is examined – Sponsor and the FDA typically present their findings to FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC), which advises the Agency regarding the safety and efficacy of the vaccine for the proposed indication • Post allowance to market – Vaccine Adverse Event Reporting System (VAERS) used to identify problems after marketing – CDC ACIP recommends clinical usage guidelines
  14. 14. Key Guidance (ICH and CBER) GCP (ICH Section E6) ( ) • International standard of ethical and scientific quality for: – Trial design – Trial conduct – Data and outcomes recording and reporting • Origin in the Declaration of Helsinki • Compliance required for all trials involving human subjects • Designed to ensure that clinical trial data are credible, verifiable, and mutually acceptable • See for excellent vaccine-specific GCP on-line training course
  15. 15. Key Guidance (ICH and CBER) Vaccine-specific guidance • See for list of all vaccine-related guidance and rules from 1997 to 2008 • Examples of key recent guidance includes: – General Principles for the Development of Vaccines to Protect Against Global Infectious Diseases (Sept 2008) – Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (Sept 2007) – Clinical Data Needed to Support the Licensure of Pandemic Influenza Vaccines (May 2007) – Clinical Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines (May 2007)
  16. 16. Key Guidance (ICH and CBER) Adverse event recording • See ―Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials‖ ( • Specifies four categories – Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3) – Potentially Life Threatening (Grade 4) • Clinical Abnormalities – Local reactogenicity, Vital signs, Systemic signs, Systemic illness • Laboratory Abnormalities – Serum, Hematology, Urine • Should inform clinical trial design for safety outcomes and safety database structures
  17. 17. Key Guidance (ICH and CBER) Animal Rule (CFR 601.90) • When it is unethical or infeasible to conduct human efficacy studies, the FDA may grant marketing approval based on animal studies which establish that the drug or biological product is reasonably likely to produce clinical benefit in humans. Demonstration of the product‘s safety in humans is still necessary. • See ―New Drug and Biological Drug Products; Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible; Final Rule‖ (May 2002) ( • See also ―Animal Models — Essential Elements to Address Efficacy Under the Animal Rule‖ (Sept 2008) (
  18. 18. Key Guidance (ICH and CBER) Animal Rule (continued) • Application of the animal rule requires four criteria – Reasonably well-understood pathophysiological mechanism of the toxicity of the (chemical, biological, radiological, or nuclear) substance and its prevention or substantial reduction by the product – Effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model (meaning the model has been adequately evaluated for its responsiveness) for predicting the response in humans – The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity – The data or information on the (pharmaco) kinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans allows selection of an effective dose in humans
  19. 19. Key Guidance (ICH and CBER) Accelerated approval (21 CFR Part 601, Subpart E) • ―May be granted for certain biological products that have been studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments‖ (End of Phase 2 meeting) • Requirements: – Adequate and well-controlled clinical trials establishing that the biological product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity – Subject to the requirement that the sponsor study the biological product further – Postmarketing studies required to verify the clinical benefit
  20. 20. Clinical Development Considerations • Practical clinical development plan design considerations include – Safety – Effectiveness/Immunogenicity – Route of administration – Dosing – Boosting – Cohort selection – Endpoints and correlates – Multi-component and combination vaccines
  21. 21. Clinical Development Considerations Safety • Safety of the new vaccine should be well characterized in pre-licensure clinical trials • Local and systemic reactogenicity events should be well defined in all age groups for whom approval of the vaccine is sought • Six month safety follow up post last dose typically required (can be telephone contact) • Serious adverse events must be monitored and collected for all subjects throughout the duration of all studies – SAE: any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
  22. 22. Clinical Development Considerations Safety (continued) • Size of the overall safety database should be defined by – Range of the age indication(s) being sought – Signals raised during pre-clinical studies and early clinical studies – Amount of clinical experience associated with the particular manufacturing process – Adjuvant employed (if any) • For vaccines using novel manufacturing processes and/or adjuvants, laboratory safety tests including hematologic and clinical chemistry evaluations should be considered for initial studies • Typically a total safety database size of several thousand subjects in well controlled clinical trials
  23. 23. Clinical Development Considerations Effectiveness/Immunogenicity • Proof of effectiveness requires completion of controlled clinical investigations as defined in the provision for 'adequate and well-controlled studies‗ – Typically large Phase 3 field efficacy trial – Can include challenge trial in some situations – Study sample size calculations should be based on estimates of vaccine effectiveness and pathogen attack rates – Study should be powered to assess the lower bound of the two- sided 95% confidence interval (CI) of vaccine effectiveness, anticipated to be substantially above zero (e.g., in the range of 40 to 45%) – Immunogenicity evaluations in a substantial number of study participants are important elements of the clinical development plan and individual study design
  24. 24. Clinical Development Considerations Effectiveness/Immunogenicity (continued) • Immune response data collected in the course of a prospectively designed clinical endpoint efficacy study may lead to the establishment of an immune correlate of protection • Additional Studies to Support the Effectiveness of the Vaccine – Immunogenicity bridging studies can be conducted to compare the immune response to that observed in a clinical endpoint efficacy study – If an immune correlate of protection is defined, non- inferiority immunogenicity studies comparing a new vaccine to a U.S. licensed seasonal vaccine may be employed in some cases
  25. 25. Clinical Development Considerations Route of administration • Multiple routes of vaccine administration may be clinically investigated, each has potential advantages and disadvantages – Intranasal (Good for mucosal responses, may have increased risk of facial palsy and cranial nerve complications particularly combined with adjuvants, may require novel medical device) – Oral (Often less potent, most readily accepted route) – Intramuscular injection (Most traditional, may mask reactogenicity, good depot, potential risk of damage to nerve, vessel, or periosteum, may be less immunogenic than ID) – Subcutaneous (Another common route, with many of the same advantages and disadvantages of IM) – Intradermal (Difficult to master and reproduce Mantoux method, reactogenicity quite visible, may be more immunogenic)
  26. 26. Clinical Development Considerations Dosing • Relationship between dose and adaptive immune response is neither direct nor linear – Excessively high dosing can suppress adaptive immune response in some cases (―high zone tolerance‖) – Small doses can elicit very high levels of immune response if the subject has previously been exposed to the antigen (memory B, T cells, recall response) – Timing of immune response can vary (within one week for recall, within 2-3 weeks for primary) • Dose required to provide protection is a function of the pathogen challenge (enough pathogen can overwhelm) • Some evidence supporting reduced dose required when administered intradermally • Live attenuated vaccine risk increases with dose
  27. 27. Clinical Development Considerations Boosting • Booster immunization: An additional dose of an immunizing agent, such as a vaccine or toxoid, given at a time period of weeks to years after the initial dose to sustain the immune response elicited by the first dose – Adaptive immune responses ―evolve‖ or become increasingly specific and potent (hopefully!) over time – Short-term (2-3 weeks) ―boosting‖ may be required for full immunological differentiation and development of protective levels of immune response – Longer-term booster immunizations (months to years) may or may not be required to maintain protection – May need to comply with existing vaccine schedules – Timing may be critical, and must be determined empirically • High zone tolerance • Existing antibody may sequester antigen, reducing boost effect
  28. 28. Clinical Development Considerations Cohort selection • Initial safety studies (Phase 1) typically employ non- pregnant healthy normal adults 18 – 49y of age • Pre-existing or intra-study exposure to pathogen or related antigens will compromise immunogenicity analyses – Screening is problematic, as serum immune responses can drop below detection, yet memory B and T cells remain – Short term blood draw (7 days) post initial dose can help detect ―recall‖ immune responses • Seasonal and geographical fluctuations in disease incidence must inform cohort selection for all phases • ―Stepping‖ into special populations (pediatric, elderly, immunocompromised) must be preceded by demonstrating safety in related lower risk cohort
  29. 29. Clinical Development Considerations Endpoints and correlates • Safety endpoints – See CBER guidance ―Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials‖ – All studies should capture ―clinical abnormalities‖ – Initial studies may require analysis of ―laboratory abnormalities‖ • Efficacy endpoints – Protection from disease, the gold standard, may require very large (10,000 subjects or more) field trials – In some cases (lower risk pathogens, healthy adult populations), challenge studies may be employed and may inform immunologic correlates of protection – If correlates of protection have been validated (rare, especially for new vaccines!) then immunologic efficacy endpoints may be accepted
  30. 30. Clinical Development Considerations Multi-component and combination vaccines • Complexity of existing vaccine schedules (particularly pediatric) drives development of increasingly complex vaccine formulations designed to simultaneously protect against multiple pathogens – Example: diphtheria, tetanus, pertussis, polio and hepatitis B – Can complicate analysis of adverse events – Adding additional antigenic components can reduce efficacy/immunogenicity (potency) of the others • Inclusion of adjuvants or multiple biologically active components in formulation will require demonstration of contribution of each component to efficacy, and may also require independent safety analysis • See
  31. 31. Accelerating clinical vaccine testing • In contrast to many areas of clinical research, subject accrual and dosing for even large vaccine trials can be very rapid – Interventional aspects of Phase 1 and 2 trials can be completed in weeks if properly planned and coordinated – Requires carefully coordinated sites and pre-screened subjects – Randomization, monitoring and data management tasks can easily overwhelm clinical operations and monitoring staff – Rapid accrual and dosing can outpace ability of DSMB/SMC to assess safety signals in a timely fashion • Tools and techniques for accelerating vaccine trials include – Classical project management tools such as Gantt charts – Careful cost analysis and projections – Call centers for safety follow up
  32. 32. Accelerating clinical vaccine testing Benefits of integrated approach to productivity CRO Services Quality Reduced/ Reliable Productivity Timelines Control Risk Mitigation Cost Effective Clinical Patient Sites Management Vaccine trials benefit from careful control and coordination of planning, data management, clinical sites, and patient management. An investment in planning, site pre-qualification, and productivity management can yield substantial returns in reduced cost, improved quality, and reduced time to study completion and final report
  33. 33. Accelerating clinical vaccine testing Managing patient flow to avoid bottlenecks Qualification Visit A C B Review Study Design/Informed Consent Educate on Clinical Patient Recruitment: Project Plan: Trials/Research Strategy Implementation Patient Flow Discuss Compensation Branding/Market Exposure: (debit cards/checks) Resource Allocation Database Mailings/Direct Mail Review Appointment Patient Feasibility Assessment Visit Schedule Previous Participants % of Population Distribute Accelovance Material to Sites Patient Motivation Pen & Calendar Print Advertising Subjective Factors Internet Advertising Patient Pool Colleague/Doctor Network Public Transportation Send: Appointment Community Positions Reminder Magnet First Responders Send: Appointment Reminder RSVP Government Workers Reminder Calls Prior to College/Med School Students/Staff . . . Patient Pool Appointment Community Affairs/Education Health Fairs Community Events D Art Festivals Flea Markets Spring Concert Series Clinical Operations Month 1 Month 2 Month 3 -60 Days Study -90 Days -30 Days Day 1 Enrollment Period
  34. 34. Accelerating clinical vaccine testing Process planning and capacity forecasting Example Study Parameters: 2,878 Subjects Enrolled; 2,590 Randomized; 178 Average Enrolled/week; 160 Average Randomized/Week Capacity Forecast Study Week PATIENT POOLING 1 2 3 4 5 6 7 8 Patient Visits 150 200 225 250 250 275 325 325 178 340 340 500 660 660 660 756 # of Pts Enrolled 178 358 538 718 898 1,078 1,258 1,438 # of Pts Random - 160 320 480 640 800 960 1,120 CRC Hours 112.5 150.0 168.8 187.5 187.5 206.3 243.8 243.8 267.0 590.0 590.0 750.0 830.0 830.0 830.0 862.0 CRC FTEs 2.81 3.75 4.22 4.69 4.69 5.16 6.09 6.09 8.90 19.67 19.67 25.00 27.67 27.67 27.67 28.73 VAC Hours - 40.0 40.0 80.0 80.0 80.0 80.0 80.0 VAC FTEs - 2.00 2.00 4.00 4.00 4.00 4.00 4.00 PI Hours 89.0 170.0 170.0 250.0 276.7 276.7 276.7 292.7 CRF Pages 2,136 3,760 3,760 4,880 5,680 5,680 5,680 6,064 Study Week 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Patient Visits 820 820 820 825 825 830 835 835 655 493 495 330 165 165 165 66 # of Pts Enrolled 1,618 1,798 1,978 2,158 2,338 2,518 2,698 2,878 # of Pts Random 1,280 1,440 1,600 1,765 1,930 2,095 2,260 2,425 2,590 CRC Hours 883.3 883.3 883.3 893.3 893.3 898.3 900.8 900.8 630.8 301.8 302.5 137.5 55.0 55.0 55.0 22.0 CRC FTEs 29.44 29.44 29.44 29.78 29.78 29.94 30.03 30.03 21.03 10.06 10.08 4.58 1.83 1.83 1.83 0.73 VAC Hours 80.0 80.0 80.0 81.3 81.3 82.5 82.5 82.5 82.5 41.3 41.3 - - - - - VAC FTEs 4.00 4.00 4.00 5.00 5.00 5.00 5.00 5.00 5.00 3.00 3.00 - - - - - PI Hours 303.3 303.3 303.3 305.8 305.8 308.3 309.2 309.2 219.2 137.2 137.5 55.0 27.5 27.5 27.5 11.0 CRF Pages 6,320 6,320 6,320 6,370 6,370 6,405 6,430 6,430 4,270 2,632 2,640 1,485 660 660 660 264
  35. 35. Clinical Vaccine Development A Practical US Perspective Robert W Malone, MD, MS • Question and answer session • Thanks for participating! • If you wish a copy of this presentation with the associated web links, please send an email requesting a copy to the following address: