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

1. Clinical Vaccine Development
A Practical US Perspective
Robert W Malone, MD, MS
http://www.rwmalonemd.com

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. 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. 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. 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. 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. 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. 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. 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. 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. Key Guidance (ICH and CBER)
• Vaccine approval process
• Good Clinical Practices (GCP)
• Vaccine-specific guidance
• Adverse event recording
• Animal Rule
• Accelerated approval

12. Key Guidance (ICH and CBER)
Vaccine Approval Process
(http://www.fda.gov/Cber/vaccine/vacappr.htm)
• 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. 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. Key Guidance (ICH and CBER)
GCP (ICH Section E6)
(http://www.fda.gov/cder/guidance/959fnl.pdf )
• 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 http://distance.jhsph.edu/vactrial/ for excellent
vaccine-specific GCP on-line training course

15. Key Guidance (ICH and CBER)
Vaccine-specific guidance
• See http://www.fda.gov/Cber/vaccine/vacpubs.htm 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. Key Guidance (ICH and CBER)
Adverse event recording
• See ―Toxicity Grading Scale for Healthy Adult and
Adolescent Volunteers Enrolled in Preventive Vaccine
Clinical Trials‖ (http://www.fda.gov/Cber/gdlns/toxvac.htm)
• 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. 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)
(http://www.fda.gov/Cber/rules/humeffic.htm)
• See also ―Animal Models — Essential Elements to
Address Efficacy Under the Animal Rule‖ (Sept 2008)
(http://www.fda.gov/cder/guidance/8324concept.pdf)

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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 http://www.fda.gov/Cber/gdlns/combvacc.txt

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. 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. 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. 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. Clinical Vaccine Development
A Practical US Perspective
Robert W Malone, MD, MS
http://www.rwmalonemd.com
• 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:
marketing@biopractice.com