TAN VaccineProduction CIC2009
Content
Vaccinations: From Production to Injection…And Safety?!
Litjen (L.J) Tan, MS, PhD Director, Medicine and Public Health American Medical Association
Disclosures and Disclaimer
This presenter has no financial relationships with a commercial entity producing vaccinerelated products and/or services The opinions expressed in this presentation are solely those of the presenter and do not necessarily represent the official position of the American Medical Association Thanks to Chris Colwell for his guidance in preparation of this presentation
A Coming Golden Age of Vaccines?
Significant investment of both public sector and private sector capital. One of the fastest growing sectors in the lifesciences industry. Global vaccine market in 2009 is $25 billion in 2009 Expected to sustain double digit growth to reach market of more than $100 billion by 2024.
Shifting Sands in Vaccine Manufacture
Major changes are occurring in the number of businesses involved in vaccine manufacture, and in the production systems used
There are fewer companies Costs are much higher There is a shift to cell-based processes
reduces allergenicity, optimize quality, and increases output
Shifting Sands in Vaccine Manufacture
Challenges that persist include:
Scale-up, affordability, and change of pace. Ensuring good laboratory and manufacturing process. Maintenance of product stability. Ensuring a 100% safe and effective product.
Shifting Sands in Vaccine Manufacture
Trends…
Increasing importance of time-to-market and flexibility in production to improve cost-effectiveness Thus, new technologies to simplify development and manufacturing become more important Increasing technology transfer from small biotechs to large pharma – impact of corporate culture? Prompted by pandemic preparedness, emerging markets will likely dominate vaccine manufacturing by 2023 – thus, globalization is viewed as the quickest way to develop a product and increase market access.
Vaccines: Inception to Market
Time consuming: 10 -12 years $500-800m or more expended in development costs
Trial sizes, costs, facilities, personnel, equipment Post-marketing commitments increasing Vaccine candidates must compete for investment dollars against other opportunities
Douglas RG. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:47. Ebbert GB, Mascolo ED. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:53. Ulmer JB, et al. Nat Biotechnol, 2006:24(11):1377.
NVAC. Pediatrics, 1999:104:942.
Vaccines: Inception to Market
Selective: a tiny fraction of vaccines entering Phase 1 trials make it to market
Increasing standards in development – complex interaction trials Increasingly risky, technically challenging research (more difficult targets / projects) Success rate from preclinical to launch is considerably lower than that of other biopharmaceuticals. (22% by one published estimate)
Douglas RG. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:47. Ebbert GB, Mascolo ED. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:53. Ulmer JB, et al. Nat Biotechnol, 2006:24(11):1377.
NVAC. Pediatrics, 1999:104:942.
Why do we vaccinate?
Vaccine, Good! Disease, Bad! Diseases eliminated from the US:
Disease Smallpox Polio Measles Rubella
Last Case* 1949 1979 1993 2004
*Indigenous case. Importations may occur except for smallpox,
which was eradicated from the planet in 1977
Return on Investment of Childhood Immunization Program
For each birth cohort vaccinated with 7 vaccines (DTaP, Td, Hib, Polio, MMR, Hep B, Varicella) routinely included in the schedule:
Society saves $33.4B in indirect costs Direct health care costs are reduced by $9.9B 33,000 lives are saved Almost 14M cases of disease are prevented For every dollar spent, vaccine programs save society $11
Zhou F et al. Arch Pediatr Adolesc Med 2005;159:1136-1144
Direct Benefit of Vaccination: Invasive Pneumococcal Disease (IPD) Among Children <5 Years of Age
Rate/100,000 children younger than 5 years All IPD Vaccine serotypes Before vaccine 100 80 2006 24 0.5
Source: CDC, Active Bacterial Core Surveillance/EIP Network
Annual Direct Medical Savings After Pneumococcal Conjugate Vaccine Introduced
Estimated reduction in direct medical expense for all-cause pneumonia in young children †* Estimated reduction in direct medical expense related to otitis media (ear infection) §*
$310 million
$460 million
† §
Source: Arch Ped Adol Med, Dec 2007; 161:1162-8 Source: Pediatrics, Feb 2008; 121:253-260 * Some other factors might contribute to the reductions
Indirect Benefit of Vaccination: Rates of PCV7-type Invasive Pneumococcal Disease among Adults, U.S., 1998/99-2006
70 60
Cases per 100,000
2006 vs. baseline >80 yrs >80: -90% (-93,-86) 65-79: -88% (-91,-83) 50-64: -84% (-87,-79) 18-49: -88% (-91,-86) 65-79 yrs 50-64 yrs 18-49 yrs
50 40 30 20 10 0
1998
1999
2000
2001
2002
2003
2004
2005
2006
Source: William Atkinson, CDC, unpublished data 2008
Our Success! Historical Comparison of Morbidity and Mortality for VPDs
Roush, S. W. et al. JAMA 2007;298:2155-2163.
Copyright restrictions may apply.
Our Success! Historical Comparison of Morbidity and Mortality for VPDs
Roush, S. W. et al. JAMA 2007;298:2155-2163.
Copyright restrictions may apply.
Value of a Healthy Vaccine Industry
More than two-thirds of vaccines approved worldwide in the last 25 years created in the U.S. Greater value has been placed on vaccines recently:
Allows vaccine divisions to compete more effectively for increased R&D dollars and other resources More attractive return on investment (ROI) Creates more stable revenue streams Increases vaccine business appeal to venture capitalists
Douglas RG. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:47. NVAC. Pediatrics 1999;104:942. Klein JO, Myers MG. Pediatrics 2006;117:2269.
Value of a Healthy Vaccine Industry
Greater ROI creates a positive environment for continued investment and development of new vaccines
After years of contraction, vaccine industry exhibiting positive signs of expansion Newly licensed vaccines: Meningococcal conjugate, TdaP, HPV, Rotavirus, zoster Interest in US influenza vaccine market
Examples
Douglas RG. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:47. NVAC. Pediatrics 1999;104:942. Klein JO, Myers MG. Pediatrics 2006;117:2269.
Vaccine Development Process
How Long?
Identify Antigens Produce Antigens Test in Animals Phase I Safety Immuno Phase II Dose Safety Phase III Efficacy Safety File License
7 - 12 Years
2 - 3 Years
2 - 3 Years
2 - 3 Years
1 - 3 Years
Research Phase
Early Development Phase
Late Development Phase
Registration Phase
Manufacturing Financial Risks
As development proceeds, trials become larger and costs increase Clinical development involves large number of subjects Vaccines must meet a high threshold of efficacy and safety Manufacture: Companies must commit to construction of production facilities well in advance of licensure
Decision must be made 4-5 years before licensure to avoid a gap between licensure and launch Manufacturing facilities (at $50-200m per facility) require validation and licensure for each product Dose capacity per facility not entirely flexible; if demand increases, new facilities may become necessary
Douglas RG. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:47.
Regulatory burden is increasing, particularly in the US
Number of patients enrolled in prelicensure clinical trials
Prevnar 39,000 Varivax 11,000
Rotateq 75,000 FluMist 38,000
PedvaxHIB™ 6,000 Recombivax HB 1,200
1980
2006
Complexity of Vaccine Manufacturing
Manufacturing processes are extremely complex & must meet stringent quality control criteria. Involves living organisms with inherent variability. Constantly evolving regulatory environment. Varying regulatory requirements across countries.
Complexity of Vaccine Manufacturing
Increasing sophistication of manufacturing and analytical technologies Validation necessary at key steps in the process
Any change in process may result in a different product Process changes necessitate additional or new validation tests
Continual capital upgrades associated with high regulatory standards, costly downtime, and requalification/validation Highly educated personnel Long cycle-time for production to lot release
Strict Engineering and Regulatory Parameters Incorporated from Design through Operation
Vaccine manufacturing facilities take years (4-5+) to design, construct, and qualify cGMPs (current Good Manufacturing Practices) are incorporated from beginning of design phase
Design of clean rooms, sterile utilities, strict segregation of product flow and personnel traffic, cleaning and sterilization techniques
Process equipment is specified, designed, and constructed months to years in advance
Strict Engineering and Regulatory Parameters Incorporated from Design through Operation
Construction standards for process equipment, sterile utilities, and clean rooms ensure integrity of equipment
Strict tolerances, high-grade materials of construction, specialized welding
Installation Qualification / Operation Qualification (“IQ/OQ”) and Validation are performed for processes and equipment
Dedicated protocols are developed, specifications and installation verified, operations tested to meet specifications, and repeated validation studies are performed IQ/OQ and Validation can take weeks to months for each process step after construction
Purity and Specifications of Product Monitored Throughout
Process protocols and Standard Operating Procedures are developed for all aspects of manufacturing Manufacturing documentation, automated monitoring, and logs allow for tracking, monitoring, and verifying process steps Detailed employee training programs are implemented and maintained Process parameters, facility environment, personnel flow, and equipment flow are executed and monitored per specifications and procedures
Purity and Specifications of Product Monitored Throughout
Product is tested in multiple steps across processes
„in-line‟ monitoring during processing, sampling for offline monitoring through process, batch quality tests Ensures consistency of product and intermediaries throughout the process
Each batch undergoes extensive testing for quality, purity, potency
In some cases 5%+ of product or intermediary is dedicated for use in testing
Pre- and Post-licensure Role of FDA
Ensures safety and effectiveness of vaccines
Regulation of development and testing through licensure Post-licensure monitoring of product and production facilities
Klein JO, Myers MG. Pediatrics 2006;117:2269. Douglas RG. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:47.
Pre- and Post-licensure Role of FDA
FDA also oversees compliance with Current Good Manufacturing Practices (cGMP)
Evolving standards that manufacturers must meet May increase cost by altering production process or requiring more extensive record keeping Advances in technology Facilities that produced safe, effective vaccine for decades may no longer meet cGMP Manufacturers must decide if major capital investment is justified This led to some companies making decisions to cease production of several vaccines
Klein JO, Myers MG. Pediatrics 2006;117:2269. Douglas RG. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:47.
Multiple Stakeholders
Described as a “delicate fabric of public and private collaboration” Manufacturers Distributors Recommending bodies
Advisory Committee on Immunization Practices American Academy of Pediatrics American Academy of Family Physicians American College of Obstetricians and Gynecologists
Multiple Stakeholders
Food and Drug Administration Centers for Disease Control and Prevention National Institutes of Health Department of Defense State, territorial public health officials VICP / ACCV Payers – Insurance, Government
Multiple Stakeholders
Vaccine success dependent on recommendation language
Physicians look for recommendations before immunizing Another step / time for uptake – particularly if timing not aligned Recommendation may differ from labeled indication Different from other drug products
Multiple Stakeholders
Changes to recommendations & requirements from any stakeholder can greatly impact manufacturers
E.g., change in formulations, altered distribution channels, time needed to increase production, change formulations, alter distribution channels, etc.
Benefit-risk challenging to communicate to general public Factors add to additional market uncertainty
Mechanisms to Ensure Safety of New Vaccines
The Vaccine Licensure Process
Lengthy, rigorous process through FDA
Takes 5 -10 years Costs estimated at hundreds of millions of dollars Required Phase IV studies post-licensure
Federal Advisory Committees
Advisory Committee for Immunization Practices (ACIP)
Recommendations for use of the vaccine involve a thorough examination of the published and unpublished data on the safety, efficacy, effectiveness, and costbenefits analyses of the vaccine.
Mechanisms to Ensure Safety of New Vaccines
Federal Advisory Committees
National Vaccine Advisory Committee (NVAC)
Recommendations on vaccine policy, programs, and delivery are made with an eye to achieving optimum prevention of adverse events associated with vaccine use NVAC currently holding stakeholder meetings on vaccine safety
Advisory Commission on Childhood Vaccines (ACCV)
Gives advice to the DHHS Secretary on issues pertaining to the National Vaccine Injury Compensation Program (VICP)
Mechanisms to Ensure Safety of New Vaccines
Vaccine Surveillance Mechanisms
Vaccine Identification Standards Initiative (VISI)
Each vaccine will have a bar-coded sticker that can be placed on the immunization record of the immunized patient Important information that can help assess who received which vaccine and at what location, potentially enabling adverse events to be tracked
Immunization Registries
Mechanisms to Ensure Safety of New Vaccines
Vaccine Surveillance Mechanisms
Vaccine Adverse Event Reporting System (VAERS)
Most significant national system All adverse events can be reported to VAERS, analyzed, and made known to the public Passive reporting system - thus an adverse event by definition may or may not be causally associated with the vaccine in question Helps generate hypotheses for potential associations between adverse events and vaccine administration
Not for hypothesis testing!
Mechanisms to Ensure Safety of New Vaccines
Evaluating Causality from Surveillance
Vaccine Safety Datalink (VSD) Project
Collaboration between the CDC and 8 health maintenance organizations (HMOs) Directed at testing the hypotheses that are raised by the adverse event reports Large-scale post-surveillance database that captures information that allows for calculation of incidence rates, attributable risks, and background rates of illness in the absence of vaccination Still not large enough to test certain hypotheses regarding very rare events
Mechanisms to Ensure Safety of New Vaccines
Evaluating Causality from Surveillance
Clinical Immunization Safety Assessment (CISA) Centers
Network of academic centers seeking to improve scientific understanding of vaccine safety at the individual patient level Once fully established, CISA centers will evaluate VAERS reports or referred cases, and select cases with merit for more enhanced follow-up and targeted clinical evaluation As part of the National Childhood Vaccine Injury Act, the IOM was specifically tasked to review the scientific literature on vaccine-related adverse events More recently, the CDC and the NIH commissioned the IOM to set up an Immunization Safety Review Committee
Institute of Medicine
The Vaccine Injury Compensation Program (VICP)
To ensure an adequate supply of vaccines To stabilize vaccine costs To establish and maintain an accessible and efficient forum for individuals found to be injured by certain vaccines Is - no-fault alternative to the traditional tort system that provides compensation to people found to be injured by certain vaccines
Summary
Vaccine development and ongoing production is costly, complex, challenging and risky Multiple stakeholders have an impact on vaccine approval, health-care provider and consumer uptake, production, etc. Vaccination remains one of public health‟s best preventive measures and must be recognized
A thriving industry benefits society by securing current vaccine supply and developing future vaccines Vaccine divisions must compete with other products for intra-company resources
Elaborate system of safety nets at both pre-FDA approval and post-FDA approval points to monitor and ensure the safety of new vaccines.
Thank You! Questions?
The Vaccine Injury Compensation Program (VICP) - Process
Claim plus supporting documentation (medical records, etc) is filed with US Court of Federal Claims; Court sends one copy of claim and docs. to Dept. of Justice. Once filed, case is assigned to a Special Masters by the Chief Special Masters. Plaintiff also sends one copy of claim plus all supporting documents to DHHS. HHS reviews claims, sends review to DOJ lawyer. DOJ lawyer reviews legal aspects of claim, adds HHS medical review and writes one combination report with a recommendation on the action requested by the plaintiff, which is sent to the plaintiff and to the Federal Claims Court.
The Vaccine Injury Compensation Program (VICP) - Process
Special Masters reviews the report and all supporting evidence and makes a decision. Special Masters can call status conferences or evidentiary hearings if necessary. If Special Masters decides to pay the claim, then plaintiff must stipulate in writing whether they are accepting or declining. If plaintiff does not file statement, it is assumed that plaintiff is accepting the judgment. It is at this point that the plaintiff can decline the judgment and file a civil action for damages. The plaintiff can also appeal first to the Court of Appeals for the Federal Circuit, and finally, to the U.S. Supreme Court. If an appeal is started, then the plaintiff has until after the appeal process to state whether s/he is accepting the Special Master's judgment or filing a civil action.
Litjen (L.J) Tan, MS, PhD Director, Medicine and Public Health American Medical Association
Disclosures and Disclaimer
This presenter has no financial relationships with a commercial entity producing vaccinerelated products and/or services The opinions expressed in this presentation are solely those of the presenter and do not necessarily represent the official position of the American Medical Association Thanks to Chris Colwell for his guidance in preparation of this presentation
A Coming Golden Age of Vaccines?
Significant investment of both public sector and private sector capital. One of the fastest growing sectors in the lifesciences industry. Global vaccine market in 2009 is $25 billion in 2009 Expected to sustain double digit growth to reach market of more than $100 billion by 2024.
Shifting Sands in Vaccine Manufacture
Major changes are occurring in the number of businesses involved in vaccine manufacture, and in the production systems used
There are fewer companies Costs are much higher There is a shift to cell-based processes
reduces allergenicity, optimize quality, and increases output
Shifting Sands in Vaccine Manufacture
Challenges that persist include:
Scale-up, affordability, and change of pace. Ensuring good laboratory and manufacturing process. Maintenance of product stability. Ensuring a 100% safe and effective product.
Shifting Sands in Vaccine Manufacture
Trends…
Increasing importance of time-to-market and flexibility in production to improve cost-effectiveness Thus, new technologies to simplify development and manufacturing become more important Increasing technology transfer from small biotechs to large pharma – impact of corporate culture? Prompted by pandemic preparedness, emerging markets will likely dominate vaccine manufacturing by 2023 – thus, globalization is viewed as the quickest way to develop a product and increase market access.
Vaccines: Inception to Market
Time consuming: 10 -12 years $500-800m or more expended in development costs
Trial sizes, costs, facilities, personnel, equipment Post-marketing commitments increasing Vaccine candidates must compete for investment dollars against other opportunities
Douglas RG. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:47. Ebbert GB, Mascolo ED. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:53. Ulmer JB, et al. Nat Biotechnol, 2006:24(11):1377.
NVAC. Pediatrics, 1999:104:942.
Vaccines: Inception to Market
Selective: a tiny fraction of vaccines entering Phase 1 trials make it to market
Increasing standards in development – complex interaction trials Increasingly risky, technically challenging research (more difficult targets / projects) Success rate from preclinical to launch is considerably lower than that of other biopharmaceuticals. (22% by one published estimate)
Douglas RG. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:47. Ebbert GB, Mascolo ED. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:53. Ulmer JB, et al. Nat Biotechnol, 2006:24(11):1377.
NVAC. Pediatrics, 1999:104:942.
Why do we vaccinate?
Vaccine, Good! Disease, Bad! Diseases eliminated from the US:
Disease Smallpox Polio Measles Rubella
Last Case* 1949 1979 1993 2004
*Indigenous case. Importations may occur except for smallpox,
which was eradicated from the planet in 1977
Return on Investment of Childhood Immunization Program
For each birth cohort vaccinated with 7 vaccines (DTaP, Td, Hib, Polio, MMR, Hep B, Varicella) routinely included in the schedule:
Society saves $33.4B in indirect costs Direct health care costs are reduced by $9.9B 33,000 lives are saved Almost 14M cases of disease are prevented For every dollar spent, vaccine programs save society $11
Zhou F et al. Arch Pediatr Adolesc Med 2005;159:1136-1144
Direct Benefit of Vaccination: Invasive Pneumococcal Disease (IPD) Among Children <5 Years of Age
Rate/100,000 children younger than 5 years All IPD Vaccine serotypes Before vaccine 100 80 2006 24 0.5
Source: CDC, Active Bacterial Core Surveillance/EIP Network
Annual Direct Medical Savings After Pneumococcal Conjugate Vaccine Introduced
Estimated reduction in direct medical expense for all-cause pneumonia in young children †* Estimated reduction in direct medical expense related to otitis media (ear infection) §*
$310 million
$460 million
† §
Source: Arch Ped Adol Med, Dec 2007; 161:1162-8 Source: Pediatrics, Feb 2008; 121:253-260 * Some other factors might contribute to the reductions
Indirect Benefit of Vaccination: Rates of PCV7-type Invasive Pneumococcal Disease among Adults, U.S., 1998/99-2006
70 60
Cases per 100,000
2006 vs. baseline >80 yrs >80: -90% (-93,-86) 65-79: -88% (-91,-83) 50-64: -84% (-87,-79) 18-49: -88% (-91,-86) 65-79 yrs 50-64 yrs 18-49 yrs
50 40 30 20 10 0
1998
1999
2000
2001
2002
2003
2004
2005
2006
Source: William Atkinson, CDC, unpublished data 2008
Our Success! Historical Comparison of Morbidity and Mortality for VPDs
Roush, S. W. et al. JAMA 2007;298:2155-2163.
Copyright restrictions may apply.
Our Success! Historical Comparison of Morbidity and Mortality for VPDs
Roush, S. W. et al. JAMA 2007;298:2155-2163.
Copyright restrictions may apply.
Value of a Healthy Vaccine Industry
More than two-thirds of vaccines approved worldwide in the last 25 years created in the U.S. Greater value has been placed on vaccines recently:
Allows vaccine divisions to compete more effectively for increased R&D dollars and other resources More attractive return on investment (ROI) Creates more stable revenue streams Increases vaccine business appeal to venture capitalists
Douglas RG. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:47. NVAC. Pediatrics 1999;104:942. Klein JO, Myers MG. Pediatrics 2006;117:2269.
Value of a Healthy Vaccine Industry
Greater ROI creates a positive environment for continued investment and development of new vaccines
After years of contraction, vaccine industry exhibiting positive signs of expansion Newly licensed vaccines: Meningococcal conjugate, TdaP, HPV, Rotavirus, zoster Interest in US influenza vaccine market
Examples
Douglas RG. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:47. NVAC. Pediatrics 1999;104:942. Klein JO, Myers MG. Pediatrics 2006;117:2269.
Vaccine Development Process
How Long?
Identify Antigens Produce Antigens Test in Animals Phase I Safety Immuno Phase II Dose Safety Phase III Efficacy Safety File License
7 - 12 Years
2 - 3 Years
2 - 3 Years
2 - 3 Years
1 - 3 Years
Research Phase
Early Development Phase
Late Development Phase
Registration Phase
Manufacturing Financial Risks
As development proceeds, trials become larger and costs increase Clinical development involves large number of subjects Vaccines must meet a high threshold of efficacy and safety Manufacture: Companies must commit to construction of production facilities well in advance of licensure
Decision must be made 4-5 years before licensure to avoid a gap between licensure and launch Manufacturing facilities (at $50-200m per facility) require validation and licensure for each product Dose capacity per facility not entirely flexible; if demand increases, new facilities may become necessary
Douglas RG. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:47.
Regulatory burden is increasing, particularly in the US
Number of patients enrolled in prelicensure clinical trials
Prevnar 39,000 Varivax 11,000
Rotateq 75,000 FluMist 38,000
PedvaxHIB™ 6,000 Recombivax HB 1,200
1980
2006
Complexity of Vaccine Manufacturing
Manufacturing processes are extremely complex & must meet stringent quality control criteria. Involves living organisms with inherent variability. Constantly evolving regulatory environment. Varying regulatory requirements across countries.
Complexity of Vaccine Manufacturing
Increasing sophistication of manufacturing and analytical technologies Validation necessary at key steps in the process
Any change in process may result in a different product Process changes necessitate additional or new validation tests
Continual capital upgrades associated with high regulatory standards, costly downtime, and requalification/validation Highly educated personnel Long cycle-time for production to lot release
Strict Engineering and Regulatory Parameters Incorporated from Design through Operation
Vaccine manufacturing facilities take years (4-5+) to design, construct, and qualify cGMPs (current Good Manufacturing Practices) are incorporated from beginning of design phase
Design of clean rooms, sterile utilities, strict segregation of product flow and personnel traffic, cleaning and sterilization techniques
Process equipment is specified, designed, and constructed months to years in advance
Strict Engineering and Regulatory Parameters Incorporated from Design through Operation
Construction standards for process equipment, sterile utilities, and clean rooms ensure integrity of equipment
Strict tolerances, high-grade materials of construction, specialized welding
Installation Qualification / Operation Qualification (“IQ/OQ”) and Validation are performed for processes and equipment
Dedicated protocols are developed, specifications and installation verified, operations tested to meet specifications, and repeated validation studies are performed IQ/OQ and Validation can take weeks to months for each process step after construction
Purity and Specifications of Product Monitored Throughout
Process protocols and Standard Operating Procedures are developed for all aspects of manufacturing Manufacturing documentation, automated monitoring, and logs allow for tracking, monitoring, and verifying process steps Detailed employee training programs are implemented and maintained Process parameters, facility environment, personnel flow, and equipment flow are executed and monitored per specifications and procedures
Purity and Specifications of Product Monitored Throughout
Product is tested in multiple steps across processes
„in-line‟ monitoring during processing, sampling for offline monitoring through process, batch quality tests Ensures consistency of product and intermediaries throughout the process
Each batch undergoes extensive testing for quality, purity, potency
In some cases 5%+ of product or intermediary is dedicated for use in testing
Pre- and Post-licensure Role of FDA
Ensures safety and effectiveness of vaccines
Regulation of development and testing through licensure Post-licensure monitoring of product and production facilities
Klein JO, Myers MG. Pediatrics 2006;117:2269. Douglas RG. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:47.
Pre- and Post-licensure Role of FDA
FDA also oversees compliance with Current Good Manufacturing Practices (cGMP)
Evolving standards that manufacturers must meet May increase cost by altering production process or requiring more extensive record keeping Advances in technology Facilities that produced safe, effective vaccine for decades may no longer meet cGMP Manufacturers must decide if major capital investment is justified This led to some companies making decisions to cease production of several vaccines
Klein JO, Myers MG. Pediatrics 2006;117:2269. Douglas RG. In: Plotkin SA, Orenstein WA, eds. Vaccines, 2004:47.
Multiple Stakeholders
Described as a “delicate fabric of public and private collaboration” Manufacturers Distributors Recommending bodies
Advisory Committee on Immunization Practices American Academy of Pediatrics American Academy of Family Physicians American College of Obstetricians and Gynecologists
Multiple Stakeholders
Food and Drug Administration Centers for Disease Control and Prevention National Institutes of Health Department of Defense State, territorial public health officials VICP / ACCV Payers – Insurance, Government
Multiple Stakeholders
Vaccine success dependent on recommendation language
Physicians look for recommendations before immunizing Another step / time for uptake – particularly if timing not aligned Recommendation may differ from labeled indication Different from other drug products
Multiple Stakeholders
Changes to recommendations & requirements from any stakeholder can greatly impact manufacturers
E.g., change in formulations, altered distribution channels, time needed to increase production, change formulations, alter distribution channels, etc.
Benefit-risk challenging to communicate to general public Factors add to additional market uncertainty
Mechanisms to Ensure Safety of New Vaccines
The Vaccine Licensure Process
Lengthy, rigorous process through FDA
Takes 5 -10 years Costs estimated at hundreds of millions of dollars Required Phase IV studies post-licensure
Federal Advisory Committees
Advisory Committee for Immunization Practices (ACIP)
Recommendations for use of the vaccine involve a thorough examination of the published and unpublished data on the safety, efficacy, effectiveness, and costbenefits analyses of the vaccine.
Mechanisms to Ensure Safety of New Vaccines
Federal Advisory Committees
National Vaccine Advisory Committee (NVAC)
Recommendations on vaccine policy, programs, and delivery are made with an eye to achieving optimum prevention of adverse events associated with vaccine use NVAC currently holding stakeholder meetings on vaccine safety
Advisory Commission on Childhood Vaccines (ACCV)
Gives advice to the DHHS Secretary on issues pertaining to the National Vaccine Injury Compensation Program (VICP)
Mechanisms to Ensure Safety of New Vaccines
Vaccine Surveillance Mechanisms
Vaccine Identification Standards Initiative (VISI)
Each vaccine will have a bar-coded sticker that can be placed on the immunization record of the immunized patient Important information that can help assess who received which vaccine and at what location, potentially enabling adverse events to be tracked
Immunization Registries
Mechanisms to Ensure Safety of New Vaccines
Vaccine Surveillance Mechanisms
Vaccine Adverse Event Reporting System (VAERS)
Most significant national system All adverse events can be reported to VAERS, analyzed, and made known to the public Passive reporting system - thus an adverse event by definition may or may not be causally associated with the vaccine in question Helps generate hypotheses for potential associations between adverse events and vaccine administration
Not for hypothesis testing!
Mechanisms to Ensure Safety of New Vaccines
Evaluating Causality from Surveillance
Vaccine Safety Datalink (VSD) Project
Collaboration between the CDC and 8 health maintenance organizations (HMOs) Directed at testing the hypotheses that are raised by the adverse event reports Large-scale post-surveillance database that captures information that allows for calculation of incidence rates, attributable risks, and background rates of illness in the absence of vaccination Still not large enough to test certain hypotheses regarding very rare events
Mechanisms to Ensure Safety of New Vaccines
Evaluating Causality from Surveillance
Clinical Immunization Safety Assessment (CISA) Centers
Network of academic centers seeking to improve scientific understanding of vaccine safety at the individual patient level Once fully established, CISA centers will evaluate VAERS reports or referred cases, and select cases with merit for more enhanced follow-up and targeted clinical evaluation As part of the National Childhood Vaccine Injury Act, the IOM was specifically tasked to review the scientific literature on vaccine-related adverse events More recently, the CDC and the NIH commissioned the IOM to set up an Immunization Safety Review Committee
Institute of Medicine
The Vaccine Injury Compensation Program (VICP)
To ensure an adequate supply of vaccines To stabilize vaccine costs To establish and maintain an accessible and efficient forum for individuals found to be injured by certain vaccines Is - no-fault alternative to the traditional tort system that provides compensation to people found to be injured by certain vaccines
Summary
Vaccine development and ongoing production is costly, complex, challenging and risky Multiple stakeholders have an impact on vaccine approval, health-care provider and consumer uptake, production, etc. Vaccination remains one of public health‟s best preventive measures and must be recognized
A thriving industry benefits society by securing current vaccine supply and developing future vaccines Vaccine divisions must compete with other products for intra-company resources
Elaborate system of safety nets at both pre-FDA approval and post-FDA approval points to monitor and ensure the safety of new vaccines.
Thank You! Questions?
The Vaccine Injury Compensation Program (VICP) - Process
Claim plus supporting documentation (medical records, etc) is filed with US Court of Federal Claims; Court sends one copy of claim and docs. to Dept. of Justice. Once filed, case is assigned to a Special Masters by the Chief Special Masters. Plaintiff also sends one copy of claim plus all supporting documents to DHHS. HHS reviews claims, sends review to DOJ lawyer. DOJ lawyer reviews legal aspects of claim, adds HHS medical review and writes one combination report with a recommendation on the action requested by the plaintiff, which is sent to the plaintiff and to the Federal Claims Court.
The Vaccine Injury Compensation Program (VICP) - Process
Special Masters reviews the report and all supporting evidence and makes a decision. Special Masters can call status conferences or evidentiary hearings if necessary. If Special Masters decides to pay the claim, then plaintiff must stipulate in writing whether they are accepting or declining. If plaintiff does not file statement, it is assumed that plaintiff is accepting the judgment. It is at this point that the plaintiff can decline the judgment and file a civil action for damages. The plaintiff can also appeal first to the Court of Appeals for the Federal Circuit, and finally, to the U.S. Supreme Court. If an appeal is started, then the plaintiff has until after the appeal process to state whether s/he is accepting the Special Master's judgment or filing a civil action.
