How Vaccines Are Made

Vaccine 101

July 22, 2009 DynPort Vaccine Company LLC, A CSC Company

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Overview • • • • •

Vaccines and how they work Making a vaccine Vaccine manufacturing Putting things together Biodefense and vaccines

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Vaccines and How They Work Vaccine 101

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What is a Vaccine? • A vaccine is a biological material intended to induce a specific immune response in humans or animals. • Vaccines work because the body’s immune system “remembers” how to protect itself from microbes it has previously encountered. • Vaccines are one of the greatest success stories in public health. – Vaccines have ended smallpox, and lowered the incidence rates of serious illnesses including diphtheria, tetanus, measles and polio by more than 95% since the beginning of the 20th century.

DVC has experience with many kinds of vaccines.

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Some Types of Vaccines • “Live” vaccines include a live variant of the target pathogen. – Live attenuated vaccines: recombinant DNA technology removes critical pieces of the virus or bacteria genome to make it less virulent. – Subunit vaccines: made using only part of the virus or bacteria.

• Recombinant vaccines – proteins expressed in various mediums including E. coli and yeast, likely to be a heterogenous mixture of strains • DNA vaccines – employ the genes that code for specific antigens (antigen = a substance that stimulates immune response, particularly production of antibodies) – No DNA vaccines have been licensed, though several are in clinical testing

• Combination vaccines – combine protection against several diseases (e.g., MMRmeasles, mumps and rubella) 5

Making a Vaccine Vaccine 101

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From Test Tube to FDA Review

Source: CDER Handbook, FDA 3/16/98, http://www.fda.gov/cd

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Advanced Development • All DVC products are transitioned from research labs after early research and development, including proof-of-concept. • DVC specializes in “advanced development” of vaccines. – Encompasses nonclinical and clinical research, and all activities up to and including licensure by the U.S. Food and Drug Administration (FDA).

• Biopharmaceutical development is lengthy and expensive. – On average, 10 to 15 years and nearly $600 million.*

Advanced Development

*Source: http://csdd.tufts.edu/InfoServices/Outloo 8

Animal Studies in Vaccine Development Terminology • Nonclinical research – Proof-of-concept animal models (does it work?) – Toxicology, including acute/repeat-dose, and reproductive (is it safe?) – Efficacy/immunogenicity (will it protect against disease?) – Product testing using animals (is it potent and stable?)

• Preclinical research – Any nonclinical study conducted prior to use of the product in humans

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Why Can’t Computers and Cell Cultures Replace Animal Research? • Animal and non-animal models both used to answer biological questions. • Animal studies may pave way for computer models. Computer models and cell culture may extend what is learned in animals. • Computer models and cell culture still don’t reflect the complexity and dynamics of a living organism. • A complete answer currently requires animal studies.

DVC ensures that no animal will suffer needlessly, and that the fewest animals are used to obtain scientifically defensible data.

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Types of Animal Studies • Dose and schedule requirements – Animal data supports effective dose in humans

• Toxicology – is it safe? – Includes reproductive toxicology

• Efficacy – does it work? – Demonstrate that the vaccine actually works under its intended conditions of use (dose and regimen) – Demonstrates that the vaccine • Protects against what it was designed to protect against • Protects against a certain level of challenge • Protects for a certain period of time

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Human Clinical Trials • Human clinical trials are required by the FDA to test drugs and biologics (including vaccines) in humans. • The Food, Drug and Cosmetic Act requires drug manufacturers to prove that products are safe for human consumption and effective for a specific indication before licensure and marketing in the U.S. • After (years of) successful nonclinical research, the Sponsor submits an Investigational New Drug (IND) application to the FDA, which within 30 days either: – Notifies the Sponsor of deficiencies and places a clinical hold, or – Does not notify the Sponsor, which means it is OK to start the clinical trial.

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Phases of Clinical Trials • Phase 1 – Evaluate safety and tolerability of the investigational product in humans – Involves 20 to 80 normal, healthy volunteers – Typically closely monitored – Designed to determine the metabolism and pharmacologic actions or drugs, side effects associated with increasing doses, and (if possible) gain early evidence on efficacy

• DVC has successfully advanced 8 products into clinical trials in the last 10 years. Phase 1 trials completed include: – Anthrax vaccine – Botulinum neurotoxin vaccine – Butyrylcholinesterase (chemical defense therapeutic) – Influenza vaccines (seasonal and pandemic) – Tularemia vaccine – Smallpox vaccine

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Phases of Clinical Trials (continued) • Phase 2 – Evaluate safety and effectiveness for a particular indication – Typically involves several hundred subjects at multiple sites – Controlled study – DVC products in Phase 2: botulinum, plague and tularemia vaccines

• Phase 3 – Expanded controlled trial – Involves several hundred to thousands of subjects, multiple sites – Long-term safety and efficacy – DVC product in Phase 3: seasonal influenza vaccine (Baxter)

• Phase 4 – clinical evaluation is ongoing, even after FDA licensure – Post-marketing studies – Ongoing safety evaluation 14

Proving Safety and Efficacy in Humans • Safety – Safety assessments in study volunteers include: • Physical exam, vital signs, blood pressure • Clinical laboratory assessments: hematology, serum chemistry, urinalysis, pregnancy test for females • EKG • Monitoring adverse events

– Supporting pharmacology/toxicology data in animal models

• Efficacy – Immunogenicity testing in volunteers includes: • Measurement of humoral immune responses (specific antibody measurement) • Cell-mediated immune responses (T cell proliferation, cytotoxicity assay)

– Challenge data from animal models to support efficacy 15

Regulations • Good Clinical Practices (GCP) – GCP is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. – Clinical trials must be conducted following GCPs.

• Good Laboratory Practices (GLP) – Govern protocol and conduct of nonclinical (animal) studies.

• Current Good Manufacturing Practices (CGMP) – Requires manufacturers to document production, inspect and release quality drug products. – Covers all vaccine manufacturing and post-production (shipping, storage, etc.).

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Additional DoD Regulations • In addition to all applicable ICH/FDA regulations for human clinical trials, the DoD requires a second level of review and approval for DoD-sponsored research. – Human Subjects Research Review Board (HSRRB) – Approval must be obtained prior to initiation of research protocol – HSRRB policies: • • • •

Format of clinical protocol Volunteer database Informed consent Reporting of adverse events

– 13 more required clauses for additional protection of study volunteers

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Clinical Trials at DVC • DVC outsources conduct of clinical trials to contract research organizations (CROs) – DVC remains responsible for trial design, oversight and documentation/deliverables

• Clinical trial deliverables – Investigator’s brochure (IB) and trial protocols – Final clinical study reports (CSRs) – IND safety reports at various intervals – Serious adverse event reporting

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Adverse Events • An adverse event (AE) is any adverse change in health or side effect that occurs while a subject is taking part in a clinical trial. – May be related or unrelated to the investigational product. – AEs happen in every clinical trial.

• A serious adverse event (SAE) is any adverse experience that results in death, is life-threatening or requires hospitalization.

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Biologics License Application (BLA) • If products are successful in proving safety and efficacy through nonclinical and clinical testing, the Sponsor may apply for FDA licensure through the BLA process. • DVC received FDA licensure of the first biodefense product in 2005 – Vaccinia Immune Globulin, a smallpox vaccine antiserum – Many biopharmaceutical companies never reach this milestone

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Launch and Post-Marketing • Post-licensure activities may be required by licensing authority (FDA) – Further safety database – Special populations (pediatric, elderly, high-risk) – Pregnancy registry

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DVC Milestones Throughout the Product Development Life Cycle

2003-2009: DVC completes six Phase 1 clinical trials for biological and chemical defense countermeasure s

2008: DoD plague RAD allocates all future DoD plague vaccine funding to existing DVC contract

2008: DVC and Quintiles win $32M NIAID Phase 1 clinical trial unit contract

2005ongoing: DVC initiates and manages Phase 2 clinical trials for botulinum neurotoxin and plague vaccines

2005: DVC receives first-ever FDA licensure for a biodefense product (VIGIV)

2006: DVC and Baxter win $242 M HHS award to develop seasonal and pandemic influenza vaccines DVC biodefense milestone Emerging diseases / services 22 milestone

Vaccine Manufacturing Vaccine 101

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Manufacturing: Getting There • Research and development – Provides material for early studies

• Process development – Takes R&D process and develops a process for manufacturing – This is a complex endeavor, with many variables (i.e., opportunities for things to go wrong)

• Manufacturing – Executes the process in an environment compliant with Current Good Manufacturing Practices (CGMPs), as required by FDA

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Product and Manufacturing Stages • Product stages – Cell banks – Bulk drug substance – Final drug product

Testing at all stages to demonstrate control

• Stages of manufacturing – Banking – Production – Recovery – Purification – Formulation and filling – Finish NuncTM cell factory

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A Few More Notes on Manufacturing • Manufacturing biopharmaceuticals is time-intensive. – Facility: 2 to 3 years – Equipment: 6 to 12 months

• Manufacturing is expensive. • Changes in the process have huge cost/schedule implications. – Careful subcontractor management and long-term relationships required for success.

• A manufacturing facility is part of the license requirement.

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Putting Things Together Vaccine 101

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Regulatory Affairs • Guides all DVC programs in areas of regulatory strategy and compliance. – Recommends testing requirements at various stages of manufacturing (in-process, lot release, characterization, etc.). – Reviews plans for correlates of protective immunity. – Provides regulatory review and support strategies during product development.

• Regulatory strategies utilized by DVC include: – Accelerated Approval – Fast Track Designation • DVC maintains a 100% success rate for receiving Fast Track designation (four products) as compared to a 63% industry standard.*

– Orphan Drug Program – Priority Review – Rolling Submission

*Source: http://www.fda.gov/cber/inside/fastrk.htm 28

Regulatory Affairs (continued) • Acts as the DVC representative in interactions with the U.S. FDA and foreign regulatory agencies. – Prepares and assembles all required regulatory submissions, including Investigational New Drug and Biologics License Applications.

• Reviews all publicity materials (press releases, brochures, Web pages, etc.) to ensure that no unproven marketing claims are made regarding FDA-regulated products.

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FDA Animal Rule • Regulatory Affairs oversees DVC’s use of the FDA Animal Rule. – Allows for FDA licensure of vaccines and other products in which efficacy testing in humans is unethical – At least two species (nonhuman primates and rodents) – Must understand pathophysiology of the disease – Well-controlled animal studies will provide data that are likely to predict a benefit in humans

• The Animal Rule is NOT a shortcut to licensure. – So far, no vaccines have been licensed using the Animal Rule.

DVC is an industry leader in Animal Rule development.

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Quality Assurance • To ensure impartiality, the Quality Management Office (QMO) is independent of the product teams and functional departments. • The QMO performs audits, conducts quality reviews and initiates investigations to demonstrate that both DVC and its subcontractors are operating in a state-of-control to ensure compliance with Section 501(a)(2)(B) of the Food, Drug and Cosmetic Act. – Compliance failures could affect the quality of the product, which could lead to death of the volunteer/patient. – Compliance failures could lead to lost credibility with the FDA and enforcement actions including product seizure, injunctions, criminal fines and imprisonment.

• Administers (federally required) Standard Operating Procedures (SOPs) and SOP training, and Document Control. 31

Quality Assurance (continued) • QA is comprised of two arms: – Product Quality Assurance (PQA) • Ensures compliance of manufacturing, testing and storage subcontractors

– Clinical Quality Assurance (CQA) • Primary responsibilities are to manage safety risk to clinical study volunteers and to assess data integrity

• QA also monitors data integrity and oversees validation of computer systems.

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Program Management • Program managers of biopharmaceutical development programs must balance: – Cost – Schedule – Risk – Technical requirements – Product life cycle – External influences (changes in regulatory guidance, client funding profiles, etc.)

• Good program management is often at odds with “good science.” – Must curtail the “what-ifs” and stop at “good enough”

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Biosafety • Biological surety – New and evolving DoD requirements for personnel, subcontractors working with select agents – Narrows field of prospective subcontractors even further

• Shipping – Shipping biological agents is complicated and highly regulated (much more so internationally) – Temperature control is crucial for vaccines (for now) – Test shipments must be conducted with vendors before actual product is put at risk

DVC is a pioneer in this new requirement.

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Biodefense and Vaccines Vaccine 101

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Priority Pathogens • Centers for Disease Control and Prevention (CDC) identifies three threat agent categories. • Category A* – The most severe threats, Category A agents pose a risk to national security and can be transmitted person-to-person or easily disseminated. These agents result in high mortality rates and would be most likely to cause public panic and social disruption: – Anthrax – Botulinum neurotoxin – Plague – Smallpox – Tularemia – Viral hemorrhagic fevers

DVC has experience with nearly all of these.

• Filoviruses (e.g., Ebola, Marburg) • Arenaviruses (e.g., Lassa) *Source: http://www.bt.cdc.gov/agent/agentlist-category.asp

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Questions?

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