Differences Between Strategic and Tactical Development of Vaccines and Drugs

1. Differences Between Strategic and Tactical Development of Vaccines and Drugs Melanie Hartsough, Ph.D. Biologics Consulting Group, Inc

2. Structure and Approach OVRR CDER • CBER: approximately 1,000 FTEs in 2013 (~1/2 do research) • OVRR: one review division • CBER: average 11 NMEs approved per year; OVRR: average of 3 new vaccines approved per year • Primarily work on a case by case basis CDER: approximately 3,600 FTEs in 2013 18 review divisions-divided based on indication CDER: average of 26 NMEs approved per year Due to volume of work try to standardize requirements

3. Types of Products Regulated OVRR CDER • Prophylactic or therapeutic vaccines • Live attenuated bacteria, virus, parasites • Inactivated (killed whole organisms) • Recombinant proteins • Synthetic antigens • Adjuvants (lipids, proteins, oligonucleotides, etc) • Therapeutic products • Small molecules • Large molecules (recombinant proteins, monoclonal antibodies, extracted proteins, etc) • Oligonucleotides • Hormones • Peptides • Botanicals • Polysaccharides • Large volume parenterals

4. Review Teams OVRR CDER • CMC (Laboratory Personnel) • Toxicologist • Medical Officer • Statistician Recommendations and questions reflect the review team expertise CMC Pharmacologist and Toxicologist Medical Officer Virologist (Anti-viral division only) Clinical Pharmacologist Statistician

5. CMC Reviewers OVRR CDER • Review CMC , nonclinical pharmacology sections, clinical assays • Tend to focus on assay development and intricacies of study designs • More apt to ask for study reports with primary data • No training in safety risk assessment, but will make comments on nonclinical safety • Provide materials/ perform assays for sponsor; active in research • Review CMC sections, clinical immunogenicity assays (proteins only) • Tend to focus on the bigger picture • Focus primarily on regulations • Do not comment on safety , will identify components of concern for P/T reviewers • Majority are full time reviewers; not active in research

6. CMC Program OVRR CDER • Potency assays typically animal assays • General safety test performed on each lot • Three GMP lots must be evaluated in Phase 3 clinical study • Lots are released by OVRR • OVRR retest lots • Some animal studies considered as product characterization • Potency assays are typically in vitro assays for therapeutic proteins; potency assays not required for small molecule drugs • Products exempt from general safety test • One lot needed for Phase 3 clinical trial • Three lots needed for licensure • Lots released by sponsor based on C of A tests • CDER does not typically retest lots

7. P/T Reviewers OVRR CDER • P/T reviewers only responsible for toxicology studies • Tend to be more flexible in acceptance of studies and approaches to establish safety • Patient population are healthy volunteers – toxicities are not tolerated • P/T reviewers responsible for pharmacology and toxicology • Tend to be dogmatic in approach • Flexibility is division-dependent • Depending on patient population, certain toxicities may be acceptable

8. Nonclinical Program OVRR CDER • MOA: Stimulate the immune system • Immunogenicity against product important to establish activity • Adjuvant safety and activity • Immune response reactivity against other subtypes or strains of the same organism • Typical species for toxicity studies are rabbit and mouse MOA: target virus, overexpressed proteins on infected cells, target immune system, etc Binding studies, functional assays performed to establish activity Immunogenicity against product can affect product exposure /efficacy (proteins only) Product cross-reactivity against other strains Assessment of species for toxicology studies

9. Nonclinical Program OVRR CDER • Since products administered at low doses and typically no standard P450 metabolism, ADME studies usually not needed • Some exceptions • Live attenuated virus by intranasal administration - distribution, persistence study, transmission • Plasmids-distribution, persistence, integration studies Much higher doses and depending on product type P450 metabolism, thus various ADME studies needed (case by case) Pharmacokinetic (absorption) studies independent or incorporated into toxicology studies Tissue distribution studies (radioactive) Metabolism studies Excretion studies

10. Nonclinical Programs OVRR CDER • Philosophy: show safety • Safety pharmacology studies- not performed • One toxicity study • Typically rabbit or mice – model should respond in a similar manner as expected in humans • Study design based on number of administrations in clinic (n+1) Philosophy: identify toxicities Safety Pharmacology Studies- CNS, respiratory and cardiovascular prior to Phase 1 (case by case) General toxicity studies in 2 species (1 rodent and 1 nonrodent); pharmacologically relevant species for therapeutic biologic Study design based on duration, may have studies up to 6-9 months

11. Nonclinical Programs OVRR CDER • General toxicity study • Dose levels based on clinical dose- may have one dose level • Dose volume- same as in human • Acute phase response proteins included in study • General toxicity study • Dose levels based on toxicity, maximum feasible dose, dose limit, exposure multiples • Dose volume- generally not need to consider clinical dose volume • Acute phase response protein generally not included

12. Nonclinical Programs OVRR CDER • General toxicity Study • Immunogenicity to establish activity • Some products types are exempt from toxicity testing (ex: flu and oral vaccines) • General toxicity Study • Immunogenicity against therapeutic protein may cause product exposure problems or toxicities • May get a waiver from certain studies, but no product type exemptions

13. Medical Reviewers OVRR CDER • Medical officers sometimes comment on pharmacology and need for safety studies • Generally do not put much weight on animal challenge or other proof-of-principle data • Medical officers focus on clinical information

14. Clinical Programs OVRR CDER • Patient population is primarily healthy individuals; therefore safety bar is very high • Activity of product produced by human, not metabolized • Programs may include populations with immune system differences: immune compromised individuals, elderly, infants • Risk-benefit ratio may differ for certain subgroups or under certain conditions (e.g. epidemic) Besides Phase 1, Patient populations are sick individuals Activity inherent to product, may be metabolized Programs consist of special populations, such as renal impaired, diabetics, etc Risk-benefit ratio depends on disease and patient population

15. Clinical Programs OVRR CDER • Serious adverse events are major concerns • Large safety databases required for novel adjuvants, live virus vaccines and novel platforms • Clinical PK, drug-drug interactions not a concern • Clinical virology not a concern, with the exception of potential secondary transmission of live virus vaccines Serious adverse events are managed based on patient population Clinical PK, drug-drug interactions very important Clinical virology- emergence of resistance

16. Clinical Programs OVRR CDER • Endpoint typically immunogenicity although disease reduction generally required for Phase 3 • Surrogate endpoints sometimes accepted if prevalence of disease is too low to demonstrate clinical efficacy (e.g., meningococcus) • Concomitant vaccination studies often required (to assess affects on safety and/or immunogenicity), especially in infants • Endpoint: “meaningful” clinical benefit, for which definitions vary, depending on the disease and the availability of other approved therapies • Immunogenicity can be a problem

17. Clinical Programs OVRR CDER • Challenge studies (ex: influenza) performed Challenge studies not typically performed

18. Regulatory OVRR CDER • Deals with other government agencies that are developing vaccines • Will perform prepreIND reviews (for toxicology program) • Reviewers willing to have a conversations to resolve issues • May get more than one preIND meeting Primarily deals with pharmaceutical companies PrepreIND reviews not performed Limited access to Reviewers Unless a Animal Rule product, only one preIND meeting (sometimes that isn’t granted)

19. Regulatory OVRR CDER • Follow WHO guidelines and vaccine specific FDA guidances (few guidances) • Market approval through BLA process • Most vaccines require presentation to the Vaccine and Related Product Advisory Committee (VRBPAC) prior to approval • Only one regulatory pathway to approval- BLA Follow ICH guidances and specific FDA guidances (many guidances ) Market approval through NDA or BLA process depending on product type FDA Advisory Committee review for new chemical entities, otherwise not required Other pathways to approval- 505(b)(2), generics, biosimilars