1. Drug Development Overview CET Square 1 Program November 4, 2014
Carl Siekmann
President & CEO
BioAdvisory Consulting
CFS

2. Drug Development
CFS

3. Drug Development Process
Development time for a new drug = 10-15yrs.
1 in 5000 chance of success.
Development cost for a new drug = $1.0 + billion
New technologies have added cost but have not yet improved productivity of the process.
CFS

4. Drug Development FDA History 1906 Pure Food and Drug Act
Prohibited interstate commerce of misbranded and adulterated foods and drugs.
1938 Food, Drug, and Cosmetics Act (FD&C Act)
Toxic sulfanilamide elixir
Demonstrate safety prior to market approval
Authorized factory inspections
1962 Harris-Kefauver Amendments
Thalidomide scare
Demonstration of efficacy and safety now required
CFS

5. Center for Drug Eval. and Research (CDER)
Drug Development
Office of Commissioner
Office of Medical Products and Tobacco
Center for Devices and Radiologic Health
Center for Drug Eval. and Research (CDER)
Center for Biologic Eval. And Research (CBER)
FDA
CFS

6. Drug Development CDER Janet Woodcock, M.D.
As part of the U.S. Food and Drug Administration (FDA), CDER regulates over-the-counter and prescription drugs, including biological therapeutics and generic drugs. This work covers more than just medicines. For example, fluoride toothpaste, antiperspirants, dandruff shampoos and sunscreens are all considered "drugs.".
CFS

7. Discovery Fundamentals
Drug Development
Discovery Fundamentals
1872 – Ehrlich: Chemo-receptors
1905 – Langley: Receptor/Switch hypothesis.
“Lock” and “Key” Analogy : fundamental to DD today
Find a molecule (drug) that binds selectively to a target (receptor, enzyme, gene etc.) in the body to trigger a desired biological effect.
1970’s – Advent of Biotechnology
“Scientific revolution”
Synthesis of therapeutic proteins (keys)
New drug target ID methods (locks)
Screening technologies for drug-targets matches.
CFS

8. Drug Development Drug Discovery Understand the disease
Underlying patho-physiology at the molecular level.
Biochemical pathways
Target identification
Choose a molecule to target with a drug
Target validation
Test the target and confirm its role in the disease
“Drugable”lead compound identification
Find a promising molecule(s) (lead compound) that could become a drug.
Lead optimization
Alter the structure of lead candidates to improve binding properties
Create analogs; test formulations
File patents
CFS

9. Drug Development Pre-Clinical
In vitro, in vivo experiments. Two species.
Animal toxicity, efficacy, pharmacokinetics (ADME) studies.
Scale up manufacturing to pilot plant scale.
5 of 250 molecules survive to enter the clinic.
Investigational New Drug (IND) application compiled
1.5 years; $5 million
CFS

10. Drug Development File IND Pre-IND meeting-FDA (CDER)
Submit IND to allow human exposure to experimental drug
Preclinical Data ( ADME, Toxicity, Mechanism of Action, Adverse reactions) (GLP)
Chemical structure, formulation, manufacturing & control data. (GMP)
Clinical Plan (GCP)
Apply for priority review.
30 day review. No response, proceed.
IND is ongoing file at FDA, tracking drug through NDA process.
CFS

11. Drug Development Phase I
Begin 30 days after submission of IND providing no clinical hold notice from FDA.
Local IRB approvals required.
healthy volunteers. Certain life-threatening diseases require patients in Phase I.
Determine: safety, pharmacokinetics (ADME), maximum tolerable dose, side-effects.
Length: one year. Cost: $1-10 million.
CFS

12. Drug Development Phase II No need to consult FDA prior to Phase II.
First testing of drug effectiveness in humans (Proof of Concept).
Controlled trials in patients (placebo or SOC control).
Safety and side effects monitored.
Dose ranging. Assess minimum effective dose.
Results must be statistically significant vs. control group.
Length: 2 years. Cost: $ million.
CFS

13. Drug Development Phase III
End-of- Phase II meeting with FDA. Discuss Ph. III clinical plan.
Confirm efficacy/safety in large-scale, multi-center trials vs. control with final dose(s) patients.
Measure long-term efficacy, safety. Side effects.
Statistically significant results vs. control.
Length: 4-8 years. Cost: $ million.
Manufacturing scale-up to commercial scale.
Pharmaco-economic outcome studies may be considered for CMS reimbursement.
CFS

14. Drug Development
CFS

15. Clinical Testing (con’t)
Drug Development
Clinical Testing (con’t)
Orphan Drug Act 1983
Patient pop. > 200,000 US.
7 years market exclusivity
Special Protocol Assistance (SPA)
50% tax credit on R&D expenses.
Prescription Drug User Fee Act (PDUFA) 1992
User Fee paid by sponsor upon NDA submission. $2.2 mil./ 2014.
Fee is specifically earmarked for CDER resources to accelerate review process. Expanded safety surveillance.
Renewable by Congress every 5 yrs.
Greater FDA responsiveness, accountability.
CFS

16. NDA (BLA) Submission (100,000+ pages)
Drug Development
NDA (BLA) Submission (100,000+ pages)
CDER: 60 days to accept for review. PDUFA date (10 mo. standard; 6 mo. priority)
All preclinical, clinical data: provide evidence drug is safe and effective.
Proposed labeling is supported by data.
Chemical, manufacturing, and controls (CMC) data. Maintain drug identity, purity, strength. Assay methodology.
Manufacturing scale-up: Pre-approval inspection; 3 production batches.
Advisory Committee review: Assess risk-benefit; non-binding
Approval letter, Approvable letter, rejection letter.
Post-market surveillance, Ph. 4 studies.
Discovery > Development > NDA review = years. $800mil - $1,2 bil.
CFS

17. CDER Review Timeline (Standard Application)
Drug Development
CDER Review Timeline (Standard Application)
CFS

18. Drug and Device Development
CFS

19. Drug and Device Development
CFS

20. Drug Development
CFS

21. Drug Discovery Unique Challenges of Drug R&D:
Drugs have the potential to do great good or great harm to the human body.
The secrets of human biology continue to be shrouded in mystery resulting in recurring surprises and persistent uncertainty.
CFS