1. The Drug Approval Process
Q4, 2016

2. Summary of The Drug Development Process
Step 1 Discovery and Development Discovery and Development Research for a new drug begins in the laboratory. More Information Step 2 Preclinical Research Drugs undergo laboratory and animal testing to answer basic questions about safety. Step 3 Clinical Research Drugs are tested on people to make sure they are safe and effective. Step 4 FDA Review FDA review teams thoroughly examine all of the submitted data related to the drug or device and make a decision to approve or not to approve it. Step 5 FDA Post-Market Safety Monitoring FDA Post-Market Safety Monitoring FDA monitors all drug and device safety once products are available for use by the public.
Preclinical Program
IND Filing
Phase I
Phase II (Minimally effective dose and Maximally Tolerated Dose)
Phase III (in duplicate)
NDA or BLA
FDA Review
Product Launch
Phase IV***

3. FDA History 1906 Pure Food and Drugs Act
Drugs, defined in accordance with the standards of strength, quality, and purity in the United States Pharmacopoeia and the National Formulary could not be sold in any other condition unless the specific variations from the applicable standards were plainly stated on the label .
All of this resulted from misbranding and fraudulant foods and drugs; this bill was signed by President Roosevelt

4. The 1938 Food, Drug, and Cosmetic Act
The new law brought cosmetics and medical devices under control, and it required that drugs be labeled with adequate directions for safe use. It also mandated pre-market approval of all new drugs, such that a manufacturer would have to prove to the FDA that a drug were safe before it could be sold
legally mandated quality and identity standards for foods, prohibition of false therapeutic claims for drugs, coverage of cosmetics and medical devices, clarification of the FDA's right to conduct factory inspections, and control of product advertising, among other items. The final straw that broker the camels back was a sulfianilamide mixture that was essentially antifreeze and killed 100 people, including children.

5. “Efficacy”
1941: Insulin Amendment requires FDA to test and certify purity and potency of this lifesaving drug for diabetes
1945: Penicillin Amendment requires FDA testing and certification of safety and effectiveness of all penicillin products. Later amendments extended this requirement to all antibiotics. In 1983 such control was found no longer needed and was abolished.
1950: In Alberty Food Products Co. v. U.S. , a court of appeals rules that the directions for use on a drug label must include the purpose for which the drug is offered. Therefore, a worthless remedy cannot escape the law by not stating the condition it is supposed to treat.
1962 Kefauver-Harris Drug Amendments passed to ensure drug efficacy and greater drug safety. For the first time, drug manufacturers are required to prove to FDA the effectiveness of their products before marketing them. The new law also exempts from the Delaney proviso animal drugs and animal feed additives shown to induce cancer but which leave no detectable levels of residue in the human food supply.
1966: FDA contracts with the National Academy of Sciences/National Research Council to evaluate the effectiveness of 4,000 drugs approved on the basis of safety alone between 1938 and 1962
1970 In Upjohn v. Finch the Court of Appeals upholds enforcement of the 1962 drug effectiveness amendments by ruling that commercial success alone does not constitute substantial evidence of drug safety and efficacy.
FDA requires the first patient package insert: oral contraceptives must contain information for the patient about specific risks and benefits.

6. Where does the Regulatory Process Begin?
Discovery and Development- “Non-clinical research”
Translational Medicine and Basic Research
Mechanism of Action
“Proof of Concept”
ideally in validated animal model
Medicinal Chemistry
Lead optimization
Preclinical (FDA) vs. Nonclinical (in the lab)
“Draft Product Label”
Compound
Collections
Clinical Candidate
Primary Assays high through-put, in vitro
Secondary Assays, tox, counter screens, bioavailability
Lead Optimization
Lead Compounds and SAR
Rationale Drug Design

7. Preclinical Research
FDA requires researchers to use good laboratory practices (GLP), defined in medical product development regulations, for preclinical laboratory studies.  The GLP regulations are found in 21 CFR Part 58.1: Good Laboratory Practice for Nonclinical Laboratory Studies. These regulations set the minimum basic requirements for:
study conduct
personnel
facilities
equipment
written protocols
operating procedures
study reports
and a system of quality assurance oversight for each study to help assure the safety of FDA-regulated product

8. Preclinical Research (Cont’d)
Acute Toxicology
Mutagenicity Assays
Subchronic and Chronic Toxicity Assays
Cardiovascular Safety
Herg Assay
Carcinogenicity Assays
Other safety assays

9. The Investigational New Drug Process- “IND”
Drug developers, or sponsors, must submit an Investigational New Drug (IND) application to FDA before beginning clinical research.
What goes into the IND application?
Developers must include:
Form 1571 and 1572
Table of Contents
Introductory Statement and General Investigational Plan
Investigator’s Brochure
Protocols
Chemistry, Manufacturing and Controls
Pharmacology and Toxicology
Previous Human Use
References

10. Summary of Drug Development Process

12. Product Profile

13. FDA Review- “NDA”
A drug developer must include everything about a drug—from preclinical data to Phase 3 trial data—in an NDA. Developers must include reports on all studies, data, and analyses. Along with clinical results, developers must include:
Proposed labeling
Safety updates
Drug abuse information
Patent information
Any data from studies that may have been conducted outside the United States
Institutional review board compliance information
Directions for use

15. FDA Post-Market Safety Monitoring
Pharmacovigilence
Adverse Event Reporting
Medical Education
Risk Management
Phase IV studies
Post-commitment
Marketing
Safety

16. Special Programs US FDA
Priority Review
A Priority Review designation means FDA’s goal is to take action on an application within 6 months.
Breakthrough Therapy
A process designed to expedite the development and review of drugs which may demonstrate substantial improvement over available therapy.
Accelerated Approval
These regulations allowed drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint.
Fast Track
Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need.
______________________________________________________________________________
ANDA (Abbreviated New Drug Application)
For generic drugs, biosimilars
510K vs. PMA
Class I, II, III devices
DSHEA (Dietary Supplement Health and Education Act of 1994)
GMP Manufactured
Physician Sponsored IND

17. Other Regulatory Considerations
Orphan Drug Exclusivity
ODE/ODD
Temporary Authorisations for Use (ATU)
France
Compassionate Use
Veterinary Use
Priority Review Vouchers-rare diseases, pediatric use (US only)
Special Protocol Assessments

18. Regulatory Strategy

19.  
Christoffersen, R., “Biobootcamp 2009”, April 2009

20. Summary of The Drug Development Process
Step 1 Discovery and Development Discovery and Development Research for a new drug begins in the laboratory. More Information Step 2 Preclinical Research Drugs undergo laboratory and animal testing to answer basic questions about safety. Step 3 Clinical Research Drugs are tested on people to make sure they are safe and effective. Step 4 FDA Review FDA review teams thoroughly examine all of the submitted data related to the drug or device and make a decision to approve or not to approve it. Step 5 FDA Post-Market Safety Monitoring FDA Post-Market Safety Monitoring FDA monitors all drug and device safety once products are available for use by the public.
Preclinical Program
IND Filing
Phase I
Phase II (Minimally effective dose and Maximally Tolerated Dose)
Phase III (in duplicate)
NDA or BLA
FDA Review
Product Launch
Phase IV***

21. Glossary of some “regulatory” terms:
Regulatory Hurdle
Regulatory Risk
Regulatory Process
Regulatory Strategy
Regulatory Requirements
Regulatory Policy
Regulatory Law
Regulatory Matters
Regulatory Guidance