The Drug Approval Process Q4, 2016

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***

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

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.

“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.

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

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

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

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

Summary of Drug Development Process

Product Profile

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

FDA Post-Market Safety Monitoring Pharmacovigilence Adverse Event Reporting http://www.fda.gov/Safety/MedWatch/default.htm Medical Education Risk Management Phase IV studies Post-commitment Marketing Safety

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

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

Regulatory Strategy

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

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***

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