FDA DRUG APPROVAL FDA’s Lengthy Drug Approval Process in Twelve Steps Overview of the FDA Drug Approval Process Drug Developed June 13, 2016 | Emilia Varrone Sources: "Drug Approval Process", FDA, June 13, 2016; Gerald Wildmoser, Dennis Tiensvold, Nathan Thomson, Francisa Arevalo, Rafa Bosch, Lorenzo Stella, Arthur Shlain, Bybzee, Noun project, June 13, Animal Testing Phase I (20-80) IND Application Review Meeting NDA Application Drug Labeling Facility Inspection FDA Drug Approval Application Review Phase II (100+) Phase III (1000+)

FDA DRUG APPROVAL Preclinical Steps Can Take 3-4 Years Before Application for Human Testing Can Commence Pre Clinical Steps of the FDA Drug Approval Process Drug Development: Researchers discover new drugs by: gaining new insights into a disease pathology, screening of molecular compounds, or using new technologies. There may be thousands of candidates at this point, but few are selected for further study for a multitude of reasons. June 13, 2016 | Emilia Varrone Sources: "Drug Approval Process", FDA, June 13, 2016; Gerald Wildmoser, Dennis Tiensvold, Nathan Thomson, Francisa Arevalo, Rafa Bosch, Lorenzo Stella, Arthur Shlain, Bybzee, Noun project, June 13, Animal Testing: Drug sponsor tests drugs on animals to determine toxicity. Multiple species are used to determine the safety and efficacy of the drug. Data gathered includes: metabolism of drug, dosage, potential mechanisms, optimal delivery method, side effects, & drug interactions. Preclinical Testing takes on average 3-4 years before the IND or BLA application is filled out. Investigational New Drug (IND) Application or Therapeutic Biologic Application (BLA) The application includes The drug’s composition The drug’s test results from animal and laboratory studies. Documentation that the sponsor can properly manufacture the drug. The company’s proposed label, including effective uses, potential risks, and how to administer the drug. Plan for human testing If the potential investigated drug is a biologic, such as an antibody, the sponsor fills out a BLA rather than an IND. The FDA reviews the IND to make sure human subjects do not place human subjects at unreasonable risk, as well as adequate informed consent and human subject protection

FDA DRUG APPROVAL Clinical Portion is the Most Time Consuming Part of the Process and When Most Drugs are Denied Approval Clinical Steps of the FDA Drug Approval Process Phase I: Generally involves 20 to 80 healthy volunteers, and can take several months to complete Goal is to determine: frequent side effects how the drug is metabolized and excreted 70% of drugs move on to phase II June 15, 2016 | Emilia Varrone Sources: "Drug Approval Process", FDA, June 13, 2016; "Overview of Clinical Trials," Center Watch, June 15, 2016; "The FDA Drug Review Process: Ensuring Drugs are Safe and Effective," FDA, June 15, Phase II: Generally involves a few dozen to around 300 patients, and can take several months to two years Sometimes, Phase II involves controls, where patients receiving the drug are compared to those receiving a placebo Goal is to determine: effectiveness in patients with the disease or condition targeted by the drug 33% move on to phase III Phase III: Generally involves from a few hundred to 3,000 patients, and can take several years If the drug clears phase II, then phase III often begins with renewed input from the FDA This phase studies different populations and doses as well as drug interactions Goal is to determine Safety Efficacy 25-30% move on to NDA application Phase IV: The FDA will monitor a drug after the medication has been released onto the market. The sponsor, generally the manufacturer, is required to submit periodic safety updates The trials are generally conducted to find out about long- term risks, benefits and optimal use. Phase 4 trials also allow the FDA to monitor use in subsets of the population e.g. children

FDA DRUG APPROVAL Comprehensive New Drug Application (NDA) Review Final Hurdle Before Approval NDA Review Portion of the FDA Drug Approval Process Review Meeting: FDA meets with drug sponsor prior to submission of NDA June 15, 2016 | Emilia Varrone Sources: "Drug Approval Process", “New Drug Application” FDA, June 13, NDA Application: An NDA includes all animal and human data and analyses thereof. Goals include determining whether the drug is Safe and effective in proposed uses Determine whether the drug’s benefits outweigh the risks Application Reviewed: The FDA has 60 days to decide whether to file the application for review. A review team is thereafter assigned to determine whether the research on the drug is sufficient to determine that the drug is safe and effective Drug Labeling: The FDA reviews the drug label and determines whether the appropriate information is included and is properly communicated to practitioners and consumers Facility Inspection: The FDA inspects the facilities where the drug is to be manufactured

FDA DRUG APPROVAL Drugs that Meet Medically Unmet Needs Can Receive Several Designations That Accelerate Review FDA Approval and Faster Approval Designations June 15, 2016 | Emilia Varrone Sources: "Drug Approval Process", “Accelerated Approval,” FDA, June 13, Approval: If application, facility and proposed label is are reviewed, the FDA will issue an approval or a response letter. Faster Approvals : Fast Track Facilitates development and review of drugs to treat serious conditions and fill medical need that is not met A fast tracked drug has more frequent meetings and communication with the FDA, eligibility for accelerated approval and priority review, as well as a rolling review of its NDA (company can send in sections as they are completed) Breakthrough Therapy When the drug is intended to treat a serious condition and preliminary evidence suggests that the drug is a substantial improvement over available therapies. All fast track features, as well as guidance through the clinical phase. Breakthrough therapy also receives organizational commitment involving senior managers Accelerated Approval If a drug shows a surrogate benefit, rather than a tangible clinical end point (ex. The drug shrinks a tumor, but it is yet unknown whether it improves survival rates for cancer patients) a drug is eligible for accelerated approval, and the trials do not have to show a clinical end point to enter the NDA process. Priority Review If a drug presents a significant improvement over the safety or effectiveness of current drugs on the market, the drug may be eligible for priority review. Priority review compels the FDA to take action on an application within 6 months, compared with 10 months for a standard review

FDA DRUG APPROVAL From 2006 to 2014, CDER Averaged About 28 Novel Drug Approvals Per Year June 23, 2016 | Alexander Perry Sources: Center for Drug Evaluation and Research, “2015 Novel Drugs Summary,” FDA, January ■ NME/New BLA Approvals ■ NME/ New BLA Filings Center for Drug Evaluation and Research (CDER) New Molecular Entity (NME) and New Biologic License Application (BLA) Filings and Approvals 45 novel drug approvals in calendar year 2015 is more than the average number approved annually during the past decade