FDA Processes for Assuring Safety and Efficacy for Ophthalmic Drugs Wiley A. Chambers, M.D. Ophthalmology Office of New Drugs Center for Drug Evaluation and Research Food and Drug Administration

Disclaimer This presentation reflects the views of the author and should not be construed to represent Food and Drug Administration’s (FDA’s) views or policies. The speaker has no financial interest or other relationship with the manufacturer of any commercial product discussed or with the manufacturer of any competing commercial product.

Federal Food, Drug and Cosmetic Act, as amended (FD&C Act) Regulation of Interstate Commerce Food Drugs (NDA) Devices (PMA) Cosmetics

Public Health Service Act Regulation of Interstate Commerce Biologics (BLA)

Foods Articles used for food or drink for man or other animals Chewing gum

Cosmetics Articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance

Biologics Viruses, serum, toxins, antitoxins, vaccines, blood, blood components or derivatives, allergenic products or analogous products for the prevention, treatment or cure of diseases or injuries of man

Drugs and Devices Articles intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in man or other animals Articles (other than food) intended to affect the structure or any function of the body of man or other animals

Drug vs. Device A Device does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and is not dependent upon being metabolized for the achievement of its primary intended purposes

Regulation of Interstate Commerce Federal Food, Drug and Cosmetic Act (as amended)/ Public Health Service Act Regulation of Interstate Commerce Drugs pre market clearance Biologics pre market clearance Devices pre market clearance Foods Cosmetics NOT Procedures

Food and Drugs Act 1906 Prohibits interstate commerce of misbranded and adulterated foods, drinks and drugs

Lash Lure

Food Drug & Cosmetic Act 1938 Response to products such as Elixir Sulfanilamide and Lash Lure Review of Drug Safety Pre-market Review of Drugs

Amendments to FD&C Act Durham-Humphrey -1951 OTC/Rx Kefauver-Harris -1962 Require efficacy Medical Device Amendments –1976 Devices Orphan Drug Act – 1983 Orphan Incentives Hatch-Waxman – 1984 Generics PDUFA - 1992 User Fees DSHEA – 1994 Dietary Supplements Medical Device User Fee and Modernization Act of 2002 User Fee Renewals – 1997, 2002, 2007, 2012, 2017 Best Pharmaceuticals for Children Act -2002, 2007 Pediatrics Pediatric Research Equity Act – 2003, 2007 Pediatrics 21st Century Cures – 2016

FD&C Act (as amended) Prohibits interstate transportation of unapproved new drug products Requires substantial evidence of safety and efficacy as the basis of approval of new drugs Permits the FDA to grant exemptions from the FD&C Act to study new drug products

Mission of the Center for Drug Evaluation and Research Assure that safe and effective drugs are available to the American people.

Accomplished by Monitoring Drug Development Process during Investigational Stages Most of this process is confidential Approving New Drug Products that are safe and efficacious Confidential until approval and then designed to be transparent Monitoring Adverse Events after Approval

What does the FDA not do? Conduct clinical studies Choose which products a company will study Force companies to market products Regulate the practice of medicine

Clinical use may consist of Approved Use Investigational Use

Being careful about clinical trials Ask if the trial is being conducted under an IND Ask for the IND number Question any trial that charges for the investigational product Clinicaltrials.gov is a listing of clinical trials The listing is neither from the FDA nor reviewed by the FDA Only some of these listed trials may have an IND

SCIENCE A Woman Went Blind After Stem Cells Were Injected in Her Eyes And she isn’t the only one. SARAH ZHANG OCT 19, 2017 Last year, a 77-year-old woman traveled to a clinic in Georgia to have stem cells injected in her eyes. She came in hope of a cure—or at least something that could help her macular degeneration, which causes a dark spot to appear in the center of vision. The procedure was supposed to work like this: The clinic would take fat from her belly, separate out stem cells that naturally occur in fat, and inject them into her eyes to regenerate damaged tissue. The procedure cost $8,900. It had not been approved by the Food and Drug Administration and was not covered by insurance. To pay out of pocket, she had to raise money on a crowdfunding site. Her vision did not get better. It got much worse. Within three months, her retinas—the eye’s layer of light-sensitive cells—had peeled away from the rest of her eyes. As a result, she can only make out hand motions in her right eye and light in the left, according to a recent case report. She could no longer walk on her own. In March, eye doctors based primarily at the Bascom Palmer Eye Institute in Miami had published a widely covered report describing three eerily similar cases: Three elderly women with macular degeneration got stem cells derived from their own fat injected into their eyes at a different stem-cell clinic in Florida. The same thing happened: Their retinas became detached, and they went blind. The doctors ended up examining the 77-year-old woman too, which led to the recent case report describing her condition.

Study Phase 1 Initial introduction of an investigational new drug in humans Goal is to obtain sufficient information about the drug’s pharmacokinetics and pharmacological effect to permit the design of well-controlled, scientifically valid, Phase 2 studies.

Study Phase 2 Controlled clinical studies to evaluate the effectiveness of the drug and the common short term side effects and risks Relatively small number of patients usually involving no more than several hundred

Study Phase 3 Expanded controlled studies Performed after preliminary evidence suggesting effectiveness of the drug has been obtained. Evaluate the overall benefit-risk relationship and provide adequate basis for physician labeling

Risk All drugs have some risk Assessment improves as more individuals receive the drug product Usually not completely known

Basis for Approval Benefits outweigh the risks when the drug product is taken by the intended population as labeled Expected to be demonstrated in replicated adequate and well controlled studies

Clinical Trials Must have equipoise or balancing of Potential benefit from drug product Potential adverse event from drug product Potential safety from not taking a new product Potential loss from disease condition if not taking an effective therapy Missing out on an alternative therapy Bottom Line- Clinical trials benefit future populations, not the individuals in the trial

Endpoints Anatomic Objective – Instrumentation Subjective – with interpretation Patient reported –single question Patient reported – multiple domains

Anatomic Predictors Must predict a clinical benefit for patient

Objective/Instrument Measures Intraocular pressure, Refractive power, Pupil size, Tear production How much is clinically important? The ability to measure a difference does not necessarily make it clinically important.

Patient subjective endpoint with interpretation Visual function Visual acuity (ability to read letters) Color vision (ability to differentiate colors) Visual fields (how much area is seen) Contrast sensitivity (low light conditions)

Patient reported –single item Itching Pain Ocular irritation Ocular dryness

Patient Reported – Multiple domains Quality of Life (QOL) Measures Requires knowing how much weight to give to each domain None of the ophthalmology QOL measures are currently validated (qualified)

Pediatric Development Best Pharmaceuticals for Children Act (BPCA) 6 month extension on patents and exclusivity for doing studies in pediatric patients Voluntary program Pediatric Research Equity Act (PREA) Requirement to conduct studies in children Applies to new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration

Demographic Subsets Pediatrics 0-17 years Geriatrics- differences between ages <65, 65-75 >75 Gender Race Eye color

How fast is the Review? Priority Review vs. Standard Review CDER’s definition of priority- a significant improvement, compared to marketed products for a serious or life-threatening condition

Review Goals Standard 90% of submitted applications reviewed within 10 months (12 months for new molecular entities) Priority 90% of submitted applications reviewed within 6 months (8 months for new molecular entities)

Common reasons for a product NOT being approved Application never submitted. No clinical benefit demonstrated for the proposed indication (or benefit does not outweigh the risk). Quality of the product cannot be assured because the facility manufacturing the product is not in compliance with current good manufacturing practices.

FDA on the Web FDA Website www.fda.gov IND Information https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/investigationalnewdrugindapplication/ucm071098.htm Site for Clinical Investigators https://www.fda.gov/drugs/developmentapprovalprocess/smallbusinessassistance/ucm2007049.htm

FDA Website: www.fda.gov Questions FDA Website: www.fda.gov