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©2019 MB Schmid

Timeline, FDA History

Labelling/ Quality

Proof of Safety

Proof of Efficacy

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User Fees

©2019 MB Schmid

FDA Organization Today

• FDA reports into HHS

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©2019 MB Schmid

FDA Organization Today

• Eight Centers report directly to Commissioner of FDA• Acting FDA Commissioner – Norman Sharpless, MD• Overall budget (2019) - $3.2B + $2.6B User Fees - $5.7B• 17K employees (5.4K CDER; 1.8K CDRH; 1.2K CBER)

CBER CDRH CDER

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©2019 MB Schmid

Major FDA Centers – drugs, devices, biologics

• CDER – Center for Drug Evaluation & Research• Evaluation of drugs – both small molecule & biological (protein and antibod-based

therapeutics)• Includes oversight and evaluation of OTC and generic drugs• Includes diagnostic contrast agents• 5400 FTE; $1.6B budget ($0.5B budget authorization + $1.1B user fees)

• CDRH – Center for Devices & Radiological Health• Evaluation of medical devices and radiation-emitting products• Includes diagnostics• 1800 FTE; $507M budget ($330M BA + $177M user fees)

• CBER – Center for Biologics Evaluation & Research• Evaluation of biological products – blood, vaccines, allergenics, tissues, cell & gene

therapies• 1800 FTE; $359M budget ($215M BA + $144M user fees)

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©2019 MB Schmid

CDER – Evaluation of Drugs

• All new drugs treated the same• Sponsor needs to demonstrate safety, efficacy & quality of the product

• Process• IND – Investigational New Drug application

• What information is needed to file an IND? See Guidance documents and 21 CFR312• Phase 1 – Emphasis on demonstrating initial safety

• Typically in healthy volunteers, n= 20-80• Demonstrate common side effects, metabolism, excretion

• Phase 2 – Demonstrate initial efficacy in patients, n= 10’s – 100’s• Phase 3 – Pivotal trials of safety & efficacy, n=100’s-1000’s• NDA – New Drug Application – request for approval

• Compilation and evaluation of all available data• Safety, efficacy, quality

• Phase 4 – post-market surveillance

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CDRH – Evaluation of Medical Devices (& diagnostics)

• Regulations differ according to device class – I, II, III• Class I – low risk• Class II – moderate risk• Class III – high risk

• Even if clinical studies not needed for market entry, they may be required for market acceptance • What you can say about your

product will be driven by the data you collect• FDA regulates market materials

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Drugs – Resources Needed

• High Risk• ~10% that enter Phase I are

approved• Long timelines (10+ years)• High costs (est. $100-$500M)• High rewards (>$100M/yr)• Cost & time studies

• Differs by therapeutic areas• HHS/ ASPE

https://aspe.hhs.gov/report/examination-clinical-trial-costs-and-barriers-drug-development/31-costs-therapeutic-area

• DiMasi/Tufts https://csdd.tufts.edu/csddnews/2018/3/9/march-2016-tufts-csdd-rd-cost-study

• Center Point Clinical Services (JHU) https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2702287

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©2019 MB Schmid

How Much Money?

• Drugs• Out of pocket costs: Tufts Center Drug Development (2014)

• $430M preclinical• $965M clinical• …but, these include cost of failures…how to estimate how much money is

needed for your company/project?

• Devices – Makower survey (2010)• 510(k) $31M, 10 months• PMA: $94M, 54 months

• These are good starting points, but…• Use these as rough guide - every situation is different• Comparators can be very valuable (what did our competitors do?)• Making mistakes costs time and money (“do-over” is $$$ and ??)

• Study design – number of animals/subjects, controls/comparators, dosing regimen,

©2019 MB Schmid

Authority of FDA – US Federal Law

• Acts of Congress – typically reacting to public events/tragedies• 1906 - Food and Drug Act is passed by Congress, signed by Pres. T. Roosevelt

• Outlaws mislabeled and/or tainted foods, drugs• 1937 – Elixir Sulfanilamide kills 107 people demonstrating need to prove

safety before market• 1938 – Federal Food, Drug & Cosmetic Act • 1940-60 – cGMP, OTC/prescription drugs, FDA factory inspection authority• 1962 – Thalidomide causes severe birth defects in Europe• 1962 – Kevauver-Harris Drug Amendments – prove efficacy before market

approval• 1970-85 – package inserts, OTC drug review, tamper-resistant packaging,

generic drug approval

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Congressional Acts become Code of Federal Regulations (CFR)

• Laws - passed by both branches of Congress and signed by the President• Regulations - issued by U.S. agencies to

interpret and implement federal laws• Other policy documents – e.g., FDA

Guidance For Industry documents

14https://www.phe.gov/s3/law/Pages/default.aspx

©2019 MB Schmid

CFR Title 21 – Food & Drugs

• Code of Federal Regulations (CFR)• Title 21

• Parts 1–99 (FDA, General)• Parts 100–169 (FDA, Food for Human Consumption)• Parts 170–199 (FDA, Food for Human Consumption)• Parts 200–299 (FDA, Drugs: General)• Parts 300–499 (FDA, Drugs for Human Use)• Parts 500–599 (FDA, Animal Drugs, Feeds and Related Products)• Parts 600–799 (FDA, Biologics; Cosmetics)• Parts 800–1299 (FDA, Medical Devices)• Parts 1300–End (DEA and Office of National Drug Control Policy)

• Proposed new regulations• Drafts published in Federal Register• Time period for comments

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Guidance Documents

• Thousands of Guidance Documents from CDER, CDRH, CBER

• Written by FDA staff• Draft – Comment/Revision – Final process• Not always made Final, still provide important info

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FDA Authority - Inspections

• Pre- and Post-approval• Manufacturing, marketing materials,

processes• GLP, GMP, GCP,…

• Warning Letters

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Learning by Example – Warning Letters

• FDA Searchable Warning Letters• https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-

actions-and-activities/warning-letters• Look generally – June 25, 2019 KratomNC – cited for selling kratom products:

• “…your website provides a telephone number that customers can call to order various kratom products, including but not limited to, “Green Bali Powder,” “Red Indo Powder,” …. FDA has determined that these products are unapproved new drugs sold in violation of sections 505(a) and 301(d) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 355(a) and 331(d). Furthermore, these products are misbranded drugs under section 502 of the FD&C Act, 21 U.S.C. 352….”

• If you wanted to sell CBD oil, you might look at what has happened with others…• CBD search – 6 entries, but most recent is 2017. (Laws & regulations changed re: legality of CBD oil

(2018 Farm Bill)

• What classification is my medical device? • Look for comparable devices, and assess what class they are

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRL/rl.cfm

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©2019 MB Schmid

Learning by Example – CBD Oil

• If you wanted to market CBD Oil – what do you need to know?• Is it regulated as a drug? • What can you say/What should you not say in your marketing materials?• Is the process of manufacture regulated?• What else do I need to worry about? – GO TO THE FDA WEBSITE – SEE WHAT

HAS HAPPENED TO OTHERS!!• https://www.fda.gov/news-events/public-health-focus/warning-letters-and-

test-results-cannabidiol-related-products

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What about….

• Orphan drugs? https://www.fda.gov/industry/developing-products-rare-diseases-conditions/designating-orphan-product-drugs-and-biological-products

• What’s the equivalent for medical devices? Humanitarian Use Device https://www.fda.gov/industry/humanitarian-use-device-laws-regulations-and-guidances/current-regulations-21cfr-814-subpart-h-humanitarian-use-devices

• Patent exclusivities – “Orange Book” https://www.fda.gov/drugs/information-healthcare-professionals-drugs/electronic-orange-book

• What about drugs/devices for pediatric patients? https://www.fda.gov/media/91673/download

• ….USE THE FDA WEBSITE!READ - LISTEN – LEARN

CALL/EMAIL…

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FDA – Division of Industry & Consumer Education (DICE)

• Phone or email the FDA!

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https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/contact-us-division-industry-and-consumer-education-dice

©2019 MB Schmid

Need more help? Try SBDC Join OCRA – OC Regulatory Affairs

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FDA-101

• Molly B. Schmid, Ph.D.• June 26, 2019

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