FDA Requirements for Clinical Trials and Market Approval

Carl Peck MD

Adj. Professor, UCSF

Chairman, NDA Partners LLC

Carl Peck 2016

Carl Peck 2016

Why, What, How, When ?

FDA Requirements

Patent Medicine 1900 All Medicines sold without a prescription

Children and Adults die after taking cough syrup

arsenic, opium, insect parts, acetanilid, hydrochloric acid, red wine

1906 Pure Food and Drug Act

–“The Jungle”

–Prohibited adulterated or misbranded foods or drugs

–Regulated labeling

• “false or misleading”

The “Elixir of Sulfanilamide” Incident

In 1937: a chemist @ Massengill Co. used sweet-tasting diethylene glycol (antifreeze) in sulfa drug syrup form to improve taste

– Diethylene glycol is sweet but deadly

– > 100 deaths, most were children

– Company fined $300

– Chemist committed suicide

Public outrage led to passage of 1938 Food Drug & Cosmetic Act

1938 Food Drug & Cosmetic Act

• Prohibited false therapeutic claims

• some drugs by prescription only

• Increased factory inspections

Carl Peck 2016

Thalidomide

FDA did not approve for U.S

17 known U.S. cases of limb defects

• Sedative for pregnant women

• 1000’s of babies born with limb defects in

Europe and elsewhere

1962 Kefauver-Harris Amendments

• Public concern about thalidomide

• Required “substantial evidence” of effectiveness, and safe

– “substantial evidence” = based on evidence consisting of adequate and well-controlled

investigations

Carl Peck 2016

“substantial evidence” of effectiveness

“evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could be fairly and responsibly concluded by such experts that the drug will have the effect it purports or as represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.”

2+ independent, confirmatory clinical trials P < 0.05

Carl Peck 2016

FDA Today n=12,000; $ 12 B

Carl Peck 2016

Carl Peck 2016

FDA Regulated Therapeutic

Products for Human Use • Small molecules

– New molecular entities – Generic – Similar but not bioequivalent (505(b)(2))

• Biologics – Proteins – Blood products – Vaccines

–Biosimilars • Medical devices • Drug/biologic - Device Combinations

Carl Peck 2016

Carl Peck 2016

What are FDA Requirements

• Standards

– CMC

– animal pharm/tox

– human clinical trials

• Ethics

• Effectiveness

• Labeling

– INDs, & NDAs

– Post-approval safety monitoring

Biosimilars Biologics Price Competition Act, 2009

(BCPI)

• Requirements - General – “highly similar” vs “interchangeable”

– “no clinically meaningful difference” • Safety, purity, potency

• Requirements – Specific – Analytical

– Animal

– Clinical PK and PD

• 1st Approval in 2015: Zarxio (filgrastim-sndz)

Carl Peck 2016

How does FDA communicate and Enforce its Requirements ?

• Guidance – Meetings – Guidance documents

• Review –

– IND’s – NDA’s, BLA’s, IDE’s – pharmacovigilance

• Enforcement – drug quality, safety

– Inspections

– Advertising and promotion

Carl Peck 2016

Meetings with FDA n = 2800 (2015)

• Type A – immediately necessary

– Clinical Holds, Special Protocol Assessments, Disputes

• 15-20 days of request

• Type B (milestone)

– Pre-IND, End of Phase 2a, 2, Pre-NDA/BLA

• Information package due 30 days prior to meeting

• 60 days

• FDA written response prior to meeting

• Type C (Everything else)

– General advice

• 75 Days

Carl Peck 2016

Carl Peck 2016

• Written guidances – Regulations, guidelines (incl. ICH),

– guidances (>500), not binding

– Literature publications

• Face-to-face & telephonic meetings – Pre-IND, EoP2a, EoP2a Clinical Pharmacology, pre-

NDA, others as-needed

• FDA Advisory Committee meetings

• Presentations & publications Website - www.fda.gov

FDA Guidance

Carl Peck 2016

When does FDA engage?

FDA Decisions

• driven by scientific and risk/benefit evaluations,

precedents, policies

– societal safety and benefit

– regulators’ personal philosophies

• Influence of public Advisory Committees

• Political and media influences can influence

Carl Peck 2016

End of Presentation

Carl Peck 2016