Regulatory Processes I

Market Access

The ability for a medical product to legally enter and remain on the market.

Reimbursement

How the company/provider gets paid for the product or service.

Nostrum

A medicine, especially a patent medicine, that is not scientifically proven and is often marketed as a cure-all.

Lydia E. Pinkham's Vegetable Compound

A specific patent medicine marketed in the late 19th century, claimed to relieve women's ailments and was often categorized as a nostrum.

Muckrakers

Writers/journalists who exposed problems with patent medicines and their effects.

Upton Sinclair

Author of The Jungle.

The Jungle

Book that exposed horrible conditions in the meatpacking industry.

Harvey Wiley

Chemist associated with the Bureau of Chemistry who investigated unsafe food additives and pushed for stronger food regulation. His work investigating food additives and fighting the food industry helped lead to stronger food regulation and ultimately the creation of the FDA.

Bureau of Chemistry

Federal agency that enforced the 1906 Pure Food and Drug Act and later became the FDA.

Poison Squad

Group of 12 men who participated in experiments where they consumed foods containing questionable preservatives/additives to study the effects of potentially harmful food preservatives/additives on people.

1906 Pure Food & Drug Act

Federal law prohibiting misbranded and adulterated foods, drinks, and drugs from entering interstate commerce. (medical devices were not included)

Misbranded

A product that has improper/false labeling or identification.

Adulterated

A product that has been improperly contaminated, prepared, or contains unacceptable substances.

Interstate Commerce

Commerce involving movement/trade between different states.

Sherley Amendment (1912)

Amendment that prohibited labeling medicines with false therapeutic claims intended to defraud purchasers to overcome the limitation created by U.S. v. Johnson.

U.S. v. Johnson

Supreme Court case that limited the government's ability to treat false therapeutic claims as misbranding/adulteration under the existing law.

What happened in 1930?

Bureau of Chemistry became the Food and Drug Administration (FDA)

FDA

Federal agency responsible for regulating the products covered by the laws it administers.

newer/stronger regulations

major public health disasters often create pressure for

1930 Food, Drug, & Cosmetic Act

Major law that strengthened FDA authority and required manufacturers to provide evidence that drugs and medical devices were safe before marketing.

1962 Thalidomide Disaster

Thalidomide was associated with serious birth defects. The public created pressure for stronger drug testing and regulation.

Kefauver-Harris Amendments (1962)

Strengthened drug regulation by requiring FDA approval of marketing applications and evidence of both safety and efficacy.

Cooper Commission (1970)

Commission associated with investigating medical-device injuries and deaths. Demonstrated serious problems with medical devices and contributed to the movement toward stronger medical-device regulation.

Medical Device Amendments (1976)

Assure medical devices are safe, effective, and properly labeled. First time FDA clearly distinguished between a device and a drug

GMP

Good Manufacturing Practices; requirements intended to ensure products are consistently produced and controlled.

21 CFR 820

Regulation containing the Quality System Regulation for medical devices.

MedWatch

FDA system for identifying and monitoring significant adverse events involving medical devices.

MDUFMA (2002)

Medical Device User Fee and Modernization Act. Address FDA workload/bottlenecks by having industry pay user fees while FDA agrees to review timelines.

8,000/yr

Population threshold mentioned for HUD

Legislative Branch

Writes laws that establish the legal requirements FDA must follow.

Executive Branch

Implements statutes/laws through regulations and government agencies.

Rulemaking

process used to create regulations

Judicial Branch

Interprets laws through court decisions/case law.

Case Law

Legal principles established through court decisions.

FDA v. Brown & Williamson Tobacco Corp. (1996)

The U.S. Supreme Court ruled 5-4 that the Food and Drug Administration (FDA) did not have the authority under the Food, Drug, and Cosmetic Act (FDCA) to regulate tobacco products

Product Decision Flow

Process used to determine whether a product is a drug, biologic, device, combination product, or another regulated product and which pathway applies

drug

Product used to diagnose, cure, mitigate, treat, or prevent disease or affect a structure/function of the body.

biologics

Medical product made from natural sources such as humans, animals, or microorganisms, or containing large biologically active macromolecules. (vaccines, blood products…)

medical device

Instrument, apparatus, implement, machine, contrivance, implant, in-vitro reagent, or similar article intended for diagnosis, cure, mitigation, treatment, prevention, or affecting body structure/function.

1976 Medical Device Amendments

Established device safety/performance requirements, FDA premarket review, device classification, 510(k), PMA, and IDE.

the 510(k) pathway

premarket clearance

PMA pathway

premarket approval

class I, general controls

Lowest classification in the lecture; regulated through _________ (two answers need to be given)

class II, general controls and specific controls

medium risk, requires 510(k) and is regulated through _____ (two answers need to be given)

Class III, general controls and premarket approval

highest risk classification; regulated through…. (two answers need to be given)

general controls

Basic regulatory requirements that broadly apply to medical devices.

special controls

Additional requirements designed specifically for a particular type of device.

21 CFR 820

Medical-device Quality System Regulation.

180 days

PMA review time

510(k)

Premarket notification used to demonstrate that a device is as safe and effective as a legally marketed predicate device that is not subject to PMA.

demonstrate substantial evidence to a predicate

purpose of 510(k)

predicate

Device legally marketed and eligible to serve as the comparison device.

substantial equivalence

Determination that a new device has the same intended use as the predicate and meets the applicable technological comparison requirements.

1. same intended use and technological characteristics

2. same intended use but different technological characteristics and no concerns about safety and effectiveness

substantial equivalence requirements: (2 of them)

De Novo

Pathway for a device when there is no appropriate predicate or after a device receives an NSE determination.

NSE

not substantially equivalent

30 days of NSE

de novo deadline

IDE - investigational device exemption

Allows an investigational device to be used in a clinical study to support a future FDA regulatory submission.

biocompatibility

Evaluation of how a device/material interacts with the human body.

ISO 10993

Standard referenced for biocompatibility evaluation/testing.

Humanitarian Use Device - HUD

Device intended for a condition affecting a very small patient population.

Combination product

Product containing multiple regulated constituent parts, such as a drug + device, biologic + device, or other regulated combination.

1990 Safe Medical Devices Act

Act that added pre-production design and validation controls to GMPs

OCP - office of combination products

Office that assigns the combination product to a lead FDA center but does not review the combination product itself.

(PMOA) Primary Mode of Action

Determines which FDA center becomes the lead center. The most important therapeutic action or the mode of action expected to make the greatest contribution to the overall therapeutic effects.

physically combined, chemically combined, co-packaged, cross-labeled …..

Types of combination products (name 4 major)

Center for Drug Evaluation and Research

CDER ; lead center associated with drugs.

Center for Biologics Evaluation and Research

CBER; ; lead center associated with biologics.

Center for Devices and Radiological Health

CDRH; lead center associated with devices.

RFD - Request for designation

Determine the appropriate FDA center/agency jurisdiction for reviewing the combination product.

RFR - request for reconsideration

Used when the sponsor disagrees with the lead-center decision.

pre-RFD

non-binding Informal process for obtaining FDA feedback before submitting a formal RFD.

Master File

Voluntary submission to FDA containing confidential proprietary or trade-secret information about a product or process.

company proprietary information

Company information that is commercially sensitive and not intended to be publicly disclosed.

trade secret

Confidential business/technical information that provides value because it is not publicly known.

letter of authorization

Permission from the DMF/MAF holder allowing an applicant to have FDA reference the information in the master file.

Postmarket Submission

FDA submission required after marketing when certain changes are made.

Drug master file

DMF

Device master file

MAF

final rule principle

A combination product does not cause its drug, device, or biologic components to lose their individual regulatory identities.

user fee

Fee paid for FDA regulatory review.

project plan

Organizes the actual work needed to execute the regulatory strategy, including milestones, deliverables, resources, responsibilities, and timeline.

(SME) Subject Matter Expert

Person with specialized knowledge in a particular technical or regulatory area.

strategy buy in

Getting important stakeholders to support and agree with the regulatory strategy.

risk mitigation

Steps taken to reduce or address regulatory/project risks.

quality compliance

Making sure the product and company meet applicable quality and regulatory requirements.

administrative meetings/communications

Formal or informal communication between FDA and a sponsor, including email, phone, or meetings.

regulatory communications

Communication involving regulatory requirements, policies, or issues.

product application meetings

Meetings specifically related to development or review of a product/application.

public administrative proceedings

Public FDA meetings/proceedings involving regulatory or scientific issues.

federal register (30-60days)

Government publication used to announce proposed/final regulations and other FDA actions. what’s the public comment period?

Guidance (90 days)

FDA's current thinking/recommendations about regulatory issues. What is the public comment period?

• Not legally binding

21 CFR

Code of Federal Regulations containing FDA regulations.

citizen petition; FDA response is 180 days

Formal written request asking FDA to take or not take a specific regulatory action.

• FDA response: ?

pre-submission

Meeting/request used to obtain FDA feedback before submitting a marketing application.

information meeting

Meeting where the sponsor primarily provides information to FDA.

study risk determination

DA determines whether a clinical study presents significant or nonsignificant risk.

significant risk (SR)

Study presents significant risk; IDE is required.

nonsignificant risk (NSR)

Study does not present significant risk; IDE is not required, but IRB approval is still needed.

formal early collaboration meeting

DA meeting used early in development to reach agreement on important investigational-plan or clinical-protocol parameters.