Regulatory Issues Introduction to the Regulatory Approval Process; Overview of the FDA - PowerPoint Presentation

Slide1

Regulatory IssuesSlide2

Introduction to the Regulatory Approval Process; Overview of the FDA

Investigational New Drug Application (IND); Summary of regulations and guidelines

Introduction of

cGMP's

/principles of validation

Introduction to QA/QC principles

Good Laboratory Practice (GLP) compliance

Pre-clinical testing for biotechnology products; safety and toxicology

Clinical stages, design of clinical trials and protocols, evaluation of clinical data

Regulatory Filings: Biological License Application (BLA)

Pre-approval inspections

Team Biologics

International regulatory status for biotechnology products; WHO, Japan, and the EC/CPMP application

International Conference on Harmonization (ICH) update

Regulatory considerations for gene therapy and transgenic productsSlide3

FDA Structure / Organization

Center for Veterinary

Devices

Food and Drug

Administration

Center for Biologics

Evaluation and Research

Center for Devices and

Radiological Health

National Center for

Toxicological Research

Center for Food Safety and

Applied Nutrition

Center for Drug Evaluation

and Research

FDA

Structure / Organization

Office of

Combination

ProductsSlide4

Office of Device

Evaluation

Office of In-Vitro

Diagnostic

Devices & Safety

Office of Health

& Industry

Programs

Office of

Science &

Technology

Office

of

Compliance

Office of

Surveillance

& Biometrics

Center for Devices and

Radiological Health

CDRH OfficesSlide5

FDA's Three Key Development Roles:

"Gatekeeper"

to the marketplace -- the new drug approval process

"Cop on the beat"

or

"Enforcer"

-- ensuring quality compliance via inspection and enforcement actions (e.g. criminal charges)"Sentinel" of Safety Concerns - during development and post-approvalSlide6

6

FDA regulation of medical products

Among the products that FDA regulates are three categories of diagnostic, preventative, or therapeutic products:

Drugs

Biologics

Medical devicesSlide7

The Approval Gate …

Preliminary Considerations --

Determining the Regulatory Status of the product

Is it a "drug", "device" or "biologic"?

Drug:

described in

USP (

United States Pharmacopeia) orintended (via labeling)

to affect the body of man or other animalsto be used in the diagnosis, cure, mitigation, treatment or prevention of disease in man or other animalsSlide8

The Approval Gate …

Regulatory Status of the product -

con'd

…

Is it a "drug", "device" or "biologic"?

Device: defined as involving: "instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or "similar or related article including any component, part or accessory."

in USP/NF (the National Formulary) or

intended to be used in diagnosis … cure, mitigation, treatment or prevention of disease or other conditionsintended to affect the body of manSlide9

The Approval Gate …

Regulatory Status of the product

-

con'd

…

Is it a "drug", "device" or "biologic"?

Thus -- device definition can capture products that resemble drugs if they do not achieve their result via being metabolized in the body or via chemical action within or on the body -- regulated by FDA Center for Devices & Radiological Health (CDRH)

Examples of "drug-like" devices:Ultrasound contrast media

Contact lens solutionsSlide10

The Approval Gate …

Regulatory Status of the product -

con'd

…

Is it a "drug", "device" or "biologic"?

Biologic --Generally, if derived from human or animal tissue;

used to be regulated by FDA Center for Biologics (CBER) using approval standards similar to CDERtherapeutic biotech products going to CDERvaccines – remain behind

NOTE: "true" biotech products usually are biologicsSlide11

The Approval Gate …

Regulatory Status of the product

-

con'd

…

Is it a "drug", "device" or "biologic"?

OR BOTH??"Combination" or "hybrid" products --

are regulated per their "primary mode of action" --but this may be difficult to discern -- get clarification very early as will impact FDA Center you deal withcan request in writing -- under FDAMA

§ 416, FDA can't later change its mind w/o your consent or public health reasons existSlide12

The Approval Gate …

Regulatory Status of the product

-

con'd

…

What type of submission

is needed to get FDA approval or clearance?Drugs:Full New Drug Application (NDA)

505(b)(2) NDA or "Paper NDA"Abbreviated New Drug Application

The OTC Drug route -- Abreva (Avanir/SKB)NDAOTC Review monograph changeSlide13

The Approval Gate …

Regulatory Status of the product -

con'd

…

What type of submission

is needed to get FDA approval or clearance?

Devices:Premarket Approval Application (PMA) -- clinical studies will be needed

Premarket Notification under § 510k -- clinical studies MAY be needed (or wanted)Slide14

The Approval Gate …

Regulatory Status of the product -

con'd

…

What type of submission

is needed to get FDA approval or clearance?

BiologicsBiologic License Application (BLA)

no generic versions now possible – may change …Slide15

The Approval Gate …

Regulatory Status of the product -

con'd

…

What quantity and quality of data will be demanded by FDA to show safety & effectiveness?

Will vary -- FDA has extensive discretion here

Key task -- try to get clarity as soon as possible in the process -- Ways to do so:

Pre-IND meeting -- encouraged by FDA prior to start of human clinicals

End of Phase 2 Meeting - also encouraged -- here's where you want to "lock" them inSlide16

Overview of Typical Pharmaceutical Product Development

16

FILING

APPROVAL

VALIDATION

IP

Marketing Research

Marketing Plan

1

In 2000 Dollars - Estimates by the National Cancer Institute for all new pharmaceutical. Estimate does not consider R&D costs that are not associated with the development of the drug in question. Most drug companies use a system of cost estimates that

includes the valuation of money if it had been invested andthe cost of drug development not approved by the FDA. Most studies conclude that the rate of commercialization success to be 1:5000.

How Much does it cost to develop a new drug

- James Love Consumer Project on Technology

http://www.cptech.org

April 2, 20002 Drug Approval Overregulation, MR Ward - CATO Regulation - http://www.cato.org/pubs/regulation/reg15n4e.htm

3 New York Times - November 8 1995

Cost:

1

Preclinical to Phase II - Approximately 1-7 million

Phase III - 2 - 8 million

Time:

2,3

Validation Batches - Product Costs

and Labor X 3 to 5 batches

Production Start Up Costs based on Contract or Facility

Total Costs =

10-25 million

USD

Preclinical to Completed Clinicals - 3-5 years

FDA Approval - 13.5 months

3

Validation and Production Launch - 6-18 months

Total Time =

4.5 - 7.5 years

Product LaunchSlide17

Welcome to the Jungle

17

Pre Clinical Work

Clinical Trials

Registration

Validation

Commercial

Production

Filing

Approval

Pre Approval Inspection

Stability

Stable

Unstable

FAIL

GO

Animal

Effective

Ineffective

FAIL

GO

Toxicology

Safe

Toxic

FAIL

GO

Micro

Antimicrobial

& Aseptic

Grows

Bugs

FAIL

GO

Chemistry

Passes ID

&

Description

Degradants

&

Impurities

FAIL

GO

Reformulation Egg

START OVER

REFORMULATE

Death of Product

Phase

I

Proof of

Concept

Phase

II

Efficacy

Phase

III

Definition

FAIL

Ineffective

Effective

GO

FAIL

Ineffective

Inferior

Effective

GO

Tweak Formula

Re-Evaluate

FAIL

Ineffective

Effective

GO

Clinical Report

Failure is Unlikely

Min. Energy Batch

Max. Energy Batch

Nominal

Batch

FAIL

FAIL

GO

FAIL

GO

PASS

GO

PASS

PASS

Reset

Parameters

Reset

Parameters

RESET ALL PARAMETERS

Quarantine

Product

Scale Up

Production

Launch

Ad Campaign

Fill Sales &

Warehouse

Pipeline

Launch

Validation Report

Stability Testing

Sell Product

Validation Sign Off

Phase

IV

FDA

STUDIES

Formula Improvement

Geriatric or Pediatric

Drug Interaction

Define LT & Side EffectsSlide18

And the next step…

You’ve got the device or drug okayed—now you have to manufacture it…Slide19

19

GMPs

Current good manufacturing practices (GMPs) are the methods by which manufacturers, holders, and transporters of drugs, biologics, or devices assure that every product that they make, hold, or transport is, and continues to be until it is used, safe and effective.

Failure to comply with GMPs (and for devices, failure to comply with the quality system regulations) makes a product “adulterated” and its distribution or sale illegal.Slide20

The Early Beginnings

1900s house-calls

Home remedies, ointments and “miracle elixirs”

Entertainment and music

No regulations until 1902

Fig. 1. Animation of ancient medicine showSlide21

Public Involvement

1905 - The Jungle by Upton Sinclair

Exposure of unsanitary conditions in meat packing plants

Public awareness and involvement

Pure Food and Drug Act

False labeling became illegal

Fig. 2. The Jungle by Upton Sinclair

Fig. 3. 1906 Meat processing plantSlide22

What is GMP?

Good Manufacturing Practice is a set of regulations, codes, and guidelines for the manufacture of drug substances and drug products, medical devices, in vivo and in vitro diagnostic products, and foods.

Fig.4 GMP handbooks for every industrySlide23

Good Manufacturing Practices Worldwide Enforcement

Good Manufacturing Practices are enforced in the United States by the FDA

In the United Kingdom by the Medicines and Healthcare Products Regulatory Agency

GMPs are enforced in Australia by the Therapeutically Goods Administration

In India by the Ministry of Health, multinational and/or foreign enterprises

Many underdeveloped countries lack GMPsSlide24

1941 Initiation of GMP

Sulfathiaziole

tablets contaminated with

phenobarbital

1941 - 300 people died/injured

FDA to enforce and

revise

manufacturing and quality control requirements1941 - GMP is born

Fig. 5 1906 Certificate of Purity signed by doctorSlide25

1962 Kefauver-Harris Drug Amendments

Thalidomide tragedy

Thousands of children born with birth defects due to adverse drug reactions of morning sickness pill taken by mothers

Strengthen FDA’s regulations regarding experimentation on humans and proposed new way how drugs are approved and regulated

“Proof of efficacy” lawSlide26

1976 Medical Device Amendments

1972 and 1973 -Pacemaker failures reported

1975 - hearing-

Dalkon

Shield intrauterine device caused thousands of injuries

Class I, II and III medical devices – based on degree of control necessary to be safe and effective

Fig.7 President Gerald Ford signs the Medical Device AmendmentsSlide27

1980 Infant Formula Act

1978 - major manufacturer of infant formula reformulated two of its soy products

1979 - Infants diagnosed with

hypochloremic

metabolic alkalosis

Greater regulatory control over the formulation and production of infant formula

Modification of industry’s and FDA’s recall procedures

Fig.8 Parody on Infant Formula ActSlide28
Slide29

Part 211 –Selected cGMP For Finished Pharmaceuticals

Subpart A-General Provisions

Subpart B-Organization and Personnel

211.22 Responsibilities of quality control unit.

211.25 Personnel Qualifications.

211.28 Personnel responsibilities.

Subpart C-Buildings and Facilities

211.46 Ventilation, air filtration, air heating and cooling.

211.58 MaintenanceSubpart D-Equipment211.63 Equipment design, size, and location.211.65 Equipment construction.211.67 Equipment cleaning and maintenance.211.68 Automatic, mechanical, and electronic equipment.211.72 Filters.

Subpart E-Control of Components and Drug Product Containers and Closures211.80 General requirements.211.82 Receipt and storage of untested components, drug product containers, and closures.211.84 Testing and approval or rejection of components, drug product containers, and closures.211.86 Use of approved components, drug product containers, and closures.Subpart F-Production and Process Controls211.100 Written procedures; deviations.211.101 Charge-in of components.

211.103 Calculation of yield.211.105 Equipment identification...............Slide30

§ 211.25 Personnel qualifications

(a) Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee's functions. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them.

(b) Each person responsible for supervising the manufacture, processing, packing, or holding of a drug product shall have the education, training, and experience, or any combination thereof, to perform assigned functions in such a manner as to provide assurance that the drug product has the safety, identity, strength, quality, and purity that it purports or is represented to possess.

(c) There shall be an adequate number of qualified personnel to perform and supervise the manufacture, processing, packing, or holding of each drug product.Slide31

Quality Assurance vs. Quality Control

Quality Assurance

An overall

management plan to

guarantee the

integrity of data

(The “system”)

Quality Control

A series of

analytical measurements usedto assess thequality of the analytical data(The “tools”)Slide32

True Value vs. Measured Value

True Value

The known, accepted value of a quantifiable property

Measured Value

The result of an individual’s measurement of a quantifiable propertySlide33

Accuracy vs. Precision

Accuracy

How well a measurement agrees with an accepted value

Precision

How well a series of measurements agree with each otherSlide34

Systematic vs.

Random Errors

Systematic Error

Avoidable error due to controllable variables in a measurement.

Random

Errors

Unavoidable errors that are always present in any measurement. Impossible to eliminateSlide35

Quality Control Measures

Standards and Calibration

Blanks

Recovery Studies

Precision and Accuracy Studies

Method Detection Limits

State LawsSlide36

Standards and Calibration

Prepared vs. Purchased Standard

Signals: Peak Area, Beer’s Law

Calibration Curves

Continuing Calibration Checks

Internal Standards

Performance TestingSlide37

Calibration Curves

Graphical representation of the relationship between:

The analytical signal

The concentration of the

analyte

andSlide38
Slide39

Continuing Calibration Verification

Many methods don’t require that daily calibration curves are prepared

A “calibration verification” is

analyzed with each batch of samplesSlide40

Sample Batch

10 - 20 samples (method defined) or less

Same matrix

Same sample prep and analysis

Contains a full set of

QC samplesSlide41

Internal Standards

A compound

chemically similar to the

analyte

Not expected to be present in the sample

Cannot interfere in the analysisAdded to the calibration standards

and to the samples in identical amountsSlide42

Internal Standards

Refines the calibration process

Analytical signals for calibration standards are compared to those for internal standards

Eliminates differences in random and systematic errors between samples and standardsSlide43

Performance Testing

Blind samples submitted to laboratories

?

?

?

Labs must periodically analyze with acceptable results in order to maintain accreditationSlide44

Blanks, Blanks, Blanks

Laboratory Reagent Blanks

Instrument Blanks

Field Reagent Blanks

Trip BlanksSlide45

Laboratory Reagent Blanks

Contains every reagent used in the analysis

Is subjected to all analytical procedures

Must give signal below detection limit

Most methods require one with every batchSlide46

Instrument Blank

A clean sample (e.g., distilled water) processed through the instrumental steps of the measurement process; used to determine instrument

contaminationSlide47

Field Reagent Blanks

Prepared in the lab, taken to the field

Opened at the sampling site, exposed to sampling equipment, returned to the lab.Slide48

Trip Blanks

Prepared in the lab, taken to the field

Not opened

Returned to the lab

Not always required in EPA methodsSlide49

Recovery Studies

Matrix Spikes

Laboratory Control Samples

Surrogates Slide50

Matrix Spikes

Sample spiked with a known amount of

analyte

Subjected to all sample prep and analytical procedures

Determines the effect of the matrix on

analyte

recovery

Normally one per batchSlide51

Laboratory Control Sample

Subjected to all sample prep and

analytical procedures

Analyte

spiked into reagent waterSlide52

Precision and Accuracy

Required for initial certification and annually thereafter

A series of four laboratory control samples

Must meet accuracy (recovery) and precision (standard deviation) requirements, often in methodSlide53

Method Detection Lim

it

“The minimum concentration of a substance that can be measured and reported with 99% confidence that the

analyte

concentration is greater than zero”

Slide54

Method Detection Limit

MDLs are determined according to 40 CFR, part 136, Appendix B

Seven replicate laboratory control samples, analyzed for

precisionSlide55

Method Detection Limit

Must be performed initially for certification

Must meet criteria specified in method

Must be performed with change in instrumentation or test method

Annually with

ELCP (

Environmental Laboratory Certification

Program)Slide56

State Laws

Each state has laws governing

laboratories and their personnel.