regulatory issues. introduction to the regulatory approval process; overview of the fda...

Regulatory Issues

• 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 products

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 / OrganizationOffice of Combination Products

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 Offices

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-approval

6

FDA regulation of medical products

• Among the products that FDA regulates are three categories of diagnostic, preventative, or therapeutic products:– Drugs– Biologics– Medical devices

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) or– intended (via labeling)

» to affect the body of man or other animals» to be used in the diagnosis, cure, mitigation, treatment or

prevention of disease in man or other animals

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 conditions– intended to affect the body of man

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 solutions

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 CDER– therapeutic biotech products going to CDER

» vaccines – remain behind

• NOTE: "true" biotech products usually are biologics

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 with• can request in writing -- under FDAMA § 416, FDA can't later

change its mind w/o your consent or public health reasons exist

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)

– NDA– OTC Review monograph change

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)

The Approval Gate …

• Regulatory Status of the product - con'd…– What type of submission is needed to get FDA

approval or clearance?– Biologics

• Biologic License Application (BLA)• no generic versions now possible – may change …

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 in

Overview of Typical Pharmaceutical Product Development

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PreClinicalWork

ClinicalStudies

RegistrationValidation

CommercialProduction

FILING

APPROVAL

VALIDATION

IPIP Marketing Research

Marketing Research Marketing PlanMarketing 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.htm3 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 Costsand 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 Launch

Welcome to the Jungle

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Pre Clinical Work

Pre Clinical Work

Clinical Trials

Clinical Trials

RegistrationValidation

RegistrationValidation

CommercialProductionCommercialProductionFilingFiling ApprovalApproval Pre Approval

InspectionPre Approval

Inspection

StabilityStability

Stable

UnstableFAIL

GO

AnimalAnimal

Effective

Ineffective

FAIL

GO

ToxicologyToxicology

Safe

ToxicFAIL

GO

MicroMicro

Antimicrobial & Aseptic

Grows BugsFAIL

GO

ChemistryChemistry

Passes ID& Description

Degradants& Impurities

FAIL

GOReformulation

EggSTART OVER

Reformulation Egg

START OVERREFO

RMU

LATE

Death of Product

PhaseI

PhaseI

Proof of Concept

PhaseII

PhaseII

Efficacy

PhaseIII

PhaseIII

Definition

FAIL

Ineffective EffectiveGO

FAIL

IneffectiveInferior

EffectiveGO

Tweak Fo

rmula

Re-Evaluate

FAIL

Ineffective Effective GO

Clinical ReportClinical Report

Failure is Unlikely

Min. Energy Batch

Min. Energy Batch

Max. Energy Batch

Max. Energy Batch

NominalBatch

NominalBatch

FAIL

FAILGO

FAIL GO

PASSGO

PASSPASS

Rese

tPa

ram

eter

s

Rese

tPa

ram

eter

s

RESET ALL PARAMETERS

QuarantineProduct

Scale UpProduction

Scale UpProduction

LaunchAd Campaign

LaunchAd Campaign

Fill Sales &Warehouse Pipeline

Fill Sales &Warehouse Pipeline

LaunchLaunch

Validation ReportValidation Report Stability TestingStability Testing

Sell Product

Sell Product

Valid

ation

Sign

Off

PhaseIV

PhaseIV

FDA

STUD

IESFD

A STU

DIES

Formula ImprovementFormula Improvement

Geriatric or PediatricGeriatric or Pediatric

Drug InteractionDrug Interaction

Define LT & Side EffectsDefine LT & Side Effects

And the next step…

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

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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.

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 show

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 plant

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 industry

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 GMPs

1941 Initiation of GMP

• Sulfathiaziole tablets contaminated with phenobarbital

• 1941 - 300 people died/injured

• FDA to enforce and revise manufacturing and quality control requirements

• 1941 - GMP is born

Fig. 5 1906 Certificate of Purity signed by doctor

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” law

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 Amendments

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 Act

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 Maintenance• Subpart D-Equipment• 211.63 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 Closures

• 211.80 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 Controls• 211.100 Written procedures; deviations.• 211.101 Charge-in of components.• 211.103 Calculation of yield.• 211.105 Equipment identification.• ..............

§ 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.

Quality Assurance vs. Quality Control

Quality Assurance

An overallmanagement plan to guarantee theintegrity of data(The “system”)

Quality Control

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

True Value vs. Measured Value

True ValueThe known, accepted value of a quantifiable property

Measured ValueThe result of an individual’s measurement of a quantifiable property

Accuracy vs. PrecisionAccuracyHow well a measurement agrees with an accepted value

PrecisionHow well a series of measurements agree with each other

Systematic vs. Random Errors

Systematic ErrorAvoidable error due to controllable variables in a measurement.

Random ErrorsUnavoidable errors that are always present in any measurement. Impossible to eliminate

Quality Control Measures

• Standards and Calibration• Blanks• Recovery Studies• Precision and Accuracy Studies• Method Detection Limits• State Laws

Standards and Calibration• Prepared vs. Purchased Standard• Signals: Peak Area, Beer’s Law• Calibration Curves• Continuing Calibration Checks• Internal Standards• Performance Testing

Calibration Curves

Graphical representation of the relationship between:

• The analytical signal

• The concentration of the analyte

and

Calibration Curve for DDT

y = 9.3005x + 4.3313

0

100

200

300

400

500

0 10 20 30 40 50 60

Parts per trillion DDT

Pea

k ar

ea x

10

6

R2 = 0.9989

Continuing Calibration Verification

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

• A “calibration verification” is analyzed with each batch of samples

Sample Batch• 10 - 20 samples (method defined)

or less• Same matrix• Same sample prep and analysis

• Contains a full set of QC samples

Internal Standards• A compound chemically similar to the

analyte• Not expected to be present in the

sample• Cannot interfere in the analysis• Added to the calibration standards and

to the samples in identical amounts

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 standards

Performance TestingBlind samples submitted to laboratories

??

?Labs must periodically analyze with acceptable results in order to maintain accreditation

Blanks, Blanks, Blanks

• Laboratory Reagent Blanks

• Instrument Blanks

• Field Reagent Blanks

• Trip Blanks

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

batch

Instrument Blank

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

Field Reagent Blanks

• Prepared in the lab, taken to the field

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

Trip Blanks• Prepared in the lab, taken to the

field• Not opened

• Returned to the lab

• Not always required in EPA methods

Recovery Studies

• Matrix Spikes

• Laboratory Control Samples

• Surrogates

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 batch

Laboratory Control Sample

• Subjected to all sample prep and analytical procedures

• Analyte spiked into reagent water

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 method

Method Detection Limit “The minimum concentration of a

substance that can be measured and reported with 99% confidence that the analyte concentration is greater than zero”

Method Detection Limit• MDLs are determined according to

40 CFR, part 136, Appendix B• Seven replicate laboratory control

samples, analyzed for precision

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)

State Laws

• Each state has laws governing laboratories and their personnel.