Role of FDARole of FDA

FDA was designed to promote and FDA was designed to promote and protect the public’s healthprotect the public’s health

Food and Drug Cosmetic ActFood and Drug Cosmetic Act first first passed in 1906 to prevent the sale of passed in 1906 to prevent the sale of unacceptable food and drugsunacceptable food and drugs

Role of FDARole of FDA

Minimum requirement for release of Minimum requirement for release of a drug is that it has to a drug is that it has to safe and safe and effectiveeffective There are always risks and side effectsThere are always risks and side effects

The FDA has to determine when the The FDA has to determine when the benefits out weigh the risksbenefits out weigh the risks Vaccines and life threatening diseasesVaccines and life threatening diseases Clinical trials: when is enough enough?Clinical trials: when is enough enough?

Thalidomide incidentThalidomide incident

Center for Drug Evaluation Center for Drug Evaluation & Research& Research

CDERCDER Group which assures the safety and Group which assures the safety and

effectiveness of effectiveness of drugsdrugs available in available in the U.S.the U.S.

Monitors for adulterated or Monitors for adulterated or contaminated drugscontaminated drugs Adulterated: drug or food produced by Adulterated: drug or food produced by

methods which do not conform to cGMPmethods which do not conform to cGMP

Center for Biologics Center for Biologics Evaluation and ResearchEvaluation and Research

CBERCBER Reviews applications for new Reviews applications for new

biologics produced from microbes biologics produced from microbes and virusesand viruses Examples: vaccines, allergens, Examples: vaccines, allergens,

monoclonal antibodiesmonoclonal antibodies Regulates all aspects of the process Regulates all aspects of the process

from mfg. to QC, to labeling and from mfg. to QC, to labeling and advertisingadvertising

Center for Devices & Center for Devices & Radiologic HealthRadiologic Health

CDRHCDRH Regulates medical devices and some Regulates medical devices and some

in vitro diagnostic kitsin vitro diagnostic kits Examples of devices:Examples of devices:

Pace maker, ultrasonic cleaners for Pace maker, ultrasonic cleaners for cleaning medical instruments, insulin cleaning medical instruments, insulin monitors, thermometersmonitors, thermometers

Examples of in vitro diagnostic kitsExamples of in vitro diagnostic kits CK-MB kitsCK-MB kits

Center for Food Safety & Center for Food Safety & Applied NutritionApplied Nutrition

Protects and promotes health & Protects and promotes health & economic interests by ensuring that economic interests by ensuring that foods are safe, nutritious, and foods are safe, nutritious, and honestly labeledhonestly labeled

Also oversees cosmeticsAlso oversees cosmetics

FDA ActionsFDA Actions

Facility InspectionsFacility Inspections 483483: inspector’s note documenting a : inspector’s note documenting a

deficiencydeficiency Not following procedureNot following procedure Incomplete recordsIncomplete records

Warning letter: written letter citing Warning letter: written letter citing cGMP violations. Requires a written cGMP violations. Requires a written response of corrective actions to be response of corrective actions to be implemented.implemented.

FDA ActionsFDA Actions If a company does not comply with If a company does not comply with

FDA requests the FDA can do any FDA requests the FDA can do any and all of the following:and all of the following: Take the product(s) off of the marketTake the product(s) off of the market Sue and or arrest executivesSue and or arrest executives Detain imports / exportsDetain imports / exports

FDA cannot do nothingFDA cannot do nothing when they when they know there are issues at a companyknow there are issues at a company

Product Development: Product Development: Ideas to MarketIdeas to Market

Computer ModelingComputer Modeling In vitro studiesIn vitro studies Pre-clinical Animal studiesPre-clinical Animal studies Investigation New Drug ApplicationInvestigation New Drug Application Clinical studiesClinical studies New Drug Application and ApprovalNew Drug Application and Approval ManufacturingManufacturing Marketing and SalesMarketing and Sales

GLPGLP

Good Laboratory PracticesGood Laboratory Practices Prescribes practices for Prescribes practices for

conducting non clinicalconducting non clinical lab lab studies that support or are studies that support or are intended to support applications intended to support applications for research or marketing of for research or marketing of regulated products.regulated products. Required for research applications to Required for research applications to

be submitted to the FDAbe submitted to the FDA Intended to assure the quality and Intended to assure the quality and

integrity of safety data filedintegrity of safety data filed Does not include human studies or Does not include human studies or

clinical studiesclinical studies

Examples of what’s Examples of what’s includedincluded

Good lab practicesGood lab practices Labeling reagent bottles w/ proper info.Labeling reagent bottles w/ proper info.

Reagent name, date, initials or name of who Reagent name, date, initials or name of who prepared itprepared it

Equipment monitoringEquipment monitoring Calibrated, cleaned and verification logsCalibrated, cleaned and verification logs

Written proceduresWritten procedures Filled out, reviewed by QA, and maintainedFilled out, reviewed by QA, and maintained

Personnel should be qualified or at Personnel should be qualified or at least knowledgeableleast knowledgeable

Standard Operating Standard Operating Procedures: SOPsProcedures: SOPs

Procedures for the following:Procedures for the following: Manufacture the productManufacture the product Test and release the productTest and release the product Train personnelTrain personnel Label and packaging the productLabel and packaging the product How to handle non conforming productHow to handle non conforming product How to design new productsHow to design new products

Standard Operating Standard Operating ProceduresProcedures

Good SOPs contain the following:Good SOPs contain the following: Purpose or scopePurpose or scope MaterialsMaterials ProcedureProcedure

Must be written in proper orderMust be written in proper order Must include sufficient detail for operator to Must include sufficient detail for operator to

followfollow Should include “checkers” for calculationsShould include “checkers” for calculations Must include initials and signature of operatorMust include initials and signature of operator Must have Supervisors review and sign off\Must have Supervisors review and sign off\

Should be reviewed and updated as neededShould be reviewed and updated as needed

Clinical InvestigationClinical Investigation

Definition: any experiment that Definition: any experiment that involves a test article and one or involves a test article and one or more human subjects and that is more human subjects and that is either subject to requirements for either subject to requirements for submission to FDA or is not subject submission to FDA or is not subject for submission but results are for submission but results are intended to be submitted later.intended to be submitted later.

Phases of Clinical TrialsPhases of Clinical Trials Phase 1Phase 1: small number of patients, : small number of patients, (10-20)(10-20)

Can take 9-18 months to completeCan take 9-18 months to complete May continue with animal studies for long term dataMay continue with animal studies for long term data

Phase 2Phase 2: continues to test safety and evaluates how well : continues to test safety and evaluates how well the new drug is working. More patients enrolled the new drug is working. More patients enrolled (100-300)(100-300)

May take 1-2 years to completeMay take 1-2 years to complete Phase 3Phase 3: most extensive study,1-3 years: most extensive study,1-3 years

Fully assess safety and effectiveness of drugFully assess safety and effectiveness of drug 100-1000 patients involved, diverse group, multiple sites100-1000 patients involved, diverse group, multiple sites May compare old and new drug treatmentsMay compare old and new drug treatments Evaluating side effects Evaluating side effects

Phase 4Phase 4: long term side effects and effectiveness: long term side effects and effectiveness

Single and Double Single and Double Blinded StudyBlinded Study

Single-Blind studySingle-Blind study: clinical trial : clinical trial study in which the study in which the human subjects human subjects do not know if they are receiving do not know if they are receiving the active product or a placebo.the active product or a placebo.

Double-Blind studyDouble-Blind study: study in which : study in which neither the subject nor the neither the subject nor the investigator knows the treatment investigator knows the treatment assignedassigned. . (usually subjects, investigators, (usually subjects, investigators, monitors and data analysts are unaware) monitors and data analysts are unaware)

Participants in clinical Participants in clinical trialstrials

InvestigatorInvestigator SponsorSponsor Sponsor InvestigatorSponsor Investigator Human SubjectHuman Subject InstitutionInstitution Institution Review BoardInstitution Review Board

Clinical Trial Data Clinical Trial Data AnalysisAnalysis

Data analyzed by Statistics or Data analyzed by Statistics or Biostatistics groupBiostatistics group

Use well defined, accepted and pre-Use well defined, accepted and pre-determined data analysis formulas and determined data analysis formulas and methods.methods. Looking for levels of significance 99% still Looking for levels of significance 99% still

means 1% error possible of 1/100 (0.01).means 1% error possible of 1/100 (0.01). Is that good enough?Is that good enough? How do you balance the data with the delay in How do you balance the data with the delay in

releasing a product?releasing a product? OutlierOutlier: data point outside of the : data point outside of the

average range and is usually larger or average range and is usually larger or smaller than the rest of the pointssmaller than the rest of the points

Clinical Trial Data Clinical Trial Data AnalysisAnalysis

INCLUSION/EXCLUSION CRITERIA: INCLUSION/EXCLUSION CRITERIA: The medical or social standards The medical or social standards determining whether a person may or may determining whether a person may or may not be allowed to enter a clinical trial. not be allowed to enter a clinical trial. These criteria are based on such factors as These criteria are based on such factors as age, gender, the type and stage of a age, gender, the type and stage of a disease, previous treatment history, and disease, previous treatment history, and other medical conditionsother medical conditions. It is important to . It is important to note that note that inclusion and exclusion criteria inclusion and exclusion criteria are not used to reject people personally, are not used to reject people personally, but rather to identify appropriate but rather to identify appropriate participants and keep them safeparticipants and keep them safe..

Institutional Review Institutional Review BoardBoard

Definition: any board, committee or Definition: any board, committee or group formally designated by an group formally designated by an institution to review biomedical institution to review biomedical research involving human subjectsresearch involving human subjects

IRB approval MUST be obtained IRB approval MUST be obtained before an investigator can begin a before an investigator can begin a studystudy

Institutional Review Institutional Review BoardBoard

Usually comprised of medical and Usually comprised of medical and lay persons lay persons (at least 5 members, (at least 5 members, no conflict of no conflict of interestinterest))

Established to Established to protectprotect the human the human subjects and ensure fair enrollmentsubjects and ensure fair enrollment

Review and Review and Approve Informed Approve Informed ConsentConsent

Conduct periodic reviews to ensure Conduct periodic reviews to ensure integrityintegrity of the study of the study

What are cGMP’s Designed To What are cGMP’s Designed To Do?Do?

Protect consumers from adulterated Protect consumers from adulterated productproduct

Protect consumers from products that Protect consumers from products that do not contain what is claimed on the do not contain what is claimed on the labellabel

Provide consistent industry-wide Provide consistent industry-wide requirementsrequirements

Ensure quality of product Ensure quality of product not safety not safety or efficacy of dietary ingredientsor efficacy of dietary ingredients

Operations Operations responsibilitiesresponsibilities

This is where cGMP comes into play

General ProvisionsGeneral Provisions

cGMP should apply to activities cGMP should apply to activities associated withassociated with manufacturingmanufacturing packagingpackaging holdingholding distributingdistributing

Manufacturer would need to comply with Manufacturer would need to comply with requirements applicable to operations requirements applicable to operations performedperformed

Components of a cGMPComponents of a cGMP

PersonnelPersonnel Physical plant internal Physical plant internal

environmentenvironment Equipment and utensilsEquipment and utensils Production and process controlsProduction and process controls Records and RecordkeepingRecords and Recordkeeping

QSRQSR

QSR: Quality System RegulationsQSR: Quality System Regulations Standard produced by the FDA which Standard produced by the FDA which

companies MUST followcompanies MUST follow Include standards such as training, Include standards such as training,

document control, process control, design document control, process control, design controlcontrol

cGMP and QSR are essentially the cGMP and QSR are essentially the samesameMandated by FDA; only in USMandated by FDA; only in US

Batch RecordsBatch Records

FDA RequirementFDA Requirement cGMP requirementcGMP requirement QSR requirementQSR requirement ISO requirementISO requirement Failing to do so can get you into a Failing to do so can get you into a

heap of trouble!heap of trouble! Used to ensure consistent productUsed to ensure consistent product

Batch Record: Record Batch Record: Record KeepingKeeping

What are some record keeping What are some record keeping requirements?requirements? Black inkBlack ink No white outNo white out Single line, date, initialSingle line, date, initial No blanks, N/A any lines which do not No blanks, N/A any lines which do not

applyapply LegibleLegible

Label Approval and Label Approval and ControlControl

Regulatory, Quality Assurance and Regulatory, Quality Assurance and Marketing are the groups who Marketing are the groups who “approve” the final label“approve” the final label

Materials, QA, QC, and Mfg. Materials, QA, QC, and Mfg. “control” the label from receipt, “control” the label from receipt, through inspection to application to through inspection to application to product, through finished product product, through finished product inspection.inspection.

Labeling and Packaging Labeling and Packaging ControlControl

Why would this be an area to be audited?Why would this be an area to be audited? Label text: pre-approved and inspectedLabel text: pre-approved and inspected Label adhesion: pre-approved and inspectedLabel adhesion: pre-approved and inspected Label accountability: verified at every stepLabel accountability: verified at every step Package insert content: pre-approved and Package insert content: pre-approved and

inspectedinspected Package insert accountability: verified at every Package insert accountability: verified at every

stepstep

CONTROLLED TO PREVENT MIXUPSCONTROLLED TO PREVENT MIXUPS

Label TextLabel Text

Fixed TextFixed Text Text that does not change with each lotText that does not change with each lot

Company name, address, Company name, address, Product Name, storage temp, ingredientsProduct Name, storage temp, ingredients

Variable TextVariable Text Text that does change with each lotText that does change with each lot

Lot number and or serial numberLot number and or serial number Expiration DateExpiration Date Concentration or PotencyConcentration or Potency

Marketing InformationMarketing Information

Labels and Package inserts are Labels and Package inserts are highly controlled highly controlled

Marketing information such as Marketing information such as product informational flyerproduct informational flyer Approved by Regulatory and MarketingApproved by Regulatory and Marketing Marketing distributes w/out controlMarketing distributes w/out control

AuditsAudits

The evaluation of the company, the The evaluation of the company, the process, and the product to assure process, and the product to assure quality and reliabilityquality and reliability

Management ResponsibilityManagement Responsibility Auditing (internal and external)Auditing (internal and external) Design ControlDesign Control Document ControlDocument Control Purchasing ControlPurchasing Control Identification and TraceabilityIdentification and Traceability

Process of AuditingProcess of Auditing

Meeting to review process and Meeting to review process and timingtiming

Tour of companyTour of company Ask for recordsAsk for records Review recordsReview records

Ask for interviewees if necessaryAsk for interviewees if necessary Write preliminary reportWrite preliminary report Review prelim report w/mgmtReview prelim report w/mgmt