Regulatory Issues. Introduction to the Regulatory Approval Process; Overview of the FDA...
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Transcript of 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
16
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
17
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…
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.
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.