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Initial Product Development Process

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					Initial Product Development
           Process
       Martha A. Feldman, RAC
       Drug & Device Development Co., Inc.
  P.O. Box 3515 Redmond, WA 98073-3515 USA
      1-425-861-8262 FAX: 1-425-869-5854
          mfeldman@druganddevice.com

            FDA/Health Canada Seminar   20
                    February 2003
Drugs and Biotechnologically-
      Derived Products




         FDA/Health Canada Seminar   20
                 February 2003
    Overview of Product Development Process
              for Drugs/Biologics
•   Product concept
•   Product requirements
•   Product specifications: formulation
•   Testing: bench, animal
•   Initial submissions
•   Human testing (Phases 1, 2 and 3; Post-marketing)
•   Pilot plant - scale up - manufacturing
•   Quality Assurance: clinical, manufacturing
•   Submissions

                     FDA/Health Canada Seminar   20
                             February 2003
                Product Concept
• Drug substance: an active ingredient that is intended to
  furnish pharmacological activity or other direct effect in
  the diagnosis, cure, mitigation, treatment, or prevention of
  disease or to affect the structure or any function of the
  human body


• A“biologic product”: any virus, therapeutic serum, toxin,
  antitoxin or analogous product applicable to the
  prevention, treatment or cure of diseases or injuries of man


                     FDA/Health Canada Seminar   20
                             February 2003
           Product Concept
• Ideas come from: consumers, healthcare
  practitioners, academia, pharmacists,
  serendipitous findings (e.g., Merck -
  Timoptic)
• May be entirely new product, modification
  of existing product, new use for existing
  product (e.g., Thalidomide)

              FDA/Health Canada Seminar   20
                      February 2003
           Product Requirements
• What product will do:
    – Diagnose disease; cure disease; mitigate disease; treat
      disease, injuries; prevent disease, injuries; affect
      structure or function of human body
•   To what patient population
•   To what degree
•   With what amount of risk
•   Over what time
•   At what cost: to consumer; to manufacturer
                     FDA/Health Canada Seminar   20
                             February 2003
         Product Specifications
•   Strength, potency
•   Purity
•   Dosage(s)
•   Route(s) of administration
•   Formulation
•   Stability
•   Toxicity
                 FDA/Health Canada Seminar   20
                         February 2003
             Bench Testing
• Chemical characterization: name, chemical
  formula, structural formula, etc.

• Physical properties: molecular weight, odor,
  color, polarity, boiling point, etc.



               FDA/Health Canada Seminar   20
                       February 2003
               Animal Testing
• Testing depends on intended duration of use, route
  of administration target population
• Pharmacological profile
   – pharmacokinetics
   – dose ranging
• Toxicology
   – standard tests (ADME, pharmacodynamics)
   – additional tests (e.g., mutagenicity)

                  FDA/Health Canada Seminar   20
                          February 2003
             Animal Testing
• Efficacy testing
  – need to have validated animal model for
    disease, clinical condition
  – duration of testing depends
     • on proposed duration of human dosing
     • route of administration
     • stage of product development



                 FDA/Health Canada Seminar   20
                         February 2003
             Clinical Testing
• If there are any reports of prior use in
  humans, can use to plan further studies
  – same or other indications, dosages, populations
  – can develop safety profile
• Overall Investigation Plan
  – Phase 1: usually normals; safety, dose ranging
  – Phase 2: first use in patients; early efficacy info
  – Phase 3: wide use; multicenter
                 FDA/Health Canada Seminar   20
                         February 2003
      Initial FDA Submission
• Investigational New Drug (IND)
  Application (21 CFR Part 312) - permission
  to ship drug for the purpose of testing in
  humans; request for exemption of laws
  prohibiting interstate shipment of
  unapproved drugs or biological products
• IND is amended (updated) with each phase
  of the clinical investigation
              FDA/Health Canada Seminar   20
                      February 2003
                IND Contents - 1
                     (21 CFR 312.23)
• Cover sheet
• Table of contents
• Introductory statement and general investigational
  plan:
   –   rationale
   –   indications for use
   –   clinical study plans for first year
   –   number of patients
   –   known possible risks
                      FDA/Health Canada Seminar   20
                              February 2003
             IND Contents - 2
• Investigator’s Brochure
   – chemical and physical information on drug
   – summary of animal toxicology and pharmacology
   – summary of pharmacokinetics and ADME
   – summary of safety and efficacy from prior human
     studies, if any
   – summary of possible risks




                  FDA/Health Canada Seminar   20
                          February 2003
              IND Contents - 3
• Protocols
  – one for each study
  – Phase 1: more flexible, less detailed than Phases 2, 3
  – general contents
     • objectives and purpose
     • names and qualifications of investigators; facility address; IRB
       information
     • patient selection criteria; number of subjects
     • study design; controls to be used
     • dosages chosen and why; duration of treatment
     • description of observations, clinical procedures
                     FDA/Health Canada Seminar   20
                             February 2003
             IND Contents - 4
• Chemistry, Manufacture and Controls
  – for both the drug substance and drug product
  – methods to ensure identification,quality, purity,
    strength
  – methods of preparation of dosage form and amount
  – update as clinical studies proceed from Phase 1 to 3
    (i.e., pilot plant, scale-up, full GMP manufacturing)
  – labeling
  – environmental analysis, or exclusion

                   FDA/Health Canada Seminar   20
                           February 2003
             IND Contents - 5
• Pharmacology and Toxicology
  – data on which the sponsor feels it is safe to proceed
    with human studies; qualifications of those deciding
  – animal and in vitro studies
  – pharmacology and drug disposition (ADME)
  – toxicology
     • acute
     • subacute
     • chronic


                   FDA/Health Canada Seminar   20
                           February 2003
              IND Contents - 6
• Previous human experience
   – safety profile
   – efficacy data if studied under controlled conditions
   – where marketed, or withdrawn from market
• Additional information
   – dependency potential
   – radioactive drugs
   – pediatric studies
• Relevant information (if requested by the FDA)
                    FDA/Health Canada Seminar   20
                            February 2003
Medical Devices




  FDA/Health Canada Seminar   20
          February 2003
    Overview of Product Development Process
              for Medical Devices
• Product concept
• Product requirements
• Product specifications: components
• Classification of medical device
• Testing: bench, animal, human (may need initial
  submission for Class III product)
• Pilot plant - scale up - manufacturing
• Quality Assurance: clinical, manufacturing
• Submissions

                   FDA/Health Canada Seminar   20
                           February 2003
                 Product Concept
• "an instrument, apparatus, implement, machine,
  contrivance, implant, in vitro reagent ...including a
  component part, or accessory which is:
            recognized in the National Formulary, or the U.S.
             Pharmacopoeia,
            intended for use in the diagnosis of disease or other conditions,
             or in the cure, mitigation, treatment, or prevention of disease, or
            intended to affect the structure or any function of the body...and
             which does not achieve any of it's primary intended purposes
             through chemical action within or on the body ….. and which is
             not dependent upon being metabolized for the achievement of
             any of its primary intended purposes."

                        FDA/Health Canada Seminar   20
                                February 2003
            Product Concept
• Ideas come from: consumers, healthcare
  practitioners, academia,engineers,
• May be entirely new product, modification
  of existing product (e.g., ultrasound for
  metal fatigue testing), new use for existing
  product (e.g., ultrasound to cause cavitation
  to help dissolve clots)

               FDA/Health Canada Seminar   20
                       February 2003
      Product Requirements - 1
• performance for intended use
• operating conditions, e.g., temperature, humidity,
  altitude limits
• reliability
• durability; robustness
• stability; shelf life
• biocompatibility
• ergonomics, e.g., ease of use
                 FDA/Health Canada Seminar   20
                         February 2003
       Product Requirements - 2
•   sterility
•   electromagnetic compatibility
•   radio frequency interference
•   cost of components
•   complexity of manufacturing process
•   environmental assessment
    – manufacturing process
    – disposal issues

                   FDA/Health Canada Seminar   20
                           February 2003
        Product Specifications
• Performance ranges in intended
  population(s); tolerances
• Ease of use; training requirements
  (especially for home use devices)
• Safety of patients, of operator
• Sterilization, (and resterilization if needed)


                FDA/Health Canada Seminar   20
                        February 2003
   Human Factors Engineering
• Guidance Documents:
  – Do it by Design: An Introduction of Human
    Factors into Medical Devices (Dec. 1996)
    http://www.fda.gov/cdrh/humfac/doitpdf.pdf
  – Medical Device Use-Safety: Incorporating
    Human Factors Engineering into Risk
    Management, July 18, 2000
    http://www.fda.gov/cdrh/humfac/1497.pdf

               FDA/Health Canada Seminar   20
                       February 2003
Classification of Medical Devices
• Class 1: General Controls
• Class 2: General controls and performance
  standards
• Class 3: General controls, performance
  standards, clinical studies to demonstrate
  safety and effectiveness


               FDA/Health Canada Seminar   20
                       February 2003
                 Bench Testing
• Type of testing depends on product
  –   electromagnetic compatibility
  –   radio frequency interference
  –   electrical leakage
  –   power output
  –   material strength, flexibility, durability, etc.
  –   sterility
  –   reliability
                   FDA/Health Canada Seminar   20
                           February 2003
                Animal Testing
• Biocompatibility
   – type, duration of testing dependent upon human
     exposure, e.g., permanent/long-term implant versus
     one-time/ short use
• Effectiveness
   – animal model available for disease, clinical condition
   – parameters to be measured comparable to human
     condition (e.g., pig heart valve)


                    FDA/Health Canada Seminar   20
                            February 2003
            Clinical Testing - 1
• Clinical testing not always required
• Feasibility test; proof of concept:
   – 3-5 subjects
   – one site
   – usually investigator-sponsored
• Pilot test protocol
   – 10-30 subjects
   – one or two sites
   – “test drives” protocol and operator’s manual
                   FDA/Health Canada Seminar   20
                           February 2003
            Clinical Testing - 2
• Pivotal Study
   – consult guidance document, if any (may be on type of
     product or disease/clinical condition)
   – number of subjects varies
      • experiential study
      • confirmatory study
      • statistically significant
   – multiple sites
   – duration depends on human exposure to device

                   FDA/Health Canada Seminar   20
                           February 2003
      Initial FDA Submission
• May need only IRB approval to proceed
  with study on non-significant risk device,
  i.e., no prior FDA approval to conduct study
• Investigational Device Exemption (IDE)
  needed for significant risk device or
  condition of use
• IDE may be needed for studies on Class II
  (510K) or Class III (PMA) products
               FDA/Health Canada Seminar   20
                       February 2003
             IDE Contents - 1
                (21 CFR 812.20)
• Cover sheet
• Table of contents
• Report of prior investigations
• Investigational plan
• Methods, facilities and controls for manufacturing,
  packaging, storing, installation
• Example of Investigator Agreements
• Certification of Investigator Agreement
                 FDA/Health Canada Seminar   20
                         February 2003
            IDE Contents - 2
• IRB information
• Other institutions studying the device that
  are not listed above
• Sale or charges for investigational device
  – why not considered commercialization
• Environmental assessment
  – or request for categorical exclusion

                FDA/Health Canada Seminar   20
                        February 2003
             IDE Contents - 3
• Labeling
  – labels
  – instructions for use; operator’s manual
• Informed consent documents
• Other relevant information, as requested by
  FDA


                FDA/Health Canada Seminar   20
                        February 2003
        Investigational Plan
                (21 CFR 812.25)
•   Name and intended use of the device
•   Objectives and duration of the investigation
•   Protocol
•   Risk analysis
•   Device description
•   Monitoring procedures
•   Labeling
•   Consent materials
•   IRB information
•   Other institutions
•   Additional records and reports

                 FDA/Health Canada Seminar   20
                         February 2003
        Premarket Notification
• The official means of providing the FDA with
  information regarding safety & effectiveness
• The “510(K)” - named after that section of the
  Food, Drug & Cosmetic Act.
• It demonstrates that the device is “substantially
  equivalent” to a device legally on the market
• Once submitted, FDA has to make an SE
  determination within 90 days of receipt
• FDA “clears” the device for marketing.
                  FDA/Health Canada Seminar   20
                          February 2003
Premarket Notification (510[K])
• When a 510(K) is required
  –   marketing of new devices
  –   first time marketing of devices
  –   importing device into US for first time
  –   significant change or modification to a device
       • major material supplier, design change, new facility
  – change in labeling
       • new indication, new population
                    FDA/Health Canada Seminar   20
                            February 2003
Exemptions from filing a 510(K)
• Already in commercial distribution before May
  28, 1976
• Custom devices
   – for one patient under prescription
   – for one practitioner for use in his/her practice (e.g.,
     surgical instrument for surgeon with missing fingers)
• Distributors and repackagers
   – who only adds name to the device
• Class I medical devices (as of Feb 19, 1998)
                    FDA/Health Canada Seminar   20
                            February 2003
        The “510(K)” - contents
                  (21 CFR 807.87)
•   device name (trade, common, classification)
•   establishment registration number
•   device class
•   compliance with performance standards
•   proposed labels, labeling, advertisements
    – intended use, instructions for use
• predicate comparison
                  FDA/Health Canada Seminar   20
                          February 2003
          510(K) Contents - 2
• for a modified or new device, state effect of
  change on safety and effectiveness profile
  of original product
• summary or statement (21 CFR 807.92)
• financial certification or disclosure
• for SE to a reclassified Class III device, list
  of S&E issues

                FDA/Health Canada Seminar   20
                        February 2003
         510(K) Contents - 3
• statement of truthfulness of contents
• any additional information requested by the
  FDA




               FDA/Health Canada Seminar   20
                       February 2003
In Vitro Diagnostic Devices




        FDA/Health Canada Seminar   20
                February 2003
    Overview of Product Development Process
            for In Vitro Diagnostics
• Product concept
• Product requirements
• Product specifications: reagents, analytes, antibodies
• Classification of medical device
• Testing: bench, human (rarely need initial submission for
  human studies)
• Pilot plant - scale up - manufacturing
• Quality Assurance: clinical, manufacturing
• Submissions

                    FDA/Health Canada Seminar   20
                            February 2003
           Product Concept - 1
• In vitro diagnostic products are those reagents,
  instruments, and systems intended for use in the
  diagnosis of disease, or other conditions, including
  a determination of the state of health, in order to
  cure, mitigate, treat or prevent disease or its
  sequelae. Such products are intended for use in
  the collection, preparation and examination of
  specimens taken from the human body.


                  FDA/Health Canada Seminar   20
                          February 2003
          Product Concept - 2
•   screening
•   diagnosis
•   monitoring
•   prognosis
•   prevention



                 FDA/Health Canada Seminar   20
                         February 2003
          Product Requirements
•   Sensitivity and specificity
•   Accuracy and precision
•   Rapidity of results
•   Linearity
•   Reproducibility: operator and unit
•   Built-in quality control
•   Small amount of specimen needed
•   Stability of reagents
                   FDA/Health Canada Seminar   20
                           February 2003
         Product Specifications
• Examples:
  –   sensitivity and specificity
  –   upper and lower limits of detection
  –   limited number of interfering substances
  –   rapidity of obtaining results
  –   robust
  –   if for home use or physician office use, then
      ease and simplicity of use
                  FDA/Health Canada Seminar   20
                          February 2003
             Bench Testing
• fresh/frozen samples; freeze-thaw of
  samples; shelf-life of samples
• inter- and intraoperator reproducibility
• inter- and intradevice reproducibility
• linearity, especially at “cross-over” point
• interfering substances
• stability of reagents, other components
                FDA/Health Canada Seminar   20
                        February 2003
             Clinical Testing
• Check for guidance documents
• Need Institutional Review Board approval (more
  for privacy issues than for safety)
• Prospective usually; retrospectively collected
  samples allowed in some cases
• Protocol conducted at minimum of three sites
• Special testing requirements for home use
• Clinical Laboratory Improvement Act (CLIA)
                FDA/Health Canada Seminar   20
                        February 2003
      Initial FDA Submission
• Premarket Notification (PMN) - also known
  as 510(K) after the section of the FD&C
  Act
• May or may not require prospective human
  testing
• Retrospective clinical studies may or may
  not require IRB approval - depends on
  privacy issues
              FDA/Health Canada Seminar   20
                      February 2003
  Contents of a 510(K) for IVDs
• Same as for other medical devices
• Additional requirements for home use
  – testing
  – labeling/instructions for us
• “Safety” may also be tied to false negative
  results


                 FDA/Health Canada Seminar   20
                         February 2003
   Specific references for IVDs
• In Vitro Diagnostic Devices: Guidance for the
  preparation of 510(K) submissions, Jan., 1997
  http://www.fda.gov/cdrh/manual/ivdmanul.html
• Guidance for FDA Staff: Regulating In Vitro
  Diagnostic (IVD) Device Studies
  http://www.fda.gov/cdrh/comp/ivdreg.html (Dec.
  17, 1999)Over-the-Counter in vitro diagnostic
  devices , (April 19, 2002)
  http://www.fda.gov/cdrh/ode/otclist.html
                FDA/Health Canada Seminar   20
                        February 2003
                References
• FDA web page
  – www.fda.gov
• Code of Federal Regulations Title 21
  – Part 312 Drugs and biologics
  – Part 807 Premarket Notifications (510K)
  – Part 812 Investigational Device Exemptions


               FDA/Health Canada Seminar   20
                       February 2003
          More References
• ISO
• IEC, CEN - electromechanical devices
• AAMI, BSI, CSA, etc. - standards
  organizations
• UL - electrical leakage



              FDA/Health Canada Seminar   20
                      February 2003