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‫ודיאגנוסטיקה:‬
‫מכשור רפואי ודיאגנוסטיקה:‬
         ‫תקינה‬

  ‫אנליזה וניתוח חברות ‪Health Care‬‬
Regulatory Affairs:
   R   l t    Aff i
A Multi-Task Approach

          Orna Oz, PhD
  BioMedical Strategy (2004) Ltd
Regulatory & Clinical Affairs Group

                         Health Care ‫אנליזה וניתוח חברות‬
                                 January 2010
Regulation
           Key Role in
         Due Diligence
                and
                  d
     Market proposition

Stepwise Increase in Company Valuation


                              Health Care ‫אנליזה וניתוח חברות‬
                                      January 2010
BioMedical Strategy
        (2004) Ltd
   Clinical & Regulatory Affairs Group

Founded by:
Gal Ehrlich Ami Eyal & Orna Oz
    Ehrlich,

The Team:
Scientists experts in
Clinical & Regulatory Affairs
                             Health Care ‫אנליזה וניתוח חברות‬
                                     January 2010
‫01/6/9‬
 ‫• אולטרה שייפ קיבלה חיזוק: ה'טיימס' שלח כתב עד ליוקנעם, המניה‬
                                                 ‫מזנקת %05 .‬
  ‫בכתבה מגדיר הכתב את החברה כ"עמק הסיליקון של היופי הטכנולוגי ."המנכ"ל אסף‬
‫איל ל" :‪-Bizportal‬החדשות הגדולות של החברה הגיעו אתמול, כאשר ה ‪-FDA‬הודיע על‬
                                                           ‫אישור הליך המזורז‬

                                                                         ‫01/01/81‬
        ‫• אולטרה שייפ זינקה ב-%82; עד תחילת נובמבר צפויה להגיע‬
                                 ‫תשובת ה-‪ FDA‬למוצר ההרזייה‬
                                             ‫ל‬

                                                                         ‫01/01/13‬
 ‫• אולטרה שייפ צללה: ה ‪-FDA‬לא העניק אישור למכשיר ההרזייה של‬
                                                   ‫החברה‬
  ‫אכזבה למשקיעי אולטרה שייפ לאחר המתנה של שלושה חודשים, אתמול הודיע מנהל‬
   ‫המזון והתרופות בארה"ב כי הוא דורש הבהרות ונתונים נוספים בטרם אישור מכשיר‬
                                                          ‫ההרזייה, הקונטור 1‬


                                                      ‫אנליזה וניתוח חברות ‪Health Care‬‬
                                                              ‫0102 ‪January‬‬
How does it start?

       Technology
       T h l                      Medical
                                  M di l need
                                            d


Scientifically      Clinical use of
    based                core
 rationales          technology
      &
   Use of        Benefits of clinical
                 use and expected
                             p
 valid t l
   lid tools
                  clinical outcome


                                        Health Care ‫אנליזה וניתוח חברות‬
                                                January 2010
Medical Product
        Project Assessment

•   Medical need
•   Technological solution
•   Market Analysis
•   Patentability
•   Feasible markets and competitors
•   Survey on scientific evidence
    S   e o cie tific e ide ce
•   Regulatory and Reimbursement
•   Funding
    F di


                                 Health Care ‫אנליזה וניתוח חברות‬
                                         January 2010
Medical Device
                   Definition
                   D fi i i
• an instrument apparatus … implant in
     instrument, apparatus,      implant,
  vitro reagent, or other similar or related
  article,
  article including a component part or
                                  part,
  accessory
• Used for the diagnosis treatment or prevention of
                diagnosis,
  disease or condition
   and that
• Affects the structure or function of the body
• Does not achieve its function through chemical
  action
• Is not metabolized to achieve effect
                                     Health Care ‫אנליזה וניתוח חברות‬
                                             January 2010
Medical Device
   Examples
   E    l




              Health Care ‫אנליזה וניתוח חברות‬
                      January 2010
Main Target Markets
             g

EU                       USA




                    Health Care ‫אנליזה וניתוח חברות‬
                            January 2010
US Market
Food D
F d & Drug Ad i i t ti
           Administration




                 Health Care ‫אנליזה וניתוח חברות‬
                         January 2010
FDA is part of the Public Health
Service (PHS) within the Department of
Health and Human Services (HHS).

FDA is headed by a commissioner
appointed by the President with Senate
consent.
consent

                           Health Care ‫אנליזה וניתוח חברות‬
                                   January 2010
Food & Drug Administration




                  Health Care ‫אנליזה וניתוח חברות‬
                          January 2010
FDA/CDRH FOCUS
(Center for Devices and Radiological Health)

  Ensuring that medical devices are
   “reasonably” safe and effective
    reasonably




                               Health Care ‫אנליזה וניתוח חברות‬
                                       January 2010
Types of FDA Regulated
                   Products
                   P d t
• Medical Devices (including IVD) &

   Radiation Emitting Products - Center for Devices &

   Radiological Health CDRH


• Drugs- Center for Drugs Evaluation & Research
• Biologics- Center for Biologics Evaluation & Research
• Combination Products- Office of Combination Products
• Food and Cosmetics- Center for Food Safety & Applied Nutrition
• Animal feed and Drugs- Center for Veterinary Medicine



                                                                   Health Care ‫אנליזה וניתוח חברות‬
                                                                           January 2010
Premarket Life Cycle
                y
    US market as an example




               Quality Assurance




                                   Health Care ‫אנליזה וניתוח חברות‬
                                           January 2010
Project Milestones
•   Claim – Intended Use & Indications
•   Project Initiation –Requirements            Proof of Concept

•   Regulatory Strategy
•   Product Specification and Risk Analysis
              p                          y
•   R&D Plan (development and V&V)
•   Ongoing Development
       g g           p                          •Quality System
•   Design Freeze                               •Manufacturing
•   Pre clinical Verification &Validation
•   Premarket Clinical Investigation
•   Submission for market clearance/approval
•   Post-market activities (clinical study/ies)

                                            Health Care ‫אנליזה וניתוח חברות‬
                                                    January 2010
Regulatory Strategy
    • Regulatory Classification and existing similar
      marketed devices
    • P
      Pre-clinical Testing
           li i l T i
    • Clinical Strategy (pre and post market)
    • Discussion and recommendations


•Re-assess intended use and/or indications for use
•Re-assess technological (engineering) approach and R&D plan
•Re-assess business plan – designated product, timelines and
 budget


                    Alternative approaches
                                              Health Care ‫אנליזה וניתוח חברות‬
                                                      January 2010
Claim / Intended Use

Intended Use:

  What is being done
  Sometimes where it is being done
  Sometimes why it is being done


 Indications:
  Diseases
  Patients
  P ti t
  Subsets

                                     Health Care ‫אנליזה וניתוח חברות‬
                                             January 2010
Claim
Intended Use & Indications For Use




Design Specifications          Test Plan to Verify and
Regulatory & Clinical          Validate Claim
                               V lid t Cl i
strategies (including target
markets))
                                  1. Bench T ti
                                  1 B     h Testing
                                  2. Animal Testing
                                  3. Clinical Data
                                        Health Care ‫אנליזה וניתוח חברות‬
                                                January 2010
Regulatory Implications of Claim
                   SPECIFICITY LEVEL

1. Identification of function            Tool Claim
2. Identification of tissue type
   an organ system or
                                         (higher clinical
   Identification of a specific             evidence))
   organ
3. Identification of a particular
   disease or target population
4. Identification of an effect on
   clinical outcome
                                        Clinical Claim

                                       Health Care ‫אנליזה וניתוח חברות‬
                                               January 2010
Regulatory Implications of Claim
                SPECIFICITY LEVEL

    Tool vs. Clinical – Cardiac Pacing Devices
Tool:
The Frontier Biventricular Cardiac Pacing System is
indicated for maintaining synchrony of the left and
right ventricles in patients who…….

Clinical:
Cli i l
The InSync model 8040 pulse generator is indicated for
the reduction of the symptoms of moderate to severe
heart failure (NYHA Functional III or IV) in those
patients who…….
                                     Health Care ‫אנליזה וניתוח חברות‬
                                             January 2010
Claim / Intended Use
   GENERAL VS. SPECIFIC INTENDED USE

The claim(s) for a device can be general or specific.
When deciding the claims for the device it is
              g
important to consider not only the marketing goals
but also the regulatory process.
Examples of General vs. Specific Use:
   Skin resurfacing vs. Wrinkle removal
                    vs
   Evaluation of soft tissue vs. Aid in differentiation of
   benign from malignant breast lesions
       g            g
   Cut/coagulate soft tissue vs. Photorefractive
   keratectomy (PRK) for myopia

                                         Health Care ‫אנליזה וניתוח חברות‬
                                                 January 2010
Claim / Intended Use
GENERAL VS. SPECIFIC INTENDED USE




                        Health Care ‫אנליזה וניתוח חברות‬
                                January 2010
Classification – Risk Based
              User/Pt               g
                                Mitigation




Environment              RISK                Generic
                                              type




         Circumstances          Claim


                                      Health Care ‫אנליזה וניתוח חברות‬
                                              January 2010
Classification
Class I (Low Risk)                            ~45%
Examination gloves, Sunglasses, Instruments for
general use (scalpels), Diagnostic Stethoscope




                                                                                       trol
                                                                           Level of Cont
Class II (Med. Risk)                          ~47%
Vital signs monitors, Ventilators, Infusion pumps,




                                                                                 o
Incubators, MRI, US




                                                                           L
Class III (High Risk)                              ~8
Coronary Stents, Heart Valves, Pacemakers, Implantable Lenses,
new and untested technologies, life-supporting or sustaining….


                                                Health Care ‫אנליזה וניתוח חברות‬
                                                        January 2010
Regulatory Pathway
            g      y       y
The class to which the device is assigned determines (among
other things) the type of the required regulatory pathway
and premarketing application:

Exempt
E           Class I
            Cl
510(k)
   ( )         Class I or II (Non exempt)
                             (        p)
               Class III preamendments device (on the
               market prior to 1976, or substantially
               equivalent to such a device) and PMA's have
                   i l           h d i ) d PMA' h
               not been called for
PMA         Class III
            Cl


                                         Health Care ‫אנליזה וניתוח חברות‬
                                                 January 2010
CDRH’s Risk Based Paradigm
                         g
Class I



                      Class II




          Class III
                            Health Care ‫אנליזה וניתוח חברות‬
                                    January 2010
Regulatory Pathway
          g      y       y
De Novo 510(k) (after re-evaluation of an automatic
               ( )(
class III designation) – NSE & Lower Risk device or
that contemplates “Similar Technologies” and risk
profile.

HDE “medical device intended to benefit patients in
       medical
the treatment or diagnosis of a disease or condition
that affects or is manifested in fewer than 4,000
                                             ,
individuals in the United States per year.” Similar to
a premarket approval (PMA) application, but exempt
from the effectiveness requirements
f     h ff i                i


                                       Health Care ‫אנליזה וניתוח חברות‬
                                               January 2010
Regulatory Implications of Claim
                DIAGNOSIS VS. MONITORING
                                         BLADDER CANCER KIT
                         THE UROVYSION BLADDER CANCER KIT (UROVYSION
                         KIT) IS DESIGNED TO DETECT ANEUPLOIDY FOR
                         CHROMOSOMES 3, 7, 17 AND LOSS OF THE 9P21 LOCUS
                         VIA FLUORESCENCE IN SITU HYBRIDIZATION (FISH) IN
                         URINE SPECIMENS FROM PERSONS WITH HEMATURIA
                PMA      SUSPECTED OF HAVING BLADDER CANCER RESULTS
                         SUSPECTED OF HAVING BLADDER CANCER.
                         FROM THE UROVYSION KIT ARE INTENDED FOR USE, IN
                         CONJUNCTION WITH AND NOT IN LIEU OF CURRENT
                         STANDARD DIAGNOSTIC PROCEDURES, AS AN AID FOR
UroVysion Kit                AS AN AID FOR INITIAL DIAGNOSIS
                         INITIAL DIAGNOSIS OF BLADDER CARCINOMA IN
                         PATIENTS WITH HEMATURIA AND SUBSEQUENT
                         MONITORING FOR TUMOR RECURRENCE IN PATIENTS
                         PREVIOUSLY DIAGNOSED WITH BLADDER CANCER.

                510(K)   THE UROVYSION BLADDER CANCER RECURRENCE
                         KIT (UROVYSION KIT) IS DESIGNED TO DETECT
                         ANEUPLOIDY FOR CHROMOSOMES 3, 7, 17, AND LOSS
                         OF THE 9P2L LOCUS VIA FLUORESCENCE IN SITU
                         HYBRIDIZATION (FISH) IN URINE SPECIMENS FROM
                         SUBJECTS WITH TRANSITIONAL CELL CARCINOMA
                         OF THE BLADDER. RESULTS FROM THE UROVYSION
                         KIT ARE INTENDED FOR USE AS A NONINVASIVE
                         METHOD FOR MONITORING FOR TUMOR
                         RECURRENCE IN CONJUNCTION WITH CYSTOSCOPY
                         IN PATIENTS PREVIOUSLY DIAGNOSED WITH
                         BLADDER CANCER.
                                              Health Care ‫אנליזה וניתוח חברות‬
                                                      January 2010
Regulatory Implications of Claim
                DIAGNOSIS VS. MONITORING
                         THE UROVYSION BLADDER CANCER KIT (UROVYSION
                         KIT) IS DESIGNED TO DETECT ANEUPLOIDY FOR
                         CHROMOSOMES 3, 7, 17 AND LOSS OF THE 9P21 LOCUS
                         VIA FLUORESCENCE IN SITU HYBRIDIZATION (FISH) IN
                PMA      URINE SPECIMENS FROM PERSONS WITH HEMATURIA
                         SUSPECTED OF HAVING BLADDER CANCER. RESULTS
                         FROM THE UROVYSION KIT ARE INTENDED FOR USE, IN
                         CONJUNCTION WITH AND NOT IN LIEU OF CURRENT
                         STANDARD DIAGNOSTIC PROCEDURES, AS AN AID FOR
UroVysion Kit            INITIAL DIAGNOSIS OF BLADDER CARCINOMA IN
                         PATIENTS WITH HEMATURIA AND SUBSEQUENT
                         MONITORING FOR TUMOR RECURRENCE IN PATIENTS
                         PREVIOUSLY DIAGNOSED WITH BLADDER CANCER.

                510(K)
                   ( )   THE UROVYSIONBLADDER CANCER RECURRENCE
                                        BLADDER CANCER
                         KIT (UROVYSION KIT) IS DESIGNED TO DETECT
                         ANEUPLOIDY FOR CHROMOSOMES 3, 7, 17, AND LOSS
                         OF THE 9P2L LOCUS VIA FLUORESCENCE IN SITU
                         HYBRIDIZATION (FISH) IN URINE SPECIMENS FROM
                         SUBJECTS WITH TRANSITIONAL CELL CARCINOMA
                         SUBJECTS WITH TRANSITIONAL CELL CARCINOMA
                         OF THE BLADDER.
                         OF THE BLADDER. RESULTS FROM THE UROVYSION
                         KIT ARE INTENDED FOR USE AS A NONINVASIVE
                               MONITORING FOR TUMOR RECURRENCE
                         METHOD FOR MONITORING FOR TUMOR
                         RECURRENCE IN CONJUNCTION WITH CYSTOSCOPY
                         IN PATIENTS PREVIOUSLY DIAGNOSED WITH
                         BLADDER CANCER.
                                              Health Care ‫אנליזה וניתוח חברות‬
                                                      January 2010
510(k)
           Determination of SE

Demonstration that a new device is substantially      y
equivalent to a legally marketed device (i.e., marketed
before May 28, 1976 or marketed after that date and
was f found substantially equivalent through the
          d      b     i ll     i l        h     h h
510(k) process).




                                       Health Care ‫אנליזה וניתוח חברות‬
                                               January 2010
510(k)
           SE Determination
A device is substantially equivalent if, in comparison
to a legally marketed device it:
has the same intended use; AND
has the same technological characteristics as the legally
marketed device,
      OR
has different technological characteristics, and
submitted information does not raise new questions of
                                             q
safety and effectiveness, and it demonstrates that the
device is as safe and as effective as the legally marketed
d i
device.
                                         Health Care ‫אנליזה וניתוח חברות‬
                                                 January 2010
510(k)
                              SE D t
                                 Determination
                                        i ti




Ref: 2010 RAPS Annual Conference, Christy Foreman, Acting Director, Office of Device Evaluation, FDA

                                                                         Health Care ‫אנליזה וניתוח חברות‬
                                                                                  January 2010
510(k)
                               SE D
                                  Determination
                                         i  i




Ref: 2010 RAPS Annual Conference, Christy Foreman, Acting Director, Office of Device Evaluation, FDA

                                                                          Health Care ‫אנליזה וניתוח חברות‬
                                                                                  January 2010
510(k)
                               SE D t
                                  Determination
                                         i ti




Ref: 2010 RAPS Annual Conference, Christy Foreman, Acting Director, Office of Device Evaluation, FDA

                                                                          Health Care ‫אנליזה וניתוח חברות‬
                                                                                  January 2010
510(k)
                               SE D t
                                  Determination
                                         i ti




Ref: 2010 RAPS Annual Conference, Christy Foreman, Acting Director, Office of Device Evaluation, FDA

                                                                          Health Care ‫אנליזה וניתוח חברות‬
                                                                                  January 2010
PMA (Premarket Approval)
Class III devices which require an approved PMA
application to be marketed include:

  High Risk devices which by regulation
  require a PMA

  New devices for which substantial
  equivalency cannot be determined
    Could undergo a down classification (de Novo
    510(k)) – risk based decision




                                    Health Care ‫אנליזה וניתוח חברות‬
                                            January 2010
Marketing Submissions


 While 510(k) devices must only demonstrate
 that there are as safe and as effective as a
 similar device already marketed

 PMA devices must demonstrate, on their
 own merit, safety and effectiveness
 through valid scientific evidence.



                               Health Care ‫אנליזה וניתוח חברות‬
                                       January 2010
De Novo 510(k)
                        ( )

If FDA determines the device is not substantially
equivalent (NSE), the applicant may:


  resubmit another 510(k) with new data,

  file a petition to reclassify the device (i.e., request
  review under section 207 of the FDAMA) OR
                                     FDAMA),
  submit a PMA application.



                                         Health Care ‫אנליזה וניתוח חברות‬
                                                 January 2010
SR vs. NSR Devices
• For the purpose of clinical investigation

Significant Risk (SR) – …presents a potential for
serious risk to the health safety, or welfare of a subject…
                            safety                 subject
Is for a use of substantial importance in diagnosing, curing,
mitigating, or treating disease……
Non
N SR (NSR) – d not pose a significant risk t the
                      do t           i ifi    t i k to th
human subjects.

• SR devices undergo FDA approval (IDE) prior to
  initiating clinical investigations in the US

• Relevant to 510(k) and PMA classified devices

                                             Health Care ‫אנליזה וניתוח חברות‬
                                                     January 2010
Marketing Submissions
                g
            DEVICE USER FEE FOR FY 2011


 Type of Application                Standard       Small
                                    Fee            Business*
                                                   B i     *

 PMA                                  $236,298
                                      $236 298         $59,075
                                                       $59 075

 180-Day Supplement                   $35,445            $8,861

 Real Time Supplement                 $16,541            $4,135

 510(k)’s
 510(k)’                              $4,348             $2,174

*S
*Small Business: (≤$100 million i annual sales)
    ll B i               illi   in     l l )
                                                  Health Care ‫אנליזה וניתוח חברות‬
                                                          January 2010
Device Approval in Europe
       CE M ki
          Marking




                  Health Care ‫אנליזה וניתוח חברות‬
                          January 2010
Device Approval in Europe
          Relevant Authorities
          R l      A h i i
• Member State of the European Union is any one of the 27
  sovereign states that have acceded to the European Union
  (EU)
• Competent Authority has the authority to act on behalf of
  the government of the Member State to ensure that the
  requirements of the Medical Device Directives are transposed
  into National Law and are applied
• The Notified Body (NB) is a private, commercial testing
  laboratory or certification organization approved by the
            y                   g           pp         y
  Competent Authority in the Member State in which they
  have their head-office to carry out some or all of the
  Conformity Assessment procedures in the medical device
  directives.



                                            Health Care ‫אנליזה וניתוח חברות‬
                                                    January 2010
Device Approval in Europe
                  EC Di
                     Directives
                           i
• Medical Devices are regulated by the EC
  Directives:
   – the Active Implantable Medical Device (AIMD) Directive -
     90/385/EEC
   – the Medical Device Directive (MDD) 93/42/EEC

   – the In Vitro Diagnostic Device Directive (IVD) - 98/79/EC.
      h I Vi      Di      i D i Di        i             / /EC
   – AIMD and MDD are now governed b the Amended Directive
     2007/47/EC
• Medical devices may be classified (risk based) as
  Class I, Class IIa, IIb and III
• MEDDEV guidance documents

                                                 Health Care ‫אנליזה וניתוח חברות‬
                                                         January 2010
Device Approval in Europe

• Within the scope of which Directive?
• Classification (The classification rules are based
  on different criteria such as the duration of contact
  with the patient, the degree of invasiveness and the
  part of the body affected by the use of the device).
• Conformity Assessment Route (design and
  manufacturing inspections, manufacturing ONLY,
  etc.)
   t )
• Technical File (Contains all the relevant
  information to demonstrate that the product meets
  the Essential Requirements of the Directive)


                                      Health Care ‫אנליזה וניתוח חברות‬
                                              January 2010
Device Approval in Europe
  Declaration of C f
  D l     i    f Conformity
                        i
We hereby declare that the distributed CE marked products,
specified in the annexed product list, are covered by the "CE
Marking of Conformity Certificate", reference
        g              y
number:.....CE.., issued on (date) and delivered by [NAME
OF NB], and conform to the required technical
documentation, in accordance with Annex ___of the "EC-
Directive
Directive", the Council Directive 93/42/EEC of 14 June 1993
amended in September 2007, concerning medical devices.

In addition we ensure and declare that the distributed CE
   addition,
marked products, as mentioned and falling within Class XX,
meet the provisions of the EC-Directive which apply to them.

         …………………………
                             .

                                           Health Care ‫אנליזה וניתוח חברות‬
                                                   January 2010
Meeting the Regulatory
     Authorities
     A th iti




                 Health Care ‫אנליזה וניתוח חברות‬
                         January 2010
Meetings with FDA

• P IDE:
  Pre IDE
  – Regulatory strategy: regulatory classification,
    test plan (
         p    (bench test methodologies animal
                                     g
    studies), clinical strategy
  – Prior to expanding clinical trials from feasibility
    to pivotal phase

• Pre-PMA
• Day 100 PMA meetings
• Post-deficiency letter for 510(k) or PMA
• Appeal a final decision on a PMA or 510(k) or an
  A     l fi l d i i
  IDE disapproval
• Agreement or determination meeting
    g                                   g
                                       Health Care ‫אנליזה וניתוח חברות‬
                                               January 2010
In Summary

Regulatory Aff i i about claiming
R g l t    Affairs is b t l i i g
          and branding


It is the umbrella that covers the Company
activities from early development through
                    y       p          g
production and up to post-marketing activities.



                                 Health Care ‫אנליזה וניתוח חברות‬
                                         January 2010
Clinical Evidence




              Health Care ‫אנליזה וניתוח חברות‬
                      January 2010
The Key to Market Penetration
      y
A breakthrough technology is great but does not
ensure
ens re market s ccess
              success

Regulatory approvals are meaningful milestones

     •In creating value for strategic agreements
      and funding
     •In entrance to the market

Clinical evidence (data) is the leading force
to successful market penetration and
positioning

                                  Health Care ‫אנליזה וניתוח חברות‬
                                          January 2010
Clinical Strategy
               gy
                   Post-market
                   Post market



.
    .
        .
Study # 3


Study #2



    FIM


            Investigational/pre-market

                  Health Care ‫אנליזה וניתוח חברות‬
                          January 2010
Health Care ‫אנליזה וניתוח חברות‬
        January 2010
Key Players in
         Strategic Pl
         St t gi Planning
                        i g
A Multidisciplinary team from:
     Management
     Medical practice (SAB)
     Clinical
     Regulatory
       g      y
     Biostatistical
     Marketing and Reimbursement
     R&D
                                   Health Care ‫אנליזה וניתוח חברות‬
                                           January 2010
Clinical Strategy

Need for premarket clinical data?
• Yes - for a PMA route
• No and Yes – for a 510(k) route
     No – all aspects of safety and effectiveness are
     covered by SE rationale and pre clinical
     performance tests
     Yes – There are still safety and efficacy aspects
     not proven by SE and pre clinical tests
                b         d      li i l


                                      Health Care ‫אנליזה וניתוח חברות‬
                                              January 2010
Clinical Strategy

Need for valid postmarket clinical data?
  Yes!
    For Postmarket surveillance (mainly for PMAs)
    For i
    F scientific publications
            ifi    bli i
    For market penetration
    For reimbursement
    For
    F a revised intended use
           i di t d d


                                  Health Care ‫אנליזה וניתוח חברות‬
                                          January 2010
Hierarchy of Medical
                       Scientific E id
                       S i tifi Evidence



                                               Randomized
                                                Controlled
                                                  Trial
                                                  T i l

                                         Observational Trial
                                            Case-control
                                            Case control
                                              Cohort

                                          Descriptive study
                                                p         y
                                        Physiologic study Case
                                        series Expert opinion
Ref: 2010 ICI Meeting, Andrew Farb MD Interventional Cardiology Devices Branch, Office of Device Evaluation
              Meeting         Farb, MD,                                 Branch

                                                                         Health Care ‫אנליזה וניתוח חברות‬
                                                                                  January 2010
Clinical Strategy
                           gy
             Premarket Phase
• Pilot       Pivotal OR One study
• US and OUS sites/ investigators/data
       d      it / i     ti t /d t
• Type of medical institute/s
   yp
          If hospitals – referral centers or others
• Type of investigators
          Opinion leader, Experienced
          practitioner, Regular practitioner

                                     Health Care ‫אנליזה וניתוח חברות‬
                                             January 2010
Clinical Strategy
                         gy
           Postmarket Phase
• Postmarket surveillance (PMA) and long-term
  observations

• First In Man (510(k)) - confirmatory/field

• Market penetration

• S i tifi publications
  Scientific bli ti

• Reimbursement



                                      Health Care ‫אנליזה וניתוח חברות‬
                                              January 2010
Clinical Study Design
       Critical El
       C iti l Elements
                      t
• Type of study
    Single arm or randomized
    Equivalency (as good as) or Superiority (better
    than)
• Study objectives and endpoints
    Safety,
    Safety Performance and/or Efficacy,
                              Efficacy
    Usability, Quality of Life
• Target population (Eligibility Criteria)

                                     Health Care ‫אנליזה וניתוח חברות‬
                                             January 2010
Critical Decisions in Study
       Management




                    Health Care ‫אנליזה וניתוח חברות‬
                            January 2010
Investigator Selection




Opinion Leader   Availability




                        Health Care ‫אנליזה וניתוח חברות‬
                                January 2010
Site Selection
    IP
                                             Laws of
                                             Country
Costs
                                                Scientific
                                                Publications
Location /
Market
                                              Availability


Personnel &
Facilities                                    Regulatory


              Expected subjects eligibility
                       subjects-
                                       Health Care ‫אנליזה וניתוח חברות‬
                                               January 2010
Financial Aspects
Costs of clinical study are mainly based on:
     1. Sample size (No of subjects)
     2. The experimented procedure
     3. Requested clinical assessments (i
     3 R           d li i l             (imaging, l b
                                             i    lab.
        tests, etc.) & medications
     4.
     4 Number of follow-up visits
     5. Required site participating personnel
     6. Requested presence of sponsor personnel
           q         p           p     p
        (technical, clinical)
     7. Costs for ethical committee
     8. Hospital overhead
     8 H      it l     h d
     9. Monitoring, data management and analysis

                                     Health Care ‫אנליזה וניתוח חברות‬
                                             January 2010
Some Common Pitfalls
• Bad study design

• Inappropriate selection of sites and/or investigators

• Incomplete and/or inappropriate study management
  tools (procedures, logs CRFs…)

• Using under-qualified clinical research personnel
  ( p
  (sponsor and/or site)
                      )

• Poor compliance with GCP– not only necessary for
  regulatory reasons b also to reduce the company’s
       l              but l       d      h           ’
  risk from potential adverse publicity and lawsuits

                                       Health Care ‫אנליזה וניתוח חברות‬
                                               January 2010
Study Management
                      Monitoring
        Inadequate monitoring continues to be the top
        deficiency cited in FDA i
        d fi i      i di        inspections of sponsors
                                       i     f




R f B ildi g Q lit i t D i T il P t 2 – M
Ref: Building Quality into Device Trails, Part Marcarelli M Et l 2006
                                                      lli M. Etal,

                                                               Health Care ‫אנליזה וניתוח חברות‬
                                                                        January 2010
Study Management
            Investigator Compliance
           The regulations require sponsors to bring
           noncompliant investigators into compliance




R f B ildi g Q lit i t D i T il P t 2 – M
Ref: Building Quality into Device Trails, Part Marcarelli M Et l 2006
                                                      lli M. Etal,

                                                               Health Care ‫אנליזה וניתוח חברות‬
                                                                        January 2010
To Sum Up

Valid Cli i l D t i
V lid Clinical Data is a Composite Result of:
                         C     it R    lt f

(1)   Team Work

(2)   Pre Pl
      P Planned Global Clinical Strategy
              d Gl b l Cli i l S

(3)   Well Designed St d /i
      W ll D i    d Study/ies

(4)   Closely controlled implementation


                                Health Care ‫אנליזה וניתוח חברות‬
                                        January 2010
Thank You!!!



Moshe Aviv Tower, 34th, Floor
7 Jabotinsky Street, Ramat Gan
E-mail: biomedical@ebms.co.il
Tel: 03-6123281




                                 Health Care ‫אנליזה וניתוח חברות‬
                                         January 2010

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BioMedical Strategy - Regulatory Presentation

  • 1. ‫ודיאגנוסטיקה:‬ ‫מכשור רפואי ודיאגנוסטיקה:‬ ‫תקינה‬ ‫אנליזה וניתוח חברות ‪Health Care‬‬
  • 2. Regulatory Affairs: R l t Aff i A Multi-Task Approach Orna Oz, PhD BioMedical Strategy (2004) Ltd Regulatory & Clinical Affairs Group Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 3. Regulation Key Role in Due Diligence and d Market proposition Stepwise Increase in Company Valuation Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 4. BioMedical Strategy (2004) Ltd Clinical & Regulatory Affairs Group Founded by: Gal Ehrlich Ami Eyal & Orna Oz Ehrlich, The Team: Scientists experts in Clinical & Regulatory Affairs Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 5. ‫01/6/9‬ ‫• אולטרה שייפ קיבלה חיזוק: ה'טיימס' שלח כתב עד ליוקנעם, המניה‬ ‫מזנקת %05 .‬ ‫בכתבה מגדיר הכתב את החברה כ"עמק הסיליקון של היופי הטכנולוגי ."המנכ"ל אסף‬ ‫איל ל" :‪-Bizportal‬החדשות הגדולות של החברה הגיעו אתמול, כאשר ה ‪-FDA‬הודיע על‬ ‫אישור הליך המזורז‬ ‫01/01/81‬ ‫• אולטרה שייפ זינקה ב-%82; עד תחילת נובמבר צפויה להגיע‬ ‫תשובת ה-‪ FDA‬למוצר ההרזייה‬ ‫ל‬ ‫01/01/13‬ ‫• אולטרה שייפ צללה: ה ‪-FDA‬לא העניק אישור למכשיר ההרזייה של‬ ‫החברה‬ ‫אכזבה למשקיעי אולטרה שייפ לאחר המתנה של שלושה חודשים, אתמול הודיע מנהל‬ ‫המזון והתרופות בארה"ב כי הוא דורש הבהרות ונתונים נוספים בטרם אישור מכשיר‬ ‫ההרזייה, הקונטור 1‬ ‫אנליזה וניתוח חברות ‪Health Care‬‬ ‫0102 ‪January‬‬
  • 6. How does it start? Technology T h l Medical M di l need d Scientifically Clinical use of based core rationales technology & Use of Benefits of clinical use and expected p valid t l lid tools clinical outcome Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 7. Medical Product Project Assessment • Medical need • Technological solution • Market Analysis • Patentability • Feasible markets and competitors • Survey on scientific evidence S e o cie tific e ide ce • Regulatory and Reimbursement • Funding F di Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 8. Medical Device Definition D fi i i • an instrument apparatus … implant in instrument, apparatus, implant, vitro reagent, or other similar or related article, article including a component part or part, accessory • Used for the diagnosis treatment or prevention of diagnosis, disease or condition and that • Affects the structure or function of the body • Does not achieve its function through chemical action • Is not metabolized to achieve effect Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 9. Medical Device Examples E l Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 10. Main Target Markets g EU USA Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 11. US Market Food D F d & Drug Ad i i t ti Administration Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 12. FDA is part of the Public Health Service (PHS) within the Department of Health and Human Services (HHS). FDA is headed by a commissioner appointed by the President with Senate consent. consent Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 13. Food & Drug Administration Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 14. FDA/CDRH FOCUS (Center for Devices and Radiological Health) Ensuring that medical devices are “reasonably” safe and effective reasonably Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 15. Types of FDA Regulated Products P d t • Medical Devices (including IVD) & Radiation Emitting Products - Center for Devices & Radiological Health CDRH • Drugs- Center for Drugs Evaluation & Research • Biologics- Center for Biologics Evaluation & Research • Combination Products- Office of Combination Products • Food and Cosmetics- Center for Food Safety & Applied Nutrition • Animal feed and Drugs- Center for Veterinary Medicine Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 16. Premarket Life Cycle y US market as an example Quality Assurance Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 17. Project Milestones • Claim – Intended Use & Indications • Project Initiation –Requirements Proof of Concept • Regulatory Strategy • Product Specification and Risk Analysis p y • R&D Plan (development and V&V) • Ongoing Development g g p •Quality System • Design Freeze •Manufacturing • Pre clinical Verification &Validation • Premarket Clinical Investigation • Submission for market clearance/approval • Post-market activities (clinical study/ies) Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 18. Regulatory Strategy • Regulatory Classification and existing similar marketed devices • P Pre-clinical Testing li i l T i • Clinical Strategy (pre and post market) • Discussion and recommendations •Re-assess intended use and/or indications for use •Re-assess technological (engineering) approach and R&D plan •Re-assess business plan – designated product, timelines and budget Alternative approaches Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 19. Claim / Intended Use Intended Use: What is being done Sometimes where it is being done Sometimes why it is being done Indications: Diseases Patients P ti t Subsets Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 20. Claim Intended Use & Indications For Use Design Specifications Test Plan to Verify and Regulatory & Clinical Validate Claim V lid t Cl i strategies (including target markets)) 1. Bench T ti 1 B h Testing 2. Animal Testing 3. Clinical Data Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 21. Regulatory Implications of Claim SPECIFICITY LEVEL 1. Identification of function Tool Claim 2. Identification of tissue type an organ system or (higher clinical Identification of a specific evidence)) organ 3. Identification of a particular disease or target population 4. Identification of an effect on clinical outcome Clinical Claim Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 22. Regulatory Implications of Claim SPECIFICITY LEVEL Tool vs. Clinical – Cardiac Pacing Devices Tool: The Frontier Biventricular Cardiac Pacing System is indicated for maintaining synchrony of the left and right ventricles in patients who……. Clinical: Cli i l The InSync model 8040 pulse generator is indicated for the reduction of the symptoms of moderate to severe heart failure (NYHA Functional III or IV) in those patients who……. Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 23. Claim / Intended Use GENERAL VS. SPECIFIC INTENDED USE The claim(s) for a device can be general or specific. When deciding the claims for the device it is g important to consider not only the marketing goals but also the regulatory process. Examples of General vs. Specific Use: Skin resurfacing vs. Wrinkle removal vs Evaluation of soft tissue vs. Aid in differentiation of benign from malignant breast lesions g g Cut/coagulate soft tissue vs. Photorefractive keratectomy (PRK) for myopia Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 24. Claim / Intended Use GENERAL VS. SPECIFIC INTENDED USE Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 25. Classification – Risk Based User/Pt g Mitigation Environment RISK Generic type Circumstances Claim Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 26. Classification Class I (Low Risk) ~45% Examination gloves, Sunglasses, Instruments for general use (scalpels), Diagnostic Stethoscope trol Level of Cont Class II (Med. Risk) ~47% Vital signs monitors, Ventilators, Infusion pumps, o Incubators, MRI, US L Class III (High Risk) ~8 Coronary Stents, Heart Valves, Pacemakers, Implantable Lenses, new and untested technologies, life-supporting or sustaining…. Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 27. Regulatory Pathway g y y The class to which the device is assigned determines (among other things) the type of the required regulatory pathway and premarketing application: Exempt E Class I Cl 510(k) ( ) Class I or II (Non exempt) ( p) Class III preamendments device (on the market prior to 1976, or substantially equivalent to such a device) and PMA's have i l h d i ) d PMA' h not been called for PMA Class III Cl Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 28. CDRH’s Risk Based Paradigm g Class I Class II Class III Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 29. Regulatory Pathway g y y De Novo 510(k) (after re-evaluation of an automatic ( )( class III designation) – NSE & Lower Risk device or that contemplates “Similar Technologies” and risk profile. HDE “medical device intended to benefit patients in medical the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4,000 , individuals in the United States per year.” Similar to a premarket approval (PMA) application, but exempt from the effectiveness requirements f h ff i i Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 30. Regulatory Implications of Claim DIAGNOSIS VS. MONITORING BLADDER CANCER KIT THE UROVYSION BLADDER CANCER KIT (UROVYSION KIT) IS DESIGNED TO DETECT ANEUPLOIDY FOR CHROMOSOMES 3, 7, 17 AND LOSS OF THE 9P21 LOCUS VIA FLUORESCENCE IN SITU HYBRIDIZATION (FISH) IN URINE SPECIMENS FROM PERSONS WITH HEMATURIA PMA SUSPECTED OF HAVING BLADDER CANCER RESULTS SUSPECTED OF HAVING BLADDER CANCER. FROM THE UROVYSION KIT ARE INTENDED FOR USE, IN CONJUNCTION WITH AND NOT IN LIEU OF CURRENT STANDARD DIAGNOSTIC PROCEDURES, AS AN AID FOR UroVysion Kit AS AN AID FOR INITIAL DIAGNOSIS INITIAL DIAGNOSIS OF BLADDER CARCINOMA IN PATIENTS WITH HEMATURIA AND SUBSEQUENT MONITORING FOR TUMOR RECURRENCE IN PATIENTS PREVIOUSLY DIAGNOSED WITH BLADDER CANCER. 510(K) THE UROVYSION BLADDER CANCER RECURRENCE KIT (UROVYSION KIT) IS DESIGNED TO DETECT ANEUPLOIDY FOR CHROMOSOMES 3, 7, 17, AND LOSS OF THE 9P2L LOCUS VIA FLUORESCENCE IN SITU HYBRIDIZATION (FISH) IN URINE SPECIMENS FROM SUBJECTS WITH TRANSITIONAL CELL CARCINOMA OF THE BLADDER. RESULTS FROM THE UROVYSION KIT ARE INTENDED FOR USE AS A NONINVASIVE METHOD FOR MONITORING FOR TUMOR RECURRENCE IN CONJUNCTION WITH CYSTOSCOPY IN PATIENTS PREVIOUSLY DIAGNOSED WITH BLADDER CANCER. Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 31. Regulatory Implications of Claim DIAGNOSIS VS. MONITORING THE UROVYSION BLADDER CANCER KIT (UROVYSION KIT) IS DESIGNED TO DETECT ANEUPLOIDY FOR CHROMOSOMES 3, 7, 17 AND LOSS OF THE 9P21 LOCUS VIA FLUORESCENCE IN SITU HYBRIDIZATION (FISH) IN PMA URINE SPECIMENS FROM PERSONS WITH HEMATURIA SUSPECTED OF HAVING BLADDER CANCER. RESULTS FROM THE UROVYSION KIT ARE INTENDED FOR USE, IN CONJUNCTION WITH AND NOT IN LIEU OF CURRENT STANDARD DIAGNOSTIC PROCEDURES, AS AN AID FOR UroVysion Kit INITIAL DIAGNOSIS OF BLADDER CARCINOMA IN PATIENTS WITH HEMATURIA AND SUBSEQUENT MONITORING FOR TUMOR RECURRENCE IN PATIENTS PREVIOUSLY DIAGNOSED WITH BLADDER CANCER. 510(K) ( ) THE UROVYSIONBLADDER CANCER RECURRENCE BLADDER CANCER KIT (UROVYSION KIT) IS DESIGNED TO DETECT ANEUPLOIDY FOR CHROMOSOMES 3, 7, 17, AND LOSS OF THE 9P2L LOCUS VIA FLUORESCENCE IN SITU HYBRIDIZATION (FISH) IN URINE SPECIMENS FROM SUBJECTS WITH TRANSITIONAL CELL CARCINOMA SUBJECTS WITH TRANSITIONAL CELL CARCINOMA OF THE BLADDER. OF THE BLADDER. RESULTS FROM THE UROVYSION KIT ARE INTENDED FOR USE AS A NONINVASIVE MONITORING FOR TUMOR RECURRENCE METHOD FOR MONITORING FOR TUMOR RECURRENCE IN CONJUNCTION WITH CYSTOSCOPY IN PATIENTS PREVIOUSLY DIAGNOSED WITH BLADDER CANCER. Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 32. 510(k) Determination of SE Demonstration that a new device is substantially y equivalent to a legally marketed device (i.e., marketed before May 28, 1976 or marketed after that date and was f found substantially equivalent through the d b i ll i l h h h 510(k) process). Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 33. 510(k) SE Determination A device is substantially equivalent if, in comparison to a legally marketed device it: has the same intended use; AND has the same technological characteristics as the legally marketed device, OR has different technological characteristics, and submitted information does not raise new questions of q safety and effectiveness, and it demonstrates that the device is as safe and as effective as the legally marketed d i device. Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 34. 510(k) SE D t Determination i ti Ref: 2010 RAPS Annual Conference, Christy Foreman, Acting Director, Office of Device Evaluation, FDA Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 35. 510(k) SE D Determination i i Ref: 2010 RAPS Annual Conference, Christy Foreman, Acting Director, Office of Device Evaluation, FDA Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 36. 510(k) SE D t Determination i ti Ref: 2010 RAPS Annual Conference, Christy Foreman, Acting Director, Office of Device Evaluation, FDA Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 37. 510(k) SE D t Determination i ti Ref: 2010 RAPS Annual Conference, Christy Foreman, Acting Director, Office of Device Evaluation, FDA Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 38. PMA (Premarket Approval) Class III devices which require an approved PMA application to be marketed include: High Risk devices which by regulation require a PMA New devices for which substantial equivalency cannot be determined Could undergo a down classification (de Novo 510(k)) – risk based decision Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 39. Marketing Submissions While 510(k) devices must only demonstrate that there are as safe and as effective as a similar device already marketed PMA devices must demonstrate, on their own merit, safety and effectiveness through valid scientific evidence. Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 40. De Novo 510(k) ( ) If FDA determines the device is not substantially equivalent (NSE), the applicant may: resubmit another 510(k) with new data, file a petition to reclassify the device (i.e., request review under section 207 of the FDAMA) OR FDAMA), submit a PMA application. Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 41. SR vs. NSR Devices • For the purpose of clinical investigation Significant Risk (SR) – …presents a potential for serious risk to the health safety, or welfare of a subject… safety subject Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease…… Non N SR (NSR) – d not pose a significant risk t the do t i ifi t i k to th human subjects. • SR devices undergo FDA approval (IDE) prior to initiating clinical investigations in the US • Relevant to 510(k) and PMA classified devices Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 42. Marketing Submissions g DEVICE USER FEE FOR FY 2011 Type of Application Standard Small Fee Business* B i * PMA $236,298 $236 298 $59,075 $59 075 180-Day Supplement $35,445 $8,861 Real Time Supplement $16,541 $4,135 510(k)’s 510(k)’ $4,348 $2,174 *S *Small Business: (≤$100 million i annual sales) ll B i illi in l l ) Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 43. Device Approval in Europe CE M ki Marking Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 44. Device Approval in Europe Relevant Authorities R l A h i i • Member State of the European Union is any one of the 27 sovereign states that have acceded to the European Union (EU) • Competent Authority has the authority to act on behalf of the government of the Member State to ensure that the requirements of the Medical Device Directives are transposed into National Law and are applied • The Notified Body (NB) is a private, commercial testing laboratory or certification organization approved by the y g pp y Competent Authority in the Member State in which they have their head-office to carry out some or all of the Conformity Assessment procedures in the medical device directives. Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 45. Device Approval in Europe EC Di Directives i • Medical Devices are regulated by the EC Directives: – the Active Implantable Medical Device (AIMD) Directive - 90/385/EEC – the Medical Device Directive (MDD) 93/42/EEC – the In Vitro Diagnostic Device Directive (IVD) - 98/79/EC. h I Vi Di i D i Di i / /EC – AIMD and MDD are now governed b the Amended Directive 2007/47/EC • Medical devices may be classified (risk based) as Class I, Class IIa, IIb and III • MEDDEV guidance documents Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 46. Device Approval in Europe • Within the scope of which Directive? • Classification (The classification rules are based on different criteria such as the duration of contact with the patient, the degree of invasiveness and the part of the body affected by the use of the device). • Conformity Assessment Route (design and manufacturing inspections, manufacturing ONLY, etc.) t ) • Technical File (Contains all the relevant information to demonstrate that the product meets the Essential Requirements of the Directive) Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 47. Device Approval in Europe Declaration of C f D l i f Conformity i We hereby declare that the distributed CE marked products, specified in the annexed product list, are covered by the "CE Marking of Conformity Certificate", reference g y number:.....CE.., issued on (date) and delivered by [NAME OF NB], and conform to the required technical documentation, in accordance with Annex ___of the "EC- Directive Directive", the Council Directive 93/42/EEC of 14 June 1993 amended in September 2007, concerning medical devices. In addition we ensure and declare that the distributed CE addition, marked products, as mentioned and falling within Class XX, meet the provisions of the EC-Directive which apply to them. ………………………… . Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 48. Meeting the Regulatory Authorities A th iti Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 49. Meetings with FDA • P IDE: Pre IDE – Regulatory strategy: regulatory classification, test plan ( p (bench test methodologies animal g studies), clinical strategy – Prior to expanding clinical trials from feasibility to pivotal phase • Pre-PMA • Day 100 PMA meetings • Post-deficiency letter for 510(k) or PMA • Appeal a final decision on a PMA or 510(k) or an A l fi l d i i IDE disapproval • Agreement or determination meeting g g Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 50. In Summary Regulatory Aff i i about claiming R g l t Affairs is b t l i i g and branding It is the umbrella that covers the Company activities from early development through y p g production and up to post-marketing activities. Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 51. Clinical Evidence Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 52. The Key to Market Penetration y A breakthrough technology is great but does not ensure ens re market s ccess success Regulatory approvals are meaningful milestones •In creating value for strategic agreements and funding •In entrance to the market Clinical evidence (data) is the leading force to successful market penetration and positioning Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 53. Clinical Strategy gy Post-market Post market . . . Study # 3 Study #2 FIM Investigational/pre-market Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 54. Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 55. Key Players in Strategic Pl St t gi Planning i g A Multidisciplinary team from: Management Medical practice (SAB) Clinical Regulatory g y Biostatistical Marketing and Reimbursement R&D Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 56. Clinical Strategy Need for premarket clinical data? • Yes - for a PMA route • No and Yes – for a 510(k) route No – all aspects of safety and effectiveness are covered by SE rationale and pre clinical performance tests Yes – There are still safety and efficacy aspects not proven by SE and pre clinical tests b d li i l Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 57. Clinical Strategy Need for valid postmarket clinical data? Yes! For Postmarket surveillance (mainly for PMAs) For i F scientific publications ifi bli i For market penetration For reimbursement For F a revised intended use i di t d d Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 58. Hierarchy of Medical Scientific E id S i tifi Evidence Randomized Controlled Trial T i l Observational Trial Case-control Case control Cohort Descriptive study p y Physiologic study Case series Expert opinion Ref: 2010 ICI Meeting, Andrew Farb MD Interventional Cardiology Devices Branch, Office of Device Evaluation Meeting Farb, MD, Branch Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 59. Clinical Strategy gy Premarket Phase • Pilot Pivotal OR One study • US and OUS sites/ investigators/data d it / i ti t /d t • Type of medical institute/s yp If hospitals – referral centers or others • Type of investigators Opinion leader, Experienced practitioner, Regular practitioner Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 60. Clinical Strategy gy Postmarket Phase • Postmarket surveillance (PMA) and long-term observations • First In Man (510(k)) - confirmatory/field • Market penetration • S i tifi publications Scientific bli ti • Reimbursement Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 61. Clinical Study Design Critical El C iti l Elements t • Type of study Single arm or randomized Equivalency (as good as) or Superiority (better than) • Study objectives and endpoints Safety, Safety Performance and/or Efficacy, Efficacy Usability, Quality of Life • Target population (Eligibility Criteria) Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 62. Critical Decisions in Study Management Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 63. Investigator Selection Opinion Leader Availability Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 64. Site Selection IP Laws of Country Costs Scientific Publications Location / Market Availability Personnel & Facilities Regulatory Expected subjects eligibility subjects- Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 65. Financial Aspects Costs of clinical study are mainly based on: 1. Sample size (No of subjects) 2. The experimented procedure 3. Requested clinical assessments (i 3 R d li i l (imaging, l b i lab. tests, etc.) & medications 4. 4 Number of follow-up visits 5. Required site participating personnel 6. Requested presence of sponsor personnel q p p p (technical, clinical) 7. Costs for ethical committee 8. Hospital overhead 8 H it l h d 9. Monitoring, data management and analysis Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 66. Some Common Pitfalls • Bad study design • Inappropriate selection of sites and/or investigators • Incomplete and/or inappropriate study management tools (procedures, logs CRFs…) • Using under-qualified clinical research personnel ( p (sponsor and/or site) ) • Poor compliance with GCP– not only necessary for regulatory reasons b also to reduce the company’s l but l d h ’ risk from potential adverse publicity and lawsuits Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 67. Study Management Monitoring Inadequate monitoring continues to be the top deficiency cited in FDA i d fi i i di inspections of sponsors i f R f B ildi g Q lit i t D i T il P t 2 – M Ref: Building Quality into Device Trails, Part Marcarelli M Et l 2006 lli M. Etal, Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 68. Study Management Investigator Compliance The regulations require sponsors to bring noncompliant investigators into compliance R f B ildi g Q lit i t D i T il P t 2 – M Ref: Building Quality into Device Trails, Part Marcarelli M Et l 2006 lli M. Etal, Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 69. To Sum Up Valid Cli i l D t i V lid Clinical Data is a Composite Result of: C it R lt f (1) Team Work (2) Pre Pl P Planned Global Clinical Strategy d Gl b l Cli i l S (3) Well Designed St d /i W ll D i d Study/ies (4) Closely controlled implementation Health Care ‫אנליזה וניתוח חברות‬ January 2010
  • 70. Thank You!!! Moshe Aviv Tower, 34th, Floor 7 Jabotinsky Street, Ramat Gan E-mail: biomedical@ebms.co.il Tel: 03-6123281 Health Care ‫אנליזה וניתוח חברות‬ January 2010