regulatory 101

REGULATORY STRATEGY Developing a Long-‐Term Regulatory Strategy for Medical Devices April 24, 2013

AGENDA

•  IntroducHons •  Background -  ApplicaHon types and other regulatory factors

•  Who is involved?

•  Why should you care? •  What makes a good Regulatory Strategy?

•  When do you need a Regulatory Strategy and what does it contain?

•  10 elements of a good regulatory strategy desgin

•  Recent client example

•  Conclusion

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STRAT·∙E·∙GY

•  a : a careful plan or method : a clever stratagem

•  b : the art of devising or employing plans or stratagems toward a goal

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Background Applica1ons and Other Regulatory Factors

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APPLICATION TYPES

• MulHple Types of Regulatory ApplicaHons for Devices -  United States   510(k) Premarket NoHficaHon, Premarket Approval (PMA) ApplicaHon, Product Development Protocol (PDP), Humanitarian Device ExempHon (HDE), InvesHgaHonal Device ExempHon (IDE), Exempt

-  European Union   Technical File   Design Dossier

-  Canada   License ApplicaHon

-  Others   Various types of regulatory submissions

CONFIDENTIAL

APPLICATION TYPES

• MulHple Device ClassificaHons -  Risk Based Device CategorizaHon Scheme   US – Class I to III   EU – Class I, Class IIa, Class IIb, Class III   Canada – Class I to IV

•  ClassificaHon determines applicaHon

CONFIDENTIAL

APPLICATION TYPES -‐ US

•  If Class I or II, and not exempt, a 510(k) is required

•  If Class III, a PMA is required -  Unless device is a preamendment device and a PMA has not been called for. In that case, a 510(k) will be the route to market.

  Preamendment device: on the market prior to the passage of the medical device amendments in 1976, or substanHally equivalent to such a device

-  Unless not classified   Postamendment device: new or a final classificaHon decision has not been made

-  Class III devices -‐ support or sustain human life, are of substanHal importance in prevenHng impairment of human health, or which present a potenHal, unreasonable risk of illness or injury.

CONFIDENTIAL


•  510(k) Premarket NoHficaHon -  Premarket submission made to FDA to demonstrate that the device to be marketed is at least as safe and effecHve (i.e., substanHally equivalent) to a legally marketed device that is not subject to PMA.

-  Must compare device to one or more similar legally marketed devices.   A legally marketed device is a device that was legally marketed prior to May 28,

1976 (preamendments device), for which a PMA is not required, or a device which has been reclassified from Class III to Class II or I, or a device which has been found SE through the 510(k) process.

-  The legally marketed device(s) to which equivalence is drawn is the "predicate.”

-  Low risk, no predicate = de novo

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•  Premarket approval (PMA) -  PMA is the most stringent type of device markeHng applicaHon required by FDA. The applicant must receive FDA approval of its PMA applicaHon prior to markeHng the device. PMA approval is based on a determinaHon by FDA that the PMA contains sufficient valid scienHfic evidence to assure that the device is safe and effecHve for its intended use(s).

-  Requires clinical data •  Product Development Protocol (PDP) -  A contract that describes the agreed upon details of design and development acHviHes, the outputs of the acHviHes, and acceptance criteria for outputs. Includes reporHng milestones. A PDP declared completed by FDA is considered to have an approved PMA.

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•  Humanitarian Device ExempHon (HDE) -  An applicaHon that is similar to a premarket approval (PMA) applicaHon, but is exempt from the effecHveness requirements. For Humanitarian Use Devices (HUD).

•  InvesHgaHonal Device ExempHon (IDE) -  Allows the invesHgaHonal device to be used in a clinical study in order to collect safety and effecHveness data. Required for all significant risk studies prior to markeHng applicaHon.

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APPLICATION TYPES – EU

•  Technical File -  Self cerHficaHon -  Must meet essenHal requirements

-  Requires clinical evaluaHon •  Design Dossier -  Must be approved by a NoHfied Body -  Must meet essenHal requirements

-  Requires clinical evidence (generally)

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GLOBAL REGULATORY ENVIRONMENT

•  Various applicaHon types and requirements (guidance documents, standards, in vitro/in vivo tesHng, etc.)

•  Clinical data requirements variable

•  Differing regulatory bodies (government, 3rd party) or self declaraHon

•  Pre-‐approval audit requirements differ per country and submission type

•  Post-‐market requirements differ per country, requirement type, and submission type

•  Different quality systems – QSR vs. ISO

CONFIDENTIAL

Who is involved?

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REGULATORY AFFAIRS

• Manage operaHonal acHviHes such as preparing, submilng, and maintaining submissions

•  Communicate with regulatory bodies •  Ensure compliance

•  Greater value -‐ regulatory strategy - For devices this is more than where do I need approval

- Omen different submission strategies

- Omen different clinical trial strategies - Higher level of RA input omen needed

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Why should I care?

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YOU SHOULD CARE BECAUSE…

• Medical device execuHves omen: - Are unaware of or undervalue the importance of gelng early regulatory guidance on long-‐range development strategies

- Direct their resources to immediate needs

- Develop regulatory strategies too late in the game   StarHng well before clinical trials are iniHated, companies need to understand both the regulatory landscape (i.e., guidelines, important stakeholders, emerging policies) and relevant precedents.

  Prevents rework – saves Hme and therefore $$$

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What makes a good Regulatory Strategy?

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A GOOD REGULATORY STRATEGY…

•  Provides framework for the overall development plan •  Summarizes scope of technical, nonclinical, and clinical tesHng required for markeHng

•  Allows for understanding of expectaHons and risks •  Provides plan to proacHvely address risks early in development

•  Takes into account short and long-‐term corporate objecHves

•  Aids in determining the fastest and/or greatest value path to market

Strategy to meet regulatory requirements and obtain fastest method to market in idenHfied regions.

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A GOOD REGULATORY STRATEGY… •  Helps the team in: -  Understanding the development pathway

  IdenHfying submission types and requirements (addressing early to prevent rework)

  IdenHfying required tesHng (bench, animal, clinical, etc.)

  Understanding associated risks   Determining Timelines

-  Assessing the value of the product   How long will it take?   What unique claims can I make?

  Where can I market the fastest?

  How do I get to market the fastest?

-  Understanding what can be accomplished before, or determining when, addiHonal financing may be needed

-  IdenHfying if unique requirements have substanHal impact on the Hme to market (e.g., size of the clinical trial, length of pre-‐clinical and/or clinical follow-‐up)

-  Understanding if the regulatory environment/requirements/expectaHons shim during the development (precedents, compeHtors, poliHcal environment)

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•  Starts with quesHons…not answers -  There are numerous potenHal variables that must be considered

•  Is not created in a vacuum -  Cross-‐funcHonal project team (regulatory, markeHng, medical/clinical, engineering, reimbursement, manufacturing, quality, regulatory bodies, etc.)

•  Is created early -  Before tesHng (other than R&D) begins

•  Takes into account how it will be marketed -  PaHent populaHon, compeHHve claims, markeHng specificaHons

•  UHlizes regulatory intelligence -  Regulatory history, approval requirements, postmarket concerns, compeHHon/precedents, environment

•  Is global in nature -  Addresses global regulatory requirement for all potenHal market regions

•  Is a living document

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•  Primary funcHons: -  Tracking tool, summarizing key agreements reached with health authoriHes

-  Planning tool, documenHng Hmelines and lisHng topics to address in future meeHngs with health authoriHes

-  Risk index recording key open issues that could potenHally impact Hmelines, cost, or commercial value for the project

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When do you need a Regulatory Strategy and what does it contain?

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A REGULATORY STRATEGY IS NEEDED…

• When formal wriqen submissions are required, e.g., original, supplements, revisions, etc.

•  For: -  New Product Development (proposed launch or release of a new product)

-  A change to an exisHng product -  Product recerHficaHon (requiring a submission to a Regulatory body)

- Manufacturing site change that impact regulatory filings -  Regulatory approvals needed to market a device manufactured by another company

-  Others depending upon complexity and impact

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REGULATORY STRATEGY DOCUMENT CONTENTS

•  Regulatory Strategy requirements may include: -  Submission purpose (e.g., breakthrough technology, first human use, original submission, derivaHve, design change, indicaHon change, manufacturing site change, increase market share, recerHficaHon, etc.)

-  Use of animal, biologic, drug material

-  IndicaHons for use (IdenHfy regional differences, as appropriate) -  Intended Use (The objecHve intent or descripHon of use for the device, not specific to paHent populaHon or medical condiHon. )

-  LocaHon of manufacturing/distribuHon sites

-  SterilizaHon site and method

-  Device classificaHon (by region) -  Desired market claims (IdenHfy regional differences, as appropriate)

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•  Regulatory Strategy requirements may include (cont’d): -  Product descripHon -  Regulatory Guidance Documents / Standards

-  Submission type, esHmated submission/approval Hmelines by region

-  Regulatory strategy overview by region (Document raHonales for submission type, use of pre-‐clinical and clinical data, etc.; IdenHfy potenHal for regulatory body meeHngs; use of leveraged data; potenHal for risks to strategy and planned acHviHes to miHgate risks)

-  Pre-‐clinical/Clinical tesHng by region (bench, animal, biocompaHbility, somware, electromagneHc compaHbility or other studies. Consider clinical endpoints, Hmelines, use of leveraged data, use of literature, etc.)

-  Post-‐approval regulatory requirements (post-‐approval regulatory requirements, markeHng studies, post-‐approval reporHng, etc.)

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•  Other consideraHons - Milestones (e.g., Regulatory Body meeHngs)

-  Data consideraHons based upon the regulatory intelligence -  Publicly available informaHon about successes and pitalls of compeHHve products

-  Key risks, barriers, or issues to resolve -  EvoluHon of regulatory landscape over product development Hmeline

-  Advantages and disadvantages of regulatory pathways if mulHple (e.g., fastest route vs. market exclusivity)

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10 Elements of Good Regulatory Strategy Design

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10 ELEMENTS OF GOOD REGULATORY STRATEGY DESIGN 1.  What is the purpose of the submission?

  New technology being introduced to market with unknown safety and effecHveness

  First Human Use   DerivaHve   Change in design, material, manufacturing, process, site, sterilizaHon, etc.

  Change to indicaHon for use   Increase market share, market penetraHon, market expansion

  RecerHficaHon, license renewal 2.  What markets will be the focus of approval?

  Worldwide approvals desired (regions/markets desired)

  What are the market prioriHes and why (downsides/upsides for not pursuing market approval)

  What markets are out of scope and why (downsides/upsides for not pursuing market approval)

  Submission cadence and prioriHes

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10 ELEMENTS OF GOOD REGULATORY STRATEGY DESIGN

3.  What Market Claims are desired?

  Superiority   Non-‐Inferiority   Economic (e.g., more cost effecHve)

  Ease of use   Quality of Life   Technical claims (e.g., more durable)

  Expanded claims desired

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4.  What is the current WW data requirements to support the Market

claims?

  Clinical data requirements

  Bench or pre-‐clinical data requirements

  New material, risk to project

  Regulatory classificaHon in quesHon   Implant device

  Drug/combinaHon device

  Biologic component/device

  New device regulaHons   Post-‐market trials

  Pre-‐approval inspecHons

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5.  What is the clinical control used for submission approval?   Is a clinical study required and why? What type of study will be required (randomized, registry, post-‐market, etc.)?

  Expected difference between control and test arHcle   Is foreign clinical data acceptable and why?   Is literature review acceptable to support clinical safety and effecHveness, performance and why?

6.  Is there a plan to meet with different regional Regulatory Bodies in order to solidify the WW regulatory strategy? •  What Regulatory Body meeHngs should be schedule?

•  What is the purpose?

•  When should meeHngs or recurrence of meeHngs be scheduled?

•  Should informaHon regarding meeHng outcomes be shared with other Regulatory Bodies, why or why not?

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7.  What is the fastest speed to market (may be most risk) vs. most conservaHve regulatory approach to market? •  Is it possible to gain market approval without clinical trials?

•  Clinical trial vs. literature/historical studies •  Regional locaHon of clinical trial (US, EU, Japan, InterConHnental) •  Can data (pre-‐clinical, clinical, bench) be leveraged? •  Choice of submission pathway (30-‐day, Real Time Review, etc.)

•  Acceptability of Accelerated vs. Real Time Shelf Life data

•  Planned launch with limited or staged indicaHons for use

8.  What guidance documents, standards, etc. will or will not be used (with raHonale) for regulatory approval? •  Compliance or parHal-‐compliance to standards

•  Guidance documents used, will full compliance be the norm

•  ConsideraHon of dram or transiHonal standards or guidance documents

•  ConsideraHon of standard changes

32 10 ELEMENTS OF GOOD REGULATORY STRATEGY DESIGN


9.  What are the pre-‐approval regulatory requirements? •  QMS audits (paper vs. on-‐sight)

•  QMS audit Hming •  Is the product included in the scope of the relevant QSR/QMS/ISO/MDD cerHficates?

10. What are the post-‐approval regulatory requirements? •  Post-‐approval studies •  Line extension •  Post-‐approval reports

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Example

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RECENT CLIENT EXAMPLE

•  Client had 2 versions of a product – percutaneous and open -  Percutaneous had clear predicate

•  Client want to market in the US and EU ASAP

•  Client wanted to obtaining markeHng clearance for a general as well as specific indicaHon for each -  Percutaneous general -  Percutaneous specific -  Open general -  Open specific

•  HCG idenHfied that the products could be cleared through the 510(k) pathway, but would require clinical trials first (IDE) for the specific indicaHons

•  HCG outlined several RISK BASED regulatory strategies. Strategies were based on both business and regulatory risk.

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Open Specific CE Mark Percutaneous General 510(k) Clearance 3-‐6 M Open General 510(k) Clearance 3-‐6 M Open Specific Pilot Clinical Trial 26 M Poten1al NB Review CE Mark: 3-‐6 M TOTAL TIME: 35-‐44 M

Open General Indica1on Percutaneous General Indica1on 510(k) Clearance 3-‐6 M Open General Indica1on 510(k) Clearance 3-‐6 M TOTAL TIME: 6-‐12 M

Percutaneous General Indica1on 510(k) Clearance – 3-‐6 M EU CE Mark – Self cer1fica1on

Open General CE Mark -‐ Self cer1fica1on

Percutaneous Specific 510(k)Clearance Percutaneous General Indica1on 510(k) 3-‐6 M Percutaneous Specific Clinical Trials 76-‐82 M Percutaneous Specific Indica1on 510(k) 6 M TOTAL TIME: 85– 94 M

Percutaneous Specific CE Mark Percutaneous General Indica1on 510(k) 3-‐6 M Percutaneous Specific Pilot Clinical Trial 26 M Poten1al NB Review CE Mark: 3-‐6 M TOTAL TIME: 32-‐38 M

36 Cumula1ve Timeline Analysis

RECENT CLIENT EXAMPLE Regulatory Scenario-‐Recommended

Percutaneous General IndicaHon -‐ US: 510(k) -‐ EU: Tech File w/Clinical Eval.

Percutaneous Specific IndicaHon US: File IDE-‐> Pilot-‐> Pivotal-‐> 510(k)

Percutaneous Specific IndicaHon EU: Pilot data to support CE Mark

Open General IndicaHon EU: Tech File w/Clinical EvaluaHon

Open General IndicaHon US: 510(k)

Open Specific IndicaHon US: File IDE-‐> Pilot-‐> Pivotal-‐> 510(k)

Open Specific IndicaHon EU: Pilot to support CE Mark

Open Specific 510(k) Clearance Percutaneous General 510(k) Clearance 3-‐6 M Open General 510(k) Clearance 3-‐6 M Open Specific Clinical Trials 76-‐82 M Open Specific 510(k) 6 M TOTAL TIME: 88-‐100 M

Recommended Benefits:

•  Best chance of regulatory success •  Compelling data •  Market acceptance •  Balanced cost

RECENT CLIENT EXAMPLE Other Strategies

1. Separate CE MARK •  ExcepHon from Recommended Scenario: -  Performing independent CE Mark Clinical Trials for specific indicaHon rather

than using IDE pilot data   Benefits: –  Reduce Percutaneous Specific CE Mark Timeline 3-‐6 M –  Reduce Open Specific CE Mark Timeline 6-‐12 M

  Risk: Increase cost of $1.2 M

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2. Simultaneous 510(k) + IDE •  ExcepHon to Recommended Scenario: -  510(k)s for general and IDEs for specific indicaHons occurring

simultaneously.   Benefits: –  Reduce Percutaneous Specific 510(k) 3-‐6 M –  Reduce Percutaneous Specific CE Mark Timeline 3-‐6 M –  Reduce Open Specific 510(k) 3-‐6 M

–  Reduce Open Specific CE Mark Timeline 3-‐6 M

  Risk –  FDA suspects off label use so may not clear general indicaHon 510(k)

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3. Simultaneous 510(k)+ IDE + CE Mark •  ExcepHon to Recommended Scenario: -  510(k)s for general and IDEs for specific indicaHons occurring simultaneously. -  Independent CE Mark Clinical Trial for specific indicaHon.

  Benefits: –  Reduce Percutaneous Specific 510(k) 3-‐6 M –  Reduce Percutaneous Specific CE Mark Timeline 3-‐6 M –  Reduce Open Specific 510(k) 3-‐6 M –  Reduce Open Specific CE Mark Timeline 6-‐12M

  Risks: –  FDA suspects off label use. –  No Hme savings in performing percutaneous specific CE Mark study if IDE pilot is to occur at

same Hme. Increase cost of $1.2 M

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RECENT CLIENT EXAMPLE Other Strategies 4. Simultaneous device versions •  ExcepHon to Recommended Scenario: -  Simultaneous filings of:

  Percutaneous general indicaHon   Percutaneous specific IDE   Open based general indicaHon 510(k)   Open based specific IDE

-  Benefits:   Reduce Percutaneous Specific 510(k) 3-‐6 M   Reduce Percutaneous Specific CE Mark Timeline 3-‐6 M   Reduce Open General 510(k) 3-‐6 M   Reduce Open Specific 510(k) 6-‐12 M   Reduce Open Specific CE Mark Timeline 6-‐12M

-  Risks:   FDA suspects off label use.   Cannot use Percutaneous device as predicate.   FDA determining Open Specific device is novel (PMA)

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RECENT CLIENT EXAMPLE Other Strategies 5. Simultaneous device versions + CE MARK •  ExcepHon to Recommended Scenario: -  Simultaneous filings of:

•  Percutaneous general indicaHon

•  Percutaneous specific IDE

•  Open general indicaHon 510(k)

•  Open specific IDE

-  Independent CE Mark Clinical Trial for specific indicaHons.

  Benefits: •  Reduce Percutaneous Specific 510(k) 3-‐6 M

•  Reduce Percutaneous Specific CE Mark Timeline 3-‐6 M •  Reduce Open General 510(k) 3-‐6 M

•  Reduce Open Specific 510(k) 6-‐12 M

•  Reduce Open Specific CE Mark Timeline 6-‐12M   Risks: •  FDA suspects off label use. •  Cannot use Percutaneous device as predicate. •  FDA thinking Open Specific is novel (PMA) •  No Hme savings in performing percutaneous specific CE Mark study if IDE pilot is to occur at same Hme. Increase cost of $1.2 M

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CONCLUSION

•  Regulatory Strategy may influence: -  where your product is marketed,

-  the types of data to be collected (bench, animal, clinical), -  the length/amount of data collecHon required, -  the cost of the overall development plan

•  Regulatory Strategy -  can be complex -  requires experienced device regulatory personnel -  should begin early -  allows for understanding of expectaHons and risks -  provides plan to proacHvely address risks early in development -  takes into account short and long-‐term corporate objecHves

-  aids in determining the fastest and/or greatest value path to market

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Thank You QuesHons?

Melissa Clark Principal Consultant

Halloran Consul1ng Group, Inc. 135 Beaver St., Suite 100, Waltham, MA 02452 P 781.209.5440 F 781.209.5444 M 203.906.4644

[email protected] www.hallorancg.com

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