IMDMC Regulatory 101 Pathways to Market PMA, HDE, De novo 510(k)

IMDMC Regulatory 101Pathways to MarketPMA, HDE, De novo 510(k) May 15, 2014

Pathways to Market • 21 CFR 814 Subpart B Premarket Approval Application (PMA) • 21 CFR 814 Subpart H Humanitarian Use Device (HUD) Humanitarian Device Exemption (HDE) • Section 513(f)(2) of the FD&C Act De Novo classification process

Premarket Approval Premarket approval by FDA is the required process of scientific review to ensure the safety and effectiveness of Class III devices.

Premarket Approval • Three regulatory classes for medical devices (I, II, III). • Class III is most highly regulated. • Definition of a Class III device: One that supports or sustains human life or is of substantial importance in preventing impairment of human health or presents a potential, unreasonable risk of illness or injury. Insufficient information exists on Class III devices for general controls (Class I) or performancestandards (Class II) to provide reasonable assurance of safety and effectiveness. A Premarket Approval Application (PMA) is required.

Premarket Approval 21 CFR 814.20 - Premarket Approval Application (PMA) Approval is based on a determination by FDA that the PMA contains sufficient valid scientific evidence to assure that the device is safe and effective for its intended use(s).

Premarket Approval Application (PMA) • Good science and clear scientific writing are the keys to the approval of PMA application. • A PMA should be scientifically sound and presented in a well organized format. In other words, tell a clear, coherent story.

Premarket Approval PMA Application Required Contents Well spelled out at the following website: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketApprovalPMA/ucm050289.htm Recommend creating a PMA template. Especially, if you expect to do more than one PMA in your, or your company’s, lifetime. A template to be used by the entire company (regulatory function) will help maintain consistency and prevent missing sections.

Premarket Approval Application (PMA) • What is valid scientific evidence and where do you get it? “The valid scientific evidence used to determine the effectiveness of a device shall consist principally of well-controlled investigations.” - 21 CFR 860.7(e)(2)

Premarket Approval Application (PMA) Where valid scientific evidencecomes from and where it is presented in a PMA: • Non-clinical Laboratory Studies • Biocompatibility Studies • Animal Studies • Clinical Studies

Premarket Approval Application (PMA) Where valid scientific evidencecomes from and where it is presented in a PMA:  • Non-clinical Laboratory Studies • Biocompatibility Studies • Animal Studies • Clinical Studies Done in IDE!

Premarket Approval Application (PMA) Concentrate on an excellent write-up of the clinical trial. It should include: • Summary of the study protocol • Primary effectiveness endpoint • Primary safety endpoint • Any secondary endpoints • Adverse events • Tabulation of data from all subjects • Results of statistical analyses

Premarket Approval Application (PMA) • Clear explanation of your valid scientific evidence will be paramount in getting approval. • Regarding statistical analyses… Statistics should illuminate, not compensate.

Premarket Approval Application (PMA) • Other sections are important and time consuming, but have good guidance documents.For example: • Quality System Information Quality System Information for Certain Premarket Application Reviews; Guidance for Industry and FDA Staff http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm070897.htm

Premarket Approval Application (PMA) Regulations give FDA 180 calendar days to review the PMA and make a determination (2012 Average: 297 days). In addition, it may be reviewed by FDA Advisory Committee at public meeting (Panel Meeting).

Premarket Approval Application (PMA) Modular PMA An Alternative… • Submit PMA “Shell” for approval Typically, a table describing the number of modules, contents of each module, timeline for submission of each module. For example: • Non-clinical Laboratory Studies • Biocompatibility Studies • Animal Studies …may comprise one module that is submitted early in the process.

Premarket Approval Application (PMA) The Modular PMA (continued) • Clinical trial section is usually last module. • PMA is given its “P” number and 180 day clock starts when final module is submitted. • Modules can be reviewed and “closed” before final module is submitted.

Premarket Approval Application (PMA) Questions?

Humanitarian Use Device (HUD) What is it?

Humanitarian Use Device (HUD) 21 CFR Subpart H - Humanitarian Use Devices Sec. 814.3 Definitions. (n) …a medical device intended to benefit patients in 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.

Humanitarian Use Device (HUD) Why is it?

Humanitarian Use Device (HUD) 21 CFR Subpart H - Humanitarian Use Devices Sec. 814.100 Purpose and scope. (a) This subpart H implements section 520(m) of the act. The purpose of section 520(m) is, to the extent consistent with the protection of the public health and safety and with ethical standards, to encourage the discovery and use of devices intended to benefit patients in the treatment or diagnosis of diseases or conditions that affect or are manifested in fewer than 4,000 individuals in the United States per year.

Humanitarian Use Device (HUD) Why is it?

Humanitarian Use Device (HUD) …to encourage the discovery and use of devices intended to benefit small populations of patients… A.K.A., Orphan Products

Humanitarian Device Exemption (HDE) So what is an HDE?

Humanitarian Device Exemption (HDE) 21 CFR Subpart H - Humanitarian Use Devices Sec. 814.3 Definitions. (m) HDE means a premarket approval application submitted pursuant to this subpart seeking a humanitarian device exemption from the effectiveness requirements of sections 514 and 515 of the act as authorized by section 520(m)(2) of the act.

Humanitarian Device Exemption (HDE) What does that mean?

Humanitarian Device Exemption (HDE) • Sort of a PMA Lite • An application seeking marketing approval for the HUD despite the absence of reasonable assurance of effectiveness that would otherwise be required. • That is, it is exempt from the effectiveness requirement of a PMA.

Humanitarian Device Exemption (HDE) • What’s the incentive for a company? • Good will – do the right thing for patients • No user fee for submitting HDE • *** Remember the PMA user fee is $258,520 *** • Can charge for the device… sort of…

Humanitarian Use Device (HUD) Allowable Charges The HDE holder is prohibited from making a profit, but is allowed to recover the cost of research, development, fabrication, and distribution. However, if the amount is more than $250/device… Need a report by independent CPA, or an attestation by a responsible individual of the organization (someone to throw in jail), verifying that the amount charged does not exceed the costs of research, development, fabrication, and distribution.

Humanitarian Use Device (HUD) The Exception: HDEs indicated for pediatric use and approved on or after September 27, 2007, may be sold for profit as long as the number of devices distributed in any calendar year does not exceed the annual distribution number (ADN) assigned by the FDA.

Obtaining Marketing Approval for a HUD • Step 1: Submit Request for Designation (RFD) • Obtain designation of the device as an HUD from FDA’s Office of Orphan Products Development (OOPD) • Step 2: Submit HDE • Submit an HDE to the appropriate FDA Center (CRDH, CBER)

Request for HUD Designation Required Content • Description of the rare disease or condition • Description of the proposed indication(s) • Reasons such therapy is needed • Description of the device • Scientific rationale for the use of the device • Documentation (with authoritative references) demonstrating the device is designed to treat or diagnose a disease that affects <4000 people per year in the U.S.

Humanitarian Device Exemption (HDE) • FDA will consider an HDE application if: • No comparable device is available to treat or diagnose the disease or condition • A comparable device is only available under another approved HDE • A comparable device is being studied under an approved Investigational Device Exemption

Humanitarian Device Exemption (HDE) FDA cannot grant an HDE for a HUD once a comparable device with the same indications for use is marketed through either the PMA process or the 510(k) process.

Humanitarian Device Exemption (HDE) • What does FDA consider a “comparable device”? • A “comparable device” need not be identical to the device submitted under the HDE application. • In determining whether a comparable device exists, FDA will consider: • the device's indications for use and technological characteristics • the patient population to be treated or diagnosed with the device • whether the device meets the needs of the identified patient population.

HDE Application • So you decide to go ahead and file an HDE application anyway… • What’s involved?

HDE Application Required Content Copy of the HUD designation by OOPD Explanation of why the device would not be available unless an HDE is granted and a statement that no comparable device is available (other than another approved HUD or device under IDE investigation) Discussion of risks/benefits of currently available devices or alternative forms of treatment

HDE Application Required Content – continued • 4) Include the following statement on labeling: • “Humanitarian Device. Authorized by Federal law for use in the [treatment or diagnosis] of [specify disease or condition]. The effectiveness of this device for this use has not been demonstrated” • Amount to be charged for the device • All information required in a PMA except: • An HDE application is not required to contain the results of scientifically valid clinical investigations demonstrating that the device is effective for its intended purpose.

HDE Application Summary An HDE application must contain sufficient information for FDA to determine that the device does not pose an unreasonable or significant risk of illness or injury, and that the probable benefit to health outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment.

Humanitarian Device Exemption (HDE) http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/HDEApprovals/ucm161827.htm • 58 HDEs approved since 1997 (3+/year) • Most recently: • H1100021 - Argus7II Retinal Prosthesis System • Second Sight Medical Products, Inc.February 2013 (1st in over 2 years) • H1100022 - Kaneka Liposorber7LA-15 System Kaneka Pharma America, LLC October 2013

Humanitarian Device Exemption (HDE) Questions?

De Novo classification process Still in flux… Confusing, but worth it?

De Novo classification process • Guidance issued Feb 19, 1998 New Section 513(f)(2) – Evaluation of Automatic Class III Designation • Draft Guidance issued Oct. 3, 2011 De Novo Classification Process (Evaluation of Automatic Class III Designation) • FDASIA – Signed into law July 9, 2012 • CDRH is currently working on a new draft de novoguidance document

De Novo classification process Originally the law required that if FDA found a new device to be “not substantially equivalent” (NSE) to a legally marketed predicate device it must be automatically put into Class III. - Not really sensible for low-to-moderate risk devices. The Concept: Develop a regulatory pathway to approve such novel low-to-moderate risk devices to be legally marketed.

De Novo classification process Thus, was born the De Novo classification process… The de novo petition should establish the risk profile of the new device, the benefits of device use, and provide data demonstrating that general and/or special controls support a classification of Class I or Class II.

De Novo classification process Original De Novo Petition Pathway • Submit a 510(k) • If information is not sufficient for FDA to complete review, FDA will ask for additional information • Supply enough information so FDA can complete review. • FDA must find your 510(k) NSE based on lack of a predicate device. • Now you can submit a De Novo petition (but must be submitted within 30 days of NSE finding) • Still need to supply sufficient information, FDA will ask • If FDA finds requirements for Class I or II are met, petition is granted. If not, you have a PMA path device.

De Novo classification process Improved De Novo Pathway from 10/3/11 Guidance • First submit a “Pre De Novo Submission” (PDS) The PDS should contain sufficient information to enable FDA to provide guidance on the test methods and protocols to be used for the collection of performance data. • May request a PDS Meeting • With luck, FDA finds device suitable for De Novo submission • Submit 510(k) and concurrent De Novo petition • FDA screens – Hopefully issues NSE and files De Novo • FDA reviews against requirements for Class I or II device. • If requirements met, De Novo petition is granted.

De Novo classification process What did FDASIA do to the De Novo process?

De Novo classification process FDASIA … included provisions to streamline the de novo classification pathway for novel devices of low-to-moderate risk. Sponsors of these devices may now submit a de novo request for classification without being required to first submit a 510(k) premarket notification to FDA and receiving a “not substantially equivalent” determination. FDA is using its authority under this new provision to review “direct” de novo petitions from sponsors... FDA has also implemented process improvements to increase the efficiency, transparency, and accountability of the Agency’s de novo review process. For example, we are encouraging utilization of the pre-submission process for sponsors to engage in active dialogue with FDA to further encourage efficiencies related to de novo review. - Nov. 15, 2013 Jeffry Shuren before the House Subcommittee on Health

De Novo classification process CDRH is working on a new draft de novo guidance, that when finalized, will represent the FDA’s current thinking on this topic. Until the new draft de novo guidance is published, please contact 510(k) Staff at 301-796-5640 for information regarding the de novo process.

IMDMC Regulatory 101 Pathways to Market PMA, HDE, De novo 510(k)