Humanitarian Device Exemption (HDE) Regulation - FDA 510(m)(2)

The long awaited final guidance, issued July 8, 2010 by CDRH/ODE, for HDE Holders, Institutional Review Boards (IRBs), Clinical Investigators and FDA Staff is now available to interested parties. The last updated draft was issued August 5, 2008 and a previous regulation was issued July 18, 2006. This document supersedes all others. The guidance provides application and clinical submission information pertaining to Humanitarian Device Exemption for Humanitarian Use Devices (HUDs) authorized by FDA 510(m)(2) and sets forth additional requirements for Pediatric Device Safety and Improvement.

An HDE is an application guided by 21 CFR 814.3(n), for medical devices for intended use that will benefit "in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4000 individuals in the US per year". The HDE is similar to the premarket (PMA) approval application, but does not require effectiveness requirements as described in the guidance. Medical HUDs cannot be sold for profit and only can be used for its intended use under the approved direction of an IRB, except in certain emergencies described in the guidance. The guidance provides distinction on when a HUD can be "used" vs "investigational use" / "clinical investigation".

FDA Considerations:

• FDA will approve or deny HDE applications 75 days from the date of receipt
• a 30 day filing period starting at the file date, will be used by FDA to determine "completeness"
• if the file is not complete, a RTF, a refusal to file will be issued and the file returned to the submitter
• if the file is incomplete and a RTF is issued with a request for additional information, the clock re-starts, the 75-day period is reset
• the review time for amendments, supplements and additional reports is 75 days
• HDE amendments, supplements and additional reports are subject to the same regulations as PMAs
• there are no user fees due FDA for the filing
• QRS regulation applies and is focused on manufacturing processes relevant to the safety of the device
• an exemption from QRS regulation may be requested and considered.

An HDE may be regulated by CDRH or CBER or both. The first step, when considering a clinical application or a clinical submission for HUD or HUD "Exemptions" is to determine which review division and center the file will be submitted. QC must be used to ensure fileability, completeness of components and to ensure quality of data and documentation, ensure previous submitted consistency in file content and regulatory compliance.

HUDs and HDEs are meaningful to patients who fall into a "special" small, treatable and/or diagnosed disease and/or emergent situation. These applications, as well can be used as strategic "planning" tools. contactus@danteresources.com or danteresources@yahoo.com

How to Manage and Prepare a 501(k) for Clinical Submission

In the last several months, a number of medical device product companies and manufacturers have contacted me with a similar question. The question pertains to approval in Europe, Australia, Japan, Canada and how that relates to a US approval, and secondly, what type of 510(k) to prepare in the US? Is there a fast track to approval in the US since they have device, detection and diagnostic non-US CE Marks of approval to market in non-US countries? There is much debate with IVDMIA status, STED Pilot Programs and LDT clinical submissions, which does not exist with Traditional, Abbreviated and Special 510(k) types of clinical submissions. The answer is to understand and assess where you are, where you want to go, and plan the most expeditious way to get there while conducting activities in accordance with FDA CDRH guidance and requirements. Assess the status of the device, this means to assess the status as it relates not only to guidance and regulatory requirements, but to assess the integrity and quality of data and documentation, statement, label, claim, completeness of application and submission, intended use, omission, missing data and documentation, translation, standard for development and quality review systems, compliance to the Federal Register and otherwise.

Each medical device product will be reviewed according to its intended use and if it relates to an unmet medical need or emergent or life threatening serious need, but beware, these applications are not easily regulated and approved and will be reviewed with regulatory rigor.

Yes, there are 3 types of PMA 510(k)s that may be submitted to FDA, Traditional, Special and Abbreviated. The Special and Abbreviated regulatory paths were developed under "The New 510(k) Paradigm" to help streamline the 510(k) review process at FDA. The Special 510(k) and Abbreviated 510(k) regulatory methods can only be used if certain criteria are met. The Traditional regulatory path can be used under any circumstances. Information required at the time of filing can be found in 21 CFR 807 Subpart E.

A 510(k) PMA Notification does not require a "form" to complete for submission. There is no form. The 510(k) concept is based on substantial equivalence (SE) to a legally marketed (predicate) device(s). All 510(k)s must provide a comparison between the device to be marketed and the predicate device or devices already marketed.

A most important consideration is the predicate device. A company must identify a predicate device as a component of their clinical submission. That predicate device will be used as a source comparison to your device at the time of clinical submission and regulatory review. The choice of the predicate device is crucial and I strongly recommend that the 501(k) number of the predicate device be identified in the clinical submission - be transparent, be clear, be open. Choose a device for your comparator, that is similar to your device. You may claim SE to more than one predicate. The predicate device of choice will and must be recently cleared and approved by FDA. There is additional guidance at http://www.fda.gov/ pertaining to "How to Find a Predicate Device".

Additional Steps to Aid in Management and Preparation:

• Locate Guidance Documents
• Locate Design Control Requirements 21 CFR 820.30
• Locate QS Regulation
• Locate Content and Format for the "Type" of clinical submission to be filed.

Components of a Traditional 510(k), for example:

• Form FDA 3601
• PRS Cover Sheet
• Form FDA 3674
• Cover Letter
• TOC
• Indications for Use
• 510(k) Summary 21 CFR 807.92 or 510(k) Statement 21 CFR 807.93
• Standards Data Report Form FDA 3654
• Truthful and Accuracy Statement 21 CFR 807.87(k)
• Class III Certification and Summary 21 CFR 807.94.

Items required under 21 CFR 807.87 required for a PMA Notification are numerous, please visit the Federal Register and create a checklist of submittable, required components as it pertains to each device to ensure complete submissions and to minimize potential RTFs - Refusal to File.

FDA CDRH 513(g) Medical Device Classification and Clinical Submission

The FDA CDRH 510(k) submission is the most common regulatory pathway to filing for most medical devices in the US. The 510(k) clinical submission is designed to demonstrate that a medical device product under clinical development is at least as safe and effective or substantially equivalent (SE) to a predicate device, already approved and legally marketed and follows safety surveillance. The information collected, compiled and presented in a 510(k) medical device clinical submission includes but is not limited to the following data and documentation:

• preclinical
• nonclinical
• clinical
• performance
• comparative
• supportive
• supplemental
• competitive
• predicate
• intended use
• QRS
• QA
• QC
• SOPs
• label
• inserts
• instructions for use
• brochure
• WIs
• QMP
• DMP
• CDP
• protocol, process, procedure
• safety
• efficacy
• previously submitted regulatory data and documentation US, non-US
• previously approved clinical submission US, non-US
• literature
• briefing documents
• CE Mark - Europe
• ROW and Country-Specific "Notified Body" Opinions
• IRB
• software, hardware, array, platform, otherwise
• other.

Within FDA/CDRH, 2 offices for medical device evaluation exist, the Office of Device Exemption (ODE) and the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD).

Under FD&C Act, Section 513(g), a sponsor, manufacturer, submitter or person may request a medical device classification for clarity and decision, when a question arises pertaining to a regulatory path to filing or simply "how to submit". The FDA guidance in such cases will evaluate and examine each medical device product case by case and come to a decision as a result of filing a 513(g) clinical submission.

Section 513(g) of the Act:

• "Within 60 days of the receipt of a written request of any person for the information respecting the class in which a device has been classified or the requirements to a device under this Act, the Secretary shall provide such person a written statement of the classification, if any, of such device and the requirements of this Act applicable to the device".

Section 513(g) Clarity and Classification Inquiries - to determine regulatory / clinical submission path:

• determine whether a medical device is subject to FDA regulations
• determine whether a medical device is exempt from the 510(k) requirements of the Act
• determine whether a 510(k) is needed for a modification to the respective device
• determine the regulatory path for the medical device.

Determination of medical device classification provides important decision making information for future manufacturers, investors, co-development partners, strategic alliances, strategic partners, marketing partners, and otherwise. This guidance provides valuable information pertaining to the appropriate and applicable standards of a successful clinical submission, regulatory timelines, development costs, resources, helps to estimate "realistic" time to submission, "realistic" time to market, regulatory strategy for successful, comprehensive, "real-time" product commercialization.

As always, ensure quality, accuracy, consistency of data, documentation, format, presentation, statement and previously submitted filings. Lead submissions, manage issues, QC, QC, QC, monitor, monitor, monitor CROs and all outsourced resources and contracts. Ensure on time quality, compliant and complete contracted deliverables. Go to http://www.danteresources.com/ for expert gate keeper clinical development and submission leadership, resources, teams, quality management and services. Visit our live interactive seminar/webinar page.

Differences in EU and US 510(k) Market Approval

Often asked by sponsor pharma and medical device manufacturers - is there a difference in clinical criteria and regulatory submission requirements? Differences in Class II and Class III medical device 510(k) regulatory clearance processes do exist. In particular is the process pertaining to issuance for a 510(k) medical device CE Mark. The EU CE Mark process requires medical device demonstration of safety only, and not efficacy and relies heavily on non-governmental opinion leaders or "Notified Bodies (NBs)" to regulate acceptance criteria, regulatory process, approval registration and post-approval post marketing surveillance for safety. In contrast, approval in the US of a new moderate to high risk Class II or Class III medical device requires demonstration of both safety and efficacy and is more regulated by a central governmental agency, CDRH/FDA. European Union Member Countries most often utilize CE review and approval from NBs, particularly because there is a huge savings in clinical development and clinical submission costs and thus time, with shorten timelines to registration and marketed medical device. Remember, EU approval is based only on data and documentation relating to safety and thus the NBs are often seen and chosen as a quick outlet to success and market CE approval. NBs can issue the CE Mark, they are independent, commercial organizations which implement regulatory control, monitor performance and safety of EU approved Class II or Class III medical devices.

NBs:

• review
• monitor
• audit
• critique medical device design
• assess safety
• verify quality systems
• review clinical submission data and documentation
• guide regulatory process
• approve medical devices
• issue CE Marks
• establish EU post marketing safety surveillance programs
• regulate country-specific requirements and governance.

A medical device sponsor or manufacturer is free to choose an NB within the European Union. Within the European Union, there are more than 50 active NBs to date currently reviewing CE applications and registrations.

In the US, a 510(k) application is submitted to CRDH/FDA. The medical device must be safe and efficacious. The 510(k) application typically requires prospective, randomized, controlled clinical trials. To receive clearance from CDRH/FDA, clinical trial results must demonstrate safety, performance and efficacy, significantly demonstrate acceptable intended use. Clinical trials supporting a Class II or Class III medical device 510(k):

• includes ~800 patients
• multi-center
• randomized
• controlled
• comparative.

A typical clinical trial including 800 patients with the above bulleted design criteria will cost the medical device sponsor or manufacturer 10M-20M, 24 months to perform, 6-8 months to prepare and submit depending on literature, references and supported by previously submitted "global" supplemental and supportive data from CE Marks, if applicable.

In the next post - more information on SE clearance from FDA/CDRH.

International Clinical Trial Site Inspections by FDA

A question often asked by pharmaceutical sponsors pertains to criteria for assigning inspections at foreign clinical trial sites - what triggers an onsite inspection by FDA CDER? International clinical trial sites will be audited if there is insufficient domestic data supporting a US clinical submission and non-US data becomes primary data and not supplemental or supportive for a drug marketing approval. Inspections are announced by FDA CDER when foreign clinical trial data is submitted for a US marketing application and inconsistencies in domestic and international clinical trial data and documentation are discovered on review. Inconsistencies between domestic and international data will trigger serious issues pertaining to unreported, under-reporting of AEs, data validity, data integrity and quality.

When conflicting data is identified by FDA CDER and when those results are pertinent to decision-making actions impacting resolve, FDA will arrive onsite, announced or unannounced. Refusal to file will be one action taken by FDA, other investigative actions involving suspicion of fraud, clinical, financial or otherwise, scientific misconduct, significant human subject protection violation - penalties, fees, loss of license, imprisonment, other enforcements will be swift and rigorous.

Facts:

• There is a rise is the number of foreign clinical investigators and clinical trial sites inspected in the last 6 years, with 2010 inspections already exceeding those published in 2009
• Clinical inspections by FDA CDER are highest in Europe, South/Central America and Africa, with Asia and the Pacific Rim second, while Eastern Europe was last.

In the last 2 years, non-US clinical site inspections by country:

• Canada 117
• U.K. 92
• Germany 54
• France 54
• Russia 36
• Italy 35
• Sweden 31
• South Africa 30
• Belgium 26
• Poland 22
• Netherlands 21
• Spain 16
• Argentina 16
• Finland 15
• Denmark 14
• Czechoslovakia 13
• Australia 11
• Brazil 11
• ROW country by country less than 10.

www.fda.gov provides lists of clinical investigators who have been disqualified, restricted or provided assurances.

FDA Regulation Regarding Acceptance for Foreign Data for US Marketing Approval

A pharmaceutical sponsor who relies on foreign data from a clinical study to support an Investigational New Drug (IND) application and clinical submission for US marketing approval must adhere to requirements cited in 21 CFR 312(b). The pharmaceutical sponsor must submit the following information to FDA:

• Description of clinical investigator's qualifications
• Description of clinical research facilities
• Description of clinical trial site
• Detailed summary of the clinical study protocol
• Finished, complete, ICH compliant final clinical study report (CSR)
• Patient Case Report Forms (CRFs) maintained by the clinical investigator at the clinical trial site - FDA will request CRFs, often there is a question as to whether a request by FDA will be made - prepare ahead of time - the compilation, collation, collection and submission of CRFs is time and labor intensive - the submitted file must be properly formatted, quality-controlled and quality-assured by qualified documentation experts
• Description of drug product and drug substance including components, formulation, specifications and bioavailability, CMC for starters
• If the clinical study is intended to support effectiveness and safety, the data and documentation must be collected, maintained and managed in accordance with 21 CFR 314.26 GCP.

Regarding Good Clinical Practice and foreign data, GCP must be followed to protect clinical study participants and ensure data and documentation integrity and quality. Final clinical study reports must be prepared in accordance with ICH GCP, including review and approval by an Independent Ethics Committee (IEC). FDA directs the review, inspection efforts and acceptance of foreign clinical study data for marketing approval under the Proposed Rule for Human Subject Protection published June 2004. The rule may be viewed at www.fda.gov/OHRMS/DOCKETS.

Under special consideration, FDA may consider foreign clinical study data to support a marketing approval on its own merit. The criteria for such a marketing application and clinical submission are cited in 21 CFR 314.106(b). Under 21 CFR 314.106(b), foreign clinical study data used to support a marketing application and clinical submission on its own merit must comply with the following requirements:

• Data and documentation are applicable and consistent with US medical practice and population demographics and statistical considerations
• Clinical investigators are qualified
• Data and documentation are of high quality
• Data and documentation are valid without FDA inspection
• Data and documentation are ICH compliant
• Data and documentation are collected under GCP
• Data and documentation are complete, quality-controlled and quality-assured
• Data and documentation are quality managed
• Data and documentation are collected by qualified clinical research associates (CRAs)
• Data and documentation are adequately monitored in accordance with GCP
• FDA may and will inspect the clinical trial site (facility) to ensure validity of data and documentation.

Clinical Submission Approval under FDA Section 505(b)(1)

A clinical submission filed under FDA Section 505(b)(1) is an NDA, is required to demonstrate clinical meaningful treatment benefits and statistically significant safety and efficacy objectives and endpoints, is a new chemical entity, with a new indication. The new investigational drug will be administered to the patient in a new formulation, with a new dosage form, new dose strength and is patented. The pharmaceutical company and/or manufacturer seeks market exclusivity for the NDA. Approval of the NDA under Section 505(b)(1), is granted by FDA only after an extensive Phase 1, 2, 3 clinical development program. When all 3 clinical phases are complete, the pharmaceutical company and/or manufacturer, submits an NDA including all results from all studies, nonclinical, preclinical, CMC, clinical, bioanalytical, pharmacologic and pharmacokinetic to FDA. The NDA is filed, reviewed for filing completeness and then sent to the appropriate division at FDA for review. The regulatory "clock" begins for the file.

An NDA is the culmination of 10-15 years of discovery, R&D, clinical development and by the time an NDA is approved by FDA, the pharmaceutical company and/or manufacturer, has invested numerous years and many millions for the approval. Post-marketing, post-approval is the next step and requires a 12 - 36 month commitment to monitor and assess new drug attributes such as risk, benefit, safety, effectiveness, SAE reports and otherwise. At the time of approval of an NDA, FDA grants a period and right of exclusivity to the submitter for the newly approved drug. The approved drug and patent(s) are protected for up to 20 years from the date of the first filing of the patent application.

Under the Hatch-Waxman Act, a new drug application and clinical submission process will fall into one of two categories depending on drug profile and background. The two categories are NDAs and ANDAs (Abbreviated) New Drug Applications. Under FDA Section 505(b), a new drug application and clinical submission is further divided into Sections 505(b)(1) and 505(b)(2). An ANDA is further delineated with respect to Bioequivalence requirements and is submitted as a 505(j) application and clinical submission. The 505(j) drug moiety is not a new chemical. Pharmaceutical companies and/or manufacturers filing under Section 505(j) must follow the "generic" approval process for drug application and clinical submission.

NDAs and ANDAs require QC and QA to ensure fileability, quality content, accurate, consistent data and documentation and a successful clinical and regulatory approvability outcome with FDA and otherwise. NDAs and ANDAs are submitted in a CTD (Common Technical Document) presentation and format. CTD content, completeness and format must be quality-controlled and quality-assured to ensure regulatory compliance and reviewer friendly dossier navigation. For expert clinical submission service and consultation contactus@danteresources.com, danteresources@yahoo.com.