Dante's Informative Posts

...will be back in September 2010.

Enjoy the rest of a safe and sunny summer.

From the desk of Dante Resources, Inc.

Lixiviant Product Development and FDA Regulation

Lixiviants, the science, the biotechnology and intended use, are well-known to the industry. Lixiviant biotechnology dates back to the time of Egyptian slaves who used lixiviant-like ingredients and processes to clean clothes and preserve food. The word lixiviant comes from Latin - "lix" - lye. The process is based on basic science where adjusting "pH" of solutions releases insoluble materials from soluble. In 2010, several companies inquired about FDA testing requirements, preclinical and clinical trial guidance pertaining to lixiviant product development.

Lixiviants fall into a category that is FDA regulated through GRAS, "generally recognized as safe". All GRAS ingredients allow for safe use for food contact areas such as but not limited to counter tops, cooking utensils and food containers. This applies to all contact, tactile or ingested GRAS substance, detailed processes for the quality management and development leading to successful marketed products. GRAS is a list which provides safety guidance and recommendations, issued by FDA, pertaining to "how to use, the use of certain ingredients, compounds, chemicals and otherwise that preserve, protect, sustain food, clothes and surfaces". Lixiviant ingredients, found on GRAS, are "generally recognized as safe" by industry standards of testing, invitro and invivo. FDA emphasizes that although ingredients are suggested to be acceptable to the environment, vegetation, animals and humans, on touch or consumption, testing is recommended to determine and ensure safety and effectiveness.

Testing required, such as but not limited to:

• mutagenicity
• toxicology
• reproductive
• organ
• carcinogenicity
• otherwise.

FDA recommends testing, invitro and invivo, preclinical and clinical testing in tissue culture (mammalian cells), bacteria, animals, rodents to canine and human clinical trials to assess safety. It is recommended that although one formulation may test "ok" by safety standards, any change to the process, ingredient, sequence of ingredient addition, formulation, concentration, pH, new patent, new product, new intended use, must be re-tested to ensure safety and effectiveness. Similar to drug development CMC requirements.

It is essential for the consumer, the development company and the investor to ensure safety, product consistency, batch to batch, lot to lot, stability, shelf life, all constituents that apply to drug CMC development. All participants must consider consumer health, safety, risk and benefit. FDA with the Department of Labor, Public Health, Occupational Safety requires safety testing which must be addressed proactively when considering lixiviant-like products. Hazards may not be immediately apparent and thus must be researched in depth during development. As always, data results, preclinical testing and clinical trials must be conducted with FDA GCP. QC (quality control) of data and documentation must be accurate and consistent. Development, intended use must be in compliance with FDA and industry standards.

Development of Antibody-Based Therapeutics

The antibody-based therapeutic market continues to demonstrate an impressive growth and expansion within the pharmaceutical arena. Since 2000, the monoclonal antibody market has grown in the number of approved clinical submissions to FDA as well as expansion in therapeutic indication and focus. Currently the top therapeutic indications and market focus are oncology, autoimmune, infectious disease and AIID. Brand products or products in discovery and in clinical development or on the regulatory pathway to clinical submission are generated by large pharma in the past. Since 2000, more companies, large and small will be in the market and discovery modes involving therapeutic monoclonal antibody-based products.

The market forecast for antibody-based products will continue to rise between 2010-2011. AIID emerging discovery is gaining dominance over R&D oncology targets and treatments. The science is unique and discriminates itself from other therapeutic modalities such as devices, small and large molecules, synthetics, otherwise. Successful strategies for clinical development require integration of relevant knowledge pertaining to target antigen properties, antibody design, affinity, isotope selection, isolation, characterization, PK/PD properties, biophysical, biochemical characterization, cross-reactivity, sensitivity and specificity analyses. The first product in this class of therapeutics was approved by FDA in 1986, Muromonab-CD3, a T cell CD3 Receptor, for Transplant Rejection. Since the first approval by FDA, there are numerous approved products successfully marketed and demonstrating predicted "intended use" directives. The clinical development plan is generic, however specific to each product on its way from discovery to the clinic. R&D, characterization, preclinical, clinical, regulatory, submission, via PMA, 510(k) is the general path. Quality management plans and systems are essential and often reviewed first by FDA before substantive content is considered. Use quality control measures to ensure data and documentation accuracy and consistency, adhere to process, procedures and ensure regulatory compliance for success.

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.