Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)

Dr. Jack Snyder, RAC, DABT, CPI, CPE
CATO Research Washington

“Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)” and “FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs)” (issued Oct. 3, 2014)

On October 3, 2014, FDA issued draft guidance entitled “Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs).” If the guidance is finalized, laboratories seeking to maintain their ability to offer LDTs will be required to submit applications for premarket review as medical device manufacturers – a complex, time consuming and costly process.

FDA appears to be taking the position that the agency doesn’t have to go through full APA (Administrative Procedures Act) rulemaking procedure (including economic analysis) because FDA is not actually issuing a binding rule. Rather, FDA is asserting that the agency has always had regulatory authority over LDTs, and they’re just being transparent about when and how they’re going to exercise it. According to an FDA spokesperson, “We believe that LDTs serve an important role in health care and that there are many good tests on the market. Unfortunately, FDA is also aware of faulty or unproven LDTs, including problems with several high-risk LDTs . . . FDA is concerned that people could initiate unnecessary treatment, or delay or forego treatment altogether, for a health condition, which could result in illness or death.”

In its Federal Register notice, FDA said it expects approximately 650 laboratories will be required to provide notification about 17 LDTs each in the first year after guidance is finalized. In New York alone, 565 labs submitted 9,800 lab-developed tests for review under that state’s law in 2014. FDA also noted that the National Institutes of Health Genetic Test Registry includes about 7,600 tests that are not FDA-approved or -cleared. Assuming genetic tests represent roughly 70 to 80 percent of all LDTs, FDA estimated a total of 11,050 LDTs as the total annual response in the first year. By contrast, CMS says more than 11,000 CLIA-certified labs perform high-complexity testing, including LDTs, and some lab directors estimate that dozens of molecular markers are offered as LDTs by hundreds, if not thousands, of laboratories across the country, translating into potentially tens of thousands of premarket submissions to the FDA.

According to the draft guidance, when deciding whether to require premarket review for laboratory-developed tests, the FDA will consider:

  • Whether the test is intended for use in high-risk diseases, conditions, or patient populations
  • Whether it is used for screening or diagnosis
  • The nature of the clinical decision made based on the test result
  • Whether a clinician or pathologist would have information beyond the LDT result to help guide diagnosis or treatment
  • What alternative testing and treatment options would be available to the patient
  • The potential consequences of erroneous results
  • The number and types of adverse events associated with the LDT.
How oversight would change after FDA finalizes LDT guidance

How oversight would change after FDA finalizes LDT guidance

 

Proponents of enhanced FDA oversight of LDTs have advocated as follows:

  • FDA should review novel and/or high-risk tests, regardless of who develops them, as a critical step to help assure test accuracy and patient safety.
  • In contemporary oncology practice, a patient’s treatment options are increasingly driven by detection of molecular abnormalities in the tumor that drive treatment selection. LDTs used to detect those abnormalities must be of the highest quality and thoroughly validated before being offered to doctors and patients.

By contrast, expressions of concern (or opposition) from healthcare professionals and organizations (as reflected in publications from the College of American Pathologists and other organizations representing laboratory professionals) have included the following:

  • FDA may not have the statutory authority to regulate LDTs.
  • FDA seeks to convert almost all clinical laboratories into manufacturers.
  • Laboratories currently use a lot of FDA-approved kits but without following the standard operating instructions that come with those kits. Rather, the kits are modified to make them better.
  • If 510(k) submissions are required, the sponsor would have to state an LDT’s intended use. Frequently, however, an LDT’s intended use changes with time. As knowledge accrues, more intended uses arise. For many LDTs, it is hard to pre-specify the intended labeling and then never deviate from it.
  • A rulemaking (rather than guidance) process would require FDA to explain how FDA regulation of laboratories would be harmonized with current CLIA regulation of laboratories.
  • Risk-benefit balancing will vary significantly among the LDTs used for cancer (CA), infectious disease (ID), and genetic (GENE) testing.
  • Risks raised by most LDTs are dwarfed by the benefits to patient care.
  • Proposed oversight of LDTs may threaten innovation and impede patient access to existing high quality or state-of-the-art tests, especially in major medical centers that lack the financial and administrative resources for 510(k) or PMA (pre-market approval) submissions.
  • Many clinical laboratories will forsake LDTs and adopt commercial and/or reference testing, with rising costs, increased turnaround time, and increased investment in new instruments.
  • Clinical laboratories will lose the flexibility needed to make improvements to already approved or cleared tests, essentially freezing outdated tests in time.
  • FDA should convene experts to identify LDTs that have appropriate information that establishes safety and clinical validity.
  • Tests for transplant-related viruses should be moved from “high-risk” to “moderate risk” category.
  • “High-risk” LDTs should be compared to “high-risk approved devices” as predicates.
  • Clinical laboratories should not be precluded from testing patients being treated at a facility outside a laboratory’s healthcare system.
  • FDA should delay regulatory oversight of LDTs for unmet medical needs for at least 2 years and until at least 2 commercial tests are approved.
  • The need to test non-intended specimens represents an unmet need.
  • FDA should propose a simple regulatory mechanism to allow validation and unhindered access to databases other than FDA-approved options.
  • Proposed oversight of LDTs interferes with the practice of medicine, since board-certified professionals use emerging medical knowledge and patient care needs to continuously monitor every stage of the development, performance, and interpretation of LDTs.
  • Patient access to Laboratory Developed Procedures (LDPs) should not be impaired by implementing guidance or regulations that duplicate the role of CLIA, MDA, proficiency testing, accreditation, and other quality measures in routine use by clinical laboratories. LDPs have been defined as “professional services that encompass and integrate the design, development, validation, verification, and quality systems used in laboratory testing and interpretative reporting in the context of clinical care.”
  • “Devices” and “articles,” as defined in the Medical Device Act, may not be the same as, and may not encompass “clinical laboratory testing services.”

 

FDA held a public workshop on January 8-9, 2015 to discuss the agency’s draft guidance on LDTs. The workshop highlighted various areas of discussion, including: components of a test and LDT label considerations; clinical validity and intended use; categories for continued enforcement discretion; notification and adverse event reporting (MDRs); public process for classification and prioritization; and quality system regulation. Comments on the draft guidance were due to the agency by February 2, 2015.

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New FDA Guidances for February 2015

By Sheila R. Plant, Ph.D., R.A.C., Regulatory Scientist at Cato Research

FDA draft and final guidances, released from CDER, CBER, and CDRH in February 2015, are posted.  Two updates to the CDER Manual of Policies and Procedures (MAPP) are included.  In addition, upcoming advisory committee meetings to be held in the next couple months are listed below with links to more information.

Special Interest Guidances/Information Date Posted
Classifying Resubmissions of Original NDAs, BLAs, and Efficacy Supplements in Response to Action Letters – MAPP (CDER) 26 Feb 2015
Tertiary Review of Genetic Toxicology Studies Resulting in a Recommendation for a Clinical Hold or Conduct of Additional Studies – MAPP (CDER) 25 Feb 2015
Investigating and Reporting Adverse Reactions Related to Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Regulated Solely under Section 361 of the Public Health Service Act and 21 CFR Part 1271- Draft Guidance 19 Feb 2015
Guidance For Entities Considering Whether to Register As Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act – Draft Guidance 13 Feb 2015
Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities - Draft Guidance 13 Feb 2015
Adverse Event Reporting for Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act – Draft Guidance 13 Feb 2015
Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application – Draft Guidance 13 Feb 2015
Complicated Urinary Tract Infections: Developing Drugs for Treatment – Final Guidance 13 Feb 2015
Alcoholism: Developing Drugs for Treatment – Draft Guidance 11 Feb 2015
Complicated Intra-Abdominal Infections: Developing Drugs for Treatment – Final Guidance 09 Feb 2015
Brief Summary and Adequate Directions for Use: Disclosing Risk Information in Consumer-Directed Print Advertisements and Promotional Labeling for Human Prescription Drugs – Draft Guidance 06 Feb 2015
Individual Patient Expanded Access Applications: Form FDA 3926 – Draft Guidance 04 Feb 2015
Technical Performance Assessment of Digital Pathology Whole Slide Imaging Devices – Draft Guidance 25 Feb 2015
Premarket Studies of Implantable Minimally Invasive Glaucoma Surgical (MIGS) Devices – Draft Guidance 11 Feb 2015
Upcoming Meetings (* = New)
  Vaccines and Related Biological Products Advisory Committee Meeting; 04 Mar 2015; Silver Spring, MD
  Science Board to the FDA Meeting; 04 Mar 2015; Silver Spring, MD
  Dermatologic and Ophthalmic Drugs Advisory Committee Meeting; 9 Mar 2015; Silver Spring, MD
* Anesthetic and Analgesic Drug Products Advisory Committee Meeting; 18 Mar 2015; Gaithersburg, MD
* Joint Meeting of the Pulmonary-Allergy Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee Meeting; 19 Mar 2015; Gaithersburg, MD
* Neurological Devices Panel of the Medical Devices Advisory Committee Meeting; 17 Apr 2015; Silver Spring, MD
* April 29, 2015: Joint Meeting of the Cellular, Tissue and Gene Therapies Advisory Committee and Oncologic Drugs Advisory Committee Meeting Announcement; 29 Apr 2015; Silver Spring, MD

* new entry
Last updated: 1 March 2015

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Authoring for eCTD – Know the Requirements and Think Like a Reviewer

By Jessica Long, B.S., R.A.C., Regulatory Associate II/Submissions Specialist at Cato Research

“Before you judge a man, walk a mile in his shoes.” 
― Cherokee Proverb

Judgment has nothing to do with this post; seeing things through a different perspective has everything to do with it. There are many guidances on the content of granular electronic Common Technical Document (eCTD) sections, but many authors new to eCTD find it difficult to find guidance on best practices. When in doubt, put yourself in the shoes of a reviewer at the regulatory agency to which you are submitting and use that perspective to help structure documents that clearly present relevant information, as well as ensure intuitive future searches for data. Readers will find a U.S. slant to this post, as the bulk of my submissions are to the FDA, but the principles apply to nearly every other regulatory authority as well. A quick search will locate comparable regional guidances to the ones I have provided.

For the past several years, Refuse-To-File (RTF) decisions have been on the rise from FDA. The timelines provided in PDUFA legislation require that reviewers plow through mountains of data quickly in an effort to shorten the time to market for pharmaceuticals. Reviewers have the equivalent of tons of information thrown at them. In the old days of regulatory submissions, the volume of paper for a single New Drug Application (NDA) submission was enough to fill up four or more semi-trailers. In those days, reviewers spent a great deal of time checking things in and out of the document control room at FDA and shuffling through mounds of paper just to find needed material.

These days, the life of a reviewer is easier. Data arrives electronically and is always easily accessible in a reviewer’s computer. eCTD organizes data into higher level summaries supported by more detailed data. Reviewers can start with the summaries and navigate between documents using either the pre-defined eCTD structure or, in many cases, by the use of inter-document hyperlinks. With this in mind, what is the most effective way for authors to produce documents optimized for eCTD format?

I find myself often asking ‘What Would a Reviewer Want’ (WWRW) as I try to assist document authors with more complex issues that might not always have clear-cut answers. It never hurts to gain some fresh perspective.

 

Know the Specs

Take time to familiarize yourself with the current specifications for Portable Document Format (PDF). While most submission documents are PDFs, much of the requested format must be built into the Word version. Be sure to share these specifications with any vendors from which you might receive submission deliverables. For example, if you are using a nonclinical vendor, you’ll want to ensure the final study report received is submission-ready, per the specifications for PDF. Many publishers charge extra for remediation of documents and it can be difficult, if not impossible, to fully remediate PDF documents.

Create an Overall Table of Contents

When planning your submission, start by determining which documents are necessary and go ahead and map them out in the eCTD. Knowing what will be submitted and where it falls in the CTD is essential to cross-referencing between documents. Additionally, applications often have multiple authors to cover multiple disciplines. It is essential that all authors understand and are in agreement with what will be submitted. By now, most authors are familiar with the structure of the CTD, but there is a misconception that a document must be present in your application for every section in the CTD. This is not true. If a section of the CTD does not apply to your application, there is no need to submit a document stating that the section does not apply. Reviewers will note the absence of a document in that section and infer that there is no data for it. For FDA, refer to the Comprehensive Table of Contents (CTOC) guidance to organize necessary documents based upon their placement in the eCTD structure. This tool can also be used to assist with version control and can be handy as you track documents through review cycles.

Granularity

I often see companies who restructure their existing Investigational Medicinal Product Dossier (IMPD) into the various Module 3 sections. Occasionally, I am asked why we need more granular sections, when, in some sections, additional granularity is optional. First of all, when we speak of granularity in the eCTD context, what we’re really referring to is how we’re going to break information up into separate documents. Will we have an entire 3.2.P document? Or will we have many – 3.2.P.1.1, 3.2.P.1.2, etc. – all as individual documents? The advantages of working at a higher level of granularity (3.2.P.1.1 as opposed to 3.2.P) become apparent over the life cycle of the application, as new information becomes available and documents are amended. Section 3.2.P.8.1 is OFTEN amended, as new stability data is available all the time. Having a separate 3.2.P.8.1 document prevents you from having to resubmit all the data from other sections every time you have new stability information. It is important that all authors are familiar with the level of granularity being used so they understand how to cross-reference other sections.

Is too much of a good thing a bad thing? It can be when it comes to granularity. In Module 1, in particular, if you have attachments to meeting packages; it might be best to go ahead and merge them with the PDF for the package. In sections where the CTD does not provide a structure for additional granularity, multiple documents end up floating in the same section and will not always stay in the same order as other documents are updated over the life cycle of the application. Plan carefully and use your best judgment when submitting attachments separately from the document to which they belong.

Use Templates for Authoring

If your organization does not already utilize eCTD templates, consider investing in some. There are many templates available for use, along with industry-specific toolbars designed to make authoring easier. The use of templates is an excellent way to ensure consistency between document authors and can save time formatting the document for eCTD.

Use a Style Guide

The use of a style guide is another way to create consistency between authors. Style guides can address the use of abbreviations, how certain documents will be cited, fonts, headers and footers, style headings in Word, terminology, the citation of publications, etc. A corporate style guide that aligns with the format specifications of the regulatory agency(ies) to which you are submitting can be a useful tool in assessing a vendor’s ability to produce submission-ready documents.

Of Bookmarks and Word Styles…

On the left side of a PDF document, there is a bookmark section that should match the document Table of Contents. Generally, these bookmarks are generated through the use of styles and headings in Word. It is important to use styles consistently throughout your Word document to facilitate the generation of bookmarks from a PDF rendering tool. The Acrobat plug-in available for Microsoft Word 2010 allows you to select which styles and headings are used in the creation of bookmarks. Authors must be careful with any information cut and pasted into their document, as style information from external sources can be brought with it, creating inconsistency within a document.

To link or not to link?

This is the time I most recommend authors ask themselves WWRW? It might seem helpful to fill every paragraph with links so the reviewer can easily access the hard data your summary documents are citing. However, excessive hyperlinking can make a document more difficult to read. It also takes time to generate all those internal cross-references and can make the eCTD submission expensive to publish. Sometimes it is inevitable that the same piece of information might be cited multiple times on the same page. In those cases, an author might only link the first instance of the citation on each page.

In addition, it’s important to consider HOW you will cite something. Often times, we know exactly to what we might wish to refer, but if someone else will be responsible for creating hyperlinks in your document, the citation should make it clear to what the text should be linked. Be specific.

Also, understand that inter-document hyperlinks are just that; between PDF documents. It is not possible to link to an entire eCTD node. If, for example, Section 4.2.1.3 contains five studies, make sure you cite the individual study to which you wish the text to be linked. If you wish to refer to all five studies, list them out, one after another, so each study can be linked.

Whatever convention you decide to follow in making references, be consistent.

Lifecycle Management

Also important is to consider how the lifecycle of documents will be managed. This is a discussion that goes hand in hand with deciding how granular your documents should be. The argument for greater granularity is that in eCTD, when you update a section, the appropriate way to manage the lifecycle for that section is to ‘replace’ the previously submitted document with the updated one. This is performed using an operator attribute within the backbone of the submission. While there is an option to ‘append,’ FDA has stated they prefer this function is not used (it might be going the way of the dodo in publishing software before too long). What this means is that if you decide to go less granular and, for example, submit an entire 3.2.P section as opposed to breaking it up, every time you make an update, you’ll have to resubmit the entire 3.2.P document (even if you only changed 3.2.P.2.1). This becomes costly from a publishing perspective. Unfortunately, once granularity has been set within an application, it can be difficult, if not impossible to change.

Review, Review, Review!

In this industry, we’re used to checking things many, many times to ensure the quality. It is sometimes easy, however, to get so caught up in review of the content of these documents that we forget to have someone review for formatting and styles. Once the document has been rendered into a PDF for submission, any inconsistencies become very difficult to work around, so it’s always a good idea to leave the style/formatting check for after all content changes have been finalized. Then, of course, once the documents have been published for submission, it’s critical to check the individual submission files to make sure bookmarks and hyperlinks are functional.

In Summary…

There are a lot of things to remember when authoring for eCTD, but if you set your goals around making sure documents are well-organized, concise, and consistent, you’ll be off to a good start. From there, place yourself in the role of reviewer and ask yourself what you would want if you were required to read all this information.

Cato Research has extensive experience with regulatory filings. Please visit our website for a list of services.

 

 

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New FDA Guidances for January 2015

By Sheila R. Plant, Ph.D., R.A.C., Regulatory Scientist at Cato Research

FDA draft and final guidances, released from CDER, CBER, and CDRH in January 2015, are posted. In addition, upcoming advisory committee meetings to be held in the next couple months are listed below with links to more information.

Special Interest Guidances/Information Date Posted
Current Good Manufacturing Practice Requirements for Combination Products – Draft Guidance 27 Jan 2015
Medical Devices and Clinical Trial Design for the Treatment or Improvement in the Appearance of Fungally-Infected Nails – Draft Guidance 27 Jan 2015
S10 Photosafety Evaluation of Pharmaceuticals – Final Guidance 26 Jan 2015
Mitigating the Risk of Cross-Contamination from Valves and Accessories Used for Irrigation through Flexible Gastrointestinal Endoscopes – Draft Guidance 20 Jan 2015
General Wellness: Policy for Low Risk Devices – Draft Guidance 20 Jan 2015
Medical Device Accessories: Defining Accessories and Classification Pathway for New Accessory Types – Draft Guidance 20 Jan 2015
Evaluating Drug Effects on the Ability to Operate a Motor Vehicle – Draft Guidance 15 Jan 2015
User Fee Waivers, Reductions, and Refunds for Drug and Biological Products - Final Guidance 06 Jan 2015
Upcoming Meetings (* = New)
* Pharmacy Compounding Advisory Committee Meeting; 23-24 Feb 2015; Silver Spring, MD
* Joint Meeting of the Dermatologic and Ophthalmic Drugs Advisory Committee and Ophthalmic Devices Panel of the Medical Devices Advisory Committee Meeting; 24 Feb 2015; Silver Spring, MD
General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee Meeting; 27 Feb 2015; Silver Spring, MD
Vaccines and Related Biological Products Advisory Committee Meeting; 04 Mar 2015; Silver Spring, MD
* Science Board to the FDA Meeting; 4 Mar 2015; Silver Spring, MD
* Dermatologic and Ophthalmic Drugs Advisory Committee Meeting; 9 Mar 2015; Silver Spring, MD

* new entry
Last updated: 31 Jan 2015

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New FDA Guidances for December 2014

By Sheila R. Plant, Ph.D., R.A.C., Regulatory Scientist at Cato Research

FDA draft and final guidances, released from CDER, CBER, and CDRH in December 2014, are posted. In addition, upcoming advisory committee meetings and other public meetings hosted by FDA in 2015 are listed below with links to more information.

Special Interest Guidances/Information Date Posted
DSCSA Implementation: Product Tracing Requirements — Compliance Policy-Final Guidance 23 Dec 2014
Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) from Adipose Tissue: Regulatory Considerations-Draft Guidance 23 Dec 2014
Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products -Draft Guidance 22 Dec 2014
Providing Regulatory Submissions in Electronic Format — Submissions Under Section 745A(a) of the Federal Food, Drug, and Cosmetic Act- Draft Guidance 17 Dec 2014
Providing Submissions in Electronic Format — Standardized Study Data- Final Guidance 17 Dec 2014
Bacterial Detection Testing by Blood and Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion- Draft Guidance 12 Dec 2014
Patient Counseling Information Section of Labeling for Human Prescription Drug and Biological Products — Content and Format - Final Guidance 09 Dec 2014
General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products - Draft Guidance 08 Dec 2014
How to Obtain a Letter from FDA Stating that Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable REMS for RLD 04 Dec 2014
DSCSA Implementation: Annual Reporting by Prescription Drug Wholesale Distributors and Third-Party Logistics Providers- Draft Guidance 08 Dec 2014
Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products-Content and Format – Draft Guidance 03 Dec 2014
SUPAC: Manufacturing Equipment Addendum – Final Guidance 01 Dec 2014
Radiation Biodosimetry Devices- Draft Guidance 30 Dec 2014
Transfer of a Premarket Notification (510(k)) Clearance – Questions and Answers – Final Guidance 22 Dec 2014
Minimizing Risk for Children’s Toy Laser Products – Draft Guidance 19 Dec 2014
Establishing Safety and Compatibility of Passive Implants in the Magnetic Resonance (MR) Environment – Final Guidance 11 Dec 2014
Infusion Pumps Total Product Life Cycle – Final Guidance 02 Dec 2014
Recommendations for Labeling Medical Products to Inform Users that the Product or Product Container is not Made with Natural Rubber Latex – Final Guidance 02 Dec 2014
Upcoming Meetings (* = New)
Endocrinologic and Metabolic Drugs Advisory Committee Meeting; 12 Jan 2015; Hyattsville, MD
Anti-Infective Drugs Advisory Committee Meeting; 22 Jan 2015; Silver Spring, MD
* General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee Meeting; 27 Feb 2015; Silver Spring, MD
* Vaccines and Related Biological Products Advisory Committee Meeting; 04 Mar 2015; Silver Spring, MD

* new entry
Last updated: 10 Jan 2014

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