Amid the partisan gridlock of the past few years, one of the few things Democrats and Republicans have agreed on is the need to reform FDA!  Accordingly, Congress has just passed, and the President has indicated he will sign, the 21st Century Cures Act (Cures Act) (H.R. 34).  The numbers were lopsidedly in favor of the bill (392-26 in the House and 94-5 in the Senate).  A copy of the final version that is expected to be signed by the President is available here.

The Cures Act has a host of provisions intended to improve how the FDA reviews and approves drugs and medical devices.  The following is a quick summary of the device related provisions:

Section 3051.  Breakthrough Devices.  This section requires FDA to establish a program to provide priority review and management attention for devices that provide “more effective treatment or diagnosis of life threatening or irreversibly debilitating human disease or conditions” and that represent “breakthrough” technologies for which no cleared or approved alternatives exist, that offer significant advantages over existing alternatives, or “the availability of which is in the best interest of patients.”

This section would allow a sponsor to request priority review designation from FDA at any time prior to the device submission.  FDA would be required to respond within 60 days of receiving the request for priority review designation.

This program will no doubt build on FDA’s already-established Expedited Access Pathway (EAP). Unlike the EAP program, the legislation opens priority review to device types subject to 510(k) clearance and not just PMA approval or de novo requests.

Section 3052.  Humanitarian Device Exemption. FDA’s existing HDE program allows approval of devices addressing rare diseases or conditions with relaxed effectiveness data (a showing of “probable benefit” rather than “effectiveness”).  The existing HDE program is limited to disease or conditions affecting up to 4,000 persons annually.  This provision doubles the ceiling to 8,000.

Section 3053.  Recognition of Standards.  This provision allows any party to obtain a ruling from FDA within 60 days on recognition of a standard, and requires FDA to make the ruling public in a manner deemed appropriate by FDA.  It also has some other modest improvements, such as periodic training of FDA employees in the use of standards in premarket review.

Section 3054.  Certain Class I and Class II Devices.  FDA will now be required in early 2017 and once every 5 years to review class I and class II devices and consider whether they may be declared 510(k) exempt with reasonable assurance of safety and effectiveness.  Instead of amending the classification regulations, which can take a long time, FDA will accomplish the exemption by publishing a list of newly exempted device types.  The class II exemptions will require a proposed list, public comment, followed by a final list.  Both the class I and class II lists will be deemed to amend the pertinent classification regulations.  This provision is an excellent house cleaning measure that will now allow FDA to more easily prune the list of device types that require 510(k) clearance.

Section 3055.  Classification Panels.  This section would require FDA to ensure that any classification panel has “adequate expertise” to assess “the disease or condition which the device is intended to cure, treat, mitigate, prevent, or diagnose,” and “the technology of the device.”  FDA must also provide an opportunity for the company whose product is being reviewed to provide recommendations on the expertise needed among the voting members of the panel.

“Adequate expertise” is defined to include “two or more voting members, with a specialty or other expertise clinically relevant to the device under review” and “at least one voting member who is knowledgeable about the technology of the device.”  FDA must provide an annual opportunity for patients, representatives of patients, and sponsors of medical device submissions to provide recommendations for individuals with appropriate expertise to fill voting member positions on classification panels.

This provision will hopefully fix past problems with panels that do not have the right expertise.

Section 3056.  Institutional Review Board Flexibility.  This provision allows for a single IRB to oversee a multicenter device trial (rather than an IRB at each center).  This additional flexibility should make IRB oversight more efficient.

Section 3057.  CLIA Waiver Improvements.  This provision takes aim at a section of FDA’s 2008 guidance on Clinical Laboratory Improvement Amendment (CLIA) waivers for in vitro diagnostic devices.  FDA has a year to revise the 2008 guidance to allow demonstration of accuracy through comparable performance between a waiver user and a moderately complex laboratory user.  This approach would replace the requirement to demonstrate accuracy based upon a gold standard.  This provision will make it easier for some IVD tests to be exempted from routine inspections and most CLIA requirements.

Section 3058.  Least Burdensome Device Review.  This section is intended to address the device industry’s long-held position that CDRH does not comply with the statutory requirement to review only the data necessary to make a determination of substantial equivalence or device effectiveness, and to determine the “least burdensome means” of establishing substantial equivalence or effectiveness.

Section 3058 would amend section 513 of the FD&C Act by requiring each reviewer at CDRH to receive training “regarding the meaning and implementation of the least burdensome requirements” and would require FDA to assess implementation of the least burdensome requirements to ensure that they are “fully and consistently applied.”

This section also requires the CDRH Ombudsman to conduct an audit of the required training with respect to implementing the least burdensome provisions, and to interview industry representatives to obtain their perspective regarding the application of the least burdensome provisions to “premarket review and decision making.”

This provision also adds section 515(c)(5) to the FD&C Act, stating that whenever FDA requests additional information from a PMA applicant, FDA “shall consider the least burdensome appropriate means necessary to demonstrate a reasonable assurance of device safety and effectiveness.”  “Necessary” is defined to mean “the minimum required information that would support a determination by [FDA] that an application provides a reasonable assurance of the safety and effectiveness of the device.”  FDA is also directed in PMA review to consider the “role of postmarket information in determining the least burdensome means of demonstrating a reasonable assurance of device safety and effectiveness.”

Section 3059.  Cleaning Instructions and Validation Data Requirement.  The recent crisis over disease transmission between patients due to inadequate cleaning of duodenoscopes led to this provision.  FDA had already upped its game in this area as a result of the duodenoscope situation, and this provision solidifies it.  Within 180 days of enactment of the Cures Act, FDA must publish (and revise when appropriate) a list of reusable device types where 510(k) submissions must include validated instructions for use and validation data for cleaning, disinfection and sterilization.

This provision also includes an unrelated requirement for FDA to finalize its draft August guidance (see our previous post here) on when a new 510(k) is required for modifications to a cleared device.  This guidance, of course, is of critical importance to the device industry.

Section 3060.  Clarifying Medical Software Regulation.  There has been a great deal of uncertainty about the degree to which FDA can and should regulate stand alone medical software.  This type of software is steadily increasing in importance and capability.  This provision modifies the definition of a “device” to remove a number of categories of software from FDA’s jurisdiction.  The categories of software removed from the device definition are:

1. Software that provides administrative support of a healthcare facility.  This is non-controversial and arguably was never subject to the device definition in the first place.
2. Software for maintaining or encouraging a healthy lifestyle, and not related to the diagnosis, cure, mitigation, prevention, or treatment of a disease or condition.   This is non-controversial and is consistent with FDA’s General Wellness and Mobile Medical Applications guidance documents.
3. Software that serves as electronic patient records, provided (among other things) that such function is not intended to interpret or analyze patient data or images for the diagnosis, cure, mitigation, prevention, or treatment of a disease or condition.  This codifies policy already implemented by FDA as a matter of enforcement discretion.
4. Software for transferring, storing, converting formats, or displaying data/results and associated findings by a healthcare professional (e.g., medical device data systems (MDDS)), unless intended to interpret or analyze the data, results or findings.  This codifies FDA’s exemption of MDDS technology from regulation.
5. Software for:  (i) displaying, analyzing, or printing medical information about a patient or other medical information (such as practice guidelines); (ii) supporting or providing recommendations to a healthcare professional (i.e., clinical decision support) about prevention, diagnosis or treatment of a disease or condition, AND (iii) enabling the health professional to independently review the basis for such recommendations rather than primarily rely on it when making diagnostic and treatment decisions.  There is an exclusion for medical images, signals from in vitro diagnostic devices and signals or patterns from signal acquisition systems, i.e., they are not part of this carve out from the definition of a medical device.

The last carve out from the device definition is important.  FDA has long regulated image analysis software and IVD technology and wanted to make sure they would continue to regulate these devices, which could arguably be said to provide clinical decision support.  This provision appears to give FDA continued jurisdiction in these areas.  But, importantly, this provision removes FDA from regulating evolving software that uses “big data” and advanced computing capability to provide sophisticated clinical decision support to health care professionals.

This provision has an escape hatch if FDA believes that software of the types described above in C, D, and E, “would be reasonably likely to have serious adverse health consequences.”  To bring this software back under FDA regulation, the agency must issue a final order in the Federal Register providing its rationale based upon the potential for and severity of patient harm if the software does not perform as intended, the extent to which the software is intended to support the judgment of a healthcare professional, whether a healthcare professional has a reasonable opportunity to review the basis of the information or treatment recommendation provided, and the intended user and use environment.

Finally, this section also provides that FDA shall regulate accessories based upon their intended use and not that of the parent device with which they are intended to be used.  This comports with FDA’s 2015 draft guidance on accessories.  FDA historically had taken the position accessories take on the classification of their parent devices.  This position has not worked very well when it comes to recent software products.

If you have questions or need more information, contact:

• Jeffrey K. Shapiro, jshapiro@hpm.com, 202-737-9633
• Jeffrey N. Gibbs, jgibbs@hpm.com, 202-737-4288
• Jennifer D. Newberger, jnewberger@hpm.com, 202-737-4292
• Allyson B. Mullen, amullen@hpm.com, 202-737-9639

There has been a spate of recent news articles about the potential use of the Congressional Review Act (CRA) to overturn final rules issued toward the end of the Obama Administration. That prompted us to see which of FDA’s recently issued final rules might be vulnerable.

By way of background, the CRA established a mechanism for Congress to disapprove a final rule issued by a federal agency. In relevant part, the CRA provides that a final rule submitted to Congress on or after the 60th day before adjournment is subject to review in the next session of Congress. A disapproval resolution requires a simple majority vote, but can be vetoed by the President; thus, as a practical matter, a disapproval resolution requires a supermajority vote for enactment. However, given the pending change in administrations, there is an opportunity for the next Congress to work with President-elect Trump to invalidate rules issued by the Obama administration in the last 60 days of this Congressional session. Because the 60 days are measured not as calendar days, but as days of session in the Senate and legislative days in the house, the Congressional Research Service (CRS) has estimated that final rules submitted to Congress after June 2, 2016 could be subject to disapproval under the CRA.

Below is a list of all FDA final rules issued between May 15 and last Friday, December 2. We opted to go back to May 15 because of uncertainty associated with CRS’s estimation of the date as of which disapproval might be an option. For the sake of clarity, we marked with an asterisk those rules issued between May 15 and June 2. Many of the rules are of interest mainly as an illustration of the many types of FDA actions that require rulemaking. However, some significant rules are potentially affected, such as the rule on safety and effectiveness of OTC topical antimicrobial drug products issued on September 6. Some significant rules – such as FDA’s nutrition labeling rule – were issued before June 2, but might not be entirely out of the woods given the softness of that date.

Food/Supplements:

• Uniform Compliance Date for Food Labeling Regulations
• 21 CFR Part 101 Food Labeling CFR Correction
• Indirect Food Additives: Paper and Paperboard Components
• Food Additives: Permitted in Feed and Drinking Water of Animals; Guanidinoacetic Acid
• Food Additives: Permitted in Feed and Drinking Water of Animals; Feed Grade Sodium Formate
• Indirect Food Additives: Adhesives and Components of Coatings
• Current Good Manufacturing Practice, Hazard Analysis, and Risk-Based Preventive Controls for Human Food and Current Good Manufacturing Practice, Hazard Analysis, and Risk-Based Preventive Controls for Food for Animals; Definition of Qualified Auditor; Announcement of Effective Date
• Food Labeling: Technical Amendments
• The Food and Drug Administration Food Safety Modernization Act; Extension and Clarification of Compliance Dates for Certain Provisions of Four Implementing Rules
• Food Labeling; Calorie Labeling of Articles of Food in Vending Machines; Extension of Compliance Date
• Emergency Permit Control Regulations; Technical Amendments
• Food Additives Permitted for Direct Addition to Food for Human Consumption: Vitamin D2 and Vitamin D3
• Amendments to Registration of Food Facilities
• Food Additives Permitted in Feed and Drinking Water of Animals; Chromium Propionate; Extension of the Comment Period
• Food Additives Permitted in Feed and Drinking Water of Animals; Chromium Propionate
• Substances Generally Recognized as Safe
• Substances Generally Recognized as Safe – Correction
• *Food Labeling: Revision of the Nutrition and Supplement Facts Labels
• *Mitigation Strategies to Protect Food Against Intentional Adulteration
• *Food Labeling: Serving Sizes of Foods that Can Reasonably Be Consumed at One Eating Occasion; Dual-Column Labeling; Updating, Modifying, and Establishing Certain Reference Amounts Customarily Consumed; Serving Size for Breath Mints; and Technical Amendments

Drugs/Biologics:

• Use of Ozone-Depleting Substances
• New Animal Drugs for Use in Animal Feed; Category Definitions; Confirmation of Effective Date
• Food and Drug Administration Review and Action on Over-the-Counter Time and Extent Applications
• Additions and Modifications to the List of Drug Products That Have Been Withdrawn or Removed From the Market for Reasons of Safety or Effectiveness
• Abbreviated New Drug Applications and 505(b)(2) Applications
• New Animal Drugs: Approval of New Animal Drug Applications; Change of Sponsor’s Address
• New Animal Drugs for Use in Animal Feeds: Chlortetracycline and Sulfamethazine; Chlortetracycline, Procaine Penicillin, and Sulfamethazine
• Safety and Effectiveness of Consumer Antiseptics: Topical Antimicrobial Drug Products for Over-the-Counter Human Use
• Requirements for Foreign and Domestic Establishment Registration and Listing for Human Drugs, Including Drugs That are Regulated Under a Biologics License Application, and Animal Drugs
• New Animal Drugs for Use in Animal Feed; Withdrawal of Approval of a New Animal Drug Application
• New Animal Drugs; Approval of New Animal Drug Applications; Withdrawal of Approval of New Animal Drug Applications; Changes of Sponsorship; Change of Sponsor’s Name and Address; Change of Sponsor’s Address
• New Animal Drugs for Use in Animal Feed; Category Definitions
• New Animal Drug Applications; Contents of Notice of Opportunity for a Hearing; Correction
• Standard Preparations, Limits of Potency, and Dating Period Limitations for Biological Products; Confirmation of Effective Date
• New Animal Drugs: Change of Sponsor
• Removal of Review and Reclassification Procedures for Biological Products Licensed Prior to July 1, 1972; Technical Amendment
• New Animal Drugs; Withdrawal of Approval of a New Animal Drug Application
• New Animal Drugs: Approval of New Animal Drug Applications; Withdrawal of Approval of New Animal Drug Applications; Changes of Sponsorship
• Revisions to Exceptions Applicable to Certain Human Cells, Tissues, and Cellular and Tissue-Based Products

Medical Devices:

• Listing of Color Additives Exempt from Certification; Titanium Dioxide and Listing of Color Additives Subject to Certification; [Phthalocyaninato (2-)] Copper
• Medical Gas Containers and Closures; Current Good Manufacturing Practice Requirements
• Medical Devices: Ear, Nose, and Throat Devices; Classification of the Eustachian Tube Balloon Dilation System
• Medical Devices: Physical Medicine Devices; Classification of the Upper Extremity Prosthesis Including a Simultaneously Powered Elbow and/or Shoulder With Greater Than Two Simultaneous Powered Degrees of Freedom and Controlled by Non-Implanted Electrical Components
• Medical Devices; Cardiovascular Devices; Classification of the Apical Closure Device
• Medical Devices: Custom Devices; Technical Amendment
• Medical Devices; Exemption From Premarket Notification: Method, Metallic Reduction, Glucose (Urinary, Nonquantitative) Test System in a Reagent Tablet Format
• Medical Devices: Neurological Devices; Classification of the Evoked Photon Image Capture Device
• Medical Devices; Ophthalmic Devices; Classification of Strabismus Detection Device
• Medical Devices: General and Plastic Surgery Devices; Classification of Magnetic Surgical Instrument System
• Regulatory Hearing Before the Food and Drug Administration; General Provisions; Technical Amendment
• Physical Medicine Devices; Reclassification of Iontophoresis Device Intended for Any Other Purposes
• Medical Devices: Gastroenterology-Urology Devices; Classification of the Metallic Biliary Stent System for Benign Strictures
• Medical Devices; Neurological Devices; Classification of the Thermal System for Insomnia
• Medical Devices: General and Plastic Surgery Devices; Classification of the Electrosurgical Device for Over-the-Counter Aesthetic Use
• Medical Devices; Obstetrical and Gynecological Devices; Classification of the Gynecologic Laparoscopic Power Morcellation Containment System
• Use of Symbols in Labeling
• Medical Devices: Ophthalmic Devices; Classification of Nasolacrimal Compression Device
• *Medical Devices: Ophthalmic Devices; Classification of the Diurnal Pattern Recorder System
• *Cardiovascular Devices: Reclassification of External Cardiac Compressor; Reclassification of Cardiopulmonary Resuscitation Aids

Tobacco:

• Refuse to Accept Procedures for Premarket Tobacco Product Submissions; Withdrawal
• Refuse to Accept Procedures for Premarket Tobacco Product Submissions

Other:

• Amendments to Regulations on Citizen Petitions, Petitions for Stay of Action, and Submission of Documents to Dockets
• Submission of Food and Drug Administration Import Data in the Automated Commercial Environment
• Revision of Organization and Conforming Changes to Regulation
• Maximum Civil Money Penalty Amounts; Technical Amendment
• Change of Address; Technical Amendment
• Administrative Actions for Noncompliance; Lesser Administrative Actions; Confirmation of Effective Date
• Advisory Committee; Transmissible Spongiform Encephalopathies Advisory Committee; Termination

Most of our readers come to the blog to read posts that are well-researched, provide thoughtful analysis, and often practical advice. This is not that post.   This is a post that will be filled with rank speculation, perhaps a little wishful thinking, and a soupçon of advice. The latter may be food for thought; the former almost certainly will not be.

Many writers and analysts who are far more thoughtful and in the loop than this blogger have spilled ink on what will happen to FDA. Will the Trump Administration retain the commissioner and Chief Counsel or will they be replaced?  Will there be dramatic changes or only changes at the margin? Those issues are beyond my ken and beyond the scope of this blogpost. Rather, we will spend a few minutes and a few ones and zeroes across the interwebz to focus in on promotional activities, that is, free speech.

Your faithful blogger can claim no special knowledge or access other than hallway conversations with colleagues and a Twitter feed that is replete with all sides of the spectrum (other than Pepe the frog.  My Twitter feed is a frog-free zone.) And thus, we descend into speculation.

Here’s what we know – when Republican administrations take over from Democrat administrations, there tends to be some relaxation of enforcement taken against industry for promotional activities. In an N=1 situation, for example, when the Bush administration took over from the Clinton administration, the warning letter process was centralized in the hands of the Chief Counsel of FDA, who was, at the time, one of the foremost proponents of the First Amendment protections for industry sponsored speech.  This resulted in a dramatic decrease in the number of warning letters related to promotional activities. We apologize for our N=1 exercise, but your loyal blogger was still in knee pants when President Reagan took over from President Carter – the next most recent such event. Moreover, this is a relatively risk-free area for deregulators to play in – it doesn’t carry the same dangers as say product safety.

But what does that mean in the context of a Donald Trump presidency? As avid followers of such issues know, the First Amendment is already ascending.  Indeed, our friends at FDA have issued only five promotional enforcement letters for pharmaceutical products in 2016 to date, which is a sharp dropoff from years past, and many of them are not the typical letters of days of yore, but are much more circumscribed to speech that is arguably not protected by the First Amendment.

But will the typical progression from a Democratic administration to a GOP one hold true in this instance where Candidate and now President-Elect Trump has made numerous comments on the campaign trail suggesting his view that the First Amendment might not be as fixed in the firmament as it has been in the past. Granted, his targets have been the press and flagburning, neither of which are politically popular, but nevertheless, it gives one pause to think about how aggressive an FDA under President Trump might expand the First Amendment protections given to industry.

Another related area is social media. @realDonaldTrump is an inveterate Twitterer and an avid Facebook user as well. As this blogger has frequently complained, FDA has only barely dipped their toes into the issue of social media.  One area of interest that remains in flux is the ability to use Twitter and other space limited platforms where it may be necessary to communicate safety information. Would a tweet @realDonaldTrump help convince the President-Elect that the time has come for allowing companies with therapeutic products to use Twitter to engage with other users? (We will, of course be tweeting this blogpost to try to catch his attention.) Will tweeting @mike_pence help? Anyone from Eli Lilly (@LillyPad) or other Indiana-based companies want to pass this along to their governor/Vice President-Elect? (Yes, we are attention seekers.)

Ok, enough with the speculation. Here’s the practical bit of advice (not legal advice, this is just a blogpost). Stay the course for now. The First Amendment is already front and center at the Agency. They just held a public meeting about off label information in which the presenters appeared to be evenly divided between those who favored more speech and those who didn’t (see our previous post here).  FDA will have a difficult time threading that needle without offending the courts who seem inclined to permit truthful and not misleading speech.   If you have data that can be presented in a truthful and not misleading manner, it seems that that will not readily draw a letter from FDA. Note, however, that if there is even a whiff of fraud or a kickback or some other hook, that the protected speech aspect may not be enough to protect the entirety of the challenged conduct.

In short, we are not predicting that the floodgates can open and all speech will be unchallenged. This is in part because FDA has already reined itself in to some extent in light of the court challenges. Thus the transition from the Clinton to Bush administrations may not be an apposite example. So proceed as before, but continue to proceed with caution. (In terms of predictions, I also predicted that the New York Jets would take their division, so definitely proceed with caution.)

How about social media? I suppose it depends on how much risk a company is willing to take. FDA has stated:

Regardless of character space constraints that may be present on certain Internet/social media platforms, if a firm chooses to make a product benefit claim, the firm should also incorporate risk information within the same character-space-limited communication. The firm should also provide a mechanism to allow direct access to a more complete discussion of the risks associated with its product.

It would be hard to back off of that without a lot of internal effort. But it will be interesting to see if companies are willing to test this, perhaps by tweeting and including a tinyurl to risk information rather than including it directly.

We appreciate you sticking through to the end of our meanderings and will now return you to our regularly scheduled program of thoughtful analysis and informative blogposts.

Last month, FDA announced the publication of a revised version of the Draft Quality Metrics Guidance that it had published back in July of 2015. We had blogged about the original Draft Guidance at that time (see prior posting here).  Below we provide a brief summary of the some of the more noteworthy changes.

Overall, the document has been substantially revised. That said, the agency’s stated objectives for the quality metrics program have remained pretty consistent, though perhaps they are explained in greater detail in the revised Draft Guidance, namely:

1/ establishing a signal detection program as one factor in identifying establishments and products that may pose significant risk to consumers;

2/ identifying situations in which there may be a risk for drug supply disruptions;

3/ improving the effectiveness of establishment inspections;

4/ improving FDA’s evaluation of drug manufacturing and control operations; and

5/ identifying potential shortage signals and engaging with manufacturers to mitigate the likelihood of their occurrence.

Intriguingly, the Notice of Availability (NOA) for the revised Draft Guidance states that:

After evaluating the results of the voluntary phase of the quality metrics program in 2018, FDA intends to initiate notice and comment rulemaking under existing statutory authority to develop a mandatory quality metrics reporting program.

So it appears that the agency has changed course as, to the best of our knowledge, it had not previously stated its intent to utilize notice and comment rulemaking to implement this program. The program was supposed to be implemented simply upon the finalization of the Quality Metrics Guidance.  This also explains why the Legal Authority section of the document has been removed.

One has to wonder whether the agency’s confidence in its legal authority for this program (i.e., the combination of sections 706 and 711 of FDASIA) has waned somewhat since the initial publication of the original Draft Guidance in July of 2015. After all, the right to request “…any records or other information that the Secretary may inspect under [Section 704 FDCA]…,” together with a firm’s responsibility for “…oversight and controls over the manufacture of drugs to ensure quality [Section 501 FDCA]…” do not necessarily constitute legal authorization to demand that regulated industry create new records in order to satisfy the agency’s curiosity that a firm’s manufacturing process is in a state of control.  Far from it.

Perhaps with an eye to eliminating that legal line of attack, FDA added the following in the revised Draft Guidance section entitled “Quality Metrics that FDA Intends to Calculate:”

FDA used the following selection criteria in developing the set of data that it is inviting covered establishments to submit: (1) objective data to provide consistency in reporting; (2) of the type contained in records subject to inspection under section 704 FDCA; and (3) a valuable component in assessing the overall effectiveness of a pharmaceutical quality system. [Emphasis added]

No doubt the decision to engage in notice and comment rulemaking will strengthen the agency’s hand should industry decide to contest the FDA’s statutory authority to require such quality metrics, as courts generally offer more deference to an agency’s statutory interpretations when they are backed up by an administrative record, and after the agency has sought formal public input.

What is unclear is whether the agency changed course in favor of notice and comment rulemaking before, or after, the November 8^th Presidential election.  While engaging in notice and comment rulemaking strengthens the agency’s hand in the event of litigation, President-Elect Trump has often emphasized his aversion to “excessive regulation.”  For the record, we do not know whether the President-Elect would consider this program to constitute excessive regulation – however that would need to be an agency consideration at this point.

So, by engaging in rulemaking, the agency is likely reducing the probability that the quality metrics reporting program will be dismantled by a court; however, this formal elevation of the program through the rulemaking process also likely increases the probability that it will be placed on the chopping block by the incoming administration.

Back to the changes brought about by this revised Draft Guidance. The document explains that FDA is initiating a ‘voluntary reporting phase’ of the quality metrics reporting program, whereby FDA expects to learn more about a limited set of quality metrics, associated analytics, and to generally improve the FDA quality metrics reporting program.  During this voluntary phase, FDA will accept submissions of data from owners and operators of human drug establishments.  The revised Draft Guidance describes two types of quality metric data reports that can be submitted: product reports and site reports.

The document goes on to add that FDA may not be able to accomplish the overall goals of an FDA quality metrics reporting program (i.e., the five objectives summarized above) from voluntary reporting alone. For example, if, during the voluntary reporting phase, FDA does not receive a large body of data from the establishments that fall within the ambit of the program, the utility of the data obtained will be limited.  Hence, the expectation is that, during the voluntary reporting phase, the information collected will be primarily used for the more narrow purposes of:

1/ working with establishments towards early resolution of potential quality problems and to reduce the likelihood of a disruption in supply (i.e., no signal detection program per se and no commitment to be able to broadly identify situations in which there may be a risk for supply disruptions);

2/ helping to prepare for, and direct, FDA inspections; and

3/ using the calculated metrics as an element of the post-approval manufacturing change reporting program.

The revised Draft Guidance adds that FDA intends to accept reports with quality metrics data that are “inconsistent with the metrics and definitions” in the document, as well as reports about establishments and products that are not the focus of the voluntary reporting phase of the quality metrics program, with the caveat that the agency does not intend to include these inconsistent reports on the quality metrics reporters list (see explanation below), and may not be able to integrate the submission of the report into FDA’s risk-based inspection model.

Furthermore, FDA intends to publish a list of the names of establishments that voluntarily report all, or a subset of, the quality data described in this guidance (i.e., both product reporting establishments and site reporting establishments). FDA believes that there is a public benefit to sharing this information because, through their participation, establishments demonstrate a willingness to proactively engage with the agency in pursuit of the agency’s goals.  Also, participation contributes to improving quality monitoring.  FDA also suggests that such public information might be useful to pharma when selecting contract manufacturers and component suppliers, and the information could also be helpful to healthcare purchasing organizations, healthcare providers, patients and consumers in sourcing drugs.

In the revised Draft Guidance, FDA has reduced the scope of the quality metrics program from the four proposed metrics in the July 2015 Draft Guidance (i.e., lot acceptance rate, product quality complaint rate, invalidated out-of-specification rate, and product quality review on time rate), down to three proposed metrics. It thus proposes to eliminate the product quality review on time rate, which wasn’t likely to provide much useful information to the agency to begin with.  FDA has also removed the three optional metrics from the prior draft, including CAPA effectiveness and the percentage of corrective actions that involve retraining of personnel.

Also, now explicitly included within the ambit of the quality metrics program are both non-recombinant and recombinant versions of plasma derived products, as well as transgenic versions of same, and explicitly excluded from the program are in vitro diagnostics and all biological products that meet the definition of a device under section 201(h) FDCA.

The NOA states that FDA anticipates that the electronic submission platform will be available to test in 2017, and that FDA expects to ‘encourage’ reporting establishments to submit quality metrics data reports where the data is segmented on a quarterly basis throughout a single calendar year. The agency intends to open the electronic portal in January 2018 to receive these submissions of data.

Also new, reporting establishments will be able to submit 300 word text comments to provide an explanation of submitted data, and in order to report improvement plans. The NOA states that FDA may refer to the comments if unusual data or trends are identified, or as preparation for an onsite inspection.

The NOA also states that, in the context of the voluntary reporting phase, FDA is proposing a common timeframe to facilitate publication of the quality metrics reporters list, particularly given the need to identify duplicate data if both the product reporting establishment and the site reporting establishment (for the same product) submit data. FDA had considered supporting flexible data collection timeframes for the purposes of reporting, but the agency concluded that such flexible timeframes would only be feasible in the context of a program that mandated product-based reporting (i.e., under the current scenario, subsequent to the notice and comment rulemaking).

In conclusion, the modifications made to the revised Draft Guidance are substantial (indeed, even the name of the document was changed). It will be interesting to see whether the quality metrics reporting program, a cornerstone of FDA’s framework for building quality into drug products, advances as planned.  The path for the program over the next few years is perilous, whether the agency seeks to finalize it via notice and comment rulemaking or simply via guidance.

On December 1, 2016, FSIS announced its proposal to amend the nutrition labeling regulations for meat and poultry.  The proposed regulations contain few surprises and appear to be identical to FDA’s regulations. In addition, FSIS proposes to remove minor existing differences, such as the option to label stearic acid (according to FSIS, companies rarely would choose to include stearic acid as a nutrient). Although FDA has since 2003 required the declaration of trans fat in nutrition labeling for FDA-regulated food, declaration of trans fat for meat and poultry has been voluntary. Now that it is revising the regulation, FSIS proposes to make trans fat mandatory. The alignment of FSIS requirements with FDA requirements is intended to create uniformity and should help prevent consumer confusion.

As FSIS has done when amending other regulations concerning poultry and meat, the Agency proposes to consolidate the regulations for meat and poultry and move them to a new section, 9 C.F.R. Part 413.

FSIS discusses various alternatives for compliance dates and appears to prefer alternative 2, which would provide all but small businesses two years after the issuance of the final rule to amend their label. Of course, since the FSIS proposal was published more than 6 months after FDA published its final rule, this compliance date would result in a significant period of inconsistency between nutrition labeling of meat and poultry products and nutrition labeling of FDA-regulated products. However, this may be mitigated somewhat by FSIS’s decision to allow use of the FDA Nutrition Facts format on meat and poultry products while FSIS is working on the amended regulations.

Comments to the FSIS proposal must be submitted within 60 days of the publication date.

By Kurt R. Karst –

Wikipedia (oh that font of knowledge and easy reference that it is for us bloggers) describes schizophrenia as a mental disorder characterized by, among other things, “failure to understand what is real.”  That pretty much sums up FDA’s impressions of a September 2016 Citizen Petition (Docket No. FDA-2016-P-2654) submitted by Vanda Pharmaceuticals Inc. (“Vanda”) requesting that the Agency refuse to approve any ANDA referencing Vanda’s FANAPT Tablets, 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg, until the expiration of a period of 3-year exclusivity on May 26, 2019 stemming from a May 26, 2016 approval of FANAPT under a supplemental NDA (S-015) for maintenance treatment of schizophrenia. FDA initially approved FANAPT on May 6, 2009 under NDA 022192 for the acute treatment of schizophrenia in adults, and then later removed the word “acute” to make FANAPT’s labeling more consistent with other similar drug products. FDA, in the Agency’s November 28, 2016 Denial Response to Vanda once again discusses the metes and bounds of 3-year exclusivity, but in a rather interesting context. We should also note that on the same day the petition response was handed down, FDA approved Inventia Healthcare Private Limited’s ANDA 207231 for Iloperidone Tablets, 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg. 

As noted above, Vanda’s Citizen Petition is the result of FDA’s May 26, 2016 approval of a supplemental NDA for maintenance treatment of schizophrenia, which supplement contained the results of a clinical study known as “REPRIEVE.” The REPRIEVE study demonstrated that FANAPT “is more effective than a placebo in preventing or delaying relapse when administered for longer than six weeks,” according to Vanda, and “provided valuable new information about the use of Fanapt for treating schizophrenia.”  Because the REPRIEVE supplemental NDA met the requirements for 3-year exclusivity, FDA granted it.  The exclusivity is coded in the Orange Book as “M-180,” which is defined in an addendum to the publication to mean “INFORMATION ADDED TO THE LABELING REGARDING THE ADDITION OF MAINTENANCE TREATMENT IN PATIENTS WITH SCHIZOPHRENIA.”

With the approval of S-015, FDA added information to the labeling of FANAPT concerning maintenance treatment. But other labeling information was removed.  Specifically, the following information in Section 1 (Indications and Usage) and Section 2.3 (Dosage and Administration; Maintenance Treatment) was removed from labeling:

The effectiveness of FANAPT in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use FANAPT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.3)]. 

Although there is no body of evidence available to answer the question of how long the patient treated with FANAPT should be maintained, it is generally recommended that responding patients be continued beyond the acute response. Patients should be periodically reassessed to determine the need for maintenance treatment.

According to FDA, “[t]his language was deleted to make labeling more accurate, given the addition of information about the REPRIEVE study and maintenance treatment, and consistent with FDA’s approach to schizophrenia treatments in general.” Vanda, however, saw things differently, and argued that FDA’s grant of 3-year exclusivity should be a total bar to ANDA approval, both because of the scope of the 3-year exclusivity granted and because of the inability of an ANDA applicant to carve-out protected information.  According to Vanda:

The removal of the limitation on maintenance treatment satisfies the applicable legal standards for eligibility for three-year exclusivity to the same extent as the addition of information about Fanapt’s efficacy for maintenance treatment. Both types of changes “derive[] from” the REPRIEVE study and that study “relate[s] to” those changes because REPRIEVE is the sole source of reliable clinical evidence supporting the efficacy of iloperidone for maintenance treatment.  Without the REPRIEVE results, there would be no basis for statements describing the efficacy of iloperidone for maintenance treatment, nor would there be support for deleting statements describing the lack of such efficacy data. Because “there are no other data available that could support approval of” these labeling changes made in Supplement 15, REPRIEVE is “essential to approval” of the changes. The direct and logical link between REPRIEVE and the labeling changes is the kind of “substantive relationship between new clinical studies and changes in the supplement” that is required for both types of changes to be covered by three-year exclusivity. . . .

Because Fanapt’s three-year exclusivity covers both the addition and omission of labeling information relating to maintenance treatment, no ANDA referencing Fanapt may be approved before the expiration of three-year exclusivity because no generic iloperidone product can bear approvable labeling. Fanapt’s three-year exclusivity precludes ANDA labeling from omitting statements describing the lack of evidence of safety and efficacy for maintenance treatment.  At the same time, however, ANDA labeling may not include those statements because they are now inaccurate, and because their inclusion would violate the “same labeling” requirement. . . .

Carving out information about maintenance treatment from the labeling for a generic iloperidone product would leave the product less safe or effective than Fanapt for the remaining, non-protected condition of use: namely, the treatment of adult patients with schizophrenia. A carve-out would leave prescribers with no information about the safety and efficacy of continued treatment for those patients who respond initially to iloperidone—contrary to the requirement that labeling “contain a summary of the essential scientific information needed for the safe and effective use of the drug.” A labeling carve-out should be denied where, as here, the protected information “is necessary to enable physicians to adequately assess the risks and benefits of” the drug product for “the general population” of patients for whom the drug product is indicated.

Or, said another way (by FDA):

You contend that the 3-year exclusivity FDA granted Vanda for the REPRIEVE study results protects both (1) the addition of information to Fanapt’s labeling about the product’s efficacy for maintenance treatment and (2) the deletion of statements describing a lack of evidence for maintenance treatment (Petition at 1, 7). You argue that this exclusivity bars approval of any ANDA that references Fanapt that either includes the maintenance treatment information added in S-015 or omits the prior statements on maintenance treatment limitations (which are no longer in the RLD labeling) (Petition at 10).  You additionally argue that ANDA labeling may not include statements describing the lack of evidence of safety or efficacy for maintenance treatment because they are now inaccurate and their inclusion would violate the “same labeling” requirement (Petition at 10).  Finally, you contend that the new information about maintenance treatment cannot be carved out of generic iloperidone labeling because doing so would render the generic product less safe or effective than Fanapt for the remaining non-protected conditions of use (Petition at 1, 13).  Thus, you argue that the 3-year exclusivity related to the REPRIEVE study prohibits FDA from approving a generic iloperidone referencing Fanapt for any use, including any unprotected use.

With respect to the scope of the 3-year exclusivity FDA granted, FDA disagreed with Vanda’s characterization of it as having two-way effect (a kind of zen moment in Hatch-Waxman). “We disagree with your argument that 3-year exclusivity can cover the deletion of statements from previously approved labeling.”  Here, wrote FDA, “the addition of labeling describing the REPRIEVE study data is the exclusivity-protected change approved in the supplement envisioned by the Hatch-Waxman Amendments.”  Continuing on, FDA said:

This was the labeling supported by “new clinical investigations” that were “essential” to approval of the supplement, within the meaning of section 505(j)(5)(F)(iv). But as the preamble to the 1989 proposed rule for part 314 made clear, it is only the labeling claims on the approved product that describe the REPRIEVE study that are covered by the 3-year exclusivity, not other accompanying changes.  The fact that when adding these claims to the labeling FDA also approved conforming changes – removal of previous statements that would no longer be accurate and that no longer reflected the standard of care for schizophrenia treatment – does not mean that those conforming changes are swept into the scope of exclusivity, or that no ANDA that omits this outdated information can be approved during the 3-year exclusivity period.  FDA does not believe that such conforming deletions are changes for which new clinical investigations are essential.

We were a bit intrigued by FDA’s general statement that 3-year exclusivity does not  cover the deletion of statements from previously approved labeling.  After all, way back in August 2008, we wrote a post titled “FDA Clarifies that 3-Year Exclusivity can be Granted for the Removal of Labeling Information.” In that post, we discussed an instance involving ACZONE (dapsone) Gel, 5% (NDA 021794), in which FDA granted a period of 3-year exclusivity and coded it in the Orange Book as “M-76.”  That exclusivity code is defined as: “REMOVAL OF SCREEN REQUIREMENT IN PTS WITH G6PD DEFICIENCY PRIOR TO INITIATING ACZONE TREATMENT; REMOVAL OF BLOOD COUNT & RETICULOCYTE MONITORING DURING TREATMENT IN G6PD DEFICIENT PTS AND IN PATIENTS WITH HISTORY OF ANEMIA” (emphasis added).  There’s also a “D-121” exclusivity code defined as “CHANGE TO REMOVE 20 MG MAXIMUM DOSAGE RESTRICTION” (emphasis added) related to the approval of a supplemental NDA in October 2009 for FOCALIN XR (dexmethylphenidate HCL) Extended-release Capsules (NDA 021802).  Of course, an exclusivity code is only shorthand for the scope of exclusivity, and each exclusivity scenario must be considered on a case-by-case basis. 

In any case, FDA does go on to address the situation in which the Agency does recognize exclusivity for the deletion of labeling information. “Even if the Agency were to agree that in certain circumstances deletions of information can be protected by exclusivity when supported by new clinical investigations essential to the approval of the deletion (which it does not),” writes FDA, “in this case, the new clinical investigations that earned exclusivity were not essential to the deletions you identify.”

With respect to Vanda’s ANDA labeling carve-out arguments, they fell on deaf ears. “FDA has determined as a scientific matter that it is not necessary to retain the information about the REPRIEVE study that was added in S-015 in the labeling for generic iloperidone to assure safe use,” writes FDA.  “FDA has also determined that generic iloperidone with the protected REPRIEVE study information carved out remains safe and effective for the remaining non-protected conditions of use.  Accordingly, a carve-out of the REPRIEVE study information is permissible in this case.” 

Earlier this week, we received notification from the editors of the American Bar Association (“ABA”) Journal announcing that Hyman, Phelps & McNamara, P.C.’s FDA Law Blog was selected to the 2016 (and 10th annual) ABA Blawg 100.  The Blawg 100 is a list of the top 100 “most compelling” legal blogs in the blogosphere, as selected by the ABA from a list of more than 4,000 blogs.  This is the sixth time we have made the list (we were previously given the honor in 2009, 2010, 2013, 2014, and 2015).  Thank you to our loyal readers who nominated us!  We’ve already added the coveted badge handed out by the ABA to the “Awards & Honors” section of the FDA Law Blog. 

In addition to the Blawg 100, the December issue of the ABA Journal includes an interesting piece on the state of the legal blogosphere.  We’re happy to report that legal blogging is healthy and thriving. That’s certainly our experience as we near the end of our 10th year of blogging (we officially turn 10 years old on March 6, 2017), and as we close in on 3,000 posts. As we’ve noted before, a successful legal blog requires thoughtfulness, creativity, timeliness, dedication, and teamwork. These are all attributes of the team at Hyman, Phelps & McNamara, P.C.

REMINDER: You can follow FDA Law Blog on Twitter @fdalawblog.

In a new article published by the American Bar Association in its Business Law Today November 2016 issue, Hyman, Phelps & McNamara, P.C.’s Andrew J. Hull discusses the state licensing issues present in corporate transactions involving pharmaceutical companies.  In the article, entitled “A Practical Roadmap for Transitioning State Licenses for Sales of Prescription Drugs and Devices in Corporate Transactions,” Mr. Hull writes:

Pharmaceutical companies, such as manufacturers, distributors, and pharmacies that dispense, distribute, and sell prescription drugs and devices are subject to state licensing and other regulatory requirements. Corporate transactions involving these companies, including mergers, acquisitions, changes of ownership, or even corporate restructurings, can trigger a requirement to transition or obtain new licenses on top of the many other corporate and tax matters that are also at play.  Moreover, there are many traps for the unwary for failure to follow the state requirements on transitioning these licenses that can delay a corporate transaction or result in potential suspension of authority to conduct business.

Article at 1.

The article discusses the numerous pitfalls a buyer can face without paying careful attention to these state licensing requirements or allowing an appropriate amount of time to effect a successful change of ownership.  The article also provides a practical roadmap for transitioning these state licenses in order to help ensure continuity of business operations.

The article concludes:

Navigating any form of corporate transaction is time-consuming and requires detailed work. The added detail in transactions involving pharmaceutical companies of ensuring appropriate state licensure adds yet another level of nuance and difficulty. This roadmap provides buyers and their corporate counsel with some of the information needed to ensure that these regulatory details do not present an issue after closing.

Id. at 5.

By Kurt R. Karst –      

We recently came across what we think is a pretty interesting FDA Exclusivity Letter Decision on 180-day exclusivity for generic versions of EDLUAR (zolpidem tartrate) Sublingual Tablets, 5 and 10 mg (NDA 021997; approved on March 13, 2009). The 180-day exclusivity forfeiture provision at play in the case is our old friend FDC Act § 505(j)(5)(D)(i)(IV), which we’ve blogged about on many, many occasions over the nearly 10 years this blog has been around.  

By way of background, 180-day exclusivity eligibility is forfeited under FDC Act § 505(j)(5)(D)(i)(IV) if:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.

The 2007 FDA Amendments Act clarified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final Agency action on the petition (inclusive of such beginning and ending dates) . . . .” FDC Act § 505(q)(1)(G).

Section 1133 of the 2012 FDA Safety and Innovation Act (“FDASIA”) also addressed FDA’s application of FDC Act § 505(j)(5)(D)(i)(IV) with respect to certain ANDA cohorts. In particular, under FDASIA § 1133(a), for an ANDA submitted to FDA between January 9, 2010 and July 9, 2012 initially containing a Paragraph IV certification (or that is amended during that time to first contain a Paragraph IV certification), the time to obtain timely tentative approval (or final approval if tentative approval is not warranted) is 40 months during the period of July 9, 2012 and September 30, 2015, and not 30 months, and 36 months during the period of October 1, 2015 and September 30, 2016, and not 30 months.

Shortly after the enactment of FDASIA, we made the observation that the provision extending the 30-month period to 36 months seemed pretty useless. At the time, we wrote that “the 36-month extension date is inapplicable (absent an applicable 505(q) citizen petition, or some change in review that occurs during the last 6 months of the 36-month period making the forfeiture provision irrelevant).  By the time this provision takes effect on October 1, 2015, the youngest ANDA to which it could apply – i.e., an ANDA submitted to FDA on July 9, 2012 – will be nearly 39 months old.  If such an ANDA is tentatively approved on September 30, 2015 when the tentative approval period is still 40 months, there would not be a forfeiture.  If, however, that same ANDA is tentatively approved one day later, on October 1, 2015, there would be an automatic forfeiture.”

It turns out, however, that FDA found some utility for the 36-month tentative approval provision under FDASIA § 1133(a) after all. FDA explains the Agency’s interpretation in a footnote in its June 2, 2016 Exclusivity Letter Decision with respect to Par Formulations Private Limited’s (“Par’s”) ANDA 201509 for generic EDLUAR:

For applications submitted between January 9, 2010, and July 9, 2012 containing a Paragraph IV certification (or amended to first contain a paragraph IV certification during that period of time), and approved or tentatively approved during the period of time beginning on July 9, 2012, and ending on September 30, 2015, section 1133 of the Food and Drug Administration Safety and Innovation Act (FDASIA) (P.L. 112-144) extends this period to 40 months. For applications submitted between January 9, 2010, and July 9, 2012 (or amended to first contain a paragraph IV certification during that period of time), and approved or tentatively approved during the period of time beginning on October 1, 2015, and ending on September 30, 2016, section 1133 of FDASIA extends this period to 36 months.  In addition, if an application was submitted between January 9, 2010, and July 9, 2012 containing a Paragraph IV certification (or amended to first contain a paragraph IV certification during that period of time), and FDA has not approved or tentatively approved the application but must consider whether the applicant has forfeited exclusivity because a potentially blocked application is ready for approval, FDA will apply the 36-month period if it makes the forfeiture determination between the period of time beginning on October 1, 2015, and ending on September 30, 2016.  For all other applications, the 30-month period set forth in FD&C Act section 505(j)(5)(D)(i)(IV) applies.

FDA apparently settled on this interpretation earlier this year. Indeed, there are a handful of ANDA approval letters, starting with ANDA 201970 for Rasagiline Mesylate Tablets, 0.5 mg and 1 mg (approved on March 15, 2016), that include text similar to the paragraph above.  Other affected ANDAs include ANDA 202103 for Dasatinib Tablets, 20 mg, 50 mg, 70 mg, and 100 mg (approved on June 10, 2016), ANDA 202402 for Ibuprofen Lysine Injection, 20 mg/2 mL (10 mg/mL) single-dose vials (approved on March 30, 2016), and ANDA 202349 for Estradiol Valerate Tablets, 1 mg and 3 mg, Estradiol Valerate and Dienogest Tablets, 2 mg/2 mg and 2 mg/3 mg (approved on May 5, 2016).

With respect to generic EDLUAR, Par ANDA 201509 was submitted to FDA on April 29, 2010 containing a Paragraph IV certification to Orange Book-listed patents on the Reference Listed Drug (“RLD”). As the first substantially complete ANDA submitted to FDA containing a Paragraph IV certification, Par qualified as a “first applicant” eligible for 180-day exclusivity.  Because ANDA 201509 was submitted to FDA within the FDASIA § 1133(a) “window,” the augmented 40-month and 36-month timeframes for obtaining tentative approval applied.  The 40-month period came and went.  And then something triggered FDA to assess Par’s eligibility for 180-day exclusivity.  As FDA explains in a footnote in the Agency’s Exclusivity Letter Decision, “[b]ecause FDA has not approved or tentatively approved Par’s application, but now must determine whether Par has forfeited exclusivity because a potentially blocked application is ready for approval, FDA will apply the 36-month period described in section 1133 of FDASIA.” 

Applying the 36-month date, FDA was then tasked with determining under FDC Act § 505(j)(5)(D)(i)(IV) whether or not there was, as of April 29, 2013 (i.e., 36 months after April 29, 2010), a “change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.”  And that’s where FDA’s Exclusivity Letter Decision provides another noteworthy takeaway.  FDA lays out the Agency’s policy on “hot pursuit” (à la Roscoe P. Coltrane) vis-à-vis the exception provision at FDC Act § 505(j)(5)(D)(i)(IV).  Here’s what FDA says in the decision: 

[T]he labeling review for ANDA 201509 was found acceptable on July 30, 2012. FDA approved changes to the RLD labeling (NDA 021997) on April 19, 2013, ten days before the 36-month forfeiture date.  These changes included new safety information relating to zolpidem tartrate, including several changes to the “Dosage and Administration” section of the RLD labeling.  Despite these changes to the RLD labeling, Par did not submit a labeling amendment to ANDA 201509 to address these changes until October 21, 2013, six months after the approval of the RLD labeling updates.  In fact, Par’s July 22, 2013 request for final approval of ANDA 201509 noted that “[t]here has been no change in Labeling. . . .”

FDA generally will presume that the failure to obtain tentative approval or approval was caused by a change in or review of approval requirements if, at the forfeiture date, the evidence demonstrates that the sponsor was actively addressing the change in or review of approval requirements (or FDA was considering such efforts), and these activities precluded tentative approval (or approval) at that time. Where the evidence fails to demonstrate that the sponsor was actively addressing the change in or review of approval requirements, and these activities precluded tentative approval (or approval) at the forfeiture date, FDA generally does not presume that the failure was caused by a change in or review of approval requirements.

Without any evidence that Par was in hot pursuit to address the RLD labeling changes, FDA concluded that Par forfeited eligibility for 180-day exclusivity:

We conclude that there were changes to the requirements for approval with respect to labeling, as outlined above. Changes to the RLD labeling required Par to revise its labeling. However, we do not find that these labeling changes caused Par’s failure to obtain tentative approval by the forfeiture date.  At the 36-month date of April 29, 2013, Par had not yet submitted an amendment to address the RLD labeling updates approved on April 19, 2013, and no evidence indicates that Par was actively addressing the labeling deficiencies that resulted from the change in approval requirements at that time.  Par’s submission related to the labeling changes was almost 6 months after the forfeiture date.  The six-month lag between the change in approval requirements with respect to labeling and Par’s labeling amendment supports an inference that Par was not actively addressing the labeling changes at the forfeiture date.  Therefore, we conclude that the RLD labeling changes were not a cause of Par’s failure to obtain tentative approval.

By Riëtte van Laack –

As we previously reported, in May 2016, FDA published a final rule amending the nutrition labeling regulations. Among other things, FDA defined dietary fiber as non-digestible soluble and insoluble carbohydrates (with three or more monomeric units), and lignin that are intrinsic and intact in plants and isolated or synthetic non-digestible carbohydrates (with three or more monomeric units) that FDA determines to have a physiological effect that is beneficial to human health. The final rule identified only 7 isolated or synthetic fibers that would meet the definition of dietary fiber.  FDA indicated that there was insufficient evidence of a beneficial physiologic effect for more than twenty additional non-digestible carbohydrates, and that the Agency would issue a document summarizing that evidence.  In addition, FDA announced that it would issue guidance regarding the type of evidence and the scientific evaluation process the Agency would (and presumably did) use in determining the strength of the evidence for the relationship between an isolated or synthetic non-digestible carbohydrate and a physiological effect that is beneficial to human health.  On November 22, FDA announced the availability of both the report and the draft guidance.

In its report, FDA summarizes the results of the Agency’s scientific review of the evidence for beneficial physiological effects of 26 non-digestible carbohydrates: Gum Acacia; Alginate; Apple Fiber; Bamboo Fiber; Carboxymethylcellulose; Corn Hull Fiber; Cottonseed Fiber; Galactooligosaccharides; Inulin/Oligofructose/Synthetic Short Chain Fructooligosaccharides; Karaya Gum; Oat Hull Fiber; Pea Fiber; Polydextrose; Potato Fibers; Pullulan; Rice Bran Fiber; High Amylose Corn/Maize Starch (Resistant Starch 2); Retrograded Corn Starch (Resistant Starch 3); Resistant Wheat and Maize Starch (Resistant Starch 4); Soluble Corn Fiber; Soy Fiber; Sugar Beet Fiber; Sugar Cane Fiber; Wheat Fiber; Xanthan Gum; Xylooligosaccharides. As with the memorandum in which FDA described the isolated dietary fibers included in the final rule, the report provides brief summaries of each study that meets FDA’s criteria and lists studies that were not considered because they did not meet all criteria for inclusion (e.g., the study did not include a control group, or was in a foreign language). However, there is no final conclusion or comment regarding the strength of the evidence for any of the 26 fibers. 

Since the publication of the final rule, FDA has received several citizen petitions to amend the definition of dietary fiber by including additional non-digestible carbohydrates. Other than a footnote referencing the citizen petition for soluble corn fiber, FDA does not mention these citizen petitions and it is not clear whether FDA considered any non-public information provided in those citizen petitions in its review.

FDA asserts that its review is consistent with the approach laid out in the draft guidance, which the Agency issued on the same day. The approach laid out in the draft guidance appears similar to the approach described in the 2009 guidance for evaluation of health claims.

In addition to the draft guidance and the report, FDA published Questions and Answers for Industry on Dietary Fiber.

FDA invites additional scientific data and information and comments regarding the physiological endpoints that the Agency addressed in the review of scientific evidence for each of the 26 non-digestible carbohydrates, and possible other beneficial physiological endpoints, e.g., blood pressure and the data for any of these or other non-digestible carbohydrates.

Comments regarding FDA’s review of the 26 isolated and synthetic non-digestible carbohydrates are due January 9, 2017.  Comments regarding FDA’s draft guidance are due January 23, 2017.

By Jay W. Cormier –

After three years of considering public comments on the draft, in last Wednesday's Federal Register, FDA issued its final FDA Guidance for Industry regarding Contract Manufacturing Arrangements for Drugs: Quality Agreements.

With this Final Guidance, FDA has clarified its scope, specifically with respect to the parties to which it applies. For a detailed background on this matter, see our blog post regarding the draft guidance (here).

In brief, FDA expects that “owners” will enter into written quality agreements with “contract facilities” whereby the parties define and establish each party’s roles and responsibilities with respect to ensuring that drug substances and drug products are manufactured in accordance with current good manufacturing practice. These quality agreements ideally state which party engages in which activities, and which party has primary responsibility for fully complying with cGMPs under section 501(a)(2)(B) of the Act and 21 C.F.R. Parts 210, 211, and 600-680, as those regulations may apply to the specific product or substance involved.

Companies should be aware that FDA intends to review quality agreements during facility inspections, so FDA (and we) recommend that quality agreements be separate from other contracts between owners and contract facilities.

In the draft guidance, FDA defined an owner as any party that “introduces (or causes the introduction of a drug into interstate commerce.” As we noted in our earlier post, this definition was so broad it seemed highly unlikely that FDA actually intended the guidance to apply to all entities that would meet that definition (e.g., distributors). Not only did it seem illogical to require distributors or other down-stream “owners” to be responsible for certain non-delegable cGMP requirements such as product release, the effect would have been to nullify section 303(c) of the Act, which allows down-stream entities to rely on written product guarantees from up-stream manufacturers.

Therefore, it is reassuring that the Final Guidance takes a more measured approach. Under the Final Guidance, an “owner” for purposes of the guidance includes only “manufacturers of APIs, drug substances, in-process materials, finished drug products, including biological products, and combination products.” As with the draft, FDA excludes “retail pharmacies, drug stores, supermarkets, discount warehouse stores, or other retailers who purchase finished drug products to sell over the counter as a store brand” from the definition of an owner. The Final Guidance goes on to specifically state that it does not include “entities that engage in manufacturing related solely to drug distribution (e.g., distributors, brokers, private label distributors, own label distributors)” in the definition of an owner. FDA still encourages such entities to use quality agreements or the general concepts of quality agreements when it would be helpful for those entities to have such an agreement in place. In case there is any doubt, FDA states that its “focus [], however, is on the roles and manufacturing activities of the owner and contract facility.”

It is important to also note that, as FDA acknowledged in the draft guidance, FDA’s cGMP “regulations do not explicitly require Owners and Contracted Facilities to document their respective responsibilities in contract manufacturing arrangements.” The full quote in the draft guidance states:

Although the CGMP regulations do not explicitly require Owners and Contracted Facilities to document their respective responsibilities in contract manufacturing arrangements, the regulations do require that Quality Unit responsibilities and procedures be in writing (21 CFR 211.22(d)). FDA believes that implementing a written Quality Agreement facilitates compliance with § 211.22(d). Therefore, FDA recommends that Owners and Contracted Facilities establish a written Quality Agreement to record their respective responsibilities in contract manufacturing arrangements.

Interestingly, the Final Guidance plays this point less candidly, which is as disappointing as its original honesty was refreshing. In the Final Guidance, FDA states merely:

Implementing a written quality agreement can facilitate compliance with CGMP and, in particular, with 21 CFR 211.22(d), which states that quality unit activities and procedures should be in writing. FDA recommends that owners and contract facilities establish a written quality agreement to describe their respective CGMP-related roles, responsibilities, and activities in drug manufacturing.

To be clear for our readers, FDA’s original statement, and the implied statement in the Final Guidance are correct: there is no statutory or regulatory requirement for a quality agreement between owners and contract facilities. That being said, we have seen a significant increase in clients seeking assistance in writing and negotiating quality agreements between many different types of parties – it is clear that the use of quality agreements is both becoming standard industry practice and is useful in clarifying specific roles and responsibilities between parties. Such agreements can have both tangible and intangible benefits to all parties throughout the life of the relationship.

By Karla L. Palmer –

The Government Accountability Office (GAO) released a detailed Report last week addressing FDA’s efforts to regulate compounding since Congress’ passage of the Drug Quality and Security Act in November 2013. U.S. Gov’t. Accountability Office, GAO-17-64, FDA: FDA Has Taken Steps to Implement Compounding Law, but Some States and Stakeholders Reported Challenges (2016) [hereinafter “Report”].  To inform its conclusions, among other activities, the GAO interviewed and surveyed state regulatory pharmacy bodies in 50 states and U.S. territories, reviewed documents,  interviewed dozens of pharmacy stakeholder organizations, reviewed relevant laws, interviewed FDA officials, and reviewed FDA data on compounding inspections and regulatory actions.  Summaries of data and information collected concerning various drug compounding legal issues and regulatory activities by states and FDA are dispersed throughout the numerous charts in the Report. 

Although somewhat difficult to follow (it would be more helpful if FDA instead detailed in an appendix, for example, exactly what particular states required of compounders and how they are regulated), the Report itself points out that FDA and states need more coordination on regulatory activities affecting compounding. These regulatory activities affect thousands of compounding physicians and pharmacies that engage in compounding on a much needed, daily basis.  The GAO describes the various settings in which compounding occurs; however, the reader is quickly left with impressions of confusion concerning how any particular state regulates compounding.  Not surprisingly, the Report demonstrates that state compounding laws and regulations are quite inconsistent not only among the states, but also among the states and FDA. Some highlights:

(1)          FDA and states surveyed note that compounding by physicians – permitted under Section 503A – is not necessarily regulated by state pharmacy compounding laws.  Only 9 states reported having laws or regulations specific to compounding by physicians and non-pharmacies; most medical boards consider compounding to be part of the practice of medicine.  (Report at 24-27).

(2)         State laws, regulations and other policies addressing sterile compounding vary greatly across those states surveyed.  However, the Report points out various enforcement actions states may take (from fines to licensing suspension).  State data is not necessarily tracked concerning cases involving compounded medications.  States also do not track volumes of drugs compounded.

(3)          While most states are satisfied with FDA’s communications with states concerning compounding matters, 23% of states surveyed report they were not necessarily satisfied.  Among other comments, one state commented that FDA was making insufficient progress in providing guidance regarding FDA’s intended regulatory approaches, and FDA seemed burdened with “red tape.”  (Report at 33-36). 

(4)          FDA’s risk models used to determine what facilities to inspect do not consistently collect reliable and timely information on inspections and enforcement actions, including correct inspection classifications as either official action indicated, voluntary action indicated, or no action indicated from the results of the inspection.  (Report at 42-43).        

(5)          On the general data collection front: From May 11, 2012 to April 22, 2016, FDA conducted 265 inspections of 210 facilities that are not outsourcing facilities.  It issued 228 FDA Form 483s, 81 warning letters, 72 voluntary recalls, 31 state referrals, and requested 1 regulatory meeting.  The Agency conducted 75 inspections of 51 outsourcing facilities (it tries to inspect outsourcing facilities within 2 months of registration); these have resulted in 24 facilities have received warning letters, one untitled letter, 14 voluntary recalls, and obtained two injunctions.  (Report at 44-47).  The Report itself does not mention the number of Form 483s issued to outsourcing facilities (but this information is available on FDA’s outsourcing facility page because it posts them). 

(6)          Some stakeholders commented that the amount of time FDA has taken to finalize guidance and other documents is “challenging” and creates uncertainty on how compounders (both outsourcing facilities and traditional) move forward under the DQSA’s undefined regulatory rubric.  Among other issues, they cite FDA’s delays in finalizing the “difficult to compound” list and the Memorandum of Understanding (MOU) between states and FDA that would govern interstate distribution/dispensing of compounded products.  The Report specifically notes that several stakeholders are concerned with the proposed MOU’s interchangeable (and inexplicable) definition and use of the terms “dispensing” and “distribution” of compounded drugs to be included in the proposed 30% interstate limit calculations.  (Report at 47-48) 

(7)         States and stakeholders also expressed concerns about differences in inspection protocols between states and FDA.  Compounding pharmacies have been floating this complaint since FDA first dramatically increased the number of pharmacy inspections back in late 2012 (and holding the sites to a cGMP standard instead of traditional state pharmacy standards that generally encompass USP <795> and <797>).  GAO notes that FDA has attempted to clarify its inspection protocol, through release of a notice changing inspection procedures on August 1, 2016.  (FDA, Notice (Aug. 1, 2016)) (see our previous post here).  FDA’s August 2016 notice describes a “preliminary assessment” that FDA makes upon commencement of a pharmacy inspection as to whether the pharmacy should be held to FDA’s cGMP regulations for manufacturers or whether it should be entitled to Section 503A’s exemption from cGMP.  The outcome depends on FDA’s determination whether, among other things, the pharmacy is engaging only in patient specific compounding, and the more complicated determination of whether the pharmacy is violation of other FDCA provisions (i.e., compounding under insanitary conditions).  It would be interesting to know how many pharmacies, inspected since August 1, 2016, have been held to cGMP versus the appropriate state/USP standards. 

(8)          Several states and stakeholders report concerns related to FDA’s responsibilities in its implementation of the DQSA which may affect the availability of compounded drugs for office use.  States and stakeholders note that the DQSA’s prohibition on office use compounding is inconsistent with laws in 27 states that currently permit office use compounding.  Respondents in 23 states reported concerns related to access to compounded medications for patients with a medical need for drugs.  This is because, for certain drugs for which there is not a great demand yet are compounded for office use, outsourcing facilities will not undertake to compound them (presumably because the cost is too great given the limited demand, and thus limited profit).  If compounding pharmacies cannot compound drugs under Section 503A, patients could lose access to needed drugs.  (Report at 48-49).

The Report does not address how many traditional compounding pharmacies still engage in office use compounding notwithstanding its prohibition in Section 503A versus 27 states’ legal permission of office use compounding.  The HHS responded to the GAO’s findings.  FDA stated it has stepped up efforts to increase collaboration with states, and that it plans to take or has taken action concerning other issues, such as compounding by physicians, access to compounded drugs (i.e., office use).  

By Serra J. Schlanger –

The Department of Health & Human Services Office of Inspector General (“HHS OIG”) recently released its work plan for fiscal year 2017.  The annual work plan summarizes what HHS OIG plans to review during the upcoming year as part of its mission to protect the integrity of the Department of Health & Human Services and the Federal health care programs.  It is unclear whether HHS OIG’s priorities will change with the new administration; however, the work plan still provides insight into areas of potential concern.  Although much of the work plan focuses on health care providers (e.g., hospitals and home health agencies), below we’ve highlighted a few areas of interest for other players in the health care industry.

Medical Devices

HHS OIG is planning to review the “Medicare Costs Associated with Defective Medical Devices” as well as “Payment Credits for Replaced Medical Devices That Were Implanted.” Each of these areas of interest are related to the costs associated with defective or recalled medical devices and whether the Medicare program is properly paying for services associated with the replacement of such devices.

Clinical Diagnostic Laboratory Tests

Section 216 of the Protecting Access to Medicare Act of 2014 (PAMA) requires CMS to replace the current system of determining payment for Medicare Part B clinical diagnostic laboratory tests. Pursuant to PAMA, HHS OIG plans to conduct an analysis of the top 25 laboratory tests by Medicare payments to monitor the implementation of the new Medicare payment system for these tests.

Open Payments Reporting

The work plan includes two items related to the Physician Payment Sunshine Act and the Open Payments website. HHS OIG plans to analyze the 2015 data from the Open Payments website to determine the number and nature of financial interests.  Following this analysis, HHS OIG will determine how much Medicare paid for drugs and durable medical equipment ordered by physicians who had financial relationships with manufacturers and group purchasing organizations.

In a separate analysis, HHS OIG plans to determine the extent to which data in the Open Payments website is missing or inaccurate, the extent to which CMS oversees manufacturers’ and group purchasing organizations’ compliance with data reporting requirements, and whether the required data for physician and teaching hospital payments are valid.

Prescription Drugs

HHS OIG has identified a few new areas of interest related to prescription drugs. HHS OIG is concerned about the “Drug Waste of Single-Use Vial Drugs” and hopes to identify examples of single-use-vial drugs where a smaller vial size could significantly reduce waste.  HHS OIG also plans to examine “Potential Savings from Inflation-Based Rebates in Medicare Part B” by determining, for a sample of 50–100 Part B drugs, the amount the Federal Government could potentially collect from pharmaceutical manufacturers if inflation-indexed rebates were required under Medicare Part B as they are under the Medicaid Drug Rebate Program.

In the Medicare Part D context, HHS OIG plans to assess “Medicare Part D Rebates Related to Drugs Dispensed by 340B Pharmacies” and billing for topical compounded drugs. HHS OIG also plans to review increases in the prices for brand-name drugs by evaluating the rate of change in pharmacy reimbursement under Part D and the rate of inflation from 2011 to 2015.

FDA

The HHS OIG work plan also includes a short section for FDA-related reviews. HHS OIG states that “[a]reas of particularly high risk include food safety, drug compounding, a complex drug supply chain, and improper marketing activities.”  New and expanded FDA reviews may include “investigations of fraud and misconduct at FDA facilities; oversight of blood establishments and laboratory-developed diagnostic tests; management of IT modernization initiatives; hospital contracting with compounding pharmacies that have registered with FDA, and prescription drug user fees.”  HHS OIG identified eight FDA-specific reviews for the upcoming year.

A new area of HHS OIG review related to “Hospitals’ Reliance on Drug Compounding Facilities” will determine the extent to which hospitals obtain compounded sterile preparations from compounders and the extent to which these compounders have registered with the FDA as outsourcing facilities.

HHS OIG identified two revised plans to review networked medical device cybersecurity. In one review HHS OIG will examine FDA’s premarket review of the cybersecurity controls of networked devices.  In a separate analysis, HS OIG will examine FDA’s plans and processes for timely communicating and addressing a networked medical device cybersecurity compromise.

HHS OIG also plans to continue its review of FDA related to prescription drug user fees, the registration and listing of tobacco establishments under the Tobacco Control Act, domestic and imported food recalls, inspections of domestic food facilities, and drug traceability and the security of the drug supply chain.

By Riëtte van Laack –

This case concerns small, high-powered magnet sets that users can arrange and rearrange in various geometric shapes. They were once a popular product, marketed as an adult desk toy and for making art works.  The magnet sets consist of 100-200 magnets that have diameters of approximately five millimeters and are unusually powerful. The Consumer Product Safety Commission (CPSC) got involved because of reports of injuries of children swallowing the tiny magnets. (The primary purpose of the CPSC is “to protect the public against unreasonable risks of injury associated with consumer products.”).

The CPSC took several actions to remove the product from the market, including recalls and a rule setting a standard that would effectively ban the sale of this type of magnets. Apparently, most of the companies marketing this type of magnets discontinued the sale of the products in the United States. One company, however, Zen Magnets, LLC (“Zen”), refused to do so and challenged CPSC’s standard. On November 22, the Court of Appeals of the 10^th Circuit vacated the rule setting the standard.

The opinion provides a detailed history of the events surrounding the marketing of these magnets. Briefly, in 2011, the CPSC began evaluating whether this type of magnets complied with a standard by the American Society for Testing and Materials (ASTM) for children’s toys and concluded they did not; the magnet sets marketed by Zen and others were ten times more powerful—or, alternatively, six times smaller—than permissible under the toy standard.

In response to notices of noncompliance and a variety of enforcement actions, a number of companies discontinued the marketing of magnet sets that did not meet the ASTM standard. However, the ASTM standard was for products marketed to children younger than 14 years of age. To get at all magnet sets including those marketed to adults, CPSC issued a rule setting a standard for the size and strength of all magnets. The standard was the same as the ASTM standard but was not limited to magnet sets designed or marketed as toys for children under fourteen years of age, but rather applied to all magnet sets that are“[a]ny aggregation of separable magnetic objects that is a consumer product intended, marketed or commonly used as a manipulative or construction item for entertainment” without age limitation.

Zen challenged this final rule as not meeting the requirements under the Consumer Product Safety Act (CSPA) for a variety of reasons. Specifically, under the CSPA, 15 U.S.C. § 2058(f), the CPSC may promulgate a safety standard only if it reaches and articulates several conclusions, including:

• “that the rule . . . is reasonably necessary to eliminate or reduce an unreasonable risk of injury”;
• that the . . . rule is in the public interest”;
• “that the benefits expected from the rule bear a reasonable relationship to its costs”; and
• “that the rule imposes the least burdensome requirement which prevents or adequately reduces the risk of injury for which the rule is being promulgated.”

The court concluded that the CPSC lacked substantial evidence demonstrating that the rule is necessary to avoid an unreasonable risk. The court also concluded that the CPSC had failed to address the “public’s need for the sets as scientific and mathematics education and research tools, and the rule’s probable effect on magnet sets’ availability and usefulness for those purposes.” Without such information, it is not possible to do a proper cost benefit analysis. As a result, the court vacated the standard and remanded the case to the CPSC. Judge Bacharach dissented.  

In light of the dissent, a CPSC request for a re-hearing (before the same panel) and/or rehearing en banc appears likely.

By Allyson B. Mullen & Jeffrey N. Gibbs –

All this year, FDA had signaled it intended to finalize the guidance for Laboratory Developed Tests (LDTs). On Friday November 18, 2016, FDA abandoned the effort, stating that it will not provide the requisite 60-day notice to Congress to finalize the Draft Guidances for LDTs (see here and here).  FDA issued the draft guidances in late July 2014, and since then the draft guidances have received a mix of praise and criticism, as we have discussed in our earlier blog posts (here, here, and here).

FDA’s announcement is unsurprising in the wake of the unexpected election results. While this announcement is framing the current status of the draft guidances as delayed, given the current political landscape, these draft guidances are dead for all intents and purposes. Republican members of Congress have been among some of the harshest critics of FDA’s proposal to expand regulatory oversight of LDTs. FDA did say it would “continue to work with stakeholders, our new administration, and Congress to get our approach right.” FDA also said, “We plan to outline our view of an appropriate risk-based approach in the near future.” Nevertheless, with a Republican President committed to less regulation and Republican majorities in both the House and Senate, we believe FDA’s efforts to issue far-reaching LDT guidance is moribund for many years.

With that in mind, what does that mean for laboratories currently running LDTs? If sweeping guidance is off the table, it still does not mean FDA will ignore labs. We don’t have a crystal ball, but we do have a few ideas (i.e., pure speculation).

First, it is unlikely that FDA will view its core mission of ensuring that only “accurate, reliable, and clinically valid” tests are available to customers as changed even with a new administration. Nor do we expect some of FDA’s major concerns with LDTs to abate. Therefore, we expect FDA will take enforcement action against tests that it believes are providing “inaccurate or false test results.” A few ways that we could see this manifest are:

• Stepped Up Enforcement of the 2013 Final RUO/IUO Guidance. Since FDA finalized its Guidance Document regarding Research Use and Investigational Use devices in October 2013, there has been virtually no public enforcement action. This lack of activity came as a surprise to many, including us. After release of the draft LDT guidances less than a year later, it appeared that FDA was focusing on an even broader initiative: LDT regulation. Now that the LDT efforts are done (at least in their current incarnation), FDA may turn its attention back to the marketing of RUOs and IUOs used in LDTs.

• Expansion of Tests that Do Not Meet the Definition of an LDT (e.g., direct-to-consumer (DTC) tests). As many of you are well aware, FDA says it will not exercise enforcement discretion over DTC LDTs. What, exactly, is DTC remains undefined. We had thought that a test ordered by a physician was not DTC, since there was a physician intermediary. FDA disagrees. It is not enough that a physician order the test. FDA has looked at other factors, such as the degree of physician independence. FDA has not, however, publicly articulated these criteria for determining DTC status. Thus, many laboratories struggle to understand how much and what kind of physician interaction is necessary to make a test non-DTC. Now that FDA’s attempt to broadly regulate all LDTs has ended for now, FDA may well attempt to narrow exempt LDTs by expanding the scope of LDTs deemed DTC.  

• Collection Devices. FDA has also historically attempted to regulate (i.e., stop availability of) certain LDTs by preventing the distribution of the collection device necessary to obtain a patient sample for testing. FDA has claimed that the collection device is adulterated and/or misbranded for failure to have clearance or approval for sample collection for the LDT’s intended use. Numerous LDTs use general purpose patient sample collection devices. FDA could try to assert greater oversight of the lab test process by requiring premarket clearance or approval for collection devices for specific intended uses. 

• Public Announcement of “Safety” Concerns. FDA could take another approach and tell consumers and physicians that there are perceived “safety” risks with a particular test or group of tests. In fact, almost a year ago FDA issued a guidance regarding “Public of Emerging Postmarket Medical Device Signals” (see our blog post here). We criticized the draft post for failing to consider industry input before FDA makes an announcement because it could, in part, stop the use of a clinically valid and scientifically sound product. We saw FDA take such action recently with respect Ovarian Cancer Screening Tests. In September, FDA issued a safety communication stating that individuals should not use such tests. FDA did not cite a single confirmed instance of harm from any of these tests – all of the harm cited was theoretical. If FDA chooses to regulate LDTs in this way, we could see an increase in the number of “safety” communications. As a practical matter, this kind of notice and the resulting publicity can kill a test, even though the company never got a chance to address FDA’s concerns before publication.

• Narrowing LDTs. FDA has rarely, in recent years, challenged laboratory tests as not qualifying as LDTs. FDA, though, has done so in the past, and could do so in the future. Given the elastic definition of an LDT, it would not be hard to imagine FDA saying that certain tests don’t qualify as LDTs.

Thus, while many in the lab community have been praising the announcement from FDA, in our view, this fight may not be over. It may now shift from a battle over sweeping guidelines to case-by-case challenges using ill-defined criteria.

As our readers know, a tremendous amount of resources from both FDA and industry was dedicated to the LDT regulatory efforts of the last two years (and before that). For example, the Diagnostic Test Working Group (DTWG), an independent group consisting of representatives from diagnostic manufacturers and clinical laboratories was created to develop alternatives to FDA draft guidances. Congress worked on legislative alternatives to the draft guidances, and the administrative agencies related to LDTs created an interagency task force, which included FDA, CMS, CDC, and NIH, to work on revising the draft guidances. FDA spent countless hours revising its draft guidances, and industry spent countless hours commenting and then lobbying.

While some of the discussions were unproductive, reflecting polarized views, we hesitate to say that these efforts were all wasted because certainly some good ideas have come out of the process. FDA has learned much about the scope, nature, and importance of LDTs, and industry has learned about FDA’s perspective. This may, however, also mean that FDA now has greater knowledge of how to expand enforcement actions to regulate LDTs. Only time will tell. We will certainly be keeping a close eye on how FDA proceeds from an enforcement standpoint and will keep you all updated.

Finally, FDA first announced its authority to regulate LDTs over 24 years ago. Even if the path to broad LDT regulation is blocked for now, FDA may continue to bide its time. In 2021, LDTs will still be around, and so will FDA. The story may not be over.