By Carmelina G. Allis –

Since September 2009, the Center for Devices and Radiological Health (“CDRH”) has been reviewing the operation of the 510(k) program and the way CDRH uses science in the decision making process.  This week, the 510(k) Working Group and the Task Force on the Utilization of Science in Regulatory Decision Making each released a preliminary report with a series of recommendations. 

The preliminary reports are now open for public comment.  You can find them here.  Once CDRH has assessed public input, it will announce which recommendations it will adopt, along with projected timelines for doing so. 

It is clear that the proposals would have a significant impact on the process by which industry brings devices to market.  Dr. Shuren’s cover letter summarizing the reports restated the agency’s goals in this review process as looking at ways to foster medical device innovation, enhance regulatory predictability, and improve patient safety.  It is an open question whether all of the proposed changes would actually serve these goals.  Some of the proposals seem likely to increase industry’s regulatory burden without much improvement in patient safety, such as, for example, a requirement that manufacturers provide regular, periodic updates to CDRH listing any device modifications that were implemented without the submission of a new 510(k).

The reports do acknowledge the importance of enhancing innovation.  The twin goals of protecting patients from harm and promoting the development of safe and effective devices are given equal billing.  However, in our view, the majority of the recommendations will result, if implemented, in an increased burden on manufacturers, CDRH reviewers, and the 510(k) regulatory program.  It is not apparent that the recommendations, if implemented, will foster medical device innovation or enhance regulatory predictability.  If anything, these recommendations may add new scientific requirements, new regulatory hurdles, and additional uncertainty to a regulatory process that is already non-transparent and unpredictable.

The reports assert that the recommendations are preliminary and have not been implemented.  However, CDRH staff in recent months appear to already be following some of these recommendations.

Below we discuss the most significant recommendations issued by the 510(k) Working Group:

(1) “CDRH should clarify the meaning of ‘substantial equivalence’ through guidance and training for reviewers, managers, and industry.”

The 510(k) Working Group found that there is confusion both within CDRH and the public at large as to what constitutes the “same” versus a “new” “intended use,” and about when “different technological characteristics” raise “different questions of safety and effectiveness.”  As a remedy, the Working Group first recommends that the concepts of “indication for use” and “intended use” be consolidated into a single term, “intended use.”  (The dual terms “indications for use” and “intended use” have created confusion for years.)

Second, the Working Group recommends that CDRH better train reviewers and managers on how to determine “intended use” based on information available in the 510(k) submission.  The main intent of these proposals is to “reduce inconsistencies in [the] interpretation and application” of the term “intended use.”

Third, the Working Group recommends that CDRH explore the possibility of amending the Federal Food, Drug, and Cosmetic Act (“FDC Act”) to provide the agency authority to consider an off-label use of the proposed device when determining its “intended use.”  The declared intent of this proposed measure is to ensure that the manufacturer of the device does not seek clearance for a use that is not the actual use for which the device was intended to be marketed.

If FDA has sufficient evidence that the manufacturer is going to market the device for an intended use different from that proposed in its 510(k) submission, then the agency would likely deny 510(k) clearance or require that additional information be submitted in support of the off-label use.  This proposal would effectively revert to the days prior to the Food and Drug Administration Modernization Act of 1997 (“FDAMA”) when FDA would allege an “implied” intended use based upon off label capabilities of a device.  Since FDAMA, FDA has been required to accept the manufacturer’s characterization of its intended use, absent a finding by the CDRH Director that there is a reasonable likelihood that the device will be used for an intended use not identified in the proposed labeling for the device and that such use could cause harm.

It is not clear whether the agency would apply this change to a general class of devices or target specific device manufacturers based, for example, on their compliance history or publicly available information on their product development and marketing intentions.  It also raises the question as to whether FDA could unfairly subject a manufacturer to additional unnecessary pre-clearance scrutiny due to the bad acts of manufacturers of devices of the same type.

Fourth, the report alleges that FDA existing guidance does not “fully articulate a clear standard that may be applied consistently by reviewers and managers in determining which ‘technological characteristics’ to consider in their decision making, and how to determine whether such characteristics raise ‘different questions of safety and effectiveness.’”  The Working Group acknowledges that such lack of standard or criteria has resulted in inconsistencies in the 510(k) decision making process.  In fact, FDA’s determination whether technological differences raise different questions of safety or effectiveness has been notoriously subjective.

The report recommends revising existing FDA guidance to ensure conformance with language in the FDC Act regarding “different technological characteristics” and “different questions of safety and effectiveness.”  In addition, the Working Group proposes to revise existing FDA guidance to provide clear criteria for identifying different questions of safety and effectiveness, and to identify a core list of technological changes that generally raise different questions.  The goal of providing greater clarity is laudable, but achieving at will be challenging.  Unfortunately, it seems likely that, unless the revisions are device-specific, the proposed guidance, like existing guidance, will have to be written at a high level of abstraction given the heterogeneity of devices regulated as Class II.  It also seems unlikely that revised guidance could make this determination any less subjective and may result in ad hoc decision making.

(2) “CDRH should explore the development of guidance and regulation to provide greater assurance that any comparison of a new device to a predicate is valid and well-reasoned.”

Currently, all devices with 510(k) clearance are potentially available as predicate devices with no time limit.  The Working Group raised concerns about the continued availability of predicate devices that have either been withdrawn from the market for safety reasons or that have become obsolete due to technological advances.  The Working Group also recognized that the public 510(k) database often does not provide sufficient information to help submitters identify an adequate predicate device – and, according to the report, an adequate predicate device is one which raises no safety and/or effectiveness issues, does not have substandard performance, and has not been withdrawn from the market.  (This is not the definition in the FDC Act.)  The recommendations provided in the report include the development of a guidance document to address when a device should no longer be available for use as a predicate device.

The Working Group believes that rescission authority would be useful to eliminate inappropriate predicate devices.  Although the FDC Act does not state that the agency has 510(k) rescission authority, FDA believes that this authority is implicit in the statute.  The Working Group therefore recommends that CDRH consider issuing a regulation to define the scope, grounds, and procedures for exercising its authority to rescind a 510(k). 

FDA issued a proposed rule in 2003 allowing rescission of 510(k)s.  The proposed rule has languished ever since.  This proposal essentially revives the idea.  The problem is that the FDC Act did not really contemplate rescission of 510(k)s, and the withdrawal of a 510(k) creates a potentially cascading effect on other devices cleared in reliance upon that predicate, and also potentially compromises the regulatory status of devices remaining in the field.  What if the manufacturer has discontinued sale of a device with a rescinded 510(k), but still needs to ship accessories to the installed base?  Would that be lawful?  These kinds of practical issues have the potential to create a great deal of mischief.  It will be interesting to see if the agency can make rescission work without significant statutory changes.

The Working Group report also discusses the need to develop guidance on the use of more than one predicate device to establish equivalence, such as when the proposed device combines the intended use and technological characteristics of multiple devices.  One concern with the use of multiple predicate devices is that an analysis conducted for the report shows a greater mean rate of adverse event reports for those devices that cited more than five predicates in the 510(k) submission, something which the Working Group recommends that CDRH analyze further.  (The data used to support this conclusion are not described in the report.)  Recently, we have seen the agency require that manufacturers identify no more than two predicate devices, often times preferring that only one predicate be identified.

Moreover, the Working Group recommends that CDRH no longer allow the use of “split predicates,” which refers to those submissions where the manufacturer uses one predicate to claim intended use and another predicate to claim technological characteristics.  As stated in the report, “[c]oncerns have been raised that the use of a ‘split predicate’ may not allow for a valid comparison of safety and effectiveness because no such device exists . . . and therefore there is no real-world information about its risks and benefits.”  We believe that the agency has already started to implement this recommendation.  This approach may prove to be a formidable obstacle to technological innovation.  The report does not analyze the impact on innovation of a ban on “split predicates,” and, in the absence of “split predicates,” some devices may be inappropriately placed in Class III, requiring premarket approval.  On the other hand, if FDA improves the de novo process, making it less cumbersome and available more often, then a prohibition against “split predicates” might be more palatable.

(3) “CDRH should reform its implementation of the de novo classification process to provide a practical, risk-based option that affords an appropriate level of review and regulatory control for eligible devices.”

The Working Group recognized that CDRH’s implementation of the de novo classification process has been inefficient and has not been utilized optimally across the Center.  CDRH has averaged only about four de novos per year; the last de novo clearance was over a year ago.  One of the reasons is that the FDC Act requires a full 510(k) review prior to initiating the process, even when it is clear that there is no predicate for the proposed device.  Another challenge has been reviewers’ reluctance to agree to de novo review at the outset of the discussions.  Also, the agency develops device-specific guidance to serve as special controls for each device classified into Class II through the de novo classification process, which is a time-consuming process.

The Working Group recommends that CDRH revise existing guidance to streamline the de novo classification process, and proposes the use of pre-submission meetings to discuss the type of information that should be submitted to facilitate the de novo classification process.  The report also said that the Center should consider establishing a generic set of controls that could serve as baseline special controls for devices classified into Class II through the de novo classification process.

(4) “CDRH should take steps through guidance and regulation to facilitate the efficient submission of high-quality 510(k) device information, in part by better clarifying and more effectively communicating its evidentiary expectations through the creation, via guidance, of a new ‘class IIb’ device subset.”

One of the agency’s concerns is its inability to sometimes determine whether a predicate device identified in a submission is a modification of the original cleared device, therefore raising the question of whether it is a valid predicate.  To address this issue, the Working Group made several recommendations for the agency to have better control of unreported device modifications.

The Working Group recommends that CDRH revise existing guidance to clarify the types of changes to a device that do or do not warrant submission of a new 510(k).  Although this would be valuable, it will be impossible for the guidance document to capture all types of changes for all device types regulated via the 510(k) requirements.  Therefore, it is unclear that a revision to existing guidance will help streamline the 510(k) process, facilitate the submission of high-quality device information, or even enhance the agency’s control over unreported device modifications.  There is also a risk that CDRH will use the occasion to revise guidance to require more device modifications to undergo 510(k) clearance, which could slow iterative innovation and improvement in devices, to the detriment of patients.

Another recommendation suggests that CDRH require each manufacturer to provide regular, periodic updates to CDRH listing any device modifications that were implemented without the submission of a new 510(k).  It is unclear how this would be implemented or in what way submitting these tens of thousands of reports annually would foster medical device innovation, but it is certain to burden manufacturers and increase the workload on CDRH reviewers and managers.

The Working Group further recommends that FDA develop guidance to explain manufacturers how to make adequate, structured, and well-supported predicate comparisons in their 510(k)s.  Moreover, CDRH should explore the possibility of requiring each 510(k) submitter to provide as part of the 510(k), non-proprietary photographs and schematics of the device, as well as samples of the device so that CDRH staff could examine the device hands-on as part of the review of the device itself, or during future reviews in which the device in question is a predicate.  The prospect of release of proprietary information is of considerable concern to industry.

The Working Group also recommends providing additional guidance and training for submitters and reviewers on the appropriate use of consensus standards.  In addition, the Working Group recommends that CDRH consider revising Part 807 regulations to require, as is required for the more burdensome PMA applications, a list and brief description of all scientific information regarding the safety and/or effectiveness of the device reasonably known to the submitter.  While generating these summaries may sound like a minor task, for some devices the process will require substantial effort.

Another recommendation is the proposal to develop guidance to define a subset of Class II devices, called “Class IIb” devices, for which clinical information, manufacturing information, pre-clearance manufacturing site inspections, and/or additional post-market surveillance requirements would likely be required to support a substantial equivalence determination.  In addition to delineating the Class IIb types of devices, the Working Group recommends that the same guidance discuss what type of clinical data would be adequate to support clearance.  The Working Group also recommends that the agency continue its ongoing effort to implement a unique device identification system, and consider using “real world” clinical data, such as data from electronic health record systems, as a requirement for future 510(k) submissions.

These recommendations, if implemented, would not likely foster medical device innovation, as it would subject certain Class II devices to more stringent regulatory requirements.  It is unclear that these would be offsetting benefits in improved effectiveness or safety.  The purpose of the 510(k) process is to allow devices fast access to market.  Requiring the submission of clinical and manufacturing information for 510(k) clearance would defeat the purpose of the 510(k) program, making it into a lengthy and burdensome process, similar to that for PMAs, and seems better calculated to hinder, not foster, device innovation.  The review of manufacturing information currently is only required for a very small subset of devices; the intent here seems to apply this requirement more widely.  A small silver lining would be that companies would at least have greater certainty up front as to whether clinical data will be required.
 
(5) “CDRH should take steps to enhance its internal and public information systems and databases to provide easier access to more complete information about 510(k) devices and previous clearance decisions.”

Some of the most useful recommendations include: developing procedures and guidance for the development and assignment of product codes and developing a publicly searchable database for each cleared device that includes a 510(k) Summary, non-proprietary photographs/schematics of the cleared devices, and information identifying the predicate device and corresponding data in support of the clearance.  The Working Group also recommends developing a standardized electronic template for 510(k) Summaries to ensure they contain all information required by regulation.  Another recommendation involves requiring manufacturers to submit final device labeling post-clearance and periodic labeling updates.  The Working Group also recommends developing guidance and regulations to document 510(k) transfers of ownership, which is currently not required by the agency.

Implementing those changes would enhance a manufacturer’s ability to identify an adequate predicate device and provide accurate and up-to-date information on the intended use and technological characteristics of predicates.  All of these reforms are much overdue.  The current CDRH 510(k) database lacks meaningful data to help manufacturers identify adequate predicates.  For example, most 510(k) Summaries do not contain a detailed description of the cleared device, or a discussion of the data submitted in support of clearance.  Without that information, it is difficult and sometimes impossible to identify a predicate device or to determine the likely data support requirements.  And a lack of information on predicate devices introduces unpredictability and uncertainty to the decision-making process.

(6) “CDRH should enhance training, professional development, and knowledge-sharing among reviewers and managers, in order to support consistent, high-quality 510(k) reviews.”

The Working Group recommends that CDRH explore new avenues to enhance the professional development of its review staff and engage outside experts.  Most of these recommendations are reasonable reforms not likely to be controversial within industry.

A specific proposal is to establish a Center Science Council to serve as a cross-cutting oversight body to facilitate knowledge-sharing across offices.  The report also recommends developing a process for regularly evaluating the third-party program; for enhancing third-party reviewer training programs; and for sharing more information with third-party reviewers.  They currently are at an informational disadvantage compared to CDRH reviewers.

The Task Force also made several recommendations which, for the most part, are general in applicability to all of CDRH’s pre-market review programs.  For example, there is a proposal for CDRH to revise its 2002 “least burdensome” guidance to clarify the Center’s interpretation of the “least burdensome” statutory provisions, evaluate the success of the pre-IDE program and agency-industry interactions during the pre-IDE process, and create a mechanism whereby review offices can assemble an ad hoc team of reviewers from different divisions to accommodate unexpected surges in workload. 

In addition, the Task Force recommends that CDRH develop better data sources, methods, and tools for collecting and analyzing post-market information, and take steps to develop a model to help the agency respond to new scientific information, such as using “Level 1- Immediately in Effect” guidance documents or “Notice to Industry” to address a public health concern or a change in regulatory expectations regarding a particular type of device.  The “Notice to Industry” suggestion highlights one of the fundamental challenges for CDRH.  The concept is commendable.  The problem is that communicating “expectations” after they have been set is not very helpful.  Companies need advance notice of changes, and in at least some instances, the opportunity to comment on the changes.  Learning about “evolving expectations” that already have been set is too late for a company that has completed its 510(k) development program.

By Dara Katcher Levy -

In what we believe is DDMAC’s first foray into tackling one of the “gray-areas” created by social media, on July 29, DDMAC issued an Untitled Letter to Novartis Pharmaceuticals for Rx drug content “grabbed” by a Facebook Share widget. 

For those that aren’t familiar with Facebook Share (yes, we know you’re out there), it is a widget placed on a webpage by the webpage operator that allows users to share a link and brief description of that page on Facebook.  The brief description and link are often fed through a “news feed” and shared with Facebook friends.  Although users can add comments to the brief description, they cannot modify the brief description – which is “grabbed” by the widget from the page itself, and may be a “directed grab” of content through the website’s use of html tags. 

The website for Tasigna (nilotinib) capsules contained a Facebook Share widget, located on the right hand side, under efficacy claims, but above the Important Safety Information for the drug.  The brief description grabbed by the widget came from the upper portion of the page, and included the headline and a graphic.  DDMAC’s objection was that the grab contained no safety information, and in some cases, broadened the drug’s indication and made unsubstantiated superiority claims.  DDMAC did not cite the full website itself for any violations, only the grabs created by the Facebook Share widget.

Further, DDMAC cited Novartis for not submitting the Facebook Share grabs on Form 2253.

As industry anxiously awaits DDMAC’s Guidance on the use of the internet and social media (promised by the end of this year), in the interim, we can likely expect some “previews” of the Guidance through further Warning and Untitled Letters on the topic. 

Fortunately, FDLI is publishing in September a book on social media for FDA-regulated companies.  Order now, they make a great Labor Day gift!  (Full disclosure:  HPM co-blogger in chief, Jeff Wasserstein, wrote one of the chapters.)

By Kurt R. Karst –   

Yesterday, Senator Sam Brownback (R-KS) (along with Sen. Sherrod Brown (D-OH)) introduced S. 3697, the Creating Hope Act of 2010.  The bill would amend FDC Act § 524 to change the transferable Priority Review Voucher (“PRV”) program created by the 2007 FDA Amendments Act (the so-called “treat and trade” program), and in particular with respect to rare pediatric diseases.  The introduction of S. 3697 comes on the heels of a July 2010 Senate Health, Education, Labor and Pensions Committee hearing, titled “Treating Rare and Neglected Pediatric Diseases: Promoting the Development of New Treatments and Cures,” at which the idea for the bill was reportedly (according to FDA Week) first floated.  Both Sens. Brownback and Brown have shown a particular interest in rare and neglected diseases, having sponsored provisions in the Fiscal Year 2010 FDA appropriations bill and spearheaded efforts to have provisions included in the Fiscal Year 2011 appropriations bill (see our previous post here).

As we previously reported (here and here), under FDC Act § 524, applicants for certain new drugs and biologics for “tropical diseases” that have received priority review may receive a PRV entitling the holder to a 6-month priority FDA review of another application that would otherwise be reviewed under FDA’s standard 10-month review clock  To our knowledge, FDA has granted only a single PRV – in connection with the April 2009 approval of NDA No. 22-268 for COARTEM (artemether; lumefantrine) for the treatment of acute, uncomplicated malaria infections in adults and children weighing at least five kilograms. 

Among other things included in the 17-page bill, S. 3697 would amend the PRV program to extend it to applications for a “rare pediatric disease” – that is, a disease “recognized in the medical community as affecting a pediatric population” and that is “a rare disease or condition, within the meaning of section 526” (i.e., the Orphan Drug Act).  Such an application must be: (1) a “human drug application” (as defined under PDUFA); (2) “for prevention or treatment of a rare pediatric disease;” (3) “that the Secretary deems eligible for priority review;” (4) “that is for an innovative treatment” (a new term defined in the bill); (5) “that relies on clinical data derived from studies examining a pediatric population and dosages of the drug intended for that population;” and (6) “that does not seek approval for an adult indication in the original rare pediatric disease product application.”

S. 3697 would also amend the PRV eligibility requirements for tropical disease applications.  Currently, in order for a drug product to be eligible for a PRV, four requirements must be met.  Under the bill, in addition to clarifying that only an application for an “innovative treatment” will be PRV-eligible, S. 3697 requires that the application “is for a drug that has not been approved for commercial marketing for any  tropical disease indication by a government authority outside of the United States for more than 24 months before the tropical disease product application is submitted.”

With respect to PRV use and transferability, S. 3697 clarifies that “[t]here is no limit on the number of times a priority review voucher may be transferred before such voucher is used.”  This is consistent with FDA’s interpretation of the current law.  Specifically, FDA clarified in a draft guidance document that although FDC Act § 524 allows for only a single actual transfer of a PRV from the original recipient to another sponsor, “contractual arrangements such as the use of an option or transfer of the right to designate the voucher’s recipient could comply with the terms of the statute.”  S. 3697 would also amend the law to add new notification requirements, timelines, and user fee procedures.

Finally, the bill would establish a process by which a sponsor can request designation of its product as one for a “rare pediatric disease” or that is an “innovative treatment.”  (Perhaps providing a back-door mechanism for a sponsor to learn whether its product would qualify for 5-year new chemical entity exclusivity under the FDC Act or 12-year reference product exclusivity under the PHS Act.)  As mentioned above, the term “innovative treatment” is a defined term in the bill – specifically, as:

(A) a human drug that is the subject of an application submitted under section 505(b)(1), if that drug contains no active ingredient (including any ester or salt of the active ingredient) that has been previously approved in any other application under section 505(b)(1), 505(b)(2), or 505(j) or section 351 of the Public Health Service Act; or

(B) a biological product that is the subject of an application submitted under [PHS Act § 351(a)], if that biological product—
 
(i) does not have the same structure as a biological product that has been previously licensed in any other application under [PHS Act § 351(a) or (k)]  or approved under [FDC Act § 505]; and

(ii) is not biosimilar, within the meaning of section [PHS Act § 351(i), to a biological product that has been previously licensed in any other application under [PHS Act § 351(a) or (k)] or approved under [FDC Act § 505]. [(emphasis added)] 

The limitation of PRV eligibility to 505(b)(1) NDAs is contrary to how FDA has interpreted the current PRV law, which some might say is not entirely clear on whether 505(b)(2) applications are also PRV-eligible.  For example, during a December 2008 public hearing concerning additions to the list of tropical diseases identified at FDC Act § 524, FDA noted that 505(b)(2) applications are eligible for PRVs. 

By Kurt R. Karst –   

FDA’s recent denial of a citizen petition concerning labeling carve-out issues related to the approval of generic versions of LYRICA (pregabalin) – which, by the way, contains some of the most useful insight in years into FDA’s thinking on the issue because it provides myriad examples of the type of alternative language the Agency might accept in a carve-out situation – made us realize that our previous version (here and here) of our Generic Drug Labeling Carve-Out Citizen Petition Scorecard is woefully out of date.  So, without further ado here is the updated scorecard. 

Generic Drug Labeling Carve-Out Citizen Petition Scorecard

FDA Citizen Petition Responses Permitting a Labeling Carve-Out

• FDA Response, Docket Nos. 2001P-0495, 2002P-0191, 2002P-0252 (June 11, 2002) – ULTRAM (tramadol HCl)

• FDA Response, Docket No. 2001P-0495/PRC (Mar. 31, 2003) – ULTRAM (tramadol HCl)

• FDA Response, Docket No. FDA-2003-P-0074 (Apr. 6, 2004) – REBETOL (ribavirin)

• FDA Response, Docket No. FDA-2005-P-0368 (Dec. 1, 2006) – OXANDRIN (oxandrolone)

• FDA Response, Docket No. FDA-2006-P-0274 (Mar. 13, 2008) – ETHYOL (amifostine)

• FDA Response, Docket No. FDA-2007-P-0169 (Apr. 25, 2008) – MARINOL (dronabinol)

• FDA Response, Docket No. FDA-2008-P-0304 (June 18, 2008) – ALTACE (ramipril)

• FDA Response, Docket No. FDA-2008-P-0069 (July 28, 2008) – CAMPTOSAR (irinotecan HCl)

• FDA Response, Docket No. FDA-2006-P-0073 (Nov. 18, 2008) – PULMICORT Respules (budesonide inhalation suspension)

• FDA Response, Docket Nos. FDA-2008-P-0343 & FDA-2008-P-0411 (Dec. 4, 2008) – PRANDIN (repaglinide)

• FDA Response, Docket No. FDA-2008-P-0343/PRC and PSA & FDA-2008-P-0411 (June 16, 2009) – PRANDIN (repaglinide)

• FDA Response, Docket No. FDA-2009-P-0411 – ACTOS (pioglitazone HCl) & ACTOPLUS MET (March 15, 2010) (pioglitazone HCl; metformin HCl) 

•  FDA Response, Docket No. FDA-2009-P-0601 (June 17, 2010) – NAROPIN (ropivacaine HCl monohydrate)

• FDA Response, Docket No. FDA-2010-P-0087 (July 30, 2010) – LYRICA (pregabalin) 

FDA Citizen Petition Responses Not Permitting a Labeling Carve-Out

• FDA Response, Docket No. FDA-2003-P-0002 (Sept. 20, 2004) – RAPAMUNE (sirolimus)

Pending Labeling Carve-Out Citizen Petitions

• Docket No. FDA-2007-P-0294 – ACTOS (pioglitazone)

• Docket No. FDA-2007-P-0113 – THALOMID (thalidomide)

• Docket No. FDA-2009-P-0597 – Fluticasone Propionate and/or Salmeterol Xinafoate Products

• Docket No. FDA-2010-P-0403 – VAGIFEM (estradiol)

BPCA Section 11 Pediatric Labeling Citizen Petitions

• FDA Response, Docket No. 2002P-0469 – ALPHAGAN (brimonidine)

• FDA Response, Docket No. 2001P-0586 – BPCA Implementation

Withdrawn or “Dead” Labeling Carve-Out Citizen Petitions

• Docket Nos. FDA-2004-P-0426 & FDA-2003-P-0081; FDA Letter – SKELAXIN (metaxalone) (see our previous post here)

• Docket No. FDA-2001-P-0445 – NEURONTIN (gabapentin) Capsules

By Kurt R. Karst –   

On August 3rd, Judge Claude Hilton of the U.S. District Court for the Eastern District of Virginia (Alexandria Division) granted  The Medicines Company’s (“MDCO’s”) Motion for Summary Judgment in a long-running dispute (involving all three branches of the federal government) over a Patent Term Extension (“PTE”) for U.S. Patent No. 5,196,404 (“the ‘404 patent”) covering MDCO’s ANGIOMAX (bivalirudin).  In an Order accompanying Judge Hilton’s 31-page opinion, the court remanded the case to the U.S. Patent and Trademark Office (“PTO”) to consider MDCO’s PTE application for the ‘404 patent “timely filed and to adopt an interpretation of § 156(d)(l) that includes a next business day construction for filing of a [PTE]  application.” 

We’ve blogged on MDCO’s efforts to obtain a PTE for the ‘404 patent on several occasions (see e.g., here, here, here, and here), so we won’t give you the blow-by-blow account and all of the twists and turns over the years, but here is the skinny on the current case . . . .

In his August 3rd Opinion, Judge Hilton agreed with MDCO that “the proper interpretation of § 156(d)(1) is a business day construction of the phrase ‘beginning on the date.’  Of the parties’ competing interpretations the business day construction is consistent with the statute’s text, structure, and purpose.”  According to Judge Hilton:

A business day interpretation is consistent with the remedial nature of § 156(d) (1) by limiting the unnecessary and arbitrary loss of property rights.  A business day construction is consistent with the notice function of § 156(d)(1), which focuses on when the product receives permission, such that it would be fair for the applicant's filing period to begin.  Just as the FDA and numerous other agencies apply a business day rule when required to act within a specified time period after receiving a document, an applicant's period to file a PTE application should not begin running until the first business day following the FDA's after-hours transmission of an approval letter.  Moreover, if § 156 is to serve its remedial purpose, it must be construed to require notice to applicants seeking to remedy their losses by filing extension applications.

Section 156(d)(1)'s use of the word "received" supports a business day interpretation. It reinforces the distinction between the act of FDA approval and the point at which an applicant is deemed to have received constructive notice of that approval. A business day interpretation ensures that the phrase "beginning on the date" is given the same meaning in both § 156(d)(1) and § 156(g)(1)(B)(ii). The parallel language and purposes of these two provisions show that Congress wanted the respective dates to be calculated in the same way.

A business day interpretation ensures that, under the PTO's new method of counting days, applicants do not lose a portion of the period Congress granted them. Congress intended for the applicant to have sixty days. The PTO interpreted the statute in a manner that deprives an applicant the sixty days that Congress intended for them to receive. [(citation omitted)]

So now the big question on everyone’s mind is whether the PTO will appeal the decision to the U.S. Court of Appeals for the Federal Circuit.  (Interestingly, the Federal Circuit recently ruled against the PTO on another PTE issue in Photocure ASA v. Kappos, striking down the PTO’s interpretataion of 35 U.S.C. § 156(a)(5)(A).)  We'll keep you posted on any word of an appeal!  And certainly FDA has to be mulling over the decision and considering what reach a business day concept could arguably be asserted with respect to approval decisions, such as after-hours ANDA tentative approvals where 180-day exclusivity forfeiture is concerned. 

By Kurt R. Karst –   

Last week, the Natural Resources Defense Council (“NRDC”) filed a Complaint in the U.S. District Court for the Southern District of New York against FDA in an effort to force the Agency to finalize its topical antimicrobial drug products Over-the-Counter (“OTC”) drug monograph with respect to triclosan and triclocarban.  Both ingredients are found in myriad OTC drug products, including antibacterial soaps.  According to the NRDC, “[t]hese chemicals are suspected endocrine disruptors linked to reproductive and developmental harm in laboratory studies. . . .  FDA needs to issue a final rule on triclosan and triclocarban now, and that rule should ban both chemicals in hand soaps.”

The NRDC alleges in its Complaint that FDA has unreasonably delayed the publication of a final OTC drug monograph with respect to triclosan and triclocarban.  According to the NRDC, “both recent and older studies associat[e] triclosan and triclocarban with significant health risks,” and as such, immediate action by FDA is needed. 

FDA first proposed to regulate topical antimicrobial drug products for OTC use (including those products containing triclosan and triclocarban) in September 1974 in an Advance Notice of Proposed Rulemaking (39 Fed.Reg. 33,103) – one of the earliest actions in FDA”s OTC Drug Review.  Both ingredients (i.e., “conditions”) were designated as “Category II” (i.e., conditions excluded from a monograph on the basis that they are not generally recognized as safe and effective) for certain uses, and triclosan was designated as “Category III” (i.e., conditions excluded from a monograph on the basis that there are insufficient data for FDA to determine their status as generally recognized as safe and effective) for other uses.  Neither ingredient was designated as a “Category I” ingredient (i.e., conditions generally recognized as safe and effective and not misbranded). 

FDA took additional actions in subsequent years, including issuing a Tentative Final Monograph (“TFM”) in 1978 (43 Fed. Reg. 1210), which was later stayed, and a second TFM in 1994 establishing OTC healthcare products as separate from first aid antiseptics (59 Fed. Reg. 31,402).  In the 1994 rule, FDA designated both triclosan and triclocarban as Category III ingredients for most uses, but singled out triclosan as a Category I ingredient for short-term use in patient pre-operative skin preparation, according to the NRDC.  Finally, in May 2003, FDA reopened the administrative record (68 Fed. Reg. 32,003) to accept comments and data on OTC healthcare antiseptic drug products.  FDA has taken no further action under the OTC Drug Review on the ingredients to date.

After meeting with FDA to ascertain a timeline for the Agency’s finalization of the OTC drug monograph for triclosan and triclocarban – and getting nowhere – the NRDC decided to take out its frustration with FDA in court, and highlighted the glacial pace at which FDA has moved to finalize the monograph:

Sixteen years after publication of the amended tentative final order, thirty-two years after publication of the original tentative final order, and thirty-six years after the initial proposed order, the FDA has yet to finalize the Monograph.  In the meantime, [OTC] antimicrobial drug products containing triclosan and triclocarban have proliferated on the market.

Although the NRDC’s Complaint is a bit sketchy on the legal details of its case, the organization broadly argues that FDA has violated the FDC Act and the Agency’s implementing regulations by failing “either to (1) establish the safety, effectiveness, and branding accuracy of products containing triclosan or triclocarban, or (2) prohibit such products from entering interstate commerce.”  In addition, the NRDC asserts that FDA has violated the Administrative Procedure Act (“APA”) by “unreasonably” delaying finalization of the monograph with respect to triclosan and triclocarban, and requests that the court declare such delay violates the APA and the FDC Act and order FDA to finalize the monograph within 90 days of granting the requested relief.

There has also been Congressional interest in the issue, notably a January 5, 2010 letter from Rep. Edward Markey (D-MA) requesting a timeline for FDA’s final action on OTC topical antimicrobial drugs.  FDA declined to provide one, but the Agency did vow to publish a proposed rule and “finalize the rule as quickly as possible thereafter.”  FDA indicated that the Agency would disclose the results of its review of the ingredients in Spring 2011.

By Kurt R. Karst –   

In a Federal Register notice scheduled for publication on August 4th, FDA will announce the Prescription Drug User Fee Act (“PDUFA”) user fee rates for Fiscal Year (“FY”) 2011.  As in all previous years under the fourth iteration of PDUFA, the rates for all three types of user fees – application, establishment, and product – will rise.  Earlier this week, FDA announced the FY 2011 user fee rates for animal drugs, animal generic drugs, and medical devices.  Missing from the litany of products subject to user fees are generic human drugs.  We understand that negotiations for generic human drug user fees are slowly moving forward, and that there is a growing sentiment that legislation will be enacted next year. 

The FY 2011 PDUFA application user fee rates have been set at $1,542,000 for an application requiring “clinical data,” and one-half of a full application fee ($771,000) for an application not requiring “clinical data” and a supplement requiring “clinical data.”  (The term “clinical data” for PDUFA user fee purposes is explained in an FDA guidance document available here.)  Annual establishment and product fees have been set at $497,200 and $86,520, respectively.  The FY 2011 fees go into effect on October 1, 2010.

Although the FY 2011 application fee increased by $136,500, the 9.7% change from FY 2010 is less than the 12.7% jump between the FY 2009 and FY 2010 application rates.  The first table below shows the percent increase since the previous FY for each of the four FYs under PDUFA IV (for each fee type), and should be used with the table from our previous post, which tracks PDUFA user fees since the inception of PDUFA.  The next three tables show the historical trend for each PDUFA user fee. 

The increases in user fee rates, although not unexpected, are sure to boil the blood of some in the industry given FDA’s less than stellar performance record – see our previous post A Not So Sweet 16 for FDA and PDUFA!

On August 4, 2010, the Food and Drug Law Institute (“FDLI”) will host a webinar, titled “FDA’s (Emerging) Oversight of Laboratory-Developed Tests.”  Hyman, Phelps & McNamara, P.C.’s Jeffrey N. Gibbs will moderate the webinar and a panel of speakers that includes FDA’s Elizabeth A. Mansfield, Ph.D., who is Director of Personalized Medicine in the Office of In Vitro Diagnostic Device Evaluation and Safety in the Center for Devices and Radiological Health.  Information about the webinar, including how to register, is available here.

As we recently reported, Laboratory-Developed Tests (“LDTs”) are a hot topic.  In July, FDA held a workshop, during which Agency officials stated that FDA plans to regulate some LDTs as medical devices, ending the enforcement discretion FDA has historically exercised over some LDTs.

By Susan J. Matthees –

POM Wonderful is still in court.  The maker of POM Wonderful pomegranate juice brought suit against Coca-Cola, alleging the Coca-Cola’s Minute Maid Enhanced Pomegranate Blueberry Flavored 100% Juice Blend is misleading and deceptive to consumers because the name suggests that the product is primarily pomegranate and blueberry, when in fact, according to POM Wonderful, the product contains only 0.3% pomegranate juice and 0.2% blueberry juice.  POM brought claims based on California state law for unfair competition and the federal Lanham Act.  As we have reported previously (here, here, and here), POM has been active in litigating numerous cases involving pomegranate juice claims.

The United States District Court for the Central District of California recently granted Coca-Cola’s motion for summary judgment with regard to state law claims that POM lost money as a result of unfair competition.  The court explained that POM cannot show that it actually lost money or property because POM does not have vested shares of the pomegranate juice market and cannot recover for a mere “expectancy” of profits.  The court also granted Coca-Cola’s motion for summary judgment with regard to POM’s Lanham Act claims for the naming and labeling of the Minute Maid juice because the name and labeling “comports with the relevant” Federal Food, Drug, and Cosmetic Act provisions and FDA regulations.  The court also granted Coca-Cola’s motion for summary judgment with regard to POM’s Lanham Act claims that the fruit vignettes on the juice label violate the Lanham Act, explaining that the fruit vignettes are not misleading under FDA’s rules.  However, the court concluded that POM should have the opportunity to demonstrate that Coca-Cola intentionally misled consumers.  

By Kurt R. Karst –   

On Thursday, the U.S. Senate Committee on Appropriations approved the inclusion of the “Preserve Access to Affordable Generics Act” in the report (Senate Report No. 111-238; pages 144-148 & 150-151) accompanying the Fiscal Year 2011 Financial Services and General Government Appropriations Bill (S. 3677).  The action follows testimony  given by Federal Trade Commission (“FTC”) Chairman Jon Liebowitz at a hearing of the House Committee on the Judiciary, Subcommittee on Courts and Competition Policy earlier this week, in which Mr. Liebowitz, a vocal opponent of patent settlement agreements, said that a top competition priority at the FTC is to stop such agreements.  Mr. Liebowitz also revealed that “in the first nine months of FY 2010, there have been more brand-generic settlements involving some sort of compensation – 21 – than in any prior full fiscal year.”

The provisions included in the report would amend the FTC Act to permit the FTC to “initiate a proceeding to enforce the provisions of [new Sec. 28] against the parties to any agreement resolving or settling, on a final or interim basis, a patent infringement claim, in connection with the sale of a drug product.”  Such agreements, if challenged, would be presumptively anticompetitive and unlawful unless it can be demonstrated “by clear and convincing evidence that the procompetitive benefits of the agreement outweigh the anticompetitive effects of the agreement.”  In addition, “[e]ach person, partnership or corporation that violates or assists in the violation of [new Sec. 28] shall forfeit and pay to the United States a civil penalty of not more than 3 times the gross revenue of the NDA holder from sales of the drug product that is the subject of the patent infringement claim for the period of the violation, starting with the date of the agreement.”  The version passed by the Senate committee on Thursday is very similar to previous versions of the “Preserve Access to Affordable Generics Act.”

The measure was supported by Sens. Herb Kohl (D-WI) and Richard Durbin (D-IL) and narrowly survived (by one vote) an amendment by Sen. Arlen Specter (D-PA) to strip the provision.  We understand that Sen. Richard Shelby (R-AL) flipped his position and provided the needed vote to pass the measure.  Earlier in the week, several Senators sent a letter to Senate Majority Leader Harry Reid (D-NV) objecting to the inclusion of the Preserve Access to Affordable Generics Act” in any Fiscal Year 2011 appropriations bill.  According to the Senators who signed the letter:

Banning settlements means that most generic drug manufacturers will not have the incentive to challenge drug patents and thus the consumer market will effectively wait a longer period of time for cheaper generics to come to the market.  While it is true that some generics may win a lawsuit without settlement, in many cases they do not. Settlements allow generic and brand manufacturers to reach agreement and allow generic drugs to come to market faster.  An outright ban of such settlements will potentially eliminate billions of dollars of consumer savings and cause an exponential rise in the average costs of consumer medication.

[Moreover, the] proposed legislation is contradictory to accepted legal reasoning regarding settlements.  Our judicial system, in the interests of efficiency and equitability, relies heavily upon out-of-court settlements. Protracted litigation benefits neither brand manufacturers, generic manufacturers, nor consumers.

The inclusion of the “Preserve Access to Affordable Generics Act” in the Financial Services and General Government spending bill follows two recent failed attempts to attach the bill to legislation.  As we previously reported (here and here), in June Senators Herb Kohl (D-WI), Charles Grassley (R-IA), and Susan Collins (R-ME) proposed an amendment – SA 4332 – during the Senate’s consideration of the Tax Extenders Act (H.R. 4213), and in July the House passed a package of amendments to the War Funding Bill (H.R. 4899) that included the “Preserve Access to Affordable Generics Act.”  The Senate later stripped the measure from the War Funding Bill. 

By Ricardo Carvajal –

FDA released a report summarizing the first seven months of the agency’s experience with its Reportable Food Registry (for more on recent developments pertaining to the RFR, see our prior posting here).  The data summarized by FDA show how the potential adulteration of a widely used ingredient such as hydrolyzed vegetable protein ("HVP") can trigger a deluge of RFR reports.  In March alone, FDA received 1001 reports related to the potential presence of Salmonella in foods containing HVP.  This accounts for almost half of all submissions received by the agency during the entire reporting period.  The data also confirm that less than 10% of submissions are what the agency refers to as “primary reports,” meaning “the initial report concerning a reportable food from either industry or public health officials, such as federal, state, or local regulators.”  The vast majority of submissions are so-called “subsequent reports,” meaning “a report submitted by either a supplier (upstream) or a recipient (downstream) of a food/feed (including ingredients) for which a primary report has been submitted.”  Put these facts together and it appears that the RFR is generating lots of data about the chain of distribution of potentially adulterated products.  Small wonder that the Deputy Commissioner for Foods is singing the RFR’s praise. 

The agency cautions that “it is too early to draw inferences concerning patterns of food and feed adulteration."  However, we can't resist the observation that the vast majority of the primary reports were precipitated by foodborne pathogens and undeclared allergens/intolerances – a pattern similar to what we have observed in Class I recalls. 

By Kurt R. Karst – 

Earlier today, the U.S. Court of Appeals for the Federal Circuit denied Caraco Pharmaceutical Laboratories, Ltd.’s (“Caraco”) and Sun Pharmaceutical Laboratories, Ltd.’s (“Sun”) Petition for Panel Rehearing and Rehearing en banc of an April 14, 2010 Federal Circuit decision in Novo Nordisk A/S v. Caraco Pharmaceutical Laboratories, Ltd. addressing whether the patent delisting counterclaim provisions at FDC Act §505(j)(5)(C)(ii)(I), as added by the Medicare Modernization Act, may be used to correct or delete an Orange Book-listed Patent Use Code (“PUC”).  Interest in the case has been high, as evidenced by the amicus briefs submitted by GPhA, Mylan, Teva, Apotex, Impax, and the Consumers Federation of America.

FDC Act §505(j)(5)(C)(ii)(I) states that:

If an owner of the patent or the holder of the approved application under [FDC Act § 505(b)] for the drug that is claimed by the patent or a use of which is claimed by the patent brings a patent infringement action against the applicant, the applicant may assert a counterclaim seeking an order requiring the holder to correct or delete the patent information submitted by the holder under [FDC Act § 505(b)] or (c) on the ground that the patent does not claim either – (aa) the drug for which the application was approved; or (bb) an approved method of using the drug.

As we previously reported (here and here), last year the U.S. District Court for the Eastern District of Michigan (Southern Division) ruled and issued an Order and Injunction requiring Novo Nordisk, Inc. (“Novo”) to change an Orange Book-listed PUC  for a patent (U.S. Patent No. 6,677,358 (“the ’358 patent”)) on its drug product, PRANDIN (repaglinide) Tablets, as a result of Caraco’s FDC Act §505(j)(5)(C)(ii)(I) counterclaim.  Novo appealed and the Federal Circuit reversed and vacated the district court’s judgment in a 2-1 decision.

The Federal Circuit, in its April 2010 majority opinion, ruled that Caraco “does not have a statutory basis to assert a counterclaim requesting” a court to enter an order to replace Novo’s new PUC with the former PUC.  First, “the Hatch-Waxman Act authorizes a counterclaim only if the listed patent does not claim any approved methods of using the listed drug.”  Second, “the terms of the counterclaim provision do not authorize an order compelling the patent holder to change its use code narrative,” just the patent number and expiration date of an Orange Book-listed patent.  Judge Dyk lodged a 28-page dissent arguing that “the majority’s crabbed view of the statute sanctions an unjustified manipulation of the Orange Book,” and that FDC Act §505(j)(5)(C)(ii)(I) should be available with respect to challenging PUCs, because “all Orange Book information is ‘patent information.’”

The Federal Circuit’s July 29th Order denying Caraco’s/Sun’s rehearing petition is brief, stating, in part, that “[t]he petition for rehearing was considered by the panel that heard the appeal, and thereafter the petition for rehearing en banc, the response to the petition, and briefs amici curiae were referred to the circuit judges who are authorized to request a poll on whether to rehear the appeal en banc.  A poll was requested, taken, and failed.” 

Judges Gajarsa and Dyk, however, took the opportunity to rail against the majority’s decision, stating that:

• The majority’s opinion construes the counterclaim provision contrary to its manifest Congressional purpose.  That construction renders 21 U.S.C. § 355(j)(2)(A)(viii) (“Section viii”) carve-out statements a virtual nullity and leaves generic drug manufacturers without a remedy to challenge inaccurate Orange Book listings with respect to method of use patents.

• With the majority’s blessing, pioneering drug manufacturers now have every incentive to follow Novo’s lead and draft exceedingly broad use codes thereby insulating them-selves from generic competition and rendering Section viii a dead letter.

• Finally, the majority opinion effectively invalidates the FDA’s effort to define “patent information” for the purposes of the counterclaim provision.  This invalidation is especially troubling given Congress’s explicit approval of those regulations.  Without even requesting the views of the FDA, the majority opinion refuses to give effect to the FDA’s interpretation of an important statutory term.

As we previously noted, the number of PUCs have doubled since FDA permitted firms to design their own descriptors in 2003.  Whether the Federal Circuit’s decision will make “section viii” statements a nullity remains to be seen.  In the meantime, we would not be surprised if there is a push to get Congress to amend the FDC Act.

By Kurt R. Karst –   

Earlier this week, the U.S. District Court for the District of Columbia denied Sanofi-Aventis’s Motion for Summary Judgment and granted Cross-Motions for Summary Judgment (here and here) filed by FDA and intervenor-defendants last fall in a dispute over FDA’s approval of applications for generic versions of Sanofi’s drug ELOXATIN (oxaliplatin).  In our previous post on the litigation over generic ELOXATIN – The Oxaliplatin Controversy – a Tale of Intrigue, Secrecy, and Suspense – we reported on the various twists and turns that eventually resulted in the approvals.  The most recent decision affirms what court decision terminates a 30-month stay of ANDA (and 505(b)(2) application) approval in Paragraph IV patent infringement litigation.

When we last left you, FDA had reinstated the approvals for generic ELOXATIN after the U.S. Court of Appeals for the District of Columbia Circuit ordered the dissolution of an administrative injunction suspending the approvals.  Shortly thereafter, on September 10, 2009, the U.S Court of Appeals for the Federal Circuit vacated a judgment (which the Court had previously stayed) from the U.S. District Court for the District of New Jersey that U.S. Patent No.5,338,874 (“the ‘874 patent”) covering ELOXATIN was not  infringed by certain generic applicants.  Just a few days later, Sanofi filed a Motion for Summary Judgment in the U.S. District Court for the District of Columbia in the case it had filed against FDA in August 2009 (Sanofi-Aventis et al. v. Food & Drug Admin. et al., No. 2009-1495) arguing that a stayed judgment is not a “judgment” within the meaning of FDC Act § 505(j)(5)(B)(iii)(I)(aa) (ANDA) and FDC Act § 505(c)(3)(C)(i) (505(b)(2)) terminating the 30-month stay on approval, and that as a result of the Federal Circuit’s September 10th decision vacating the New Jersey district court’s judgment, the 30-month stay on ANDA/505(b)(2) approval was effectively reinstated.  FDA and the intervenor-defendants argued in their Cross-Motions for Summary Judgment that regardless of the Federal Circuit’s stay and subsequent vacatur of the New Jersey district court’s decision, the FDC Act required the Agency to approve the applications once the New Jersey district court entered its judgment with respect to the ‘874 patent.

In ruling on the “purely legal issue of whether a vacatur entered by an appellate court overrides the terminating effect that the entry of a district court judgment has on the thirty-month stay under the FDCA,” the D.C. district court turned its attention to the text of FDC Act § 505(j)(5)(B)(iii) and § 505(c)(3)(C):

In short, there are two ways the thirty-month stay can terminate prematurely.  The first – addressed in the entry of judgment provisions [at FDC Act §§ 505(c)(3)(C)(i) and (j)(5)(B)(iii)(I)] – arises when the district court rules that the patent is invalid or not infringed or endorses a settlement agreement stating that the patent is invalid or not infringed prior to entering judgment.  That scenario ends with the district court; there is no provision for what happens if the district court’s judgment is appealed.  The other scenario [under FDC Act §§ 505(c)(3)(C)(ii) and (j)(5)(B)(iii)(II)(aa)] occurs when the district court determines that the patent is valid and infringed, the judgment is appealed and the court of appeals either reverses the district court judgment and determines that the patent is invalid or not infringed or endorses a settlement agreement stating that the patent is invalid or not infringed before issuing an opinion.  When viewed in context, the omission of a discussion of the appellate process in the entry of judgment provisions is glaring. Accordingly, the court takes this omission to be intentional and concludes that Congress intended the thirty-month stay to terminate upon the entry of judgment by a district court that a patent is invalid or not infringed without regard to the appellate process.

Although not implicated in the litigation, the court noted that Congress made reference to the appellate process in the ANDA 180-day exclusivity forfeiture provision at FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA).  This provision states that in a failure-to-market forfeiture analysis one event that is considered is when “a court enters a final decision from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has or can be taken.”  Thus, the court determined that “the lack of limiting language in the entry of judgment provisions – in contrast to the successive sections and the forfeiture provision – is sufficient to demonstrate Congress’s intent that the entry of judgment by the district court be the event that triggers the termination of the thirty-month stay notwithstanding any subsequent appeal or ruling by the appellate court.”

Presumably the district court’s decision will put this matter to bed, but an appeal is always possible.

By Alexander J. Varond* & Diane B. McColl –

As noted in our blogpost less than two months ago, the U.S. District Court for the District of Columbia held that FDA acted unconstitutionally in Alliance for Natural Health, US v. Sebelius when the agency limited qualified health claims (“QHCs”) concerning selenium and reduced incidence of certain cancers proposed by Wellness Lifestyles, Inc.  In part, the court held that FDA erred when it “completely eviscerated plaintiff’s claim” rather than adopting a less restrictive approach such as drafting “short, succinct, and accurate disclaimers.”  We viewed the Alliance for Natural Health (“ANH”) decision as potentially cementing in place a regime for FDA’s review of qualified health claims that is very favorable to health claim petitioners. 

Now a new challenge to FDA’s restrictive treatment of health claims in foods and dietary supplements seeks to build on ANH’s success.  In a recently filed complaint in the U.S. District Court for the District of Connecticut, Fleminger, Inc. (“Fleminger”) contests FDA’s reaction to its proposed QHC regarding green tea and the incidence of breast and prostate cancers.  The tea maker claims that by mandating the use of specific language for the QHCs, FDA violated the company’s commercial free speech rights under the First Amendment of the U.S. Constitution.

Fleminger, which sells green tea at www.teaforhealth.com, submitted its health claim petition to FDA on January 27, 2004.  The company claimed that its green tea QHC was based upon two separate studies.  In its June 30, 2005 enforcement discretion letter response, FDA acknowledged that, although the studies were “weak,” they did point to “limited credible evidence” that green tea may provide some benefit against prostate and breast cancers.  However, FDA stated that stronger, more credible studies did not show an effect of green tea on either prostate or breast cancer.  Thus, FDA decided to allow only the following heavily qualified claims:

Two studies do not show that drinking green tea reduces the risk of breast cancer in women, but one weaker, more limited study suggests that drinking green tea may reduce this risk.  Based on these studies, FDA concludes that it is highly unlikely that green tea reduces the risk of breast cancer.

One weak and limited study does not show that drinking green tea reduces the risk of prostate cancer, but another weak and limited study suggests that drinking green tea may reduce this risk.  Based, on these studies, FDA concludes that it is highly unlikely that green tea reduces the risk of prostate cancer.

Fleminger’s petition for administrative review was denied on August 19, 2008.  FDA justified its denial by stating that the two QHCs “provide the ‘precise language’ that allow Plaintiff’s qualified health claims to be ‘truthful and not misleading.’” 

Subsequently, on February 22, 2010, FDA issued a warning letter to Dr. Sin Hang Lee of Fleminger that threatened “the seizure of [Fleminger’s] illegal products and injunctions against manufacturers and distributors of those products.”  The FDA also reasserted that Fleminger was required to use  without modification, only the exact QHC language that FDA set forth in its enforcement discretion letter.

Fleminger responded by filing a complaint in the U.S. District Court for the District of Connecticut, asserting that FDA essentially required the company to “choose between speaking exactly as [FDA] wish[es], remaining silent, or risking adverse action for its own commercial speech in violation of the First Amendment.”  Furthermore, it alleges that by forcing Fleminger to use the “government’s speech or none at all,” FDA failed to use the “least restrictive means of preventing any alleged deception of consumers who choose to purchase [Plaintiff’s] green tea.” In addition, the complaint charges that FDA’s prohibition on Plaintiff’s speech was overly broad and amounted to an unconstitutional prior restraint.

A ruling in Fleminger’s favor would confirm that FDA’s ability to allow only severely restricted and narrow QHCs has been  drastically reduced.  Such a success would send yet another strong signal to the agency that FDA needs to revamp its strict approach toward food and dietary supplements QHCs.

* Law Student

By Jamie K. Wolszon & Jeffrey N. Gibbs –

FDA officials, at a July 19-20, 2010 workshop, stated that the agency intends to end the “exercise enforcement” authority over some laboratory-developed tests (“LDTs”).  Put more plainly, FDA now plans to regulate some LDTs as medical devices.  However, while FDA was clear that it plans to regulate LDTs, key FDA officials, including Center for Devices and Radiological Health (“CDRH”) director Jeffrey Shuren emphasized that the agency had not decided on the details of their regulatory scheme. 

LDTs are diagnostic tests developed and performed by a single laboratory.  They are widely used; virtually all genetic tests are LDTs, as are many tests for emerging diagnosis and for rare conditions.  Regulating these tests will raise many policy, regulatory, legal, and public health questions.

Many attendees, panelists and presenters at the meeting accepted the idea of FDA regulation of LDTs.  However, many speakers stressed that FDA must proceed carefully or the regulation of LDTs could have unintended negative consequences. 

Those potential unintended consequences include reduced innovation, delay in developing tests, fewer improvements in tests, and limiting patient access to tests.  Many speakers were particularly concerned about the effect on tests that are developed in response to new and emerging threats, and tests for rare disorders.  According to many meeting attendees, patient care could suffer and advances into personalized medicine could slow if LDT regulation is not implemented in a balanced manner.

One of the FDA speakers, Elizabeth Mansfield, Director for Personalized Medicine, Office of In Vitro Diagnostic Device Evaluation and Safety (“OIVD”) at CDRH, said that the framework for regulation of LDTs still needs to be written.  Elements that need to be outlined by the agency include: risk categorization, a phase-in period for premarket review and quality systems requirements for new LDTs; registration and listing; and inspections of laboratories.  Other speakers identified additional details that would need to be addressed.

The End of Enforcement Discretion?

Starting in 1992, FDA asserted that all LDTs are devices subject to regulation under the Federal Food, Drug, and Cosmetic Act.  Since then, the agency said it was exercising its enforcement discretion and not regulating LDTs.  Thus, the primary federal regulation of laboratories has been under the Clinical Laboratory Improvement Amendments of 1988 (CLIA).  As a number of speakers noted, LDTs are also regulated by the states (notably New York) and other bodies (notably the College of American Pathologists) (“CAP”).

Until recently, FDA has departed from this position of enforcement discretion in relatively few instances.  For example, FDA has asserted that a test was not a true LDT and advanced its controversial and now-defunct proposal to regulate a subset of LDTs, known as In Vitro Diagnostic Multivariate Index Assays (“IVDMIAs”).  (IVDMIAs are tests where the results of multiple markers are combined to generate an “index score.”)

We previously reported that FDA announced last month that it is revisiting its years-long policy of exercising enforcement discretion over LDTs, and considering adopting a risk-based framework.  The agency announced that it was holding the July 19-20 workshop as a first step to gather comment on how to more actively regulate LDTs.

FDA officials at the meeting reiterated that they intend to regulate at least for some LDTs.  FDA is still grappling with many unanswered questions as to the details of a regulatory scheme.  As shown by the debate over the less sweeping IVDMIA proposal, extending FDA regulation to LDTs will raise many questions.  Issues discussed at the meeting include the following.

Notice and Comment Rulemaking

The agency took the position that FDA does not need to pursue notice-and-comment rulemaking to implement this policy shift.  Dr. Shuren stated that because the laws which permits FDA to regulate laboratories are already in effect; the agency merely has been exercising its enforcement discretion, and therefore can implement the new regulatory framework through guidance. 

Notice-and-comment rulemaking is a more demanding process than issuing a guidance.  For example, in notice and comment rulemaking, FDA must consider and respond to each of the primary comments.  In a guidance, the agency does not have to address comments.  Rulemaking must explicitly address other factors, such as economic impact.  When FDA proposed to regulate IVDMIAs, it also did so through guidance.

A few attendees urged the agency to proceed through notice-and-comment rulemaking.  For example, Anna Longwell, of Longwell and Associates, questioned the approach of moving forward through guidance instead of rulemaking.  Ms. Longwell said there should be a formal notice of proposed rulemaking.  If FDA does proceed to regulate LDTs through a guidance document, any legal challenge is likely to assert that FDA violated the Administrative Procedure Act by skipping the rulemaking process. 

Risk Categorization and Premarket Review

The agency must determine how it will categorize risk.  Meeting presenters and attendees provided examples of possible categorization schemes.

Examples of tests that the agency might consider high risk, according to Dr. Mansfield, include companion diagnostics, such as an LDT used to help determine whether the drug is used properly.  Other examples of high-risk tests include those where an undetected false result could seriously affect the patient; tests that diagnose cancer; and tests that manage serious diseases.

Examples of medium-risk tests provided by Dr. Mansfield include those that could lead to non-serious injury; those where it is easy to detect false results; and adjunctive tests.  Medium-risk tests also could include those where it could lead to psychosocial issues and genetic tests where the assessment is based on a phenotype and the genetic tests are merely confirmatory.  They also include those tests intended to monitor patients with a known disease. 

Examples of lowest-risk tests are those that are highly adjunctive, and for medical knowledge only and evaluation without directed management.  Examples of low-risk tests also include those that have little clinical impact.

Asked whether a test intended for use in evaluating cancer recurrence would be high-risk, Dr. Mansfield responded that currently tests that monitor the cancer of someone who already has been diagnosed generally is not high-risk, although it would depend on the specific claims made.

William Clarke, representing the American Association for Clinical Chemistry (AACC), advocated a classification scheme that includes three categories: high risk, moderate risk, and low risk.  He said that IVDMIAs should be high risk under the upcoming scheme and that high-risk tests should be subject to FDA oversight.  

Gail Vance, representing CAP, proposed that low-risk LDTs be validated and placed into service.  An accredited organization would inspect the low-risk LDTs.  For moderate-risk LDTs, the laboratory would validate the test and then give the data to an accredited party to review.  For high-risk LDTs, there would be validation and the laboratory then would give the data to FDA to review.

Other speakers offered their own ideas.  A key element of any regulatory scheme will be to appropriately and precisely define which tests are subject to FDA regulation.  Ambiguous criteria will create confusion and uncertainty.  In follow-up discussions with clinicians regarding the representative classification of well-known markers, we found that they often sharply disagreed about the correct classification.  Characterizing the risk can get even more difficult with new intended uses.   
 
Quality Systems Regulation (“QSR”)

Several presenters said it will be difficult for laboratories to comply with the QSRs.  (21 C.F.R. Part 820.)  Of particular concern is the design control requirement.  There appears to be agreement that how QSRs would be applied is an important practical issue, but there was no consensus on that topic.  One suggestion was that FDA rely on inspections by third parties conducted pursuant to CLIA.

Advisory Panel IVD Classification

Some attendees noted that the agency will have to consider how to conserve resources, including staff, as it embarks on such a massive undertaking of regulating LDTs.  Depending on what LDTs are subject to regulation, FDA could receive many new pre-Investigational Device Exemption (“IDE”) requests and marketing applications.  Moreover, because of their novelty, many of these tests will place greater demands on OIVD.  Dr. Mansfield suggested that the agency is considering using advisory panels for down classifications of current IVDs, which would free up staff.  Several meeting attendees, including Elaine Lyon at the Association for Molecular Pathology, recommended use of advisory committees for risk categorization of LDTs.

Phase-In Period for new LDTs

FDA is considering phasing in new premarket review and quality systems requirements over time to help facilitate predictability and planning, according to Dr. Mansfield.  FDA could first require compliance for high-risk tests, and later implement requirements for other tests, she suggested.

Applying New Scheme to Currently Marketed LDTs

When the agency proposed to regulate IVDMIAs, it proposed a grandfather period – albeit a comparatively short one – during which companies already marketing those tests would have a certain amount of time to submit premarket review applications.  Asked how the agency would treat tests already offered, Dr. Mansfield responded that the agency does not yet know the answer to this question.  She did state, however, that the agency has no intention of disrupting clinical testing. 

One presenter suggested that FDA grandfather in all LDTs approved by the New York State Department of Health.

Registration and Listing

FDA also seeks a way to determine a list of who offers what tests.  Dr. Mansfield noted that the National Institutes of Health is in the process of establishing a voluntary genetic testing registry.  Dr. Mansfield noted that FDA probably will need to expand registration and listing to include LDTs.  A number of speakers thought that a mandatory registry could play a constructive role.

Utilizing CLIA Inspectors
 
Dr. Mansfield also noted that the agency is considering piloting third-party accreditation for inspection of LDTs.  Currently, the CLIA scheme for regulating laboratories includes an inspectional requirement.  In addition, the CAP inspects laboratories for accreditation.  FDA could use those same CLIA or CAP inspectors to conduct inspections on FDA’s behalf. 

Rare Disorders

Attendees almost universally recognized tests for rare disorders as needing special protection under the future scheme.  Some, including William Clarke, representing the AACC, recommended exempting tests for rare disorders from the future regulatory scheme.  While it was suggested by attendees that the Humanitarian Use Device/Humanitarian Device Exemption program could help, these mechanisms can play only a limited role.  The HUD/HDE process is unavailable if the number of patients to be tested exceeds 4000 per year.

Emergencies Including Infectious Diseases

Several attendees noted that when an emerging disease arises, LDTs are often the first test to meet that previously unmet need.  Delaying the introduction of these tests could hamper public health agencies in responding in the case of an emergency. 

Steve Gutman, the former Director of OIVD, noted that the agency can process with emergency use authorizations (“EUA”) rapidly; however, some attendees appeared unconvinced that the EUA program would be sufficiently timely or responsive, particularly for less common emerging diseases.

Modifications and Personalized Medicine

Attendees also warned that an unintended consequence could be to reduce modifications made to tests and to slow advances in personalized medicine.  Once a product is cleared or approved, even relatively small modifications can trigger the need for a new submission.  Thus, the ability to rapidly incorporate new information into assays could be impeded.

Conclusion

The expansion of FDA’s device regulatory scheme to LDTs – even a small subset of LDTs – will raise significant questions.  Many speakers expressed their hope that this will be a collaborative process.  The FDA’s release of series of letters issued to laboratories on the first day of the meeting did prompt some concerns as to whether this hope would be realized fully.  Given the complexity of LDT regulation and its potential consequences – both expected and unexpected – it is critical that this wish for active collaboration be granted.