By Jennifer D. Newberger –

In the Federal Register of May 8, 2013, FDA announced a public meeting titled “510(k) Device Modifications:  Deciding When to Submit a 510(k) for a Change to an Existing Device.”  The notice states that the focus of the meeting will be “FDA's interpretation of its regulations concerning when a modification made to a 510(k)-cleared device requires a new 510(k) submission.”  The meeting is to be held on June 13, 2013, from 9am to 5pm.  The registration deadline is May 30, 2013.

As discussed in our previous blog post, in July 2011 FDA issued a guidance document intended to update the 1997 guidance of the same name as the meeting.  The guidance was met with strong resistance from industry, insisting that the interpretations applied in the guidance would result in the requirement to submit a new 510(k) for numerous device modifications.  In response to the feedback from industry, Congress, in enacting the Food and Drug Administration Safety and Innovation Act ("FDASIA") in July 2012, required FDA to withdraw the guidance and prohibited FDA from implementing a new guidance until it submits a report to Congress describing when a new 510(k) should submitted.  The report must include FDA’s interpretation of several key phrases in 21 C.F.R. 807.81(a)(3), the regulation governing submission of a new 510(k) for a modification to an existing product.  In addition, the report must include “possible processes for industry to use to determine whether a new 510(k) is required, and how to leverage existing quality system requirements to reduce premarket burden, facilitate continual device improvement, and provide reasonable assurance of safety and effectiveness of modified devices.”  The public meeting is intended to solicit stakeholder feedback on these issues.  On a related note, FDA recently issued a draft guidance on when modifications must be reported to FDA, which also received substantial negative feedback from industry (see our previous post here).  Perhaps issues discussed at the 510(k) meeting will shed light on those concerns as well.

In the notice, FDA provides a number of specific policy options on which it is seeking feedback, but notes that “implementation of some of these options may require regulatory changes beyond a guidance document.”  These options appear to be new ideas that have not previously been presented by FDA, and ones that industry would likely agree require changes beyond a guidance document.  In some cases, the changes may require statutory, rather than merely regulatory, changes.

The notice sets forth five policy options, and also asks for ideas of additional policy proposals and examples of device changes that industry believes should not trigger the requirement for a new 510(k).  Under each of the five policy options, FDA poses questions on which it is seeking comment prior to the public meeting and will be discussed at the meeting.

The five policy options and examples of the questions for feedback include:

A. Risk Management

FDA says it is primarily concerned with identifying a way to incorporate risk management to ensure “appropriate and consistent modification decisions by industry and FDA staff.”  Such decisions are those “that allow for both medical device innovation and effective FDA oversight of device changes.”  FDA recognizes the importance of ensuring a process to ensure consistent results, since decisions will be made by a variety of different manufacturers and FDA reviewers.  To address these concerns, FDA seeks input on the following:

1. How can FDA tie risk management to the decision that a change or modification to a device could significantly affect the safety or effectiveness of the device?
2. Given the variability in risk management processes and guides, how can a single risk management process be chosen that leads to consistent and appropriate decisions on whether a 510(k) is required for a device modification?
3. How can the inherent subjectivity of risk management be controlled to ensure consistent and appropriate decisions on whether a 510(k) is required?
4. How can FDA assure that a company’s risk management process is comprehensive and appropriately implemented?

B. Reliance on Design Control Activities

The notice expresses FDA’s desire for effective oversight of the design control process, including the opportunity to review design control activities.  FDA states that “improper application of these activities may lead to incomplete or inaccurate evaluations of design changes and the marketing of unsafe or ineffective devices.”  In considering how FDA can affect oversight of design controls, FDA seeks input on the following:

1. Since FDA does not typically review design control information prior to clearance, how can FDA ensure that design control activities will limit the potential for marketing modified devices that may be unsafe or ineffective?
2. Manufacturers comply with design control requirements in a variety of different manners.  How can FDA ensure consistency in use of design controls to ensure that only safe and effective modified devices are marketed?

C. Critical Specifications

FDA states in the notice that critical specifications could be one way that FDA could link use of design activities to 510(k) modification decisions.  This would involve industry and FDA identifying “essential” or “critical” specifications and agreeing on limits and testing protocols for those specifications.  So long as the modified device remains within those limits, no new 510(k) would be required.  FDA indicates that it would like to discuss the feasibility of this approach with industry, and how it might be implemented.  It also states that this approach would not apply to changes to intended use or labeling, “as those aspects of a device are not associated with specifications.”

Based on information provided in the notice, it appears that this approach may be quite burdensome for manufacturers and reviewers.  FDA states that, in an initial 510(k) submission, manufacturers would have to identify the following information:  a list of potential changes that might be made; critical specifications for each change, i.e., those specifications “that are essential to safe and effective use of the device (e.g., tensile strength)”; bounds for those specifications within which a modified device must remain; and the verification and validation test protocols that will be used to examine the specifications pre- and post-modification.  Providing this information would require a significant amount of work by sponsors, and raise new issues for FDA reviewers.

Given the above, FDA is seeking input on the following questions:

1. How could critical specifications be incorporated into the review process?  For example, if FDA and the sponsor cannot agree on the critical specifications, but FDA is otherwise prepared to proceed with a substantial equivalence decision, how should that be handled?
2. How could critical specification agreements be documented?
3. Should use of critical specifications be limited to certain types of changes?  If so, which ones?
4. Are there certain specifications that could be deemed critical for all devices?  If so, which ones?
5. Could critical specifications be implemented as an optional paradigm, meaning that manufacturers could elect to use it where convenient, and if not elected, the change would remain subject to the 510(k) modifications decision-making paradigm?

D. Risk-Based Stratification of Medical devices for 510(k) Modifications Purposes

Under this framework, FDA would expect 510(k)s for modifications of higher risk devices that meet the standard in 21 C.F.R. § 807.81(a)(3), whereas for lower risk devices, not all modifications would require a 510(k) even if they meet the regulatory standard.  Certain modifications, such as a change in intended use, would always require a 510(k), regardless of the level of risk of the device.  FDA has the following questions about this approach:

1. How should FDA designate higher or lower risk devices?  Are higher risk devices only those designated as life sustaining, life supporting, or implants?
2. Should FDA require some other measure, such as periodic reports, in lieu of 510(k) submissions for lower risk devices?
3. How should FDA determine which modifications to lower risk devices require 510(k) submissions and which do not?

E. Periodic Reporting

FDA is seeking feedback on the submission of periodic reports for modifications to 510(k)-cleared devices that did not require a new 510(k) submission.  FDA acknowledges that this would “be similar to annual reporting of device changes for approved class III devices.”  It also states that FDA would review these changes to “ensure that decisions were made appropriately.”

FDA would like feedback regarding:

1. How often FDA should require periodic reports?
2. Should FDA require periodic reports for all 510(k) devices or only certain devices?  If only certain devices, which ones?
3. What information should be included in a periodic report?

This seems like an option that probably would not appeal to industry as crafted, as it would be imposing an additional obligation not currently required by the regulations.  Moreover, it would almost certainly lead to second-guessing “no-file” decisions.  If FDA and industry can work to clearly delineate when a new 510(k) is required for a modified device, there should be no need for FDA to review information about modifications that do not fit that paradigm.

Given the negative industry response to the July 2011 draft guidance, industry should take advantage of this opportunity to work with FDA to design a modifications paradigm that will meet the regulatory requirements without imposing burdens unnecessary to assure the development and marketing of safe and effective medical devices and enable further product improvements.

The issue of 510(k) modifications is both recurring and important.  This public meeting will not be the final word.  Still, it provides an important forum for responding to some novel ideas that have been broached by FDA.

On May 4, 2013, Hyman, Phelps & McNamara, P.C. Director Jeffrey K. Shapiro presented a draft paper and slides on the 510(k) medical device substantial equivalence program during a conference on FDA in the 21st Century.  The conference was held at the Harvard Law School’s Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics (see our previous post here).  The draft paper argues that the 510(k) program is an excellent approach to the premarket review of medium risk medical devices, and has strengths that critics have overlooked.

The draft paper can be found here.  The slides presented on May 4 are available here.

By Kurt R. Karst –       

Late last Friday, FDA announced that the Agency denied an August 13, 2012 Citizen Petition (Docket No. FDA-2012-P-0895) submitted by Endo Pharmaceuticals Inc. (“Endo”) requesting that the Agency determine that OPANA ER (oxymorphone HCl) Extended-release Tablets approved under NDA No. 021610 were discontinued for safety reasons in light of the availability of a reformulated version of OPANA ER approved under NDA No. 201655, and that FDA refuse to approve any pending ANDAs and suspend and withdraw the approval of any ANDAs citing original OPANA ER as its Reference Listed Drug.  The decision, which is apparently the first under the new 270-day timeframe at FDC Act § 505(w) covering discontinuation petitions submitted pursuant to 21 C.F.R. § 314.161, comes less than a month after FDA determined that OXYCONTIN (oxycodone HCl) Controlled-release Tablets approved under NDA No. 020553 were discontinued for safety reasons in light of the availability of a reformulated version of OXYCONTIN approved under NDA No. 022272 (see our previous post here).  On the same day FDA announced its decision concerning reformulated OXYCONTIN, the Agency approved abuse-deterrent labeling for the drug.  A decision on abuse-deterrent labeling for reformulated OPANA ER did not surface last week, perhaps presaging FDA’s petition decision.

Endo argued in its petition that the reformulated version of OPANA ER approved under NDA No. 201655 (referred to as “OPR”) offers safety advantages over original OPANA ER (referred to as “OP”) because, among other things, the reformulated version “is resistant to crushing by common methods and tools employed by abusers of prescription opioids . . . [and] is less likely to be chewed or crushed even in situations where there is no intent for abuse, such as where patients inadvertently chew the tablets, or where caregivers attempt to crush the tablets for easier administration with food or by gastric tubes, or where children accidentally gain access to the tablets.”  According to FDA, however, “[w]hile there is an increased ability of OPR to resist crushing relative to OP, data from in vitro and pharmacokinetic studies show that OPR’s extended-release features can be compromised, causing the product to ‘dose dump,’ when subjected to other forms of manipulation such as cutting, grinding, or chewing, followed by swallowing.”  Moreover, commented FDA, it “appears that OPR can be prepared for insufflation (snorting) using commonly available tools and methods, [and] certain data suggest that OPR can more easily be prepared for injection than OP.”  In addition, the data from the postmarketing investigations Endo relies to support the advantages of OPR over OP “are inconclusive,” determined FDA.

Citing drug product and data differences in the cases of OPANA ER and OXYCONTIN, FDA says that it is reasonable for the Agency draw different conclusions:

Based on in vitro, pharmacokinetic, clinical abuse potential, and post-marketing data, we were able to conclude that [original OXYCONTIN] posed an increased potential for intranasal abuse compared to [reformulated OXYCONTIN]. . . .  While the available data show that there is an increased ability of OPR to resist crushing relative to OP, OPR still can be prepared for insufflation (snorting) using commonly available tools and methods. . . . .  [T]he preliminary data from the Opana ER post-marketing investigations have significant limitations and are not as mature as the OxyContin postmarketing investigations . . . .

Perhaps the most important takeaway from FDA’ petition decision is this message: “Our decisions take into account the totality of the evidence for the particular drug at issue, and must be made on a case-by-case basis.”  The OPANA ER and OXYCONTIN decisions can thus perhaps be viewed as bookends (or at least two opposing points on a continuum) for how FDA will address similar issues in the future.  And it seems highly likely that the issue will arise again.  It may arise when a non-abuse-deterrent version of a drug is replaced with a reformulated version alleged to be abuse-deterrent, or perhaps where an abuse-deterrent version of a drug is replaced with a new and improved abuse-deterrent version.

A recent Freedom of Information Act (“FOIA”) decision from the U.S. Court of Appeals for the Fourth Circuit sends a strong message to federal agencies that the statutory time limits for FOIA responses must be honored.

On February 29, 2008, John J. Coleman filed a FOIA request with the Drug Enforcement Administration (DEA) seeking documents related to the scheduling of a drug, carisoprodol, under the Controlled Substances Act.  Dr. Coleman offered to reimburse appropriate costs up to $1,000.  Under FOIA, the DEA had 20 working days to respond unless it notified Dr. Coleman that “exceptional circumstances” warranted an extension.  The DEA did not provide a notice of exceptional circumstances and did not respond at all until “one year, four months, and ten days after receiving Dr. Coleman’s request.”  At that time, the DEA denied the request, on the grounds that $1,000 would not cover estimated fees of $1,780.75.  Dr. Coleman appealed the fee assessment to the Department of Justice’s Office of Information Policy (“OIP”).  He contended that fees should not apply given the DEA’s “excessive delay” and given that he was eligible for a fee waiver as a noncommercial requester.  The OIP took “seven months and eleven days” to respond.  The OIP apprised Dr. Coleman that it had remanded his request to the DEA for “reprocessing, including further consideration of [the appropriate] fee category.”  After hearing no response for another four months, Dr. Coleman filed suit pro se in federal district court.  The DEA moved for summary judgment arguing that Dr. Coleman had failed to exhaust administrative remedies and failed to pay the necessary fees for processing his request.  The district court granted the DEA’s summary judgment motion.  Dr. Coleman appealed to the Fourth Circuit.  The Fourth Circuit, in Coleman v. DEA, reversed and remanded, finding in no uncertain terms that the DEA and OIP had demonstrated an “utter lack of due diligence” and that Dr. Coleman had faced “extended and inexcusable agency delay.” 

The Fourth Circuit opinion, in effect, closes two potential loopholes in the FOIA time limits.  First, the court rejected an argument by the DEA that it and the OIP had responded to Dr. Coleman prior to his lawsuit, and that even if the responses were not timely, the responses barred suit.  The court reasoned that despite the DEA’s and OIP’s responses, to date, the continuing remand amounted to a continuing non-response and that “[a]lthough FOIA does not explicitly contemplate remands following administrative appeals, it is inconceivable that Congress intended to allow agencies to escape FOIA’s time limits by sitting on remanded requests indefinitely.”  Second, the court rejected DEA arguments that Dr. Coleman had not exhausted administrative appeals for his fee waiver request.  The court reasoned that “[t]he DEA would create a rule under which a FOIA requester must make distinct arguments addressing every individual component of an adverse fee determination before obtaining judicial review of that determination.”  It observed further that “holding an ordinary citizen . . . to such an exacting standard would impose a burden not authorized by FOIA and would frustrate the statute’s purpose of ‘assur[ing] the availability of Government information necessary to an informed electorate.’”    

It is worth noting that the OPEN Government Act of 2007 was not in effect at the time of Dr. Coleman’s FOIA request.  It now provides federal agencies another means of extending the 20 day response period, besides “exceptional circumstances.”  Under the “new” exception, if a federal agency finds that it needs additional information in order to respond to a request, it may contact the requester and, thereby, toll the 20 day period until it receives a reply.  Even with the new exception, Coleman nevertheless portends that agency delays outside of the ambits of the law will not be tolerated. 

By Riëtte van Laack –

Senator Barbara Boxer (D-Calif.) and Representative Peter DeFazio (D-Ore.) recently introduced the Genetically Engineered Food Right-to-Know Act (S. 809 and H.R. 1699) that would direct FDA to require labeling to identify genetically engineered (“GE”) foods “so that consumers can make informed choices about what they eat” (see here).

The bill would require labeling of virtually all GE whole and processed food (including dietary supplements).  Exceptions include medical foods, foods served in restaurants and other similar eating establishments, and foods containing GE processing aids, such as yeast.  The proposed bill includes a provision that allows manufacturers to rely on guarantees by their suppliers that the food ingredients supplied are not GE, thereby reducing the testing burden on manufacturers.

Under FDC Act sections 403(a)(1) and 201(n), a food is misbranded if its labeling is false or misleading in any particular, including by  failing to disclose facts material with respect to the consequences which may result from use of the food under customary or usual conditions of use.  Since 1992, however, FDA has taken the position that bioengineered foods (FDA prefers the term bioengineered to GE) as a class are not materially different from conventional foods, and therefore there is no basis to require labeling that specifies their method of production. 

However, consumers (or at least consumer activists) appear to disagree.  In 2011, several consumer advocacy organizations petitioned FDA to develop regulations requiring labeling of GE foods, arguing that there is a material difference between GE and non-GE foods (see our previous post here).  In addition, legislation that would require labeling of GE foods has been introduced in a number of states.  Thus far, these efforts have met with limited success.  Recently, some retailers have stepped in.  A couple of months ago, Whole Foods announced that it will require that any GE foods sold in its stores must be labeled as such by 2018.

Which effort will succeed remains to be seen.  However, it appears that GE labeling of foods is could well become a reality, be it through legislation or other means. 

By Kurt R. Karst –      

Growing up in the late 1970s and 1980s I was a fan of several science fiction television series and movies: Doctor Who, Star Wars, and, of course, Star Trek.  I remember well the voyages of the starship Enterprise under the command of Captain James T. Kirk (in rerun).  I also  remember the September 1987 premier of Star Trek: The Next Generation, when command of the Enterprise changed to Captain Jean-Luc Picard.  Like many Star Trek fans, I grew to like the style of Captain Picard, while still appreciating the standard set and foundation laid by Captain Kirk.  Life, like television series and the movies, is full of transitions – a “handing off of the baton.”  The Food and Drug Bar is no different. 

As I think back on my development as a member of the Food and Drug Bar, and, in particular, on my development as an attorney who specializes on drug matters, particularly with regard to the Hatch-Waxman Amendments, two memories immediately come to mind.  The first memory is as a budding attorney while working for Hoffmann-La Roche in Washington, D.C. in the late 1990s.  George Johnston, Vice President and Chief Patent Counsel at Hoffmann-La Roche, introduced me to the Hatch-Waxman Amendments.  The complexity of the statute immediately grabbed my interest.  My second memory is of being led to the library at Hyman, Phelps & McNamara, P.C. by former FDA Chief Counsel Tom Scarlett not too long after I joined the firm.  I asked Tom what publications I should read to gain an expertise in the Hatch-Waxman Amendments.  Tom picked up off the shelf a copy of Generic and Innovator Drugs: A Guide to FDA Approval Requirements authored by Donald O. Beers.  I read it and have been in awe of it ever since. 

The Eighth Edition of Generic and Innovator Drugs is a turning point for the legal treatise.  Don Beers left private practice and returned to work at FDA after completing the Seventh Edition.  As a result, Aspen Publishers/Wolters Kluwer sought another attorney to take on the task of serving as author and steward of the highly respected legal treatise.  It is a task that I am honored to take on.

The Eighth Edition of Generic and Innovator Drugs, which will be out later this month, strives to continue the high level of discussion and analysis – specifically with regard to the Hatch-Waxman Amendments, and, more generally, with regard to the FDC Act – that readers have come to expect from the publication.  Like Don, I have sought to provide a text that can be referred to on particular points as they arise, rather than a narrative that must be read from cover to cover. 

The Eighth Edition introduces several changes to the treatise, including an expanded text that accounts for significant changes to the law over the past five years, such as the Biologics Price Competition and Innovation Act and the FDA Safety and Innovation Act.  The Eighth Edition also includes several new appendices.  While I recognize that the addition of new appendices adds to the girth of the volume, I have always found it helpful to have the relevant rules and FDA interpretations of the law at my fingertips.  This is particularly true with respect to FDA’s letter decisions interpreting the statutory provisions governing marketing exclusivity relating to brand-name and generic drug manufacturers.  Many of those decisions, while public, have not been placed into a single publication.  Yet, they are the primary documents used by practitioners to understand how FDA currently interprets the law, especially FDA’s interpretations of the provisions governing the forfeiture of eligibility for 180-day exclusivity.  I include them in the volume for the first time.

I am indebted to Don for the guidance he has provided to me through the treatise he wrote, as well as to my colleagues at Hyman, Phelps & McNamara, P.C. who have assisted me through the writing process.  I am also indebted to George Johnston, who graciously agreed to write the foreword to the Eighth Edition.  As George notes in his foreword, Generic and Innovator Drugs has long been considered the “go to” source on the Hatch-Waxman Amendments and pharmaceutical law.  I hope to continue the tradition so well established by Don.

By Ricardo Carvajal –

FDA’s third annual report on the Reportable Food Registry (RFR) confirms the major patterns observed in the first two annual reports: foodborne pathogens and undeclared major food allergens (MFAs) continue to account for the vast majority of RFR entries (Salmonella accounted for 28.1% of entries, L. monocytogenes for 21.4%, and undeclared MFAs for 37.9%).  The commodities with the largest percentage of entries for Salmonella were Produce – Raw Agricultural Commodities (RAC) (34.92%) and Nuts/Nut Products/Seed Products (12.7%). The commodities with the largest percentage of entries for L. monocytogenes were Produce – Fresh Cut (31.25%), Dairy (22.92%), and Produce – RAC (20.83%).  The commodities with the largest percentage of entries for undeclared MFAs were Bakery (21.18%) and Chocolates/Confection/Candy (12.94%)

FDA notes that it is using RFR data in the agency’s implementation of the Food Safety Modernization Act ("FSMA") in various ways, such as “to identify hazards associated with products for which we have not previously made such an association and thus identify foods for which preventive controls may be needed.”  FDA also signals that it might issue an ANPRM to solicit comment on how best to implement FSMA section 211.  That section amends FFDCA section 417 to authorize FDA to require the posting of “consumer-oriented information” about a reportable food in certain grocery stores.  Given the other FSMA-related priorities currently on FDA’s plate, it appears that implementation of FSMA section 211 is not on the near horizon.

By Kurt R. Karst –      

By now everyone knows that FDA has appealed to the Second Circuit (Case No. 13-1690) the April 5, 2013 Memorandum and Order and April 10, 2013 Judgment from Judge Edward R. Korman of the U.S. District Court for the Eastern District of New York that FDA, within 30 days, make levonorgestrel-based emergency contraceptives (e.g., PLAN B and PLAN B One-Step) available Over-the-Counter (“OTC”) and without point-of-sale or age restrictions (see our previous post here).  (Judge Korman recently clarified that the 30-day deadline for compliance with his order runs from the date of his April 10th Judgment and not from his April 5th Order.)  Everyone also knows about FDA’s April 30, 2013 announcement that the Agency approved a supplement to the PLAN B One-Step NDA (NDA No. 021998) making the drug available OTC for women 15 years of age and older.  (The original July 10, 2009 approval of NDA No. 021998 made the drug available OTC to women over 17 years old, and prescription under that age.)  What folks might not yet know – or fully appreciate – however, are some of the statements FDA made in its May 1st Motion for Stay Pending Appeal, which Plaintiffs have until noon on May 6th to respond to, and for which Judge Korman will hear oral argument on at 11AM on May 7th.  (Judge Korman has already advised the parties in the case that in the event he denies a stay pending appeal, he will grant a stay to allow FDA to seek a stay from the Second Circuit.)

As an intial matter, FDA argues in its motion that the remedy Judge Korman ordered is erroneous for (at least) two reasons:

First, the Court exceeded its authority by issuing an order concerning the “one-pill product,” i.e., Plan B One-Step (PBOS), a drug product that was not the subject of the Citizen Petition that is the basis of this action before the Court.  Rather, PBOS was the subject of a supplemental new drug application (SNDA), and the Court recognized it “do[es] not have any authority to review the denial of the Plan B One-Step SNDA for the purpose of granting relief.” Tummino II, 2013 WL 1348656, at *34.  Second, the Court exceeded its authority, under principles of administrative law and the [FDC Act], by issuing a mandatory injunction ordering FDA ‘to make levonorgestrel-based emergency contraceptives available without a prescription and without point-of-sale or age restrictions within thirty days,’ rather than remanding to the agency for further administrative action.  In such a situation, the appropriate remedy is to vacate an administrative agency’s decision and to order the agency to reconsider its decision or provide a more complete explanation.  The Court cannot pretermit the rulemaking process and foreclose public participation in that process by instead immediately mandating a particular substantive outcome.

In support of its motion (and specifically that FDA and the public interest will suffer irreparable harm absent a stay), FDA makes some pretty interesting statements about the effect of Judge Korman’s order on the availability of 3-year marketing exclusivity with respect to the PLAN B One-Step NDA supplement approved on April 30th and submitted by Teva Branded Pharmaceutical Products R&D, Inc. (“Teva”).  According to FDA:

It is undisputed that, based on FDA’s representations regarding the need for additional data to support approving PBOS for use without a prescription by younger age groups, Teva conducted actual use studies that included participation by sufficient numbers of 15 and 16 year olds.  The agency deemed those studies essential to approval of non-prescription use of the drug by those age groups.  The Court nevertheless implies in its decision that FDA cannot grant Teva marketing exclusivity for a change for PBOS from prescription to OTC simply because FDA issued a complete response letter to Teva in December 2011 and Teva chose not to file a petition for review to the court of appeals.  This implication ignored the prospect that, instead of appealing, Teva could file an amended SNDA, which FDA could approve, leading to a grant of exclusivity.  That is what happened when FDA recently approved Teva’s 15-and-up amended SNDA and gave Teva three years of marketing exclusivity for the newly approved use.

To the extent the Court’s decision can be read to deprive Teva marketing exclusivity under the circumstances here – that is, to the extent it can be read to require FDA to also approve generic versions of PBOS for nonprescription use without age restrictions – it will cause irreparable harm to the regulatory process by undermining the benefits to the public and to FDA of the marketing exclusivity that the FDCA affords to drug sponsors.  As noted, such exclusivity provides a critical incentive for drug development that advances FDA’s goal of protecting and promoting public health.  To the extent the Court’s order is construed to eliminate Teva’s entitlement to exclusivity, it undermines the incentive for drug companies to conduct new clinical research studies to support new uses or indications, because it permits competitors to take advantage of the investments of market innovators free of charge.  Such a result would stifle rather than encourage innovation, to the detriment of the public.

FDA’s apparent grant of 3-year exclusivity – notwithstanding the fact that the Orange Book does not yet reflect such exclusivity as made by the appropriate FDA official under the Agency’s delegations of authority (see here) – is further discussed by CDER Director Janet Woodcock, M.D., in a declaration accompanying FDA’s Motion for Stay Pending Appeal (linked to above).  According to Dr. Woodcock:

In connection with its approval of Teva’s amended SNDA, FDA granted Teva three years of marketing exclusivity on the basis of actual use studies Teva conducted in women age 15 and 16 that FDA found essential to its approval.  The approval does not affect the prescription or approval status of Plan B or its generic equivalents.  The generic equivalents to Plan B remain available to those age 17 and older without a prescription and to those under age 17 with a prescription.  Generic equivalents to Plan B are kept behind the pharmacy counter for the prescription product to be lawfully dispensed.

What’s missing here?  That’s right, what’s missing is a reference to whether or not the PLAN B One-Step NDA supplement approved last week – apparently with 3-year exclusivity – affects the approval status of generic versions of PLAN B One-Step approved under ANDAs.  And it might be missing for good reason: the NDA supplement approval seems to raise the thorny issue of simultaneous prescription and OTC marketing of the same drug. 

As we previously discussed, FDA has relied on FDC Act § 503(b), generally, to assert that, absent a “meaningful difference,” the FDC Act does not permit the simultaneous prescription and OTC marketing of the same drug for the same indications, in the same dosage forms, and at the same strength.  FDA has also relied on FDC Act § 503(b)(4), specifically, to contend that a product whose labeling contains the “Rx-only” symbol (legend) where the same drug is approved for OTC use is misbranded and may not be legally marketed.  (FDC Act § 503(b)(4) renders a prescription drug misbranded if it fails to bear the “Rx-only” symbol and an OTC drug misbranded if it does.) 

FDA discussed its interpretation of what constitutes a “meaningful difference” in a September 2005 Advance Notice of Proposed Rulemaking involving PLAN B.  Historically, a “meaningful difference” exists if the Rx and OTC drug products differ in: (1) active ingredient; (2) indication; (3) strength; (4) route of administration; or (5) dosage form.  FDA’s mixed prescription/OTC approval of PLAN B added age as a sixth difference.

To this very day, FDA is still grappling with simultaneous prescription and OTC marketing issues.  On October 24, 2008, FDA issued a Notice for an Opportunity for Hearing (Docket No. FDA-2008-N-0549) on a proposal to withdraw approval of prescription PEG 3350 ANDAs on the basis that the statute prohibits the simultaneous marketing of the same drug as prescription and OTC.  The notice came after FDA approved NDA No. 022015 for OTC MIRALAX (PEG 3350) in October 2006, and after FDA’s Office of Generic Drugs sent letters to ANDA sponsors of prescription PEG 3350 in April 2007 stating that the FDC Act “does not permit both Rx and OTC versions of the same drug product to be marketed at the same time.”  Several ANDA sponsors requested a hearing and submitted comments to FDA challenging both the Agency’s interpretation of the statute to preclude simultaneous prescription and OTC marketing of the same drug, and FDA’s determination that no meaningful difference exists between the Rx and OTC versions of PEG 3350.  FDA has not yet scheduled a hearing; however, in January 2013, Merck & Co., Inc. sent correspondence to FDA requesting that the Agency wrap things up and withdraw ANDA approvals.

So back to the PLAN B One-Step situation . . . .  If FDA has, in fact, granted (or will grant) 3-year exclusivity vis-à-vis the change approved in the April 30th supplement (i.e., OTC use in 15 and 16 year old women), then what about the ANDAs FDA has already approved for generic PLAN B One-Step for prescription use in 15 and 16 year old women?  Is there a simultaneous prescription and OTC marketing issue there that might call into question the ANDA approvals?  This might arise because the ANDA labeling could not simply be amended to conform to the RLD labeling as a result of the exclusivity period, or is not permitted under a labeling carve-out theory.  Or is there a “meaningful difference” to maintain the status quo?  This might arise because pharmacies will keep the generic product behind the counter and control it as an prescription product, as opposed to PLAN B One-Step being available as an OTC drug on “aisle 6” at the local pharmacy.  We don’t have the answers to those questions, but resolution of whether there is a simultaneous prescription and OTC marketing issue in the first place, and then what to do about it if there is, might be an interesting side-show as the Second Circuit takes up Judge Korman’s decision.    

UPDATE:

• On May 6th, Plaintiffs filed a response in opposition to FDA's Motion for a Stay Pending Appeal. 

By Kurt R. Karst –      

Frau Rommelfanger’s seventh grade German class: that’s where we first learned to appreciate “false friends,” which are pairs of words or phrases in two languages that look or sound alike, but differ significantly in meaning.  Never write the word “gift” on a package to Germany, said Frau Rommelfanger, because while in English it means “present,” in German it means “poison.” 

That memory was triggered earlier this week when we read an article from Mike McCaughan over at the RPM Report, titled “Which Came First?  Alogliptin Avoids Possible Exclusivity Dispute.”  In his article, Mr. McCaughan discusses a “favor” FDA did for Takeda Pharmaceuticals U.S.A., Inc. (“Takeda”) when approving NDA No. 022271 for NESINA (alogliptin) Tablets as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.  The January 25, 2013 NESINA approval letter, signed on the same day FDA approved Takeda’s NDA No. 203414 for KAZANO (alogliptin and metformin HCl) Tablets and NDA No. 022426 for OSENI (alogliptin and pioglitazone) Tablets, also for type 2 diabetes mellitus, incudes a curious statement after the electronic signature of FDA Office of Drug Evaluation II Director Curtis Rosebraugh: “I am approving the single-entity alogliptin first, before approving the combination products containing alogliptin.”

Why would Dr. Rosebraugh include such a statement?  As Mr. McCaughan points out, “the explicit declaration that single-agent alogliptan was approved first [] should ensure that Takeda does not face any future challenges to the five-year new chemical entity exclusivity associated with the brand.” 

As readers of this blog know, timing really counts in the Hatch-Waxman world.  This is true regardless of whether we are talking about Orange Book patent listings and non-patent marketing exclusivity under Title I, or Patent Term Extensions (“PTEs”) under Title II of Hatch-Waxman (notwithstanding one exception).  Consider, for example, the order of NDA approval.  FDA’s long-standing position has been that in order for a fixed-dose combination drug to be eligible for 5-year New Chemical Entity (“NCE”) exclusivity, each of the active moieties in the drug product must be new (i.e., not previously approved).  That means in order for a company to to obtain NCE exclusivity for a combination drug containing new and old actives, the NCE component must be approved first, followed by the combination drug.  In that case, NCE exclusivity granted with respect to the single entity approval would apply to the combination drug under FDA’s so-called “umbrella policy.”  In the case of alogliptin, that means to get NCE exclusivity FDA needed to approve the alogliptin single-entity NDA first, because FDA has previously approved drug products containing metformin and pioglitazone.  And, in fact, FDA’s Orange Book shows a period of 5-year NCE exclusivity for each of the NESINA, KAZANO, and OSENI NDAs expiring on January 25, 2018.  (As we previously reported, two citizen petitions were recently submitted to FDA challenging the Agency’s interpretation and application of the FDC Act to deny 5-year NCE exclusivity for a combination drug containing new and previously approved moieties.  FDA has not substantively responded to either petition.)

But what helps under Title I of Hatch-Waxman may hinder under Title II of Hatch-Waxman.  That is, what appears to be an attempt by FDA to avoid controversy with respect to NCE exclusivity might raise raise controversy with respect to PTE.  Indeed, FDA and the courts have long recognized that the law that applies under Title I may not apply under Title II – see, e.g., the Federal Circuit’s May 10, 2010 decision in Photocure v. Kappos, 603 F.3d 1372 (Fed. Cir. 2010) and FDA’s May 29, 2012 Letter Decision concerning TORISEL (temsirolimus) Injection exclusivity.

The same day approvals of the NESINA, KAZANO, and OSENI NDAs raises the possibility of multiple PTE applications and the granting of multiple PTEs for different patents covering the drug products.  Indeed, several patents are listed in the Orange Book for each of the three drug products, including U.S. Patent Nos. 6,150,383, 6,211,205, 6,303,640, 6,303,661, 6,329,404, 6,890,898, 7,078,381, 7,459,428, 7,807,689, 8,173,663, and 8288539 for NESINA, and the same patents plus U.S. Patent Nos. 5,965,584, 6,150,384, 6,166,042, 6,166,043, 6,172,090, and 6,211,205 for KAZANO and OSENI, and all of the same patents plus U.S. Patent No. 6,271,243 for OSENI.  It is well after the 60-day statutory deadline for submitting PTE applications, and it seems highly likely that PTE applications have been submitted with respect to each NDA (although Public PAIR has not yet been updated with this information).

As we discussed several years ago, the PTE statute states (at 35 U.S.C. § 156(c)(4)) that “in no event shall more than one patent be extended . . . for the same regulatory review period for any product.”  The U.S. Patent and Trademark Office (“PTO”) interprets 35 U.S.C. § 156(c)(4) to permit multiple PTEs under certain circumstances – specifically, for a drug product covered by several patents the PTO may extend a different patent for each NDA approved on the same first day (even when multiple NDAs share common “testing phase” and a “review phase” dates).  That is, the PTO considers each NDA “regulatory review period” to be distinct and for which a PTE is available.  There is only a handful of cases in which the PTO has granted, or companies have been eligible for and pursued, multiple PTEs for different patents covering the same product approved under separate NDAs on the same first day.  Specifically, the ones we know of are:

• OMNICEF (cefdinir):  Approved on December 4, 1997 under NDA Nos. 050739 and 050749.  One PTE was granted for U.S. Patent No. 4,559,334 with respect to NDA No. 050739, and another PTE was granted for U.S. Patent No. 4,935,507 with respect to NDA No. 050749.  In this case, FDA approved both NDAs simultaneously under a single approval letter that does not reflect a date/time-stamp.

• LYRICA (pregabalin):  Approved on December 30, 2004 under NDA Nos. 021446 and 021723.  One PTE was granted for U.S. Patent No. 6,001,876 with respect to NDA No. 021723, and another for U.S. Patent No. 6,197,819 with respect to NDA No. 021446.  As opposed to the opther multiple PTE precedents, FDA separately approved each NDA.  The approval letter for NDA No. 021446 is date/time stamped “12/30/04 04:33:10 PM ,” while the approval letter for NDA No. 021723 is date/time-stamped “12/30/04 04:36:18 PM.”

• MYCAMINE (micafungin sodium):  Approved on March 16, 2005 under NDA Nos. 021506 and 021754.  In this case, the NDA sponsor applied for two PTEs based on both approvals – one for either U.S. Patent Nos. 5,376,634, 6,265,536, or 6,107,458 for NDA No. 021506, and one for either of these same patents for NDA No. 021754 – but ultimately decided not to elect a second PTE.  The PTO granted a PTE for U.S. Patent No. 6,107,458 with respect to NDA No. 021506.  FDA approved both NDAs simultaneously under a single approval letter date/time-stamped “3/16/05 12:54:49 PM.”

• VIMPAT (lacosamide):  Approved on October 28, 2008 under NDA Nos. 022253 and 022254.  In this case, the NDA sponsor applied for two PTEs based on both approvals – one for either U.S. Patent Nos. 5,654,301 or RE38,551 for NDA No. 022253, and one for either of these same patents for NDA No. 022254.  The NDA sponsor ultimately elected a single PTE – for U.S. Patent No. RE38,551 with respect to NDA No. 022253 – and withdrew its PTE applications with respect to NDA No. 022254.  FDA approved both NDAs simultaneously under a single approval letter date/time-stamped “10/28/2008 08:00:13 PM.”

None of these precedents involve multiple NDAs where one application is for a single entity NCE and another is for a combination of that single entity with a previously approved drug.  In 2004, the Federal Circuit stated in its decision in Arnold Partnership v. Dudas, 362 F.3d 1338 (Fed. Cir. 2004), which concerned the availability of a PTE for a combination drug, that “the [PTE] statute places a drug product with two active ingredients, A and B, in the same category as a drug product with a single ingredient . . . .  To extend the term of a patent claiming a composition comprising A and B, either A or B must not have been previously marketed.”  Thus, a patent on a combination drug may be eligible for a PTE.  But the issue raised by FDA’s alogliptin NDA approvals, which Dr. Rosebraugh’s statement – “I am approving the single-entity alogliptin first, before approving the combination products containing alogliptin” – calls out is different.  The issue is whether the time of day counts for purposes of determining PTE eligibility and whether the first single-entity NDA approval precludes PTE eligibility for patents covering the combination drugs approved later (perhaps only seconds or minutes later) the same day.

In one sense, the three alogliptin NDA approvals are similar to those for OMNICEF.  In both cases, the NDA approval letters do not include a time-stamp, just a date-stamp.  But there are differences.  In the case of OMNICEF, although there is not a time-stamp, both NDAs were approved simultaneously on the same day under the same approval letter.  Simultaneous approvals under a single approval letter (and, therefore, the same date/time stamp) also show up in the MYCAMINE and VIMPAT PTE cases.  In the case of  alogliptin, however, three different NDA approval letters were issued, with the first NDA for NESINA specifically identified as the first approval. 

That leads us to LYRICA.  In that case, FDA issued two approval letters: one date/time-stamped “12/30/04 04:33:10 PM ” (NDA No. 021446) and the other date/time-stamped “12/30/04 04:36:18 PM” (NDA No. 021723).  Although minutes separated the NDA approvals, the PTO nevertheless granted PTEs for different patents vis-à-vis the different NDA approvals.  Thus, LYRICA may be most applicable to alogliptin if multiple PTEs have been requested on different patents vis-à-vis the different NDA approvals.  But one questions remains . . . . did the PTO ever consider the date/time-stamp when considering the PTE applications for LYRICA?  And, if not, will the Office do so here in light of Dr. Rosebraugh’s statement?

Recent actions by FDA and the FTC serve as reminders that both agencies will consider the use of scientific literature in determining whether marketing for a food or dietary supplement conveys disease treatment or prevention.

FDA recently issued a warning letter to a company that sells eye health dietary supplements.  FDA alleged that the company’s website included “therapeutic claims” that established that its products were unapproved new drugs.  The warning letter cited several examples of claims that expressly referenced treating or slowing the symptoms of macular degeneration.  The letter further alleged that “online summaries of two studies” contributed to a message of disease treatment or prevention.  FDA addressed the use of the studies as follows:

[U]nder 21 CFR 101.93(g)(2)(iv)(C), a citation of a publication or reference in the labeling of a dietary supplement is considered to be a claim about disease treatment or prevention if the citation refers to a disease use, and if, in the context of the labeling as a whole, the citation implies treatment or prevention of a disease.  The home page of your website provides links to online summaries of two studies that pertain to prevention and treatment of macular degeneration: ‘Age-Related Eye Disease Study (AREDS), National Eye Institute, National Institutes of Health’ [and] ‘Age-Related Eye Disease Study 2, The Lutein/Zeaxanthin and Omega-3 Supplementation Trial.’ Your website promotes your products . . . for prevention and treatment of macular degeneration by claiming that [your products] contain the same ingredients used in these studies.

Since 2006, FDA has sent 31 warning letters that have included similar allegations and similar explanations regarding the use of scientific studies.  Last year, it sent four such letters.  The recent warning letter is the first of its kind this year.   

Unlike FDA, the FTC does not per se prohibit food or dietary supplement advertisers from making disease claims.  The FTC, however, holds disease claims to a high standard of substantiation – requiring well-designed clinical trials.  The FTC has made clear its position that an array of textual elements or imagery – including references to scientific studies – might further the message that a food or dietary supplement has been scientifically shown to be effective in treating or preventing a disease.  The FTC’s case against POM Wonderful provides a recent example of the FTC’s approach to scientific literature. 

FTC Staff challenged claims that POM Wonderful juice and dietary supplements treat, prevent, or reduce the risk of heart disease, prostate cancer, and erectile dysfunction and that clinical studies prove that POM products do so.  The POM Wonderful websites included descriptions of and links to multiple scientific studies with titles such as, “Effects of Pomegranate Juice Consumption on Myocardial Perfusion in Patients with Coronary Heart Disease.”  One site also included a discussion of various scientific studies by a medical researcher.  The FTC’s full Commission issued a decision in the case in January, following appeals from both sides of an initial decision by the FTC’s administrative law judge.  The Commission found that the references to and descriptions of “scientific studies” and “medical journals” on the POM Wonderful websites and in print ads “helped convey” the claims that FTC Staff alleged POM had made.  See POM Claims Appendix A.  The Commission noted, in particular, that “the characterization of the research specifically as ‘medical’ (as opposed to simply ‘research’ or even ‘nutritional research’) contribute[d] to the net impression that the ads conveyed the challenged claims.”  As we reported last month, the POM defendants have appealed the Commission’s decision in federal court.  For now, however, the Commission decision – including its findings on scientific literature – stands. 

The recent FDA warning letter and the FTC’s decision in POM Wonderful demonstrate that, especially where a scientific study includes the name of a disease, marketers need to proceed with caution.  The FDA and FTC actions certainly do not foreclose the use of disease-related scientific literature in marketing, but it may be that careful explanations or disclosures are necessary in order to avoid conveying disease claims.  

By Kurt R. Karst –      

Bayer HealthCare, LLC’s (“Bayer’s”) court challenge to FDA’s approval of Abbreviated New Animal Drug Application (“ANADA”) No. 200-495 submitted by Norbrook Laboratories, Ltd. (“Norbrook”) for Enroflox™ 100, a generic version of Bayer’s fluroquinolone animal drug Baytril® 100 (enrofloxacin) Injectable Solution, has paid off.  FDA, following an April 12, 2013 Order from the U.S. District Court for the District of Columbia suspending the ANADA approval (and its associated labeling) for use in cattle (but not in swine), administratively suspended the cattle approval pending completion of the Agency’s consideration of issues raised by Bayer in a June 2006 Citizen Petition (Docket No. FDA-2006-P-0010, formerly FDA Docket No. 2006P-0249).  That stay was memorialized in a Stipulated Stay and Preliminary Injunction agreed to by the court, but opposed by Norbrook, and cited in an April 24, 2013 Order remanding the case to FDA for reconsideration.

As we previously reported, Bayer sued FDA on April 10th alleging that the Agency’s approval of ANADA No. 200-495 for use in cattle violates the Administrative Procedure Act (“APA”) and FDC Act § 512(c)(2)(A)(ii) – as added by the Generic Animal Drug and Patent Term Restoration Act of 1988 (“GADPTRA”), Pub. Law No. 98-417, 98 Stat. 1585 (1988), the Hatch-Waxman equivalent in the animal drug world – and served as a constructive denial of Bayer’s 2006 Citizen Petition in violation of the APA.  Baytril® 100 is approved for two different dosing regimens: (1) Single-Dose Therapy (7.5 to 12.5 mg/kg of body weight (3.4 to 5.7 mL/100 lb)); and (2) Multiple-Day Therapy (2.5 to 5.0 mg/kg of body weight (1.1 to 2.3 mL/100 lb)).  The Single-Dose Therapy use is covered by U.S. Patent No. 5,756,506 (“the ‘506 patent”), which expires on June 27, 2015, and claims the use of enrofloxacin in a single high dose to replace multiple lower doses in bovine respiratory disease and swine pneumonia.  FDC Act § 512(c)(2)(A)(ii), as amended by GADPTRA, states that FDA will approve an ANADA unless, among other things, the Agency finds that “the conditions of use prescribed, recommended, or suggested in the proposed labeling are not reasonably certain to be followed in practice . . . .”  FDA’s regulations prohibit the extralabel use of fluoroquinolones in food-producing animals (21 C.F.R. § 530.41(a)(10)), and, in particular, extralabel use of enrofloxacin in food-producing animals (21 C.F.R. §522.812(d)(2)(iii)).

Bayer’s 2006 Citizen Petition requested that FDA refrain from approving ANADAs for generic Baytril® 100 for Multiple-Day Therapy in cattle with labeling that omits information on Single-Dose Therapy protected by the ‘506 patent.  According to Bayer, any generic approved for Multiple-Day Therapy only will be promoted and used extralabel for the protected Single-Dose Therapy, which would directly conflict with the provisions of the GADPTRA and FDA regulations and undermine the incentives for discovery and innovation that GADPTRA and patent laws were intended to protect. 

Other than a boilerplate tentative response from FDA in December 2006 saying that the Agency “is currently considering the issues raised by your citizen petition,” and that “the agency will require additional time to issue a final response because of the complexity and the number of issues raised in your petition,” the petition docket has remained dormant.  In an April 17th Opinion made public last week granting in part and denying in part Bayer’s Motion for a Temporary Restraining Order, the DC District Court (Judge Rosemary Collyer), which has previously been critical of FDA Citizen Petition decisions (see, e.g., here at pages 21-24) criticized FDA’s failure to respond to Bayer’s petition.  Judge Collyer commented in her decision:

FDA recognizes that it erred by failing to respond to Bayer’s Citizen Petition before approving Enroflox but argues that the Court cannot conclude that FDA “knew” when making its decision that off-label use was reasonably certain to occur.  The Court rejects FDA’s formulation of the issue: resolution does not turn here on what FDA “knew” in a vacuum, but whether, based on all the facts before it, FDA had found that the conditions of use specified in the proposed labeling were not reasonably certain to be followed in practice.  Since FDA offers no evidence that it considered the full record before it or made the necessary finding, FDA presents an exceptionally weak position despite the excellence of its lawyering. . . .

The facts set forth in the Petition stand unchallenged and bereft of reasoned agency response.  Although counsel for FDA claimed that someone within FDA had prepared a tentative draft response denying the Citizen Petition, neither a “tentative draft” nor the prediction that a response is forthcoming can substitute for reasoned decisionmaking at the time FDA approved the Norbrook application for Enroflox.

At this juncture, FDA presents only legal argument that the Court should presume regularity and defer to its expertise.  But, while agency action may generally be “entitled to a presumption of regularity,” here FDA itself acknowledges that its action has not been regular: it failed to respond to the Citizen Petition for years and failed to provide a reasoned basis for rejecting it before approving Enroflox.  Further, the present record is devoid of any explanation at all for the basis for FDA’s decision to approve Enroflox. [(Emphasis in original; internal citations omitted)]

FDA’s failure to timely respond to citizen petitions (or to provide a substanstantive response and not just a denial without comment) before taking an action has been a sticking point with the FDA-regulated industry for years.  See, e.g., Warner-Lambert Co. v. Shalala, 202 F.3d 326 (D.C. Cir. 2000).  Indeed, Purdue Pharma L.P. (“Purdue”) recently submitted a Petition for Reconsideration (Docket No. FDA-2012-P-0939) after FDA denied without comment an August 2012 Citizen Petition concerning the approval of generic versions of reformulated OxyContin® (oxycodone HCl controlled-release tablets) approved under NDA No. 022272.  According to Purdue, FDA’s denial of the petition on non-substantive grounds was improper and based on a flawed interpretation of FDC Act § 505(q), which requires FDA to respond to certain petitions within 150 days of receipt.  Will companies now argue, in light of the Baytril® decision, that this kind of response is inadequate?  Will FDA have to change the way the Agency handles Citizen Petitions?  Something tells us that Judge Collyer’s Baytril® decision will show up again in litigation with FDA. 

Hyman, Phelps & McNamara, P.C. is pleased to announce that Joseph (“Jay”) W. Cormier, J.D., Ph.D. has joined the firm as an Associate.  Prior to joining the firm, Dr. Cormier served as a pharmacologist in the Animal Biotechnology Interdisciplinary Group in FDA’s Center for Veterinary Medicine.  While at FDA, Dr. Cormier evaluated the manufacturing of new animal drugs and helped develop policies regarding the regulation of genetically engineered animals.  He is the recipient of several awards, including the FDA Scientific Achievement Award and the Center for Biologics Evaluation and Research Scientific Achievement Award.  Dr. Cormier has extensive knowledge of issues concerning genetic engineering, drug and medical device manufacturing and product promotion, medical device data systems, and mobile medical apps.  He also has experience advising on matters involving general FDA-regulatory compliance policies, product development and FDA-submission strategies, oversight of clinical trials, tobacco product manufacturing, and organic food labeling.

Dr. Cormier graduated from Dartmouth College in 2000 with a Bachelor of Arts in Genetics, Cell, and Developmental Biology modified with Computer Science.  He earned a Master of Arts in Pharmacology in 2001, a Master of Philosophy in Pharmacology in 2003, and a Doctor of Philosophy in Pharmacology in 2005 – all from Columbia University.  Dr. Cormier graduated from Georgetown University Law Center in 2010 with a Juris Doctor, where he served as a Notes Editor for the American Criminal Law Review.  He is admitted to practice law in the District of Columbia, New York, and Massachusetts.  Since leaving FDA, Dr. Cormier has worked as an attorney in private practice representing major pharmaceutical and medical device clients.

By Karla L. Palmer –

The Senate’s Health, Education, Labor and Pensions (“HELP”) Committee released draft legislation on Friday, April 26, 2013, that would replace section 503A of the Federal Food, Drug & Cosmetic Act (“FDCA”), amend other sections, and clarify FDA’s authority to regulate pharmaceutical compounders and compounded pharmaceutical products.  Interested persons, industry and other stakeholders are asked to submit written comments concerning the draft legislation to compounding@help.senate.gov by 6:00 PM on May 3, 2013.  The draft legislation is available here, along with a summary, and an easily digestible section-by-section analysis of the draft bill.  

Set forth below is a summary of the draft legislation: 

Compounded Drugs Would Be Considered “New Drugs.”  In a section titled, “Clarification of New Drug Status” the proposed legislation explicitly clarifies that compounded drugs are “new drugs” subject to regulation under the FDCA. This clarification would put to rest decades of ambiguity concerning whether the FDCA’s provisions relating to new drug approval requirements apply to compounded drug products.

The Proposed Legislation Seeks to Establish Clear Regulatory Boundaries By Defining “Traditional Compounder” and “Compounding Manufacturer.”  The legislation would create two categories of compounding pharmacies: “traditional compounders” and “compounding manufacturers.”

Compounding Manufacturer.  The draft defines “compounding manufacturer” as an entity that: (1) makes sterile drug products without receiving or in advance of a prescription and introduces those drugs in interstate commerce; or (2) “repackage[s] a drug using sterile preservative-free single-dose vials or by pooling sterile drugs.”  Compounding manufacturers would be required to pay FDA annual registration fees, follow statutory restrictions on drugs they can compound (both for humans and animals), submit to FDA inspections similar to those conducted of drug manufacturers, and make regular reports to FDA pursuant to a national, uniform set of rules.  Drugs compounded by newly defined compounding manufacturers that meet the requirements set forth in the new section 503A would be exempt from the Act’s requirements regarding adequate directions for use (Sec. 502(f)(1)) and the new drug approval provisions (Sec. 505 for human drugs and Sec. 512 for animal drugs), but are subject to current Good Manufacturing Practices (“cGMP”) applicable to drug manufacturers.  In order for the exemptions to apply, the compounding manufacturer would have to comply with the other provisions of the legislation, and cannot be licensed as a pharmacy in any state.

More specifically, under the legislation, compounding manufacturers would have to:

• Ensure that a pharmacist, licensed in the state where the compounding manufacturer is located, exercises direct supervision over the operations of the compounding manufacturer.

• File with FDA every six months a list of drugs compounded during the previous six month period (including active ingredients, NDC numbers, the strength of active ingredients per unit, dosage form and route of administration, number of individual units produced, the NDC of the final product, and other requirements as established by FDA pursuant to regulation).

• Report to FDA any serious adverse drug experience not later than 15 days after receipt of information about the adverse event and maintain records of serious adverse drug experiences for 10 years.

• Label compounded drugs with the following statement: “This is a compounded drug,” or a reasonable comparable alternative statement (as specified by FDA).  The label also would include the name, address, and phone number of the compounding manufacturer; the lot or batch number; established name of the medication; strength; statement of quantity; directions for use; date the product was compounded; the “beyond use date;” storage instructions; and other information that the FDA determines is necessary.

• Pay registration fees.  For compounding manufacturer establishments with more than 25 employees, the annual fee would be $15,000 (subject to inflation); those with less than 25 employees would pay roughly one-third of that fee.  To the extent that FDA must reinspect a compounding manufacturer, that entity would be responsible for 100% of the reinspection-related costs.  All fees collected will be used by FDA solely to pay costs associated with inspections.

Traditional Compounders.  As defined by the legislation, a “traditional compounder” requires a licensed pharmacist in a state-licensed pharmacy, a licensed physician or licensed veterinarian, to the extent permitted under state law, to compound a drug, but only (1) upon receipt of a prescription for an individual patient; or (2) in limited quantities before receipt of a prescription for an individual patient if such compounding is based on an “established history” of such prescriptions.  Compounded drugs meeting the requirements set forth in the new 503A would be exempt from FDA’s cGMP (Sec. 501(a)(2)(B)), adequate directions for use requirements (Sec. 502(f) (1)), and the new drug provisions of the FDCA (Sec. 505 for human drugs and Sec. 512 for animal drugs).

The Proposed Legislation Contains An Exemption for Hospital Pharmacies.  A pharmacy located within a “health system” that compounds and ships drugs for dispensing within that health system (which may include interstate shipment) is considered a traditional compounder, subject to specified conditions, if it otherwise meets the definition of a traditional compounder.

Prohibitions on Compounding Certain Drugs.  The draft legislation states that certain drugs may not be compounded except under limited circumstances.  Those drugs include complex dosage forms and biologics as designated by FDA pursuant to regulation (this may include “extended release products, metered dose inhalers, transdermal patches, and liposomal products”). 

Copies of marketed animal or human drugs, including variations of such drugs compounded from bulk substances also could not be compounded, with a few exceptions.  These exemptions include: (1) if the compounder receives a prescription order for an identified individual patient indicating that the compounded variation produces for that patient a significant difference, as determined by the prescribing practitioner; (2) for copies of marketed FDA-approved drugs, if the drug at the time of compounding and its distribution is on FDA-maintained drug shortage lists, and the compounder notifies FDA prior to compounding.

Other Provisions.  The draft legislation also contains restrictions on the bulk chemicals that can be used in compounding, prohibits compounding manufacturers from selling to middlemen or wholesalers.  Lastly, references in the draft legislation to a prescription order for an “identified individual patient” would, in the case of animals, include a prescription order for a specific herd or flock of animals.

By Kurt R. Karst –      

In a brief opinion handed down last week by the U.S. Court of Appeals for the District of Columbia Circuit, the Court affirmed a July 5, 2012 decision from the U.S. District Court for the District of Columbia granting summary judgment for FDA in a case brought by AstraZeneca Pharmaceuticals LP’s (“AstraZeneca’s”) over the approval of generic versions of the company’s blockbuster antipsychotic drug SEROQUEL (quetiapine fumarate) Tablets.  As we previously reported, the case concerns the applicability and scope of 3-year exclusivity under FDC Act § 505(j)(5)(F)(iv) based on FDA’s simultaneous approval of supplemental NDAs (“sNDAs”) that contained information on pediatric uses of quetiapine and that made changes to the drug’s labeling to add “Table 2” of the Warnings section regarding “general safety information that is not indication-specific.” 

AstraZeneca’s legal attempts to stave off FDA approval of generic SEROQUEL started in March 2012 when the company sought to enjoin FDA from granting final ANDA approvals for generic SEROQUEL after FDA denied without comment two citizen petitions (Docket Nos. FDA-2011-P-0662 and FDA-2011-P-0663) AstraZeneca submitted to FDA concerning labeling carve-out issues (see our previous post here).  The DC District Court dismissed the action without prejudice, saying that it was premature (see our previous post here).  Just days later, however, FDA approved several ANDAs for generic SEROQUEL.  AstraZeneca filed a second lawsuit seeking to vacate FDA’s ANDA approvals and to enjoin FDA from granting any further final ANDA approvals.  The DC District Court denied AstraZeneca’s Motion for Temporary Restraining Order (see our previous post here). 

The case progressed to the summary judgment stage, where the AstraZeneca argued that under the plain language of FDC Act § 505(j)(5)(F)(iv), the company is entitled to a period of 3-year marketing exclusivity for the Table 2 information until December 2, 2012, plus 6 months of pediatric exclusivity (until June 2, 2013).  FDA, following the explanation provided in the Agency’s March 27, 2012 Letter Decision, [http://www.hpm.com/pdf/blog/SEROQUEL%20-%20FDA%20Letter%20Decision%203-27-2012.pdf] primarily argued that the scope of 3-year exclusivity relates to the scope of new clinical investigations conducted by the NDA sponsor and approved in an sNDA, but that “AstraZeneca reads the statute to provide for exclusivity for any labeling change, even if the change was initially submitted through general correspondence (and not a supplement), and it was unrelated to the purpose for which the supplement was submitted, and the change occurred only coincidentally and contemporaneously with the changes relating to the new clinical investigations that were the subject of the supplements.”  Finding FDC Act § 505(j)(5)(F)(iv) ambiguous, the DC District Court ruled that under Chevron Step Two,  FDA’s interpretation of the statute – i.e., “that a substantive relationship between new clinical studies and changes in the supplement, not the format of a submission, dictates what changes receive exclusivity” – is reasonable and granted summary judgment in favor of FDA.

On appeal, FDA argued the case was moot because the period of 3-year exclusivity at issue expired on December 2, 2012.  The DC Circuit disagreed, citing the possibility of pediatric exclusivity expiring on June 2, 2013.  Moving on to the merits of the D.C. District Court’s summary judgment decision, the Court examined the core of the dispute: the reasonableness of FDA’s interpretation of FDC Act § 505(j)(5)(F)(iv), which limits exclusivity to “a change approved in the supplement” and requires that “the supplement contain[] reports of new clinical investigations . . . essential to the approval of the supplement,” to deny exclusivity in this case.  As the Court pointed out, the statutory language “is permeated by ambiguities that, under Chevron, leave discretion in the FDA to adopt reasonable interpretations of the application process outlined by the statute.”

AstraZeneca argued that FDC Act § 505(j)(5)(F)(iv) clearly entitles Table 2 to exclusivity on two grounds, thereby making FDA’s approval of ANDAs incorporating Table 2 prior to June 2, 2013 contrary to the statute.  First, AstraZeneca argued that Table 2 was “a change approved in” the pediatric supplements the company submitted to FDA, and that the supplements included “reports of new clinical investigations . . . essential to the approval of the supplement[s].”  Second, AstraZeneca argued that the labeling changes independently warrant exclusivity because some of the clinical studies that provided the data for Table 2 were “new clinical investigations” “essential to the approval” of the labeling changes.  FDA maintained that that Table 2 was not “a change approved” in any supplement, and that only changes approved in an sNDA are entitled to marketing exclusivity.  (Briefs in the case are available here, here, and here.)

Noting that FDA “has exhaustive regulations detailing the parameters of the application process, including how to amend pending supplements and applications,” the Court said that “AstraZeneca makes no attempt to show that these procedures are contrary to the statute,” and that AstraZeneca did not show “that the FDA’s application of the law to the relevant facts was arbitrary or capricious.”  As such, the Court found “nothing arbitrary or capricious about the FDA’s reasoned explanation for its actions.”  AstraZeneca’s  attempts to establish that FDA was arbitrary or capricious in its exclusivity an ANDA approval decisions by directing the Court to prior grants of exclusivity to label changes approved in supplements similarly fell flat. “FDA’s explanation that it considered Table 2 independently of a supplemental application sufficiently distinguishes this case to defeat that claim,” wrote the panel of Judges Rogers, Tatel, and Sentelle.  “The consistency of the FDA’s denial of exclusivity in this case with prior FDA actions is strikingly underscored by the fact that the agency did not extend exclusivity in seven other recent labeling changes for drugs in Seroquel’s class.”

By Carmelina G. Allis –

As we previously reported, ReGen Biologics, Inc. ("ReGen"), which has been acquired by Ivy Sports Medicine, LLC ("Ivy"), filed suit in 2011 challenging FDA’s authority to rescind the 2008 510(k) substantial equivalence determination for the company’s “Menaflex” product, a collagen meniscus implant intended to reinforce damaged meniscal soft tissue.  ReGen Biologics, Inc. v. Sebelius, No. 1:11-cv-01006 (D.D.C. filed May 31, 2011). 

The 510(k) clearance for Menaflex classified the device into Class II.  In October 2011, FDA rescinded the 510(k) substantial equivalence determination alleging that the device does not have the same intended use as the predicate devices.  By rescinding that classification, pursuant to Section 513(f)(1) of the Federal Food, Drug, and Cosmetic Act ("FDC Act"), the product is now classified as a Class III device subject to the more stringent premarket approval ("PMA") requirements.

The company argued in the U.S. District Court for the District of Columbia that FDA lacks legal authority under the FDC Act to rescind a 510(k) substantial equivalence determination.  Because the rescission resulted in a reclassification of the device from Class II to Class III, ReGen argued that FDA should have complied with the reclassification procedures in 21 U.S.C. § 360c(e).  The procedures in § 360c(e) require that the agency secure an advisory panel recommendation and a publication in the Federal Register of a recommendation regarding the device’s classification prior to reclassifying the device.

Instead, FDA administratively rescinded the 510(k) substantial equivalence determination after conducting a review of the agency’s records in the matter.  The agency concluded that the record shows that FDA decision-makers departed from administrative processes, procedures, and practices, which resulted in a failure to document and explain the bases for the substantial equivalence determination, and also resulted in misconduct that affected the integrity of the administrative process.

FDA argued in court that it acted properly within its inherent administrative authority.  And the court agreed.  District Judge Robert L. Wilkins ruled that FDA has the inherent administrative authority to reconsider and change a 510(k) substantial equivalence determination in these circumstances if it does so within a reasonable period of time, even if the agency could have invoked a statutory provision to achieve the same result.  Ivy Sports Med., LLC v. Sebelius, No. 11-cv-1006 (D.D.C. Apr. 10, 2013).

In this case, the court agreed with FDA that the administrative record was “tainted.”  Examples given by the court of procedural irregularities and misconduct include:

• The agency’s failure to respond appropriately to external pressure on decision-makers – for example, FDA allowed Ivy to meet with agency officials without members of the review team present, and allowed members of Congress to speak directly to the Commissioner and Principal Deputy in violation of agency usual procedures.
• The exclusion of individuals, if not viewpoints, from parts of the scientific debate – for example, the court found that the company was successful in excluding the review team from speaking at the panel meeting.  The court explained that such exclusion could have skewed the panel meeting discussion in Ivy’s favor, and also did not allow the panel members to consider the reviewers’ concerns.
• The excessive reliance on advisory panel deliberations – for example, the court found inappropriate that the agency based its decision “entirely or almost entirely on the views of an outside Panel,” even though those views were in conflict with those of the FDA reviewers and the decision-making documents did not address the reviewers’ concerns.  Moreover, the panel meeting was convened with such “haste” that there was little time for panel members to properly prepare on the substantial equivalence standard or FDA’s panel procedures, and key panel members could not participate.

See id. at 17.

The court also found that FDA acted within a reasonable period of time when only eight to ten months passed between the initial agency determination of substantial equivalence to when the “affected party received notice that the determination was ‘actively under reconsideration,’ not when the agency made its final decision.”  Id. at 26-27.  In this case, FDA classified the device via the 510(k) substantial equivalence determination in December 2008.  The agency then began its review of the record in April 2009, published a preliminary report in September 2009, and met with the company in October 2009 to inform them of the administrative review.  The court ruled that this time period of eight to ten months “falls comfortably within the reasonableness standard.”  Id. at 27.

Ivy also argued that the FDA acted arbitrarily and capriciously because it did not limit its review of the substantial equivalence determination on the intended use statement of the device as set forth in the proposed labeling submitted in the 510(k).  According to the court’s opinion, FDA reviewed the indications for use and instructions for use of the Menaflex and predicate devices, and the directions for preparation of the surgical site of the Menaflex and predicate devices.  The agency also considered comments from panel members on the use of the Menaflex – such as statements that they were “‘having trouble with comparing’” the Ivy device with predicate devices because they “‘really aren’t used in the same way,’” and they “‘expressed uncertainty about what the [Ivy] device is intended to do.’”  Id. at 29.  The court ruled that “there is nothing improper about” “looking beyond the Indications for Use Statement” submitted in the 510(k) even though that is not “‘[t]ypically’ what is done.”  Id.

The court also found that FDA’s determination to rescind the 510(k) is based on a “review of the relevant material, including an examination of both panels, meetings with the review team, and the overall record,” and further concluded that the agency “properly based [its] conclusion on the [Ivy] device’s proposed labeling.” Id. at 31.

In sum, FDA has always asserted that it has the inherent authority to rescind 510(k)s.  It would be a mistake to infer from this decision support for the proposition that FDA may administratively rescind a 510(k) clearance simply because new or different agency officials arrive at a different scientific or policy judgment than their predecessors.  However, this decision does appear to affirm FDA’s rescission authority if the agency gives notice of reconsideration in a reasonable time frame and if there is evidence in the record of fraud and/or other misconduct affecting the integrity of the original decision.