By William T. Koustas & Anne Marie Murphy –

We have been closely following FDA’s implementation of the Drug Supply Chain Security Act ("DSCSA") (see here and here) and waiting for this day for over a year.  As our readers may know, the DSCSA requires certain members of the pharmaceutical supply chain (i.e., trading partners) to pass certain information beginning on January 1, 2015 in any transactions involving a prescription drug product.  The DSCSA also mandates that FDA issue a draft guidance document by November 27, 2014 that establishes standards for the “interoperable exchange of transaction information, transaction history, and transaction statements…”  (Product Tracing Information).  In a recent public appearance, an FDA official suggested that the guidance document was unlikely to by issued by the statutory deadline (see our previous post here).  So it was a surprise to us that this was released on time.

Industry has been inundating FDA with a variety of DSCSA-related questions, but this draft guidance, announced last week and titled “DSCSA Standards for the Interoperable for Tracing of Certain Human, Finished, Prescription Drugs:  How to Exchange Product Tracing Information” (Draft Guidance), only addresses one issue – how certain trading partners exchange Product Tracing Information starting on January 1, 2015.  FDA appears to have heard industry’s calls for flexibility, because the Draft Guidance indicates that trading partners may pass and receive Product Tracing Information in a variety ways, including, but not limited to, the following:

• Paper or electronic invoices;
• Paper packing slips;
• Electronic Data Interchange ("EDI") standards (e.g., 856 Advance Ship Notice ("ASN")); 
• EPIC (Electronic Product Code Information Services); and
• Email or web-based platforms.

The Draft Guidance suggests that nearly any method for passing Product Tracing Information will be acceptable on January 1, 2015, as long as it can handle all of the information required by the DSCSA.  FDA notes that it may revisit what methods of passing Product Tracing Information are acceptable as processes, capabilities, and electronic systems evolve and “are more widely accessible.”  Unfortunately, the Draft Guidance does not address any of the other issues that have been brought to FDA’s attention, such as clarifying statutory terms (e.g., co-licensed partner).  FDA notes, however, that it intends to issue additional guidance documents.  Presumably, those guidance documents will address some of the remaining questions. 

By Riëtte van Laack –

The House of Representatives on Nov. 13 unanimously passed the Senate version of the Sunscreen Innovation Act (SIA), S. 2141.  The Act is currently before the President, who is expected to sign it.  The SIA amends the Food, Drug, and Cosmetic Act to provide specific deadlines for FDA’s review of time and extent applications (TEAs) for sunscreen ingredients and to require FDA to set specific deadlines for review of TEAs for non-sunscreen ingredients.  For background information on TEAs, see our previous post here. 

The SIA details timelines for FDA review of currently pending TEAs for sunscreen ingredients as well as for review of new TEAs submitted after enactment of the law.  Eight sunscreen TEAs have been under FDA review, with some pending for more than a decade.  In 2014, FDA stepped up its review efforts and issued response letters for five of the TEA applications.  Under the SIA, these five response letters  are “deemed to be . . . proposed sunscreen order[s] and [must] be displayed” on FDA’s website and “announced” in the Federal Register within 45 days of enactment of the SIA.  The pending TEAs which have not yet been reviewed must be reviewed and a proposed order for each must be published within 90 days of enactment of the SIA.  The table below shows the timing for these pending TEAs.  If FDA makes a determination that the substance is generally recognized as safe and effective (GRASE) or not GRASE based on sufficient data, the timing is predictable; a final order must be issued 135 days after publication of the proposed order.  However, there is a risk of “slippage,” in those cases where FDA determines that “data are insufficient to classify as GRASE” and additional information is necessary to allow a determination as to the status of the ingredient.

For new sunscreen TEAs, the SIA also sets specific timelines for FDA’s determination whether a sunscreen TEA is eligible for review and FDA’s substantive review of the TEA.  The outline below shows the timing for such new TEAs.  Although there are specific deadlines for FDA review, etc., there is a possibility for slippage in the determination of the eligibility and in instances where FDA determines that additional information is necessary to allow a determination whether the ingredient is GRASE.

Once FDA has issued a final order that the sunscreen ingredient is GRASE, it may be marketed.  At a later time, but within 5 years after the enactment of the SIA, FDA may amend the sunscreen monograph to include the new active ingredients subject to final orders.  (Once included in the final monograph, the final order for the sunscreen ingredient will cease to be effective).

Whether the SIA will in fact result in more sunscreen ingredients being available remains to be seen.  The SIA sets deadlines for FDA’s review.  However, it does not require that FDA find the ingredients to be GRASE.

Although named “Sunscreen Innovation Act,” the act also addresses TEA reviews for ingredients that do not fall under the sunscreen monograph.  For TEA applications for non-sunscreen active ingredients, the act requires that FDA issue proposed regulations with timelines for TEA reviews within 18 months after the SIA has been signed into law.  Sponsors of pending non-screen ingredient TEAs that have already been found eligible for evaluation of inclusion in the relevant monograph can ask FDA to provide a review framework for their TEAs rather than wait until FDA issues the regulations.  Such requests must be made within 180 days of enactment of the SIA.  FDA’s timelines “may vary based on the content, complexity, and format of the application” and must reflect public health priorities and “take into consideration[,] the resources available to [FDA].”  In light of the requirements for sunscreen ingredients and FDA’s other obligations (e.g., finalizing the monograph for antimicrobial substances), it may well be years before these TEAs will be reviewed.

By Jamie K. Wolszon –

A battle is brewing between proponents and opponents of FDA’s plans to actively regulate Laboratory-Developed Tests (LDTs), with several developments involving both camps in the past two weeks.  On the proponents’ side, on November 21, FDA announced that it will be holding a public hearing on January 8-9, 2015 at the National Institutes of Health (NIH) campus in Bethesda, Maryland.  That announcement came on the heels of a November 18 briefing on Capitol Hill by FDA, the Centers for Medicare & Medicaid Services (CMS) and patient groups advocating for the draft guidances (see our previous post here). 

Opponents of the draft guidances were similarly active during this time period.  Also on November 18, several laboratory and medical groups and laboratory directors sent FDA Commissioner Margaret A. Hamburg a letter arguing that if the agency proceeds with the framework, it must do so through notice-and-comment rulemaking.  That same day, one of the signatories of the letter, the American Clinical Laboratories Association (ACLA) announced that it had hired two very prominent litigators to help the association fight the draft guidances.  Although a new development will no doubt appear the moment after we post this blog, we detail the developments of the last two eventful weeks.

FDA announces January 8-9 public meeting at NIH campus in Bethesda.  FDA has outlined an agenda of topics for discussion at the public workshop.  According to FDA’s Federal Register notice, there will be six sessions on designated topics.  The six sessions will address the following: (1) components of a test and LDT labeling considerations; (2) clinical validity/intended use; (3) categories for continued enforcement discretion, including rare disorders; (4) notification and Adverse Event Reporting (MDRs); (5) public process for risk classification of tests and prioritization for enforcement of premarket review requirements; and (6) Quality System Regulation.  For each of the sessions, FDA provides questions in the Federal Register notice for which it seeks input during the meeting.

FDA states in the Federal Register notice that registrants wishing to present during a public comment session should identify which topics they wish to address.  FDA states that the agency “will do its best to accommodate requests to make public comment.”  Following the close of registration, “FDA will determine the amount of time allotted to each presenter and the approximate time each oral presentation is to begin, and will select and notify participants by December 17, 2014.”  It is unclear how FDA will select presenters.  It also is unclear whether a presenter could address multiple topics in different sessions, and whether presenters could make a general comment that they oppose the very concept of FDA regulation of LDTs.  Consistent with prior FDA statements, FDA is looking for feedback on its framework and not whether there should be FDA regulation of LDTs at all.  FDA also is soliciting electronic or written comments on all aspects of the public workshop by February 2, 2015. 

FDA, CMS and patient group briefing on the Hill.  The American Cancer Society Action Network, the American Heart Association, and the Ovarian Cancer National Alliance, in cooperation with Rep. Louise Slaughter (D-NY), hosted a November 18 briefing to advocate for the draft guidances, according to a press release.   Speakers at the briefing included Congresswoman Slaughter; Len Lichtenfeld, Deputy Chief Medical Officer for the American Cancer Society (Moderator); Elizabeth Mansfield, Deputy Director for Personalized Medicine, Office of In Vitro Diagnostics, FDA; Judith Yost, Director, Division of Laboratory Services, CMS; Richard Schilsky, Chief Medical Officer, American Society of Clinical Oncology; and Laura Koonz, Director of Policy, Ovarian Cancer National Alliance.  According to a Congressional Quarterly article reporting the event, “FDA’s reviews are for safety and effectiveness for the marketplace and are much more extensive types of reviews, because the [CMS] reviews for analytical validity are very narrow,” said Judith Yost, director of the laboratory services division for CMS. “The clinical validity is not approached [under CMS] at all.”

Laboratory, medical groups and laboratory directors send letter to FDA Commissioner stating that FDA must use notice-and-comment rulemaking, not guidance.  The November 18 letter states that “the draft guidance documents conflict with existing regulations and would impose substantial new requirements on clinical laboratories, hospitals, physicians, and other healthcare providers without complying with notice-and-comment rulemaking as required under the Administrative Procedure Act” (APA).  The letter was careful to preserve the legal argument that some of the signatories do not believe the agency has the statutory authority to regulate laboratories at all.  “The FDA’s statutory authority to regulate laboratory developed testing services and the scope of the proposed guidance remains a matter of significant legal controversy, and while a number of the undersigned organizations do not waive their legal claim that the FDA lacks the statutory authority to regulate laboratory developed testing services, to the extent that it is established that the FDA does have such authority, all of the undersigned are unanimous that the overwhelming weight of legal authority dictates that the proposed new requirements outlined in the draft guidance must be issued through notice and comment rulemaking.”

Signatories of the letter included, among others, the American Medical Association (AMA), ACLA, the American Hospital Association, the American Association for Clinical Chemistry, and some leading medical institutions. 

The argument that any FDA effort to actively regulate LDTs must go through notice-and-comment rulemaking is one that has repeatedly been presented to, and rejected by, FDA.  For instance, in 1992, HPM submitted a citizen petition that included the argument.  The Washington Legal Foundation’s Sept. 2006 and ACLA June 2013 citizen petition also included the argument.  FDA denied all of those citizen petitions. 

ACLA announces that it has engaged prominent litigators to help oppose FDA effort.  On November 18, ACLA announced that it had retained Paul D. Clement and Laurence H. Tribe, two distinguished constitutional and APA litigators, to help the organization oppose the framework.  “ACLA’s decision to hire Messrs. Clement and Tribe, and their decision to take this case, should be seen as an indication of the strength of our conviction that the merits favor protecting patients, labs, and physicians from this unjustified regulatory action,” the press release states.  Retaining these two litigators can be viewed as a shot across FDA’s bow.

Undoubtedly, there will be more developments as different groups seek to bolster their position on whether FDA should regulate LDTs, and if so, how.

By Ricardo Carvajal - 

The D.C. District Court granted FDA’s motion for summary judgment in a lawsuit alleging unreasonable delay in the agency’s response to a citizen petition asking for the inclusion of FDA/EPA’s seafood consumption advisory in seafood labeling and at point-of-sale.  Although the petition was filed in July 2011, the court found that “FDA’s delay in responding to Plaintiffs was not so egregious as to warrant intervention at this time.”  The court based its finding on a number of factors, including:

• The complexity of the scientific and technical issues involved, including ascertaining the risks of mercury on childhood development in light of the net effects of seafood consumption, as well as ascertaining the pros and cons of placing mercury warnings at point-of-sale;
• The fact that the agency is updating the advisory language of which the citizen petition seeks to compel expanded use;
• The absence of “certain danger” associated with the delay in FDA’s response to the citizen petition; and
• The need for FDA to have flexibility in allocating resources to address issues related to mercury consumption, as well as other priorities.

The court noted that its “calculus may change” once FDA/EPA finalize their update to the advisory, after which “further delay could become unreasonable.”  The court therefore urged FDA “to act with alacrity” once that task is completed. 

The draft updated advisory and corresponding Q&As are available here, as is a link to submit comments.

On Wednesday, December 3rd, the Food & Drug Law Institute and the University of Maryland Schools of Law and Pharmacy will hold a conference on “Emerging Issues in FDA Law: Implementation of DQSA” in Washington, D.C. The conference will include updates on implementation of the recently enacted Drug Quality and Security Act, and panel discussions addressing its two major areas: FDA’s regulation of pharmacy compounding and outsourcing faculties, as well as FDA’s implementation of the Act’s track-and-trace provisions. There will also be a “Hot Topics” panel; participants will include staff from the Senate and House of Representatives, who will discuss 21st Century Cures and PDUFA VI. HP&M Director Karla L. Palmer is one of the speakers and new Associate James E. Valentine* is moderating a panel.

Click here for a copy of the conference agenda and to register. FDA Law Blog readers can receive a 15% discount off the conference registration price. Use promotion code DQSA122014 to receive the discount. We encourage people to register for and attend this one-day conference.

*Not admitted to practice law. Working under the supervision of the Firm’s attorneys.

By James E. Valentine* & Anne Marie Murphy –

On November 19, 2014, the National Institutes of Health (“NIH”) announced the much anticipated Notice of Proposed Rulemaking on clinical trials registration and results submission (“NPRM”).  While the Food and Drug Administration Amendments Act (“FDAAA”) Section 801 is self-implementing for certain of the law’s expanded requirements, it leaves several key aspects of implementation to this rulemaking.  As we previously reported, since FDAAA was passed in 2007, there have been quite a few developments in the implementation of the ClinicalTrials.gov reporting requirements.  Once final, this rulemaking will replace all previous guidance to date.    

The NPRM would expand and clarify many aspects of the clinical trials registration and results submission requirements set out in FDAAA.  The statute left several key areas of expansion of results reporting to be considered in the rulemaking process, including results reporting for unapproved drugs and submission of summary narratives and trial protocols.   Because these items were set aside for rulemaking, they were among some of the most highly anticipated. 

Results information for trials of products that are not approved

FDAAA Section 801 explicitly mandates the submission of results information for applicable clinical trials of drugs and devices that are approved or cleared.  By contrast, whether or not to require results reporting for similar trials when products are not approved was left for NIH to determine through rulemaking.  Pursuant to this authority, the NPRM proposes to require submission of results, regardless of whether approval of the product is sought or the product is ultimately approved.  Notably, the NPRM retains the ability to delay results submission for these trials, but it is limited to a maximum three years after the completion date for products pursuing approval.

NIH set out four reasons in support of their proposal to require results information for trials of unapproved products.  They argue that making this information publically available will:

1. Mitigate the bias in information available to the public about studied medical products that stem from selective disclosure of clinical trial results;
2. Help protect the safety of participants to who volunteer to be in clinical trials by reducing the likelihood that people will unknowingly design, approve, or participate in clinical trials that are unnecessary, or are potentially harmful;
3. Broaden the evidence base for systematic reviewers and others involved in assessing the benefits and harms of classes of drugs and devices; and
4. Fulfill the agreement made with human subjects who agree to participate in clinical trials that the knowledge obtained will be available for use in advancing biomedical science.

NIH does not appear to be deterred by concerns about commercial competitiveness resulting from disclosure of results information from trials for unapproved products.  Specifically, the NPRM proposes to mitigate this concern by providing delayed results submission.  The proposal would require results submission for applicable clinical trials for unapproved drugs not later than one year after the completion date of the clinical trial, unless a certification is submitted prior to that deadline indicating that initial approval is being sought or may be sought at a future date. 

This delay in results submission would be limited to two years after the submission of the certification, and only one certification could be submitted per trial.  Thus, the total delay in disclosure of results would be up to three years after the completion date.  Although product development will frequently extend beyond this timeframe, NIH argues three years “would provide sponsors with significant lead time” in development over potential competitors.

Non-technical and technical summaries of clinical trials and results   

FDAAA Section 801 requires rulemaking to consider expanding submissions to contain non-technical and/or technical written summaries of the clinical trial, if these summaries can be included without being misleading or promotional.  In order to make this determination, NIH would like to evaluate the value to the public of such summaries. The Agency would also like to demonstrate that such narrative summaries can be consistently produced in a way that will not be objective and not misleading.  Thus, the NPRM defers the decision about whether to require submission of narrative summaries, inviting public comment on methods that might help answer this question.

Full clinical trial protocols

Similarly, FDAAA Section 801 requires consideration during rulemaking of whether to submit the full clinical trial protocol or only “information on the protocol” that may be necessary to help evaluate the results of the trial.  The NPRM outlined three ways this statutory requirement could be satisfied, by requiring submission of:

1. Additional structured data elements derived from, or describing, the protocol;
2. Portions of the final protocol or other narrative information about the conduct of the study that is associated with the protocol (e.g., a statistical analysis plan, if not part of the protocol); or
3. The full protocol at the time of results submission (i.e., the final version of the protocol, including all amendments). 

The NPRM does not propose to require any of these possibilities.  Instead, it invites public comment on whether the information that is already proposed to be required in the NPRM meets the statutory requirement  to provide “information on the protocol” or, alternatively, if any of these three proposed options for submitting additional information should be required.

The NPRM is scheduled to be published in the Federal Register on November 21, 2014.  Once published, comments can be submitted to docket number NIH-2011-0003 at Regulations.gov.  NIH also announced, in conjunction with the NPRM, a draft policy that would extend similar registration and reporting requirements to all clinical trials funded by NIH, regardless of whether they are subject to FDAAA.

*Not admitted to practice law. Working under the supervision of the Firm’s attorneys.

By Alexander J. Varond & Anne K. Walsh –

On November 17, 2014, FDA announced the availability of its draft guidance entitled, “Rare Pediatric Disease Priority Review Vouchers.” The draft guidance “is intended to assist developers of rare pediatric disease products in assessing whether their product may be eligible for rare pediatric disease designation and a rare pediatric disease priority review voucher.” Earlier this year, FDA had announced its intention to release the draft guidance as part of a larger effort to clarify issues related to pediatric drug development.

We posted here an in-depth discussion of the Rare Pediatric Disease Priority Review Voucher (“Pediatric PRV”) program in comparison to the earlier implemented Tropical Disease PRV program.  As a short recap, the Pediatric PRV program was created in 2012 to encourage development of treatments for rare pediatric diseases. (See our FDASIA summary at pages 54-56). A Pediatric PRV is granted to the sponsor of a qualifying approved “rare pediatric disease product application.” The voucher can be sold (without limitation), and the holder of the voucher can redeem it with a subsequently filed NDA or BLA, requiring FDA to meet the review goals for a priority review, versus a standard review.

To qualify to receive a Pediatric PRV, a sponsor must submit an application for a drug or biologic intended to prevent or treat a rare pediatric disease.  Such drug or biologic may not contain any active ingredient (including any ester or salt of the active ingredient) previously approved in any drug or biologic application.  The rare pediatric disease application also must be eligible for priority review (e.g., an application for a drug that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness) and rely on clinical data derived from studies examining a pediatric population and dosages of the drug intended for that population.

FDA’s draft guidance “clarifies the process for requesting [Rare Pediatric Disease] designations and vouchers, sponsor responsibilities upon approval of a rare pediatric disease product application, and the parameters for using and transferring a rare pediatric disease priority review voucher.” It is written in a Q&A format, and its questions range from the basic (e.g., “What is a priority review voucher and when is it awarded?”) to the more complex (e.g., “What does ‘Does not seek approval for an adult indication in the original rare pediatric disease product application’ mean?” or “Will a drug that receives rare pediatric disease designation also qualify for orphan-drug designation?”). In general, the draft guidance reiterates much of what was already contained in Section 908 of the FDASIA.

Nevertheless, the draft guidance is useful in that it:

• Interprets the term “rare pediatric disease” to mean “if the entire prevalence of the disease or condition in the U.S. is below 200,000 and if more than 50% of patients with the disease are 0 through 18 years of age. Another way a drug may qualify as a drug for a ‘rare pediatric disease’ is if it is for an ‘orphan subset’ of a disease or condition that otherwise affects 200,000 or more persons in the U.S., and if this subset is primarily (i.e., more than 50%) comprised of individuals aged 0 through 18 years.”
• Describes the rare pediatric disease designation process.
• Clarifies that the designation is not a prerequisite to requesting or receiving a priority review voucher.
• Details the information that should be included in the designation requests.
• Explains how sponsors should calculate prevalence estimates, breaking down the differences in estimating prevalence for therapeutic drugs and for vaccines, diagnostic drugs, and preventative drugs.
• States the terms for transferring the Pediatric PRV, for notifying FDA, and for redeeming the voucher with a subsequently filed application.

This guidance comes at an ideal time. Just two days after its publication, on November 19, 2014, Knight Therapeutics Inc. announced that it had sold its Tropical Disease PRV for $125 million to Gilead Sciences, Inc. The Tropical Disease PRV program is designed differently than the Pediatric PRV program, but the incentive program operates similarly. Gilead’s purchase nearly doubles the $67.5 million price paid in July 2014 by Sanofi and Regeneron for BioMarin Pharmaceutical Inc.’s Pediatric PRV. Perhaps these recent sales will provide further incentive to companies to develop drugs to treat rare pediatric diseases or tropical diseases, an outcome which Congress anticipated.

In addition, both the House and Senate are quickly moving toward a vote on legislation that would modify the Tropical Disease PRV program to include Ebola as a disease eligible for a Tropical Disease PRV and make the benefits of the program more favorable. If enacted, the legislation would remove the current limit on the number of times a Tropical Disease PRV can be transferred and reduce the notification time required to use the Tropical Disease PRV from one year to 90 days.

By Riëtte van Laack –

On Nov. 13, 2014, DOJ announced another Consent Decree of permanent injunction regarding the manufacture and distribution of dietary supplements.

Under the Consent Decree, contract manufacturer SciLabs, Inc. and its CEO Paul Edalat are prohibited from the manufacture and distribution of dietary supplements until FDA has determined that the company is in compliance with the dietary supplement GMPs.

According to the complaint, inspections in 2012, 2013, and 2014 revealed that SciLabs violated the dietary supplement GMP requirements causing the dietary supplements, distributed under the brand All Pro Science, to be adulterated.  In January 2013, FDA issued a Warning Letter alleging numerous violations of the GMP requirements observed during the 2012 inspection.  FDA claims that SciLabs expressed its intent to comply but the company did not provide documents to support the corrective actions.  Moreover, according to DOJ, the company failed subsequent inspections in 2013 and 2014.  Based on this record, DOJ concluded that “unless restrained by [the] Court, Defendants [would] continue to violate” the GMP requirements. 

The Consent Decree appears to, at least temporarily, put the company out of business.  The company must recall and destroy all products manufactured since August 2012 and any inventory.  In addition, the company must shut down until it has taken all required corrective actions and FDA confirms, in writing, that the company is in compliance.  The Consent Decree specifies that, if the company wants to reopen, it must hire an independent GMP expert to help with compliance issues.  The expert must certify to FDA that the company has corrected all deficiencies and is in compliance with GMP requirements.  Only once FDA confirms that it agrees with the expert may the company reopen for business.  In addition, SciLabs must “have paid all costs of FDA’s inspections, investigations, supervision, analyses, examinations, and reviews.”

Once the company resumes manufacturing, it must retain an independent expert to conduct audit inspections at least every 6 months for a period of five years.  

Earlier this year, at least three other dietary supplement manufacturers entered into similar consent decrees (see here, here, and here).  Similar to SciLabs, those companies allegedly failed several inspections and, all but one, received a warning letter alleging violation of GMPs but, according to FDA, failed to take the appropriate corrective actions. 

These cases show that FDA will aggressively pursue violators of the dietary supplement GMP requirements.   Because the consent decrees include a recall provision, a shut-down provision, and a requirement that FDA confirm that they are in compliance before they can reopen, the companies may well end up being put out of business permanently. 

FDA does not bring a lot of injunction cases per year.  Four (or more) injunctions related to dietary supplement GMP suggests that this area is a high enforcement priority for the Agency.

By Kurt R. Karst –       

Earlier this week, Mallinckrodt Inc. (“Mallinckrodt”) filed a Complaint and Motion for Temporary Restraining Order (later supplemented) in the U.S. District Court for the District of Maryland challenging FDA’s November 12, 2014 decision to downgrade from “AB” to “BX” the Therapeutic Equivalence (“TE”) rating for the company’s generic version of CONCERTA (methylphenidate HCl) Extended-Release Tablets, 27 mg, 36 mg, and 54 mg, which the Agency approved on December 28, 2012 under ANDA 202608.  FDA also downgraded the TE rating for another generic version of CONCERTA approved on July 9, 2013 under ANDA 091695 and marketed by Kudco Ireland Ltd.  Both drugs were downgraded after FDA issued a revised ANDA bioequivalence guidance earlier this month, and after FDA stated, based on “[a]n analysis of adverse event reports, an internal FDA re-examination of previously submitted data, and FDA laboratory tests,” that the generic versions of CONCERTA “have raised concerns that the products may not produce the same therapeutic benefits for some patients as [CONCERTA].”  FDA has asked both ANDA sponsors to either confirm, within 6 months, the bioequivalence of their products using the Agency’s revised bioequivalence standards, or voluntarily withdraw their products from the market.

By way of background, TE ratings are used to determine the substitutability of two drug products.  Pharmaceutically equivalent prescription drug products (i.e., generally drug products in the same strength, route of administration, dosage form, and containing the same active ingredient) are identified in the Orange Book with either an “A” or “B” therapeutic equivalence code designation.  “A-rated” drug products are considered to be to therapeutically equivalent to other pharmaceutically equivalent products, because there are no known or suspected bioequivalence problems, or such problems have been resolved with adequate evidence supporting bioequivalence.  “B-rated” drug products are not considered to be therapeutically equivalent to other pharmaceutically equivalent drug products, because actual or potential bioequivalence problems identified by FDA have not been resolved by adequate bioequivalence evidence. 

Drug products assigned an “A” rating fall under one of two categories: (1) those active ingredients or dosage forms for which no in vivo bioequivalence issue is known or suspected, and for which bioequivalence to the Reference Listed Drug (“RLD”) is presumed and considered self-evident based on other data in an application or by a showing that an acceptable in vitro dissolution standard is met; or (2) those active ingredients or dosage forms presenting a potential bioequivalence problem, but the applicant’s approved application contains adequate scientific evidence establishing (through in vivo and/or in vitro studies) the bioequivalence of the product to a selected RLD.  Drug products that fall under the first category are assigned a therapeutic equivalence code depending on the dosage form.  These codes include “AA,” “AN,” “AO,” “AP,” or “AT.”  Drug products that fall under the second category are coded “AB” (the most common code assignment).

Drug products assigned a “B” rating are designated “BC,” “BD,” “BE,” “BN,” “BP,” “BR,” “BS,” “BT,” “BX,” or “B*,” generally according to dosage form.  According to the Orange Book Preface, a “BX” code is “assigned to specific drug products for which the data that have been reviewed by the Agency are insufficient to determine therapeutic equivalence under the policies stated in this document.  In these situations, the drug products are presumed to be therapeutically inequivalent until the Agency has determined that there is adequate information to make a full evaluation of therapeutic equivalence.”

In recent year, FDA actions concerning TE ratings have been the focus of some controversy – generally in the context of 505(b)(2) applications – with a couple of Citizen Petitions and a lawsuit against FDA (see our previous posts here and here).  FDA also downgraded the TE ratings, and then withdrew the approvals, of two ANDAs for Bupropion Hydrochloride Extended-Release Tablets, 300 mg, after concerns about therapeutic equivalence were raised (see here and here).

According to Mallinckrodt, FDA’s TE rating downgrade for generic CONCERTA effectively takes the drug off the market because TE ratings are used in many states (see here) for purposes of substitution.  “That determination by FDA means that (depending on the jurisdiction) it is either unlawful or unacceptably risky for pharmacists to fill a prescription by substituting Mallinckrodt’s generic for the brand-name drug Concerta®,” says Mallinckrodt. 

Mallinckrodt also alleges that FDA exceeded its statutory authority by effectively taking the company’s drug off the market without providing Mallinckrodt with a hearing. “The FFDCA provides only one mechanism for taking a generic drug off the market: withdrawing (or suspending) ANDA approval under 21 U.S.C. § 355(e). . . . FDA has no statutory authority to take a drug off the market through other actions not specified in section 355(e).”  Citing the DC Circuit Court’s recent decision in Ivy Sports Medicine, LLC v. Burwell, 767 F.3d 81 (D.C. Cir 2014), pet. for reh’g en banc filed Nov. 11, 2014 (see our previous post here), Mallinckrodt says that that conclusion “flows directly from a recent D.C. Circuit decision construing the parallel statutory requirements governing FDA’s authority to remove a medical device from the market (following an earlier FDA decision that authorized marketing the device).”

Mallinckrodt asserts that FDA’s action has violated the company’s rights under the Fifth Amendment to the U.S. Constitution.  “The statutory hearing rights . . . derive from an underlying constitutional right to notice and a hearing guaranteed by the Fifth Amendment’s Due Process Clause. . . .  When it reclassified Mallinckrodt’s methylphenidate ER, FDA eviscerated the company’s property right in its ANDA by effectively taking the drug of the market.  FDA had no constitutional authority to impair Mallinckrodt’s property right without giving Mallinckrodt notice and an opportunity to be heard.”

Mallinckrodt’s five-count Complaint seeks both injunctive and declaratory relief from the court, including an injunction setting aside FDA’s actions, and prohibiting its future actions, and a declaratory judgment declaring that FDA has acted unlawfully. 

Update:

• On November 19th, the court issued a notice confirming that a hearing on Mallinckrodt's Motion for Temporary Restraining Order is scheduled for Tuesday, November 25, 2014, at 9:00 AM before Judge Deborah K. Chasanow.  FDA's Opposition is due by 4 p.m. on November 20th.

By Allyson B. Mullen –

Late last week, the Department of Justice ("DOJ") obtained criminal charges from a grand jury sitting in the United States District Court for the Western District of Texas against Vascular Solutions, Inc. ("VSI") and Howard Root, VSI’s CEO, for off-label promotion of the company’s Vari-Lase devices.  The Indictment alleges a conspiracy to defraud the U.S. government, along with distributing adulterated and misbranded medical devices. 

According to the Indictment, this case involves VSI’s promotion of its Vari-Lase laser ablation devices, which includes lasers, consoles, needles, fibers, sheaths, and other accessories.  The Vari-Lase devices were cleared for treatment of superficial veins.  VSI did not have clearance for treatment of perforator veins.  In 2006, however, a competitor of VSI’s obtained clearance for treatment of perforator veins. 

In response to this clearance, the government alleges that VSI began systematically promoting Vari-Lase for treatment of perforator veins.  In fact, the Indictment claims that VSI created a new “Short Kit,” a modified version of the cleared device that was specifically intended for perforator vein treatment.  The Indictment alleges that VSI unsuccessfully sought 510(k) clearance of the Short Kit, which included an expanded indication for a use that would have included perforator veins.  The Indictment further alleges that the company performed a clinical study of perforator vein treatment with laser ablation that showed poor safety and effectiveness.  Nevertheless, the government contends that VSI promoted the Short Kit and other Vari-Lase devices for the off-label intended use of perforator vein treatment. 

The Indictment goes on to allege that Mr. Root oversaw and encouraged the entire promotional campaign.  In addition, the government claims that Mr. Root was responsible for reviewing and approving various key training materials that were essential to the company’s off-label promotional activities.  The Indictment specifically claims that VSI and Mr. Root’s promotional practices were misleading because they misrepresented and concealed relevant facts regarding the Short Kit, including, telling physicians that Medicare would reimburse for perforator vein procedures performed with VSI’s devices.

As of now, we have only heard the government’s side of the case, and as we all know, there are almost always two sides to every story.  It is worth noting that this is the second case against the company on these facts this year.  According to the DOJ news release, in July of this year, VSI settled a civil case with the government, in which VSI paid $520,000 “to resolve allegations that it caused false claims to be submitted to federal health programs by marketing a medical device for the ablation (or sealing) of perforator veins without FDA approval and despite the failure of its own clinical trial.”  The civil case appears to relate to the same marketing practices that form the basis of the criminal case that was initiated last week. 

The civil case was brought in the Western District of Texas, which is the same venue where the criminal case was filed.  This is of particular note because it is representative of how the government often investigates and brings criminal cases against drug and device companies.  When a relator brings a qui tam case, the government often conducts a criminal investigation in the very same judicial district, whether or not the company is based in that district.  In fact, quite often these days the decision regarding which judicial district will conduct a criminal investigation and possible criminal prosecution is often based solely on where the relator’s counsel is based.  Qui tam counsel will often file cases in a judicial district where they live, not where the company is headquartered or even where their own client lives. 

This forum shopping starkly contrasts with “the old days” when FDA criminal cases were almost always brought in the company’s principal place of business.  This trend is troubling for companies because they are being forced to travel around the country defending against not only civil, but now also criminal cases.  This is another reminder of why there can be painful consequences when companies are investigated for off-label promotion practices.

By Michelle L. Butler & Alan M. Kirschenbaum –

On November 13, 2014, the Health Resources and Services Administration (“HRSA”) withdrew the 340B program “mega-rule” it had submitted for review to the Office of Management and Budget.  In a previous blog post we reported on a federal court decision vacating HRSA’s regulation implementing the orphan drug exclusion under the 340B program.  The court had ruled that the statute did not grant HRSA authority to issue regulations on the orphan drug exemption.  Although that case did not directly involve the mega-rule, HRSA has apparently concluded, as we foresaw in our blog post, that the holding in that decision also would preclude the issuance of the mega-rule.  (See here for an update on HRSA’s orphan drug rule.  We note that a scheduling order was just entered with summary judgment briefing to conclude in March 2015.) 

In place of the mega-rule, it appears that HRSA intends to issue guidance, as it has traditionally done in the past.  On its website,  HRSA states: “In 2015, HRSA plans to issue a proposed guidance for notice and comment that will address key policy issues raised by various stakeholders committed to the integrity of the 340B program.  HRSA is also planning to issue proposed rules pertaining to civil monetary penalties for manufacturers, calculation of the 340B ceiling price, and administrative dispute resolution.”  It is safe to assume that the proposed guidances will, at a minimum, address the topics that were originally intended to be included in the mega-rule – i.e., the definition of an eligible patient; compliance requirements for contract pharmacy arrangements; hospital eligibility criteria; and eligibility of off-site facilities.

By Kurt R. Karst –      

Last Friday, Ranbaxy Laboratories, Ltd. and Ranbaxy, Inc. (“Ranbaxy”) filed a Complaint and a Motion for a Temporary Restraining Order and Expedited Preliminary Injunction in the U.S. District Court for the District of Columbia challenging FDA’s November 4, 2014 Letter Decision stripping Ranbaxy of tentative approvals for the company’s ANDAs for generic versions of VALCYTE (valganciclovir) Tablets, 450 mg (Ranbaxy ANDA 078078), and NEXIUM (esomeprazole magnesium) Delayed-Release Capsules, 20 mg and 40 mg (Ranbaxy ANDA 077830).  In that same decision, FDA ruled that Ranbaxy forfeited eligibility for 180-day exclusivity for Valganciclovir Tablets pursuant to FDC Act § 505(j)(5)(D)(i)(IV) because Ranbaxy failed to obtain timely tentative approval within 30 months of ANDA submission.  As we previously reported, FDA approved two ANDAs for generic VALCYTE – one from Dr. Reddy’s Laboratories (ANDA 203511), and another from Endo Pharmaceuticals (ANDA 200790) – after stripping Ranbaxy of its tentative approval and cxclusivity eligibility.

FDA states in the November 4, 2014 Letter Decision that the Agency rescinded the tentative ANDA approvals because of the compliance status of the facilities identified in the ANDAs.  Specifically, FDA states:

At the time of FDA’s February 5, 2008 [tentative approval] letter [for Esomeprazole Magnesium Delayed-release Capsules, 20 mg and 40 mg], the Paonta Sahib facility had been the subject of a Warning Letter issued on June 15, 2006, based on the CGMP violations observed during FDA’s February 20-25, 2006 inspection at the Paonta Sahib facility and taking into account Ranbaxy’s March 20, April 20, and May 25, 2006 responses.  Accordingly, at the time of the tentative approval letter, the compliance status of the Paonta Sahib facility was Official Action Indicated (OAI), which is an inspection conclusion reflecting that “objectionable conditions were found and a regulatory action is recommended.”  Under such circumstances, Center for Drug Evaluation and Research Office of Compliance (CDER Compliance) will not recommend approval.  The overall compliance status for ANDA 077830 was “withhold,” and the ANDA should not have been tentatively approved at that time due to the inspectional status. . . .

At the time of FDA’s June 20, 2008 [tentative approval] letter [for Valganciclovir Hydrochloride Tablets USP, 450 mg], the Dewas facility had been the subject of a January 28 – February 12, 2008 inspection that found significant deviations from CGMP in the manufacture of sterile and non-sterile finished products and in the manufacture and control of APIs, and that resulted in the issuance of a Warning Letter on September 16, 2008.  The Paonta Sahib facility had been the subject of the Warning Letter issued on June 15, 2006, and the Paonta Sahib Batamandi (Unit II) facility had been the subject of a March 3-7, 2008 inspection that found many significant deviations from CGMP in the manufacture of finished drug products, and that resulted in the issuance of a Warning Letter on September 16, 2008.  Accordingly, at the time of the tentative approval letter, the compliance status of the Dewas facility was “potential” OAI and the status of the Paonta Sahib facility was “OAI” and the ANDA should not have been tentatively approved at that time due to the inspectional status.

Ranbaxy alleges in its court filings that “FDA has no power to correct an alleged ‘mistake’ it made six years ago,” that “FDA’s Letter Decision conflicts with the plain language of the statute’s failure-to-obtain TA forfeiture trigger, which merely requires the first-filer to receive a TA letter from the Agency within the 30-month deadline,” and that “FDA’s Letter Decision cannot be squared with the plain text and structure of the statutory provisions that set forth the exclusive requirements for obtaining TA, on one hand, and final approval, on the other.”

A hearing on Ranbaxy’s Motion for a Temporary Restraining Order is scheduled for November 19th at 2:00 PM.  Both Dr. Reddy’s (represented by Hyman, Phelps & McNamara, P.C.) and Endo have intervened in the case.

By Douglas B. Farquhar –

For years, one of the frustrations for attorneys challenging FDA in court (including us, many times) has been the degree of deference that federal courts have accorded to FDA interpretations of the Federal Food, Drug, and Cosmetic Act.  This happens when FDA says that FDCA provisions are ambiguous, and a court agrees.  But a recent and unusual statement by U.S. Supreme Court Justice Antonin Scalia (joined by Justice Clarence Thomas) invites the right party, in the right civil case, to challenge a federal agency’s interpretation of ambiguous provisions of a statute, like the FDCA, that address both criminal and administrative violations.  The statement may not only open the door – but illuminate the path – for a successful challenge, in a civil or administrative enforcement case, to FDA interpretations of FDCA provisions that have both administrative enforcement and criminal implications.  And there are plenty of provisions like that.

Historically, the so-called “rule of lenity” prohibits agency interpretations from turning ambiguous criminal statutory provisions into an acceptable basis for sending people to prison.  The principle is that it is unfair to impose harsh sanctions on an individual when an individual, examining the governing law, could reasonably believe that he or she was allowed to do what he or she did.

Douglas F. Whitman, the defendant in the case that was the subject of the recent statement by Justice Scalia, had been convicted of a violation of federal law, as interpreted by the Securities and Exchange Commission.  He appealed his conviction.  The Second Circuit Court of Appeals affirmed his conviction, deferring to the SEC on an interpretation of the relevant provision of the Securities Exchange Act.  Justice Scalia, agreeing with the decision that the Supreme Court should not further review the case (Whitman had filed a petition for a writ of certiorari), noted that the decision of the Second Circuit was consistent with numerous prior decisions in which courts “have deferred to executive interpretations of a variety of laws that have both criminal and administrative applications.”  But Justice Scalia questions whether those cases were correctly decided.  Is it appropriate, he asks, to apply a rule of lenity with regard to application of ambiguous laws in criminal cases (thus allowing courts to decide on their own whether statutory provisions are ambiguous, and to interpret statutes as they deem fit, even when in conflict with the agency interpretation), but to make courts follow the agency say-so when the same provisions are applied in administrative decisions?  Those decisions, in Justice Scalia’s view, are contrary to “many cases” holding that a law with “both criminal and civil applications” should apply a rule of lenity “in both settings.”  If the “rule of lenity” were applied to the FDCA in the civil setting, that could mean, for example, that the court and the relevant parties would not be compelled to accept FDA’s interpretation in an FDA enforcement action brought in federal court – such as a seizure of drugs or medical devices that FDA contends are adulterated, or an injunction against a company or an individual under like circumstances.

Justice Scalia did not think that the Whitman case was the appropriate platform to address these issues, because of the “procedural history of the case.”  But he is explicitly sending a signal that he wants the Supreme Court to address the issue of whether agencies are entitled to deference “when a petition properly presenting the question comes before us” – even in a civil setting (when, for example, an affected party challenges an agency enforcement decision).  In a blogpost discussing a prior Supreme Court decision, we asked the same question about interpretations of ambiguous statutory provisions that have both criminal and administrative implications.

None of the cases cited by Justice Scalia dealt with provisions of the FDCA, but it is hard to think of a reason that the same principles he discusses would not apply to the FDCA.  Courts frequently defer to FDA on interpretations of the FDCA, especially in cases dealing with the Hatch-Waxman Amendments (see, e.g., Apotex, Inc. v. FDA, 414 F. Supp. 2d 61 (D.D.C. 2006); Purepac Pharm. Co. v. Thompson, 354 F.3d 877 (D.C. Cir. 2004)), but also in at least one case about whether dietary supplements are adulterated.  This violation could result in criminal liability for distribution of adulterated dietary supplements (under Section 301(a) of the FDCA, 21 U.S.C. § 331(a)).

Justice Scalia’s invitation should not be ignored by an FDA-regulated company or individual who wants to challenge, for example, an enforcement action taken on the basis of an ambiguous provision of the FDCA, where that provision has criminal, as well as administrative, implications.  Judge Scalia is wondering whether it makes sense for a court not to defer to an agency interpretation of an ambiguous statutory provision in the criminal context, but to defer to the same agency interpretation of the same provision in the civil or administrative context.  Maybe that does not make sense.

By Andrew J. Hull* & William T. Koustas –

With the January 1, 2015 implementation of the Drug Supply Chain Security Act (DSCSA) looming over the heads of both FDA and industry, the Healthcare Distribution Management Association (HDMA) held its annual track-and-trace conference November 10-12, 2014.  Foremost on everyone’s mind was the pending and highly anticipated draft guidance from FDA—due on November 27th—regarding implementation of the new law and the creation of a national database for monitoring drug transactions throughout the supply chain.  Throughout the conference, manufacturers, distributors, and other members of the drug supply chain expressed concern over the current lack of guidance from FDA regarding compliance with federal product tracing laws with only 49 days until the DSCSA is set to begin to take effect.

Dr. Connie Jung, Acting Associate Director for Policy and Communications for the Office of Drug Security, Integrity, and Recalls in FDA’s Center for Drug Evaluation and Research, Office of Compliance, once again spoke at the conference and attempted to address some of their concerns.  Dr. Jung suggested that FDA expects supply chain members to begin complying with the DSCSA on January 1st, but was less confident about FDA’s ability to release the long-awaited draft guidance on time.  Dr. Jung stressed that FDA is diligently working to produce the draft guidance by the November 27th statutory deadline (Thanksgiving Day), but she was very reluctant to commit to the timing of its release.  Dr. Jung was less reluctant with regard to the development of the wholesaler and third-party logistics provider (3PL) databases.  She was much more confident that these databases would be running by the statutory deadlines, January 1st and November 27threspectively.

Dr. Jung also addressed numerous questions in a lively Q&A session.  Most significantly, she hinted that FDA would likely view an advanced shipment notification (ASN) system as an appropriate system to pass tracing information required under the DSCSA, and she stated that FDA would have to issue further guidance regarding proper reporting requirements for potentially fraudulent transactions.

Another highlight of the HDMA conference was HDMA’s own discussion and analysis of the federal preemption issues and ongoing state initiatives to comply with the DSCSA.  Specifically, HDMA expressed its opinion that the DSCSA preemption provision for wholesale distributor and 3PL licensing set both a floor and ceiling on state law licensing requirements, similar to the DSCSA’s preemption of state pedigree laws.  This analysis seems to run counter to FDA’s interpretation (see our previous post here) that indicates that states must only meet the minimum standards set forth by federal law.  HDMA also stated that several states (AZ, CA, CO, FL, ID, KS, MD, OK, OR, and VA) have already begun the process of updating existing licensing laws.  Most states, however, seem to be waiting for FDA to issue regulations before revising their own laws.

All in all, the members of the drug supply chain at the HDMA conference represented a level of anxious anticipation for more specific direction from FDA regarding the drug-tracing provisions of the DSCSA and a feeling that they will be more than thankful if the draft guidance actually comes as promised on Thanksgiving Day.  We here at HPM will continue to watch for the pending draft guidance and keep you posted with any new developments over the next couple of weeks.

* Not admitted in D.C.  Work supervised by the Firm while D.C. application pending.

By James E. Valentine* & James C. Shehan – 

On November 4, 2014, FDA’s Office of Health and Constituent Affairs and an Agency-wide working group posted a notice requesting comments generally on all its various patient engagement activities and specifically on FDASIA Section 1137— the provision on Patient Participation in Medical Product Discussions.

Section 1137 directs FDA to “develop and implement strategies to solicit the views of patients during the medical product development process and consider the perspectives of patients during regulatory discussions, including by—(1) fostering participation of a patient representative who may serve as a special government employee in appropriate agency meetings with medical product sponsors and investigators; and (2) exploring means to provide for identification of patient representatives who do not have any, or have minimal, financial interests in the medical products industry.”

The FDA Patient Representative Program allows patients and caregivers to become Special Government Employees (SGEs) and thereby participate in advisory committee meetings about medical products and serve as consultants to review divisions to provide input at FDA-sponsor meetings during the clinical development process.  The Program’s genesis was the HIV/AIDS activism movement in the 1980’s and it was expanded and made formal by President Clinton’s cancer initiative in the 1990’s.  According to Heidi Marchand, Pharm.D., FDA Assistant Commissioner for Health and Constituent Affairs, whose office administers the Patient Representative Program, since 2012, Patient Representatives have served on advisory committee meetings for over 150 medical products and participated in 22 FDA-sponsor product development meetings.

This notice comes on the heels of a flurry of recent activity in the arena of patient advocacy in medical product development and review, albeit not activity specifically focused on Sec 1137.  In October alone, FasterCures, BIO, NORD, and DIA hosted meetings and workshops to discuss the role of patient engagement with industry and FDA.  CTTI has embarked on a project to understand best practices for effective engagement with patient groups around clinical trials (see here).  Meanwhile, on Capitol Hill, the proposed 21st Century Cures legislation continues to contemplate expanding the role of patients in the medical product development process (see our previous post here).  In addition, FDA has spent the last couple of years piloting new initiatives to more systematically collect patient input (i.e., CDER/CBER Patient-Focused Drug Development, CDRH Patient Preferences Initiative).  Each of these efforts seeks to find ways for the patient voice to be better heard. 

FDA’s Federal Register notice is worded broadly and seeks input on all of its patient engagement activities, not just those specified in Section 1137, recognizing that all the tools for obtaining the patient perspective collectively contribute to FDA’s understanding of the patient perspective. 

While not its exclusive focus, the newly established public docket represents an opportunity to weigh in on FDA’s implementation of Section 1137 via the Patient Representative Program.  For those interested in providing comments, this public docket (here) is open until December 4, 2014.

MassBIO is hosting a Patient Advocacy Summit on November 10th (agenda here) where HP&M’s Jim Shehan will be participating in a panel on access issues.

*Not admitted to practice law. Working under the supervision of the Firm’s attorneys.