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.

By Michelle L. Butler –

We previously reported that FDA had filed a notice of appeal in Depomed Inc. v. U.S. Department of Health and Human Services et al., Case No. 1:12-cv-01592.  In another turn of events, on November 6, 2014, FDA filed an unopposed motion to dismiss the appeal.  The motion was granted and the appeal was dismissed by the Court of Appeals for the D.C. Circuit on November 7, 2014.  The Order from the Court of Appeals was docketed in the District Court’s docket on November 10, 2014. 

Apparently FDA has decided it will operate its orphan drug program within the strictures of the Depomed decision.  What effect this will have on other aspects of the program remains to be seen.

By Jamie K. Wolszon & Jeffrey N. Gibbs –

On November 6, Alberto Gutierrez, the head of the office in charge of regulating in vitro diagnostics at FDA’s Center for Devices and Radiological Health (CDRH), discussed the two Laboratory-Developed Test (LDT) draft guidances with members of a federal advisory committee devoted to laboratory issues.  (We previously reported on the draft guidances, which FDA released on October 3, here and here).  Dr. Gutierrez fielded several questions from the advisory panel members, and –even though he was interrupted by fire alarms–provided some additional insights on how the agency plans to regulate LDTs, although a plethora of questions remain to be answered.

Dr. Gutierrez, Director, Office of In Vitro Diagnostics and Radiological Health (OIR), at CDRH, discussed the draft guidances during the second day of the November 5-6 Clinical Laboratory Improvement Advisory Committee (CLIAC) meeting in Atlanta, Georgia.  CLIAC, which is managed by the Centers for Disease Control and Prevention (CDC), provides scientific and technical advice and guidance to the Department of Health and Human Services (HHS) related to laboratory issues.  The CLIAC discussion comes on the heels of an October 23 FDA webinar on the topic (previously blogged on here). 

Key points include:

• No Premarket Review Grace Period for New Highest-Risk LDTs Introduced after Final Guidance Issued.  Dr. Gutierrez stated that the need for premarket review for new LDTs that fall into the highest-risk category goes into effect the moment the final LDT guidance is published.  Those highest-risk category tests are LDTs with the same intended use as cleared/approved companion diagnostics, LDTs with the same intended use as approved Class III medical devices, and certain LDTs for determining safety and effectiveness of blood or blood products.  The draft guidance states that for the highest risk LDTs already on the market, the laboratory will have 12 months to submit an application.  That statement implies that new LDTs would not receive a similar grace period.  Dr. Gutierrez is now explicitly stating that LDTs that fall within the highest-risk category not on the market at the time the final guidance is issued will not receive a grace period from the premarket review requirements.  The upshot is that if the LDT guidance goes into effect as written, laboratories will want to begin marketing their tests before the guidance is issued.
• Determining Risk.  FDA will publish a priority list for the timeframe for premarket submissions for the remaining high-risk LDTs in year two.  FDA will publish a priority list for moderate-risk LDTs in year four.  The agency will consult advisory panels to determine these priority lists.  However, according to Dr. Gutierrez’s slides, FDA anticipates that after the highest-risk LDTs identified in the draft guidance, the next group of high-risk devices for which the agency will seek premarket submissions/applications include “devices that act like companion diagnostics; screening devices for serious diseases/conditions intended for use in asymptomatic patients without other confirmation; and diagnostics for certain infectious diseases with high-risk intended uses.”  
• In response to a question about how FDA would determine whether an LDT was high or moderate risk, Dr. Gutierrez stated that the risk depends on both the analyte and the intended use.  For instance, with a biomarker for cancer, if the test is intended to screen asymptomatic patients to determine who has cancer, this would be a high-risk test because if there is a false negative, then the clinician will miss cancer. If there is a false positive, the patient will needlessly undergo medical procedures that may result in morbidity or mortality for the patient.  The same biomarker for cancer monitoring is likely to be moderate risk, he suggested.  Monitoring involves multiple longitudinal assessments, so a false result is less risky to the patient.  Dr. Gutierrez also stated that only a small portion of IVD kits are Class III devices, and he expects that the same ratio will apply for LDTs.   
• LDTs Subject to Prohibition against False and Misleading Statements.  Dr. Gutierrez indicated that even if an LDT already on the market is not subject to premarket review yet under the phased timeline, if the company makes a statement about the test that “is not credible,” FDA can immediately initiate enforcement action.  Essentially, on the day the guidance takes effect, LDTs will be subject to the misbranding provision under Section 502(a) of the Federal Food, Drug, and Cosmetic Act, which prohibits false and misleading claims.
• Notification.  Dr. Gutierrez stated that the agency was considering having a link between the National Institutes of Health (NIH) registry of LDTs and FDA’s notification database, so that if a laboratory’s test already was registered with NIH, the laboratory would not have to duplicate that information, but would only need to complete a few fields where the information was not previously provided.  He also said that the agency has yet to decide whether to make the FDA notification database public.  He added he did not see any reason why it should not be public, as the agency can redact information such as information that could have public security implications.  In response to questions about whether the agency should require notification for LDTs that meet the “Traditional” LDT category, Dr. Gutierrez noted that this was an area where the agency solicited specific comment and that the agency was “moving toward” not requiring notification for LDTs that fall into the Traditional LDT category. 
• Manufacturing Information.  As to whether a laboratory submitting a PMA for a Class III LDT would need to include manufacturing information in the application, as is required for IVD kits, Dr. Gutierrez stated that the draft guidance as currently drafted does require such manufacturing information.  However, Dr. Gutierrez stated that the agency is reconsidering this area.  He noted that when the Quality System Regulation (QSR) went into effect in the 1990’s there was a phase-in period during which the inspections focused on education as opposed to enforcement.  The agency is considering whether a similar approach would make sense here. 
• Will there be another draft guidance before a final guidance issues? Dr. Gutierrez said that whether there will be another draft guidance issued before a final guidance is issued will be justified “by the number of changes we make to” the current proposal.  FDA issued two separate draft guidances when it was considering the In Vitro Diagnostic Multivariate Index Assay (IVDMIA) proposal.  That proposal affected significantly fewer tests than this current proposal and was much less sweeping in scope and impact. 
• January 2015 Public Meeting.  FDA will hold a two-day meeting in January 2015 to discuss the draft guidances.

CLIAC Deliberation of “Off-Label” Use of Waived Tests by Waived Laboratories.  On November 5, panel members, FDA and Centers for Medicare & Medicaid Services (CMS) representatives extensively discussed the “off-label” use of waived tests by waived laboratories.   

Under CLIA, a laboratory is either waived, moderate-complexity or high-complexity, with waived laboratories subject to the least amount of controls.  Waived laboratories are not subject to routine inspections.  A waived laboratory is only supposed to perform tests that are categorized by FDA as waived.  These waived tests are supposed to be simple enough so that they can be performed reliably and accurately in these less sophisticated laboratories.  We reported on FDA’s guidance on administrative procedures for categorization here.

Daralyn Hassan, a representative from CMS, explained that the majority of laboratories in the United States are waived.  Specifically, 66 percent of CLIA laboratories possess a certificate of waiver.  This represents a great increase, according to Ms. Hassan, from the 1990’s, when only around 20 percent of laboratories were waived.  CMS initiated a pilot program in 2002 under which the agency had inspected two percent of the waived laboratories in all 50 states.  The inspectors uncovered a number of problems in these waived laboratories during those inspections, which were announced before the inspector arrived.  CMS found that, among other issues, multiple waived laboratories were performing waived tests for off-label uses.  She said that devices used outside of the manufacturer’s requirements or intended use are considered to be test modification/off label use, and modified tests are no longer considered waived. 

FDA representatives indicated that the way FDA is dealing with the issue is to seek more narrow indications for use.   Prakash Rath, an OIR representative, said that FDA cleared indications for use are often broad, but the waived use is very narrow, and waived labs end up using the test for off-label populations or sample matrices.  Dr. Rath added that “given the only control is labeling, FDA’s approach is to request clearance/approval within a narrow intended use that may include training.”  He asked the committee to consider what else can be done to avoid the “off-label” use of waived tests by waived labs. 

Dr. Gutierrez concurred that “where we are going to is narrower intended uses.”  This conforms with our own recent experiences with OIR. 

Dr. Gutierrez noted that while the agency considers labeling to be only control it has in waived testing, the labeling must be at a seventh-grade level.  Given the requirement for a seventh-grade reading level, narrowing the intended use may not give the agency enough control over the waived testing:  He is not certain the indications for use are well enough understood to provide a successful control in the waived setting.

CLIAC agreed to make two recommendations to HHS on the issue.  First, CLIAC will recommend that the HHS facilitate development of a non-punitive and non-regulatory self-assessment checklist type tool and recommend it for use by all current CLIA-waived labs.  The committee also recommended that CMS continue to consider potential changes to address this issue and report back to the committee on this issue.

Hyman, Phelps & McNamara, P.C. has once again been ranked as a “Tier 1” law firm in the area of “FDA Law” (both nationally and in Washington, D.C.) by the folks over at U.S. News & World Report, who teamed up with Best Lawyers for the 2015 “Best Law Firms” rankings.  More than 12,000 law firms are ranked in 74 practice areas nationally and in as many as 120 practice areas on the metropolitan lists.  “[R]ankings are based on a rigorous evaluation process that includes the collection of client and lawyer evaluations, peer review from leading attorneys in their field, and review of additional information provided by law firms as part of the formal submission process,” according to U.S. News. The 2015 list of America’s Best Law Firms can be searched here, or viewed here (we’re noted on page 45).

In addition to the honors from U.S. News & World Report, LMG Life Sciences recently listed HP&M as “Highly Recommended” in the areas of Pharmaceuticals and Medical Devices.  Here’s what they had to say about us:

Hyman Phelps & McNamara represents one of — if not the most well-respected regulatory boutique firms catering to clients in the life sciences.  Tellingly, when asked for a summary of the preeminent regulatory attorneys active in the industry, one industry peer responded, “Hyman Phelps as a whole comes to mind before any-one else.”  Various practitioners with the firm inspired the praise of their peers with Jeff Gibbs, Bob Dormer and Alan Kirschenbaum the most regular recipients of accolades.  One industry peer said of Kirschenbaum, “he is absolutely top notch,” while the firm generally was described as “the most rounded FDA practice” with respondents highlighting its work on behalf of food manufacturers and pharmaceutical companies in particular.

In fact, the firm’s ability to handle all matters under the jurisdiction of the FDA, from food to drugs and devices to cosmetics, affords clients access to a substantial knowledge base exemplified through the experience of attorneys with specialized practices in every area related to the FDA as well as complementary agencies like the DEA.

One client summed up the general consensus concerning Hyman Phelps succinctly: “there are many Washington firms that focus entirely on regulatory work, with the best example of that type of dedicated practice being Hyman Phelps.”

Wow!  We’re blushing. 

By Allyson B. Mullen –

On November 3, 2014, the law firm of McKenna Long & Aldridge LLP filed suit on behalf of Plymouth Direct, Inc. (Plymouth) and Natures Pillows, Inc. (NPI) in the United States District Court for the District of Columbia against FDA claiming that FDA unlawfully detained multiple shipments of the companies’ medical device, the BeActive® Brace, that were imported into the U.S. 

According to the companies’ Complaint, BeActive is manufactured in China and sold by Plymouth and NPI in the United States through retail and mail order channels.  BeActive is a wrap brace that puts pressure on the wearer’s calf muscle, thereby reducing tension on the sciatic nerve, which can reduce lower back pain.  In April 2014, Plymouth and NPI’s supplier (Base4 Group Inc.) sent an email to FDA with BeActive’s packaging and labeling and sought FDA’s opinion as to the product’s classification (see court document here).  Based on the information provided in the court filings, the draft labeling explained that the brace was used to apply pressure to the calf muscle to relieve back pain – the device’s fundamental principle of operation.  FDA responded stating that BeActive was a Class I, 510(k)-exempt, Limb Orthosis, pursuant to 21 C.F.R. § 890.3475. 

Plymouth and NPI began selling BeActive in August 2014.  The Complaint states that between September 27, 2014 and October 20, 2014, FDA subjected seven shipments of the product to Detention without Physical Examination because BeActive lacked 510(k) clearance.  Specifically, FDA indicated that BeActive’s claim that it can relieve back pain caused by pregnancy and piriformis syndrome requires 510(k) clearance.  In addition, FDA indicated that BeActive could be an acupressure device because of how the product achieves its intended effect, and acupressure devices could be subject to 510(k) premarket notification requirements (see court document here).   FDA subsequently released all seven shipments on the grounds that although the product appeared violative, the violation was a minor violation. 

According to the Complaint, two more BeActive shipments were detained on October 28, 2014 – six days before the Complaint was filed.  As part of the detention, FDA indicated that it was in the process of adding BeActive to an Import Alert for failure to have a 510(k) clearance. 

In an effort to resolve the import detentions, the Complaint states that Plymouth and NPI proposed changing BeActive’s packaging, labeling, and promotional materials to remove the “objectionable” claims.  In addition, the companies offered to file a 510(k) for BeActive, provided that they could continue selling while the 510(k) was pending.  The Complaint reports that these proffers were made between October 24 and 28, 2014, and as of the date of the Complaint, FDA had not responded. 

The Federal Food, Drug, and Cosmetic Act (the FD&C Act) establishes procedures for the FDA and U.S. Bureau of Customs and Border Protection (CBP) to work together to admit or deny import of medical devices into the U.S.  Through this process, set out in the statute and regulations, FDA or CBP can take samples of devices to determine if they are adulterated or misbranded.  21 U.S.C. § 381(a). If samples are taken, the medical devices must be held until they are cleared for sale into interstate commerce.  21 C.F.R. § 1.90.  These procedures also allow for an informal hearing if import is denied.  21 C.F.R. § 1.94.  In addition, as an alternative to the process in the statute and regulations, FDA has created the “Detention without Physical Examination” process in its Regulatory Procedures Manual.  Through the Detention without Physical Examination process, FDA does not actually take samples of the devices.  Rather, FDA requires the recipient of the devices to hold the devices while the importer provides documentation demonstrating that the devices do not meet the criteria for import refusal. 

The Detention without Physical Examination process is the method employed by FDA in this case, and it is also the method most commonly used to detain imports of medical devices subject to enforcement action (e.g., a Warning Letter that includes an import alert).  FDA believes this process is less burdensome on FDA’s resources than having to take physical samples of products that are delivered into the U.S., when FDA has already determined that the product is adulterated or misbranded.  Thus, if a court found this process to be unlawful, it could significantly change the way that FDA and CBP handle import detentions of medical devices.

Additionally, this case raised an interesting question about how FDA handles enforcement actions that are based on a regulatory finding that is contrary to an earlier FDA opinion.  At least according to Plymouth and NPI’s recital of the facts in this case, FDA concluded that BeActive was 510(k) exempt after reviewing draft copies of the product’s packaging and labeling.  FDA’s import detention, however, was based on the premise that BeActive lacked 510(k) clearance (which would not be necessary if the product is 510(k) exempt).  Based on the materials provided in the court filings, the specific claims for piriformis syndrome and pregnancy that FDA objected to were not included in the packaging and labeling reviewed by FDA in April.  However, the April labeling appeared to explain that the device operated by applying pressure to the calf muscle to relieve back pain.  Therefore, at least from an outsider’s perspective, it appears that FDA changed its mind as to the device classification based on the devices mode of action, even though FDA knew the mode of action when it reviewed the device’s labeling in April.  Certainly, if FDA did change its mind regarding the device classification based on the mode of action without any explanation to the company, this action would appear to be arbitrary and capricious.

Given the very short timeframe in which these facts have transpired, we wonder if FDA considered Plymouth and NPI’s offer to modify BeActive’s packaging, labeling and promotional claims before the companies filed this lawsuit.  This offer was likely made about a week and a half before the companies filed this suit.  However, it appears to have worked in Plymouth and NPI’s favor. 

While the information regarding the two most recent shipments of BeActive in FDA’s import system has not been updated, this case was voluntarily dismissed by the companies on November 6, 2014.  We can assume that, based on the voluntary dismissal, that FDA and the companies likely came to an agreement to release the detained product and a pathway forward for future shipments.

Although we will not have any legal resolution as to the interesting questions raised by this case, it is a recent example of a lesson that can often be forgotten in a regulatory framework where companies usually want to work with the Agency to resolve disputes – sometimes litigation is the answer.  Particularly when it comes to import alerts and detentions that companies have trouble (or cannot) resolve with FDA, history shows us that litigation can be a very effective tool.  A recent review by HPM of cases in which companies challenged an FDA import alert or detention in court showed that the company typically prevailed.  In fact, in most of these cases, soon after the case was filed, it was dismissed, usually, if not always, because the import alert or detention was vacated by FDA.