By Ricardo Carvajal –

FDA announced its first seizure of a food that was administratively detained pursuant to FDA’s expanded authority under the Food Safety Modernization Act ("FSMA").  FSMA amended the FDC Act to make it easier for FDA to exercise the administrative detention authority that was originally conferred on the agency by the Bioterrorism Act of 2002.  Previously, FDA would have needed credible evidence that a food presented a threat of serious adverse health consequences or death to humans or animals.  Now, FDA only needs a reason to believe that a food is adulterated or misbranded – a much lower threshold.  Administrative detention is not intended to be a stand-alone enforcement tool; rather, it gives FDA a way to temporarily stop the further distribution of a food in commerce while the agency works with the Department of Justice to institute a seizure action.

It is not surprising that the agency chose food warehoused under allegedly insanitary conditions as the first target on which to exercise its expanded authority.  The agency has a long history of enforcement actions against such foods.  However, prior to FSMA, the type of evidence cited by FDA in this case might not have been sufficient to support the exercise of administrative detention.  It will be interesting to see whether the agency chooses to exercise administrative detention in cases that present more novel circumstances.

By Kurt R. Karst –      

“That’s all I can stand, I can’t stands no more.”  Those were the words spouted by Popeye the Sailor at the climax of each cartoon episode after having been threatened with bad behavior from an antagonist like Bluto or the Sea Hag.  Immediately thereafter, Popeye would squeeze open a can of spinach – or perhaps suck the spinach through his pipe – infusing him with invigorating power and he would give his adversary a thrashing. 

Popeye’s words seem to capture well the frustration that led Stat-Trade, Inc. (“Stat-Trade”) to open up its own can of “spinach” and file a Complaint and a Motion for Preliminary Injunction in the U.S. District Court for the District of Columbia seeking to compel FDA to comply with the requirements of the Prescription Drug User Fee Act (“PDUFA”) in assessing and granting waivers for prescription drug user fees in relation to the company’s NDA No. 020353 for NAPRELAN (naproxen sodium) controlled release tablets, 375 mg, 500 mg, and 750 mg. 

Under PDUFA (FDC Act §§ 735-736), FDA collects three types of user fees for a drug product that is the subject of a “human drug application”: (1) a one-time application fee that must be paid in order for FDA to accept an application for filing; (2) an annual establishment fee for “each prescription drug establishment listed in [an] approved human drug application as an establishment that manufactures the prescription drug product named in the application;” and (3) an annual product fee for each drug listed in FDA’s Orange Book (i.e., the active section of the Orange Book and not the Discontinued Drug Product List) that is the subject of an approved human drug application.  Annual establishment and product fees have been set at $520,100 and $98,970, respectively, for Fiscal Year 2012.  Those fees went into effect on October 1, 2011 – see our previous post here.  Companies that fail to pay fees are placed on an arrears list at FDA, and may be subject to certain other penalties.  FDA policy says that the Agency will refuse to accept for filing submissions from applicants in arrears.

For those companies that are subject to user fees – and in particular annual product and establishment fees – FDC Act § 736(d) provides a few mechanisms to offer relief.  For example, a company can request FDA to waive or reduce user fees under the “barrier to innovation” mechanism or under the “fees-exceed-the-costs” mechanism.  Under the “barrier to innovation” mechanism (FDC Act § 736(d)(1)(B)), a waiver is granted if “the assessment of the fee would present a significant barrier to innovation because of limited resources available to [the application holder] or other circumstances.”  Under the “fees-exceed-the-costs” mechanism (FDC Act § 736(d)(1)(C)), a waiver or reduction is granted by FDA if “the fees to be paid by such person will exceed the anticipated present and future costs incurred by [FDA] in conducting the process for the review of human drug applications for such person.” 

In addition, there are several exceptions under PDUFA that could preclude the assessment of user fees.  For example, under FDC Act § 736(a)(3)(B), a drug is exempt from product fees if it “is the same product as another product approved under an [ANDA] filed under [FDC Act § 505(j)].”  In a 1994 guidance document, FDA explained that “[i]f the [ANDA] has been approved and not withdrawn, the first approved product [(i.e., the NDA drug product)] is excluded from fees even if the generic product is not presently marketed.”  More recently, however, in a Federal Register notice concerning proposed changes to PDUFA (under PDUFA V), FDA says that a proposed technical change to FDC Act § 736(a)(3)(B) “will clarify FDA’s longstanding policy to use the active portion of the Prescription Drug Product List in the [Orange Book] to identify fee-eligible prescription drug products,” and that “FDA will assess a product fee on a prescription drug product when there are no other products on the Prescription Drug Product List that are the same as that product.”

NAPRELAN, which was approved on January 5, 1996, was not subject to generic competition until 2002 and 2003 when FDA approved generic versions of the 375 mg and 500 mg strengths under ANDA No. 075416.  In 2008, however, a U.S. district court ruled in patent infringement litigation that the ANDA sponsor infringed a patent held by Elan.  The ANDA sponsor stopped distributing its generic NAPRELAN and the products were moved from the active to the discontinued section of the Orange Book.  (Recently, the ANDA sponsor settled the patent infringement litigation with Elan.  Under the settlement agreement, the generic will not be marketed until either patent expiration or if there is a final finding of patent invalidity or unenforceability.)

Once the generic NAPRELAN was no longer marketed and was moved to the discontinued section of the Orange Book, FDA began sending invoices to Stat-Trade for annual product and establishment user fees, and in particular, fee invoices for the 375 mg and 500 mg strengths, which are the same strengths approved under ANDA No. 075416.  Stat-Trade timely submitted waiver requests to FDA under the “barrier to innovation” and “fees-exceed-the-costs” mechanisms discussed above.

In August 2010, FDA denied Stat-Trade’s barrier to innovation waiver request and informed the company that the Agency “had not reviewed Stat-Trade’s fees-exceed-the-costs waiver request, and would not do so unless and until Stat-Trade notified FDA that it would not appeal the denial of its barrier-to-innovation waiver request.”  Stat-Trade appealed the barrier to innovation waiver denial and FDA has allegedly continued to refuse to review the company’s fees-exceed-the-costs waiver request. 

Meanwhile, Stat-Trade failed to pay the invoiced user fee amounts and was therefore placed on FDA’s arrears list and was assessed more than $200,000 in penalties, interest and administrative fees.  In July 2011, Stat-Trade arranged for the payment of $1.3 million to cover all of the company’s outstanding PDUFA user fees and related penalties, interest, and administrative fees for Fiscal Years 2009-2011, thereby removing the company from the arrears list.  Stat-Trade’s user fee payment, however, did not mean that the company was abandoning its fight with FDA.  Stat-Trade further corresponded with FDA setting forth arguments why certain user fees should not be applicable and the company’s waiver requests granted. 

Just a couple of weeks after having paid FDA $1.3 million in back fees and penalties, FDA sent Stat-Trade an invoice for Fiscal Year 2012 user fees, including product fees for the 375 mg and 500 mg strengths of NAPRELAN.  Payment was due by October 1, 2011.  Stat-Trade promptly petitioned FDA (Docket No. FDA-2011-P-0696) for a stay of action concerning the assessment of product and establishment fees for Fiscal Year 2012, the application of FDA’s arrears policy, and the imposition of interest, penalties, and administrative fees with respect to Fiscal Year 2012 user fees.  On September 30, 2011, FDA responded that the Agency had “begun reviewing” Stat-Trade’s petition and would “respond promptly.”  Stat-Trade filed its Complaint on October 7, 2001, after not receiving a prompt response from FDA. 

State-Trade’s Complaint says that FDA has “adopted a final policy that violates PDUFA because it allows FDA to assess and collect annual ‘product fees’ for certain prescription drug products that are exempt from such fees pursuant to [FDC Act § 736(a)(3)(B)],” and that FDA has “applied this unlawful policy against Stat-Trade by assessing product fees for two strengths of [NAPRELAN] that are ‘the same’ as approved generic copies and thus exempt from product fees under PDUFA.”  In addition, Stat-Trade alleges that FDA’s refusal to review or process Stat-Trade’s fees-exceed-the-costs waiver request for more than nineteen months is contrary to PDUFA and violates the Administrative Procedure Act (“APA”).

Although PDUFA has been around for quite a while, legal challenges to FDA’s interpretation of the statute have been rare.  In fact, we are aware of only a single case – Winston Labs, Inc. v. Sebelius, No. 1-09-cv-04572 (N.D. Ill. 2009) – concerning what constitutes an “affiliate” for purposes of the small business user fee waiver provision.  FDA ended up losing that case – see our previous posts here and here.  

By Riëtte van Laack –

On October 4, 2011, the Center for Food Safety (“CFS”) announced the filing of what it touts as “a groundbreaking new legal petition” with FDA, demanding that FDA issue regulations that require the labeling of all food produced using genetic engineering.  CFS filed the petition on behalf of the Just Label It campaign.  Co-petitioners include various food companies, organic trade organizations, and other biotechnology opponents.

According to Petitioners, the differences between genetically engineered (“GE”) and conventionally produced foods are material, and lack of labeling that discloses that a food is GE is misleading to consumers.  Petitioners ask that FDA issue regulations that define GE as “a process that alters an organism at the molecular or cellular level by means that are not possible under natural conditions or processes . . . exclud[ing] modification that consists exclusively of breeding, conjugation, fermentation, hybridization, in vitro fertilization, or tissue culture.”  The label of a GE food would be required to indicate which ingredients are genetically engineered and include a notice “GENETICALLY ENGINEERED” followed by a statement “UNITED STATED GOVERNMENT NOTICE: THIS PRODUCT WAS PRODUCED USING GENETIC ENGINEERING.” 

Under FDC Act sections 403(a)(1) and 201(n), a food is misbranded if its labeling is false or misleading in any particular, including by virtue of failing to disclose facts material with respect to the consequences which may result from use of the food under customary or usual conditions of use.  In 1992, FDA issued a policy which states in part that bioengineered foods as a class are not materially different from conventional foods, and thus there is no basis to require labeling that specifies their method of production (FDA prefers the term “bioengineered” to GE).  FDA adhered to this position in a draft guidance on voluntary labeling of bioengineered foods issued in 2001. FDA’s current approach is to consider whether such labeling is required on a case-by-case basis.  The Agency operates a voluntary consultation program for bioengineered foods under which the agency considers numerous characteristics in its evaluation of potential differences between bioengineered and conventional foods.

According to Petitioners, "[t]he agency severely constricted what it called 'material,' limiting it to the ability of a change to be tasted, smelled, or known through the other senses.”  Petitioners assert that “whether the FDA believes that GE foods are ‘of the same or equal quality’ as their conventional counterparts is irrelevant to the question of whether it is misleading to label GE foods the same as conventional foods.  The proper focus is whether consumers are deceived and whether their right to know is abridged.”

Petitioners cite FDA’s regulations mandating labeling of irradiated foods and identification of the food source of hydrolyzed protein as precedents for FDA’s authority to mandate labeling based on production processes, even if those processes do not measurably affect the sensory and performance characteristics of the food. Moreover, citing the U.S. Court of Appeal for the Sixth Circuit decision in IDFA v. Boggs, petitioners argue that a difference does not need to be measurable; FDA may require labeling merely because conventionally produced food have a demonstrable history of safe use and there is a lack of history of safe use for GE foods.  Petitioners also mention the patentability of GE foods as evidence that GE foods are novel and cannot be equivalent to (i.e., are materially different from) conventional foods.

In light of FDA’s stance on labeling of bioengineered foods, its current strategic priorities, and its limited resources, it appears unlikely that the Agency will initiate rulemaking to mandate such labeling in the near future.  Meanwhile, Just Label It advises consumers who want to avoid bioengineered foods to “[l]ook for the USDA Organic seal and buy organic – The National Organic Standards prohibit the use of genetic engineering.”

By Kurt R. Karst –      

The first U.S. Conference on Rare Diseases and Orphan Products started with a bang today with the release of a landmark report announcing its findings of flexibility in FDA’s review of potential treatments for patients with rare (“orphan”) diseases.  The conference, which is co-sponsored by the National Organization for Rare Disorders (“NORD”), under the auspices of the Drug Information Association, is taking place in Washington, D.C. from October 11th-13th.  (Collaborating organizations include EURORDIS (the European Rare Disease Organization), FDA, NIH, and the Duke Clinical Research Institute.)  Chairman of the NORD Board of Directors and Hyman, Phelps & McNamara, P.C. Director, Frank J. Sasinowski, authored the report and presented on it at the conference.  (A copy of Mr. Sasinowski’s conference presentation is available here.)

The NORD study was designed to examine how much flexibility (if any) FDA exercises in reviewing orphan drugs.  In other words, the study was intended to determine whether FDA requires that marketing applications for orphan drug provide the conventional or traditional effectiveness data that are ordinarily expected for most drugs for more prevalent diseases.  The report examines the quantum of effectiveness evidence that provided the basis for FDA’s approval of the 135 non-cancer orphan drug new chemical entities approved between the creation of the Orphan Drug Act in 1983 and June 30, 2010.  Of the 135 drug approvals studied, NORD concluded that 45 would have met traditional data requirements, 32 reflected “administrative flexibility” based on a previously documented FDA system, and 58 reflected flexibility applied on a case-by-case basis.

“This review of FDA actions concludes that two of every three orphan drugs approved show FDA’s historic flexibility in its review of effectiveness data on orphan drug therapies, ” Mr. Sasinowski said in a NORD press release.  “Therefore, FDA has demonstrated in its actions on orphan products that it recognizes the importance of therapies for persons with rare disorders.  It would be helpful for such flexibility and importance to be recognized in a formal FDA policy, and for FDA officials to incorporate and recognize that flexibility in a systematic way in their evaluations of each new therapy in development and under FDA review for Americans with any rare disease.”

In June 2010, FDA held a Part 15 hearing, titled “Considerations Regarding Food and Drug Administration Review and Regulation of Articles for the Treatment of Rare Diseases” (Docket No. FDA–2010–N–0218), at which Mr. Sasinowski, on behalf of NORD, testified and recommended that FDA “develop and issue a specific Statement of Policy on FDA’s role in regulating therapies for rare disorders, which includes an explanation and affirmation of the FDA’s historic position that FDA flexibly applies the standards of safety and effectiveness with respect to therapies for those with rare disorders.”  That hearing was followed by a NORD citizen petition requesting “that a documented policy be established regarding the review of potential treatments for people with rare diseases.”  (See our previous post here.)  

The NORD report follows both the issuance of the proposed PDUFA V Reauthorization Performance Goals and Procedures (Fiscal Years 2013 through 2017), which state that FDA “will develop and disseminate guidance and policy related to advancing and facilitating the development of drugs and biologics for rare diseases, including . . . . encouraging flexibility and scientific judgment, as appropriate, on the part of reviewers when evaluating investigational studies and marketing applications for drugs for rare diseases,” and an FDA Report to Congress from the Agency’s Rare Disease Group (“RDG”).  As we noted last month, in the report, the RDG “identified both strengths and constraints in the current paradigm for drug and device regulation.”  Among the key areas in need of additional efforts identified in the RDG report is for FDA to “[g]ain a thorough understanding of the regulatory history of orphan drug products to help identify effective development approaches, particularly for addressing the uncertainties of biomedical knowledge along the product development pathway, so that patterns can be adapted to future development programs.”  This includes performing “a detailed analysis of FDA’s 27-year history of orphan drug approvals to identify factors and methods that have led to successful drug development and approval or have impeded development and identify areas for improvement.”  The NORD report should certainly help out in this respect. 

By John A. Gilbert, Jr. & Karla L. Palmer –

On Wednesday, October 5, 2011, the DEA published a final rule clarifying when a DEA registrant’s voluntarily surrender of its registration is effective.  The final rule amends 21 C.F.R. §§ 1301.52(a) and 1301.62(a) to make it clear that a registrant surrenders its DEA registration simply by submitting a Form 104 (for controlled substances registrants) or a Form 104c (for listed chemical registrants), or by providing written notice (in any format) to “any employee” of DEA expressing a desire to surrender a registration.  A voluntary surrender is immediately effective upon a DEA employee’s receipt of  a signed Form 104 or written notice, and thus does not require any further action on the part of the administration with respect to the surrender.

DEA’s “clarification” of a voluntary surrender is an important reminder of the perils of signing a voluntary surrender form (DEA Form 104) without the advice of counsel when presented with the form during an investigation or inspection.  The rulemaking also makes clear that a registrant can use any written notice to surrender a registration.   

Prior to this regulatory clarification, registrants, and at least one federal court, were at best unclear whether the DEA was required to issue a formal decision concerning the surrender after a registrant executed a Form 104.  For example, in 2004, a federal court in Utah found that a registrant was able to revoke his Form 104 voluntary surrender.  See Page v. Bruce, 2004 WL 72447 (D. Utah 2004).  The plaintiff physician in that case signed the Form 104 at his office during a DEA investigation.  The plaintiff stated that the DEA investigators threatened to report him to the assistant U.S. attorney’s office, stated that it was a “one-time deal,” and gave the plaintiff registrant a 30-minute window to make a decision whether to give up his registration.  Plaintiff signed the Form 104.

After having significant and immediate remorse over signing the Form 104, the plaintiff contacted DEA two hours later to revoke his surrender.  The plaintiff noted that, prior to signing the form, he was not advised, and thus did not understand, that: (a) DEA could not otherwise revoke his registration without issuing an order to show cause setting forth specific grounds, and a hearing; (2) prior to any hearing the registrant would have an opportunity to file a response and consult an attorney; (3) prior to any revocation the DEA would have the burden of proof at a hearing showing that the registrant posed an imminent danger to the public health and safety; (4) the registrant would have the right to an attorney present at the hearing, and be able to present and cross-examine witnesses; (5) the registrant would be entitled to appeal any administrative or legal decision resulting from the hearing; and, (6) the registrant would be able to retain his DEA registration throughout the course of the hearing and appeals process.  Id. at *3.

Despite DEA’s argument that the voluntary surrender was final and binding upon signing the Form 104, the court found, “[i]t is the DEA Administrator’s authority to revoke a DEA registration, not the registrant’s authority to revoke its own registration.  The statute, regulations and form do not authorize the termination or revocation of the registrant’s DEA privileges based solely on signing of a Form 104.”  Id.  Furthermore, the language in the Form 104 and federal law required the DEA to affirmatively act on a surrender to render it final; a registrant’s signing of the Form 104 was “merely a step in the process.”  2004 SL 72477. *6-7 (D. Utah 2004).        

DEA states in the final rule that a Form 104 (or Form 104c) surrender, or any surrender in writing, is effectively immediately upon receipt by any DEA employee without further action by the administration.  Thus, if a registrant signs the Form 104 when presented by a DEA investigator or agent, the registrant must be aware that he waives immediately several legal rights, including the right to notice of DEA’s allegations, legal counsel, a hearing, and appeal, among others (as described above).  In addition, DEA’s final rule would generally prohibit a registrant from later revoking the surrender if he has a case of buyer’s remorse or second thoughts about whether signing a Form 104 was a prudent course of action. 

Especially in light of DEA’s recent rulemaking, we believe even more strongly that DEA registrants should not sign a voluntary surrender without seeking the advice of legal counsel and certainly not under pressure or duress.  First, given DEA’s clarification of  21 C.F.R. §1301.52, a Form 104 is now effective immediately on receipt by a DEA employee, thus it provides a registrant no opportunity to reconsider its actions.  Second, a Form 104 itself contains many admissions, including, but not limited to, admissions that the registrant was “fully advised of its rights,” that the document was “freely executed,” and, most importantly, that it is signed “in view of my alleged failure to comply with the Federal requirements pertaining to controlled substances, and as an indication of my good faith in desiring to remedy any incorrect or unlawful practices on my part.”  

Even if the ultimate decision is to surrender the registration, registrants should consider the option of using another form of written surrender, so that the registrant will be able to make the decision knowingly, after advice of counsel, and with a full appreciation of the law, facts, circumstances and consequences surrounding the decision.  Also, the registrant can avoid unnecessary written statements or inferences on violations of the law and regulations.

By Jeffrey K. Shapiro –

A medical device manufacturer in most cases is legally required to obtain 510(k) clearance or premarket application (“PMA”) approval from the Food and Drug Administration’s (“FDA”) prior to commercial distribution.  Premarket reviews are conducted under the auspices of the Office of Device Evaluation (ODE) or the Office of In Vitro Diagnostics (“OIVD”) in the Center for Devices and Radiological Health (“CDRH”).  Unfortunately, disputes between sponsors and FDA sometimes arise during the review process.  A dispute may concern which review process is appropriate, i.e., whether a 510(k) clearance or PMA approval is required.  Or, it may be a disagreement over the type or quantity of supporting bench, preclinical or clinical data that should be required, or whether the data are adequate to support clearance or approval.  There also may be disputes in other areas – for example, the appropriate labeling for a device.  Typically, these disputes will culminate in an unfavorable decision at the ODE or OIVD Division level, such as a “not substantially equivalent” decision on a 510(k) submission or denial of a PMA application.

At present, the time required to appeal an adverse decision is uncertain, and it can easily take six to 12 months, or more.  This delay in market entry burdens applicants with higher than expected costs and retards the introduction of new technology and competitive products.  The public health would benefit if disputes between sponsors and FDA could be resolved in a more predictable and commercially reasonable time frame.

In the discussion below, I will briefly describe the available appeal processes, the problems with them, and potential strategies for a successful appeal.  I will also propose that CDRH establish an Office of Appeals for Premarket Submissions ("OAPS") in the Office of the Center Director to bring greater predictability, consistency and timeliness to the resolution of premarket disputes between sponsors and ODE reviewers.

*          *          *

A disappointed applicant has a range of appeal procedures theoretically available to obtain reconsideration of FDA actions and decisions.  Although not all options are available in all cases, and not all are immediately available after an initial denial, the potential procedural options include:  filing a petition for administrative reconsideration, 21 C.F.R. § 10.33, filing a citizen petition, 21 C.F.R. § 10.30, filing a petition for a stay of administrative action, 21 C.F.R. § 10.35, requesting a formal evidentiary hearing, 21 C.F.R. Part 12, requesting a public hearing before a public board of inquiry, 21 C.F.R. Part 13, requesting a public hearing before a public advisory committee, 21 C.F.R. Part 14, requesting a public hearing before the FDA commissioner, 21 C.F.R. Part 15, requesting a regulatory hearing, 21 C.F.R. Part 16, and requesting review of a scientific controversy by the Medical Devices Dispute Resolution Panel (“MDDRP”), 21 C.F.R. § 10.75(b)(2). 

For present purposes, it is not worth recounting the detailed requirements for these nine procedures.  (For good summaries of the first eight procedures listed, and an assessment of their advantages and disadvantages, see CDRH’s guidance document, Medical Device Appeals and Complaints: Guidance on Dispute Resolution (1998).  For a discussion of the MDDRP, see Resolving Scientific Disputes Concerning The Regulation Of Medical Devices, A Guide To Use Of The Medical Devices Dispute Resolution Panel; Final Guidance for Industry and FDA (2001).)  Suffice it to say that an applicant seeking to invoke one of these appeal options must have deep pockets, plenty of time to wait, and a willingness to accept varying degrees of public exposure and/or public participation.  Not surprisingly, most of the time these procedures are not commercially feasible.  The proof that they are impractical is that they are invoked rarely or never.

Typically, there is only one procedure that is commercially viable – a request for internal supervisory review.  The boundaries of this process are set forth in a short regulation, 21 C.F.R. § 10.75.  Section 10.75(a) describes when an internal supervisory review may be requested:

(a) A decision of an FDA employee, other than the Commissioner, on a matter, is subject to review by the employee's supervisor under the following circumstances:

(1) At the request of the employee.
(2) On the initiative of the supervisor.
(3) At the request of an interested person outside the agency.
(4) As required by delegations of authority.

The reference to “the request of an interested person outside the agency” is the authority that allows a disappointed applicant to request a supervisory review.

Section 10.75(b)(1) explains how the review will proceed:

(b)(1) The review will be made by consultation between the employee and the supervisor or by review of the administrative file on the matter, or both. The review will ordinarily follow the established agency channels of supervision or review for that matter.

As noted, the supervisor may consult the employee and/or review the administrative file.  The brevity of this provision allows FDA flexibility in the procedures to be followed.  For example, although the foregoing provision does not mention any role for the “interested person,” in practice interested persons are typically granted a meeting with the supervisor, if requested.  In some cases, but not always, the employee (or employees) responsible for the decision are also present at the meeting.  The downside of a flexible procedure is that some applicants may not know how best to proceed, since the regulation does not provide much instruction.  Indeed, the handling of these reviews tends to be fairly ad hoc.  In these situations, the CDRH Ombudsman can be a helpful resource in explaining the process and/or participating as an observer.

Section 10.75(c) specifies when a Center Director or the Office of the Commissioner will personally review an appeal:

(c) An interested person outside the agency may request internal agency review of a decision through the established agency channels of supervision or review. Personal review of these matters by center directors or the office of the Commissioner will occur for any of the following purposes:

(1) To resolve an issue that cannot be resolved at lower levels within the agency (e.g., between two parts of a center or other component of the agency, between two centers or other components of the agency, or between the agency and an interested person outside the agency).
(2) To review policy matters requiring the attention of center or agency management.
(3) In unusual situations requiring an immediate review in the public interest.
(4) As required by delegations of authority.

Finally, section 10.75(d) provides that a supervisory review is confined to information already in the administrative record:

(d) Internal agency review of a decision must be based on the information in the administrative file. If an interested person presents new information not in the file, the matter will be returned to the appropriate lower level in the agency for reevaluation based on the new information.

This requirement means that an applicant needs to think carefully about whether the administrative file contains the information upon which the appeal will be based.  If not, steps need to be taken to be sure that such information is in the administrative file (with an opportunity for the initial decision makers to consider it) prior to an appeal.

Typically, a supervisory review should be requested in writing, with an explanation why the original decision is erroneous.  The request should briefly describe the review process and then clearly explain the erroneous decision.  Applicants often damage their chances by an overly complex and detailed account of the proceedings below.  The impression of complexity may actually lead supervisory management to defer to the judgment of the reviewers.  Management also has limited time to digest the facts; keeping it simple is therefore more likely to speed the process and make the case more persuasive.

It is also a mistake to cast aspersions on the reviewers, suggesting that they are biased or simply out to “get” the company, or that they are incompetent.  Rather, it is more persuasive to focus the presentation on the facts, and to avoid questioning the good faith, competence or motives of the reviewers.  Remember:  the official reviewing the appeal is the supervisor of the reviewers, and is already working with them daily on a wide variety of matters.  The supervisory official is not likely to be easily persuaded by an assertion that the reviewers are either evil or incompetent.  Unfortunately, many appeals are presented in just this fashion.  In a supervisory review, it is far more persuasive to present the dispute as an honest difference of opinion, but one in which the reviewers made the wrong decision.

In some cases, the issue may have a legal or regulatory aspect to it.  FDA is legally required to treat like products alike.  The most common legal issue that can arise is an allegation that this requirement is not being followed, and the applicant’s product is being sent down a more difficult regulatory pathway than similar products or is subject to more burdensome data requirements.  This type of dispute may be a candidate for review by the Office of Chief Counsel (“OCC”) rather than a supervisory appeal.  There is not a specific procedure required for OCC review.  The applicant writes to the OCC, explains the issue and perhaps requests a meeting to present the case.  If the OCC agrees on the merits, they may intervene with the reviewing division at OIVD or ODE.

If the aid of the OCC is sought, it is critical that the dispute be cast in legal terms.  The OCC provides legal advice, and will not overrule a scientific decision.  Furthermore, the issue must be ripe for OCC review.  Typically, the OCC will not intervene until there is an actual decision to review.  For example, if there were a dispute over an additional information (“AI”) request during a 510(k) review, the OCC would be unlikely to intervene.  Rather, the applicant would typically need to take the process through to at least a “not substantially equivalent” decision before seeking help from the OCC.
 
The supervisory review process is usually the best and most realistic choice for an appeal.  At present, however, the process has a number of shortcomings.  First, there are no deadlines for FDA to review an appeal, hold a meeting, or make a decision.  Typically, an appeal needs to be squeezed into upper management’s busy schedule.  Matters that are “on the clock” such as a 510(k) decision or a PMA application milestone generally will take precedence.  Thus, appeals can languish for months until a meeting is held, and then sit for more months before a decision is made.   My own experience is that a supervisory review process can easily take more than six months to be completed, frustrating the applicant who remains in limbo.  There is no way for the public to know what the average time is for supervisory reviews, because no performance metrics are ever published. 

Second, there is an inherent conflict of interest in the supervisory review.  The supervisor must work with the review team daily on a wide range of matters.  The supervisor cannot afford to alienate them, and will presumptively have confidence in them.  Furthermore, they can have communications about the appeal with the review team that the applicant will not know about.  While most supervisors (in my experience) are careful to conduct a review fairly and impartially, the organizational and psychological dynamics add to the difficulty of successfully overturning an erroneous decision.

A desirable reform would be to create an Office of Appeals for Premarket Submissions (“OAPS”).  The OAPS would be located organizationally in the CDRH Director’s Office, reporting to the CDRH Ombudsman.  (This proposal could be extended to include the other Centers, in which case the OAPS should be located in the Commissioner’s Office.)  The Ombudsman would have overall responsibility for the operation of the OAPS.  The OAPS would have a dedicated staff with multidisciplinary scientific and medical expertise regarding medical devices.  Ideally, the staff would come from review division and would therefore have varied experience in conducting premarket reviews.  The staff should also have access to a dedicated OCC counsel as needed.

Crucially, the OAPS would operate under published written procedures with established milestones and timelines.  Initially, it might be necessary to offer OAPS review as a voluntary pilot project, since section 10.75(a)(3) currently offers “interested persons” a right to invoke supervisory review.  Ultimately, however, if the OAPS were successful, it might be appropriate to amend section 10.75 to incorporate review by the OAPS.  There is no reason that statutory changes should be required, since the creation of the OAPS would simply be a different way to handle supervisory reviews already established by regulation, not statute.  Ideally, all appeals would be routed to the OAPS, with appeal from the OAPS to the CDRH Director’s Office or to the Commissioner.  This approach would free up the Directors of OIVD and ODE from having to spend time and resources on appeals from the divisions, and would eliminate the conflict of interest inherent in this type of supervisory review.

There would be other benefits.  First, the OAPS could regularize the review process, creating publicly known milestones and timelines.  This would be consistent with the current “transparency” initiatives underway at FDA.  Right now, the supervisory review process is largely ad hoc, and is a mystery to many applicants.  Second, the OAPS would eventually have an experienced team focused on processing appeals.  This development would lend itself to consistency and efficiency in handling appeals.  It might even be possible to develop a database with information about dispute resolution patterns.  Such information would allow for published appeal metrics, including a data based insight into the performance of the review divisions.  For example, if a particular reviewing group develops a record of generating unusually high (or low) numbers of appeals and/or reversals, that would be valuable for FDA management to know.  Finally, the OAPS would be a single office that could be held accountable for timely and fair dispute resolution.  Right now, no one at FDA is specifically and publicly accountable for ensuring either timeliness or fairness in dispute resolution (although the CDRH Ombudsman can help impose accountability internally to a certain extent).

In conclusion, FDA offers many procedural avenues for dispute resolution.  None of them is satisfactory, however, and reform is needed.  Some day, it would be a good idea for Congress to sweep out all of the underbrush and establish by statute a few, practical and well delineated appeal procedures.  In the meantime, a more expeditious approach would be to revise internal supervisory review to have the bulk of such appeals handled by a specialized office, the OAPS.  This reform would greatly benefit the public health by bringing fairness, consistency, and, above all, timeliness to the appeals process.

By Kurt R. Karst –      

We have learned that FDA’s Office of Orphan Products Development (“OOPD”) has a new Acting Director.  Debra Lewis, O.D., M.B.A., who is OOPD Deputy Director, and who has been serving as Acting Director since the Departure of Dr. Timothy Coté earlier this year, announced earlier this week that Gayatri Rao, M.D., J.D. will become OOPD Acting Director starting the week of October 10th.  Dr. Rao graduated from the University of Medicine and Dentistry of New Jersey Medical School and earned both her law degree and bioethics masters degree from the University of Pennsylvania.  She comes to OOPD from FDA’s Office of Chief Counsel, thereby “bringing a unique medical and legal/regulatory background to move the OOPD rare disease mission forward,” Dr. Lewis wrote in an e-mail announcement.

By John A. Gilbert, Jr., Karla L. Palmer & Larry K. Houck –

The Government Accountability Office (“GAO”) recently issued a report analyzing the Drug Enforcement Administration’s (“DEA’s”) efforts to combat the diversion of legal controlled substances and listed chemicals.  As the title suggests, “DEA has Enhanced Efforts to Combat Diversion, But Could Better Assess and Report Program Results,” the report is critical of DEA’s ability to measure and report its anti-diversion efforts.  The report also concludes that DEA has adequate internal controls to ensure the quality of its criminal and regulatory investigations.

However, the GAO report fails to address a number of concerns and growing tensions about DEA’s industry guidance or lack thereof, its timeliness in responding to various issues raised by the regulated industry, and DEA’s consistency in its enforcement efforts.   

The GAO conducted the performance audit of DEA from May 2010 through August 2011.  The report responds to two questions:  (1) How DEA manages its investigation efforts to address the growing and evolving nature of prescription drug diversion; and (2) how DEA helps ensure that policies and procedures are followed for investigations, and to what extent DEA determines the results of its efforts on the diversion problem.

With respect to the first matter considered (DEA’s management of its investigation efforts), GAO reports favorably on DEA’s increased criminal and regulatory investigative efforts.  GAO reviewed DEA policies and procedures, and interviewed DEA personnel and state board of pharmacy and medicine officials at five of DEA’s twenty-one field divisions (selected on case volume and geographic diversity).  GAO also interviewed members of ten DEA Tactical Diversion Squads (“TDSs”).  Lastly, GAO interviewed officials of associations representing pharmacies and distributors, as well as certain pharmacies and distributors “to obtain regulated industry’s perspective on how DEA carries out its regulatory responsibilities and interacts with industry.”

GAO notes at the outset of the report that DEA has significantly expanded its resources  to respond to the increased rate of diversion and increased registrant population.  In particular, DEA increased the number of TDSs from five to forty.  TDSs are collaborative teams of DEA diversion investigators and special agents, and state and local law enforcement personnel, whose mission is to “detect, investigate, and refer for prosecution violators of federal and state statutes pertaining to diversion.”  DEA has significantly expanded its investigative efforts through use of the TDSs: DEA increased the number of criminal diversion investigations by 21 percent (from 1,571 in FY 2009 to 1,904 in FY 2010).  DEA plans to add sixteen TDSs over the next two years.  DEA officials told GAO that use of the TDSs has freed up DEA resources previously used to conduct criminal and regulatory investigations, resulting in the number of regulatory investigations more than tripling from 1,173 in FY 2009 to 3,731 in FY 2010.  DEA also stated that it focuses its regulatory investigation efforts on the wholesale registrants, where DEA mostly conducts unannounced investigations.  DEA believes these registrants are the “sources of supply to criminal schemes such as rogue pharmacies and pill mills.”  

The GAO report asserts that, “[i]n addition to conducting regulatory investigations, DEA has also actively engaged registrants and their industry associations to help the registrants understand current trends in diversion and the regulatory obligations they must demonstrate they have fulfilled during regulatory investigations.”  The report states, as an example of such active engagement, that DEA provides information to regulated industry on DEA’s website as well as through conferences, policy letters and correspondence.  Interestingly, the DEA Office of Diversion Control headquarters organizational and contact page on the Internet “has been temporarily removed until further notice” for many months.  The DEA also cancelled an industry conference that was scheduled to occur this fall. 

In contrast to the responsiveness that GAO noted in the report, we remain concerned about DEA’s responsiveness to the concerns and issues raised by the regulated industry.  For example, for a number of years, the regulated industry has been frustrated by the unreasonable amount of time it takes for DEA to process and issue annual manufacturing and procurement quotas.  The lack of clarity and transparency in this process continues to cause severe financial and resource allocation problems for the regulated industry.  That said, the report discusses the targeted outreach efforts that DEA conducted beginning in 2005 to inform wholesale distributors of their regulatory responsibilities to identify, monitor and report suspicious orders of controlled substances, and to assist registrants in the preparation of a DEA investigation.  Nevertheless, we believe that the regulated industry remains quite concerned that DEA’s outreach efforts still fail to provide meaningful clarification to unduly vague regulations addressing a registrant’s suspicious order monitoring, customer due diligence, or reporting suspicious orders, among other issues. 

With respect DEA’s internal controls that help ensure the quality of investigations, GAO reports that DEA has in place internal control activities to ensure that diversion investigators and special agents are skilled enough to carry out their DEA responsibilities.  These activities include guidance and training through program policy and procedure manuals, and diversion investigation courses.  For example, the report notes, DEA provides a twelve-week basic training program and a one-week refresher program for diversion investigators.  However, our experience has been that there remains an inconsistency between DEA offices as to statutory and regulatory requirements, and we have observed a number of cases where DEA offices have provided conflicting advice on those requirements.  For example, we have been told that some DEA offices will advise registrants that List I chemical products are required to be kept in a DEA security cage.  While this may be good practice in certain cases, it is not required by either the CSA or its implementing regulations.  As another example, DEA offices have also provided inconsistent guidance on what constitutes a “significant loss” for reporting purposes pursuant to 21 C.F.R. § 1301.74(c).  Some DEA offices deem the loss of a single dosage unit to be “significant” and therefore reportable.  Other offices have chastised registrants for reporting such insignificant losses.

The report also states that DEA provides a one-week program on criminal diversion for special agents assigned to the Diversion Control Program.  Interestingly the GAO report does not question whether, based on this one week of training, special agents are actually competent to conduct investigations of DEA registrants, although it appears that special agents are increasingly involved in conducting or overseeing investigations of DEA registrants.  The report also notes that “Division management” reviews cases “being elevated for disciplinary action (civil or criminal)” but does not identify whether, by referring to “Division management,” it is referring to the current thirteen career diversion investigator Diversion Program Managers (“DPMs”) who took the twelve-week basic diversion control training course or the seven special agent DPMs who took the mere one-week training program on criminal diversion.

With respect to the second issue considered — GAO’s assessment of how DEA measures the results of its enforcement efforts — GAO sheds a decidedly negative view on DEA’s ability to measure and report on its diversion control efforts.  For example, GAO reported that, although DEA has the ability to track and report on criminal investigations, DEA does not adequately identify and report on its regulatory efforts.  Importantly, given DEA’s increased focus on regulatory and criminal investigations in response to the growing diversion problem in the United States, GAO states, “it is critical for DEA to determine and report on the extent to which these additional efforts are helping reduce diversion.”  While DEA has established five core ways to measure performance and assess outcomes, GAO found that DEA could enhance these measures to better capture and report investigative outcomes and their effect on diversion.  Better reporting would help DEA target its resources, and measure how well agency programs are achieving targeted goals.  In sum, GAO questioned how DEA targets its efforts, monitors and improves performance, or meets performance goals of decreasing diversion if DEA’s core performance matrices do not “clearly explain how they demonstrate progress towards … overall program goals of reducing diversion.” 

GAO recommends that DEA develop an “outcome measure” that directly demonstrates results of the diversion control program.  This would provide better information to DEA program managers and other decision makers including Congress.  The GAO similarly observes that, given that DEA more than tripled the number of regulatory investigations that it conducted between 2009 and 2010, it is important that DEA develop a way to assess and report on the increased number and type of regulatory investigations to determine what effect they are having on compliance and decreasing diversion.  It also notes that DEA management must track the results of its efforts.  For example, rather than individually reporting on the various types of potential sanctions (i.e., administrative recordkeeping, actual diversion, or criminal sanctions, to name a few) the agency currently tallies all administrative, civil and criminal sanctions together, making it difficult to determine whether the sanctions are a result of regulatory noncompliance issues or actual diversion.  The GAO notes that an increase in sanctions does not necessarily correlate with a decrease in diversion, or meeting other program targets, if one is not informed whether those sanctions are a result of criminal investigations or administrative investigations (which could actually indicate a rise in non-compliance among registrants).  

GAO concludes by stating that, whether DEA is making progress towards meeting its goals is unclear; DEA must track whether its efforts are having any impact on diversion so that it can determine what benefits are being realized and what, if any, adjustments need to be made to make programs more effective.  

The DEA disagrees with GAO’s findings and observations concerning the agency’s failure to measure and report on its enforcement efforts.  DEA asserts that further strengthening the current performance measures would not provide any additional benefit in assisting the agency in the allocation of resources or targeting diversion.  The DEA adds that the deterrent effect of regulatory investigations cannot be measured — it is impossible to quantify the “lack of diversion” that is occurring as a result of DEA’s efforts. 

DEA’s Office of Diversion Control has a budget of $292 million, is authorized for 1,300 full-time positions, and regulates more than 1.3 million registrants.  Registration fees fund DEA diversion control activities, and DEA published a Notice of Proposed Rulemaking in July 2011 proposing to significantly increase those fees (see our previous post here).

In conclusion, we believe the DEA should take greater steps to ensure that investigators are aware of the statutory and regulatory requirements, and thus can provide and promote accurate and meaningful guidance to the regulated industry.  While we understand there will always be an inherent tension between regulators and the regulated industry, the current tension between the DEA and the regulated industry needs to be resolved.  Both DEA and the regulated industry have the same goal in mind — ensuring that legitimate patients have access to their medicine while preventing diversion and abuse of controlled substances.

By David B. Clissold & Ricardo Carvajal - 

FDA issued two draft guidance documents that set out the agency’s thinking with respect to new tobacco products and the requirement to either demonstrate substantial equivalence under FDC Act § 905(j) or secure premarket approval under § 910. 

The draft guidance titled Demonstrating the Substantial Equivalence of a New Tobacco Product: Responses to Frequently Asked Questions notes that changes to the label and packaging of a tobacco product make it a “new tobacco product” requiring either premarket approval or a demonstration of substantial equivalence.  Logically, FDA doesn’t intend to enforce those requirements with respect to labeling changes required by law, but the guidance discusses other circumstances under which demonstration of substantial equivalence would be needed.  For example, changes in the brand name of the product, tobacco blending changes that are intended to alter the chemical or perception properties of the new product, and changes in moisture content, ingredient composition, or harmful/potentially harmful constituents would all require a submission.  Even if "a supplier of a component (e.g., the filter) began using a new processing aid (e.g., an antimicrobial agent) for a sub-component (e.g., paper used for the filter's plug wrap) and the change is so minor that it is not even capable of being quantified in the finished product," that change would require a submission.  Notably, the submission of a substantial equivalence report under FDC Act § 905(j) must be accompanied by an environmental assessment ("EA") pursuant to the National Environmental Policy Act.  An EA is a public document that evaluates the potential risk for the product to cause significant environmental effects, focusing on environmental issues relating to the use and disposal of the product.  It discusses the need for the proposal and any alternatives, of the environmental impacts of the proposed action and alternatives, and a listing of agencies and persons consulted.  If potentially adverse environmental impacts are identified for an action, the EA must discuss reasonable alternative courses of action that offer less environmental risk or that are environmentally preferable to the proposed action.  Most actions regarding human drugs, devices, food, and food additives are exempt from the requirement to submit an EA.

If a new product is not found to be "substantially equivalent" to a product on the market as of February 15, 2007, then it is a "new tobacco product" subject to premarket review by FDA.  The draft guidance titled Applications for Premarket Review of New Tobacco Products explains the procedural and substantive requirements that apply to premarket tobacco product applications submitted under FDC Act § 910. Among other things, a PMTA must include:

• full reports of investigations of health risks posed by the tobacco product, which FDA interprets to mean both favorable and unfavorable studies regardless of whether the studies were conducted in the U.S. or abroad, and regardless of whether they complied with human subject protection guidelines;
• a “full statement of all components, ingredients, additives, and properties, and of the principle or principles of operation” of the product; and  
• a “full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and, where relevant, packing and installation a full description” of the product.

A PMTA must also include “information sufficient to enable FDA to make a finding that the marketing of a new tobacco product is ‘appropriate for the protection of the public health’” within the meaning of FDC Act § 910(c)(4).  As this is a new standard in the FDC Act, FDA requests comment on what type of evidence should be required to satisfy the standard, as well as comment on “establishing a baseline for determining whether a new product affects the likelihood that tobacco users will quit or the likelihood that non-users will start using such products.”  However, the guidance makes clear that FDA expects rigorous “well-controlled scientific investigations” that address the product’s comparative health risks, the product’s effect on the likelihood of quitting tobacco use, and its effect on initiation.  In specific, FDA expects comprehensive information on product chemistry; nonclinical studies that address toxicity, abuse liability, and carcinogenicity; and human studies.

By Wes Siegner –

We recently reported that on September 19th, FDA announced the issuance of a revised version of the Agency’s June 2006 final guidance document/Compliance Policy Guide (“CPG”), titled “Marketed Unapproved Drugs – Compliance Policy Guide Sec. 440.100, Marketed New Drugs Without Approved NDAs or ANDAs.”  The revised CPGs says that FDA’s risk-based approach to taking enforcement action with respect to the manufacture and distribution of marketed unapproved drugs first articulated in the June 2006 CPG continues to apply today, but only to unapproved drug products on the market as of September 19, 2011.  Since FDA issued the revised CPG, at conferences we have attended and in phone calls we have received, companies marketing or planning to market prenatal vitamin products, some of which are marketed as unapproved drugs, have been asking whether the guidance was intended to prevent the marketing of new prenatal products as unapproved drugs.

We received an answer from FDA.  The following is a quote from an FDA CDER/Office of Compliance e-mail we received:

Any unapproved drug that enters the market on or after 9/19/11 is subject to immediate enforcement action without prior notice.  Any unapproved drug on the market prior to 9/19/11 is subject to the enforcement priorities in the CPG.
 
Prenatal vitamins are not excepted from this CPG.  If firms intend their prenatal vitamins to be marketed as drugs without approval, they are subject to this enforcement policy.

The likely impact of this change of policy on prenatals will be to force new products to be marketed as dietary supplements, which for the most part appears to be a transition that can be made with appropriate label and claim changes, and possibly some formulation changes.

By Ricardo Carvajal - 

It almost escaped our notice – a blog posting by FDA asserting that “there is currently no evidence to suggest a public health risk from fruit juices, including apple juice” (emphasis added).  The posting went up the same day as the airing of an episode of the Dr. Oz Show that presented the results of independent laboratory testing conducted at the show’s behest, which purportedly showed high levels of arsenic in apple juice.

Evidently the producers of the show provided the test results to FDA prior to airing the episode, and FDA responded with a letter explaining the inadequacy of the test methodology relied on by the independent laboratory (the lab tested for total arsenic, which does not distinguish between the inorganic and potentially harmful forms of arsenic and the organic and essentially harmless forms).  The letter closed with a strong admonition: “The FDA believes that it would be irresponsible and misleading for The Dr. Oz Show to suggest that apple juice contains unsafe amounts of arsenic based solely on tests for total arsenic.”  The day before the show aired, FDA sent the producers an additional letter taking issue with the accuracy of the test results obtained by the show, and restating the agency’s admonition. 

Nonetheless, the show continues its “Arsenic in Apple Juice” campaign online, and is calling for FDA to set a standard for total arsenic in apple juice.  It won’t happen – but we hazard a guess the flap was good for the show’s ratings.

By Cassandra A. Soltis –

Last week, the Federal Trade Commission (“FTC”) announced a settlement with Reebok International Ltd. (“Reebok” or “the Company”) for charges that the Company disseminated false and misleading advertisements for its EasyTone and RunTone shoes.  The FTC’s Complaint alleged, among other things, that Reebok falsely claimed the EasyTone and RunTone shoes “will tone and strengthen the legs and the butt more than” walking and running in typical walking and running shoes.  Complaint at 9-10, Federal Trade Commission v. Reebok Int’l Ltd., No. 1:11-cv-02046-DCN (N.D. Ohio Sept. 28, 2011).  The Complaint also alleged that Reebok falsely advertised that laboratory tests showed that EasyTone shoes “improve muscle tone and strength by 28% in the gluteus maximus, 11% in the hamstrings, and 11% in the calves.”  Id. at 9.

The Judgment provides, in pertinent part, that Reebok may not advertise or otherwise represent through “use of a product name, endorsement, depiction, or illustration” footwear and apparel purporting to improve muscle tone and strength “unless the representation is non-misleading and, at the time of making such representation, [Reebok] possesses and relies upon competent and reliable scientific evidence that substantiates that the representation is true.”  Judgment at 5 (emphasis added).  The Judgment explains that “competent and reliable scientific evidence shall consist of at least one Adequate and Well-Controlled Human Clinical Study . . . that conforms to acceptable designs and protocols, the result of which, when considered in light of the entire body of relevant and reliable scientific evidence, is sufficient to substantiate that the representation is true.”  Id. at 5-6.  The Judgment includes what appears to be a new definition of “Adequate and Well-Controlled Human Clinical Study,” defining it as “a clinical study that is randomized, controlled, blinded to the maximum extent practicable, of at least six weeks duration, uses an appropriate measurement tool or tools . . . and is conducted by persons qualified by training and experience to conduct and measure compliance with such a study.”  Id. at 4.  We will have to wait and see whether this language will be used in future cases.       

Although the Judgment applies only to Reebok, it contains, as the FTC indicated, “compliance nuggets” that may be relevant to other advertisers.  Of note is the Complaint’s description of the women in the television and Internet advertisements:  “[t]hese advertisements frequently display women who are very toned, scantily-clad, and sometimes nude,” and “on screen . . . [was a] toned woman wearing a tank top and very short shorts.”  Complaint at 5 (emphases added).  In addition, the Complaint explains that after the model claims the shoes will “help make your legs and butt look great,” the camera “zooms to [the] woman’s backside” multiple times.  Id. at 5-6.  These notations, along with the Judgment enjoining misrepresentations made through “depiction” or “illustration,” suggest that advertisers should be careful to not implicitly overpromise product results by using models demonstrating results that most consumers will never achieve.  See also FTC, “How’s That Workout Working Out?  Tips on Buying Fitness Gear” (cautioning consumers to question whether the ”six-pack[s]” of the “chiseled models in the ads” are a “result of the product they’re peddling – or months in the gym and years of healthy habits”). 

In addition, the Judgment’s definition of “Adequate and Well-Controlled Human Clinical Study” is a reminder that there is no “one size fits all” study design to support product claims.  The Judgment indicates that to substantiate the types of claims Reebok made for its shoes, the duration of a clinical study must be “at least six weeks” and use “appropriate measurement tool[s].”  Judgment at 4.  Accordingly, advertisers should be sure to use appropriate experts – that is, persons “qualified by training and experience to conduct and measure” the effectiveness of the product at issue – to design studies having a proper duration and using suitable measuring tools to yield reliable results.  Id. at 4. 

Reebok has agreed to pay $25 million in consumer refunds to settle the FTC’s charges.  The court approved the Judgment on September 29, 2011.

By Kurt R. Karst –      

Since we last updated our popular Generic Drug Labeling Carve-Out Citizen Petition Scorecard in February 2011, there have been several new citizen petitions submitted to FDA raising questions about FDA approval of ANDAs with labeling that omits information protected by periods of patent or non-patent market exclusivity, or with labeling that is otherwise not the “same as” that of the Reference Listed Drug (e.g., tablet scoring).  Two recent citizen petitions of interest (here and here) concern AstraZeneca’s (“AZ’s”) quetiapine fumarate, approved as SEROQUEL (quetiapine fumarate) Tablets (NDA No. 020639) and SEROQUEL XR (quetiapine fumarate) Extended-Release Tablets (NDA No. 022047). 

SEROQUEL is listed in the Orange Book with a single patent – U.S. Patent No. 4,879,288 (“the ‘288 patent”) – the pediatric exclusivity for which expires on March 26, 2012.  The Orange Book also lists three periods of 3-year new clinical investigation exclusivity: “I-560” exclusivity (“MAINTENANCE TREATMENT FOR BIPOLAR I DISORDER, AS ADJUNCTIVE THERAPY TO LITHIUM OR DIVALPROEX”) the pediatric exclusivity for which expires on November 13, 2011, and two periods of “NPP” (New Patient Population) exclusivity from NDA supplement approvals for the treatment of schizophrenia in adolescents 13 to 17 years of age and the treatment of bipolar mania in children and adolescents 10 to 17 years of age.  The pediatric exclusivity applicable to the two periods of exclusivity coded as NPP expire on June 2, 2013. 

SEROQUEL XR is listed in the Orange Book with two patents – the ‘288 patent and U.S. Patent No. 5,948,437 (“the ‘437 patent”).  The ‘437 patent expires on May 28, 2017, but is subject to a period of pediatric exclusivity that expires on November 28, 2017.  The Orange Book also lists several periods of 3-year new clinical investigation exclusivity, four of which have expired but are subject to unexpired periods of pediatric exclusivity: (1) “I-618” (“ADJUNCTIVE THERAPY IN THE TREATMENT OF MAJOR DEPRESSIVE DISORDER (MDD)”) which expires on December 2, 2012; (2) “I-576” (“ADJUNCTIVE THERAPY IN THE TREATMENT OF BIPOLAR MANIA”) the pediatric exclusivity for which expires on April 8, 2012; (3) “I-574” (“MONOTHERAPY IN THE TREATMENT OF BIPOLAR DEPRESSION”) the pediatric exclusivity for which expires on April 8, 2012; (4) “D-117” (“50 MG TABLET FOR INITIATION OF DOSE TITRATION FOR BIPOLAR DISORDER”) the pediatric exclusivity for which expires on April 8, 2012; and (5) “I-575” (“MONOTHERAPY IN THE TREATMENT OF BIPOLAR MANIA”) the pediatric exclusivity for which expires on April 8, 2012.   

AZ’s two quetiapine fumarate petitions, which cite FDA’s February 2011 petition response concerning labeling carve-outs for generic versions of XYZAL (levocetirizine dihydrochloride) to support their position, are presumably intended to fit hand-in-glove with one another.  Both petitions raise issues with the omission of information in Table 2 of the products’ labeling concerning glucose-related data and information, and with the omission of information on suicide (contained in both the black box warnings and the “Warnings and Precautions” labeling sections for each product).  In each case, AZ argues that the omission of specific, protected information in generic drug labeling would make the generic product less safe or effective for the remaining non-protected conditions of use of SEROQUEL or SEROQUEL XR.

Of particular interest is the SEROQUEL petition, in which AZ argues against the omission of certain information protected by exclusivity FDA granted with respect to SEROQUEL XR approvals – specifically, by the periods of 3-year exclusivity concerning the treatment of bipolar disorder and MDD.  According to AZ:

FDA has periodically required AstraZeneca to revise its label to include new information concerning the use of Seroquel.  Some of this new information in the Seroquel label is based on Seroquel XR protected data that cannot be included in a generic drug’s labeling until the associated data exclusivity periods have expired.  If FDA were to permit a generic to omit such information from its labeling – after requiring its inclusion in the labeling for Seroquel – the agency would run afoul of the Administrative Procedure Act's prohibition on arbitrary and capricious agency action.

We also note a second addition under the subheading “FDA Citizen Petition Responses Not Permitting a Labeling Carve-Out.”  In May, FDA granted in part and denied in part a Citizen Petition concerning generic COLCRYS (colchicine) Tablets, which is approved under three NDAs (the parent application of which is NDA No. 022352) for the prophylaxis and treatment of gout flares in adults, and for the treatment of familial mediterranean fever in adults and children 4 years or older.  The 27-page petition response is interesting for a variety of reasons (and is a must-read for FDA’s interpretation of FDC Act § 505(b)(2) and policies concerning the granting of exclusivity), but for our purposes here, FDA appears to have determined (page 24) that certain labeling information concerning acute gout flares protected by a period of 3-year new clinical investigation exclusivity cannot be omitted from generic drug labeling.  According to FDA:

It is well-recognized that recent colchicine use (i.e., for prophylaxis of gout flares) increases the susceptibility to toxicity related to additional doses of colchicine.  To the extent that a healthcare provider determines it is necessary to use colchicine for treatment of an acute gout flare in a patient receiving colchicine for prophylaxis, adequate information about potential toxicity of colchicine dosing would be important to minimize the risk of cumulative toxicity.  Accordingly, the labeling for a single-ingredient colchicine product seeking approval for prophylaxis of gout flares should inform healthcare providers that the lower dose colchicine regimen evaluated in the AGREE trial is adequate to treat an acute gout flare that may occur during chronic colchicine use.  In addition, a Medication Guide for any subsequent colchicine product would be expected to contain information similar to the Medication Guide for Colcrys.

Below is our updated scorecard.

Generic Drug Labeling Carve-Out Citizen Petition Scorecard

FDA Citizen Petition Responses Permitting a Labeling Carve-Out

• FDA Response, Docket Nos. 2001P-0495, 2002P-0191, FDA-2002-P-0003 (June 11, 2002) – ULTRAM (tramadol HCl)
• FDA Response, Docket Nos. 2001P-0495/PRC, 2002P-0191/PRC, FDA-2002-P-0003/PRC (Mar. 31, 2003) – ULTRAM (tramadol HCl)
• FDA Response, Docket No. FDA-2003-P-0074 (Apr. 6, 2004) – REBETOL (ribavirin)
• FDA Response, Docket No. FDA-2005-P-0368 (Dec. 1, 2006) – OXANDRIN (oxandrolone)
• FDA Response, Docket No. FDA-2006-P-0274 (Mar. 13, 2008) – ETHYOL (amifostine)
• FDA Response, Docket No. FDA-2007-P-0169 (Apr. 25, 2008) – MARINOL (dronabinol)
• FDA Response, Docket No. FDA-2008-P-0304 (June 18, 2008) – ALTACE (ramipril)
• FDA Response, Docket No. FDA-2008-P-0069 (July 28, 2008) – CAMPTOSAR (irinotecan HCl)
• FDA Response, Docket No. FDA-2006-P-0073 (Nov. 18, 2008) – PULMICORT Respules (budesonide inhalation suspension)
• FDA Response, Docket Nos. FDA-2008-P-0343 & FDA-2008-P-0411 (Dec. 4, 2008) – PRANDIN (repaglinide)
• FDA Response, Docket No. FDA-2008-P-0343/PRC and PSA & FDA-2008-P-0411 (June 16, 2009) – PRANDIN (repaglinide)
• FDA Response, Docket No. FDA-2009-P-0411 – ACTOS (pioglitazone HCl) & ACTOPLUS MET (March 15, 2010) (pioglitazone HCl; metformin HCl)
• FDA Response, Docket No. FDA-2009-P-0601 (June 17, 2010) – NAROPIN (ropivacaine HCl monohydrate)
• FDA Response, Docket No. FDA-2010-P-0087 (July 30, 2010) – LYRICA (pregabalin) 
• FDA Response, Docket No. FDA-2010-P-0545 (February 24, 2011) – XYZAL (levocetirizine dihydrochloride)
• FDA Response, Docket No. FDA-2011-P-0128 (May 11, 2011) – XIBROM/BROMDAY (bromfenac)

FDA Citizen Petition Responses Not Permitting a Labeling Carve-Out

• FDA Response, Docket No. FDA-2003-P-0002 (Sept. 20, 2004) – RAPAMUNE (sirolimus)
• FDA Response, Docket No. FDA-2010-P-0614 (May 25, 2011) – COLCRYS (colchicine)

Pending Labeling Carve-Out Citizen Petitions

• Docket No. FDA-2007-P-0294 – ACTOS (pioglitazone)
• Docket No. FDA-2007-P-0113 – THALOMID (thalidomide)
• Docket No. FDA-2009-P-0581 – BAYTRIL (enrofloxacin) (Animal Drug)
• Docket No. FDA-2009-P-0597 – Fluticasone Propionate and/or Salmeterol Xinafoate Products
• Docket No. FDA-2010-P-0403 – VAGIFEM (estradiol)
• Docket No. FDA-2011-P-0482 – VAGIFEM (estradiol)
• Docket No. FDA-2011-P-0662 – SEROQUEL (quetiapine fumarate)
• Docket No. FDA-2011-P-0663 – SEROQUEL XR (quetiapine fumarate)
• Docket No. FDA-2011-P-0702 – DORYX (doxycycline hyclate)

BPCA Section 11 Pediatric Labeling Citizen Petitions

• FDA Response, Docket No. FDA-2001-P-0053 (January 24, 2002) – BPCA Implementation
• FDA Response, Docket No. FDA-2002-P-0289 (May 21, 2003) – ALPHAGAN (brimonidine)
• FDA Response, Docket No. FDA-2010-P-0545 (February 24, 2011) – XYZAL (levocetirizine dihydrochloride) 

Withdrawn or “Dead” Labeling Carve-Out Citizen Petitions

• Docket Nos. FDA-2004-P-0426 & FDA-2003-P-0081; FDA Letter – SKELAXIN (metaxalone) (see our previous post here)
• Docket No. FDA-2001-P-0445 – NEURONTIN (gabapentin) Capsules

By Jennifer D. Newberger –

On September 30, 2011, FDA announced the issuance of a Draft Guidance, De Novo Classification Process (Evaluation of Automatic Class III Designation), intended to update and streamline the de novo review process.

The de novo review process, formally known as Evaluation of Automatic Class III Designation, is established by section 513(f)(2) of the Federal Food, Drug, and Cosmetic Act ("FDC Act"), as amended.  This process is a compromise between the 510(k) clearance process by which over 95% of medical devices come to market in the U.S., and the more rigorous premarket application ("PMA") approval process, generally reserved for higher risk devices.  It was added to the FDC Act by the Food and Drug Administration Modernization Act of 1997 ("FDAMA") to address novel devices that lack a predicate device but pose only a low to moderate risk, making them ill suited to the PMA process.

Both FDA and industry agree that the de novo classification process has not been implemented very well, especially in recent years.  We have blogged on the ballooning review times.  It also has been difficult to get FDA to make timely decisions on whether a device is suitable for de novo review and what data requirements apply. 

The Draft Guidance appears intended to address these failings.  It states:

FDA believes that the process could be improved and greater clarity could be provided regarding suitability and data needed so that the de novo process may be a more viable pathway for novel low to moderate risk devices. Accordingly, FDA is issuing this draft guidance to provide updated recommendations for more efficient interactions with FDA, including what information to submit when seeking a path to market via the de novo process. This guidance describes a mechanism to provide (1) greater clarity about the suitability of a device for the de novo process, and (2) timely input on the type of data necessary to support de novo classification of a suitable device.

Under the statute, before a manufacturer may utilize the de novo process, it must submit a 510(k) notification to the agency, even if it knows no marketed predicate device exists.  It then must wait for FDA to issue an NSE determination before it can file a petition for de novo classification.  This requirement to submit a 510(k) notification and wait for an NSE determination, knowing that no valid predicate exists, significantly delays the process of classifying low- to moderate-risk devices through the de novo classification process.

The Draft Guidance proposes to transcend the statutory obstacle with a new administrative process, referred to as a “pre de novo submission,” or PDS.  This voluntary process allows for early interaction between industry and FDA regarding whether a device is likely to be suitable for de novo classification.  If FDA determines the device is likely to be suitable, the sponsor may then follow the initial review with concurrent submission of a 510(k) notification and de novo classification petition.  As described in the Draft Guidance:

The purpose of the PDS is for us to analyze whether a new device appears to be suitable for the de novo process, and, if so, to provide an opportunity to advise you on the documentation needed in the subsequent 510(k) and de novo petition. The primary advantage of the PDS process is that it provides an early opportunity to obtain our assessment of the suitability of a new device for the de novo process, our preliminary perspective on the likely classification, as well as feedback on the evidence, including performance and/or clinical data, that will likely be necessary to support the de novo petition. By obtaining this early feedback, you are more likely to optimize your resources in collecting the necessary safety and effectiveness evidence needed to support a de novo petition, without the need to perform additional tests.  This should also facilitate the review of a subsequent de novo petition.

After a PDS is submitted, FDA may request, within 60 days, any additional information it feels is needed.  The sponsor also may submit a meeting request to discuss the PDS.  FDA intends to issue a suitability determination within 60 days, after which the sponsor may submit a concurrent 510(k) notification and de novo petition.  FDA will then review the 510(k) notification, issue the NSE (unless a predicate device has been classified through the de novo process in the interim), and then proceed directly to reviewing the classification petition.  

The proposed PDS process has the potential to make the de novo pathway a more realistic option.  It will presumably allow an early assessment of whether the product is likely suitable for the de novo pathway, and could shorten the overall review time currently associated with de novo classification. 

A key question left unanswered by the Draft Guidance is whether FDA will be willing to designate a wider variety of devices as eligible for the de novo pathway.  In the past, FDA has been quite limited in this regard.  If the PDS process makes the de novo pathway more viable, we would urge FDA to allow more devices to take advantage of it than has been the case in the past.  Interestingly, increased use of the de novo pathway also would move the FDA away from the 510(k) process and review for substantial equivalence, as critics have urged.  One wonders whether FDA’s implementation of this Draft Guidance might be a baby step toward a new review process that ultimately could replace 510(k) clearance.

By Ricardo Carvajal –

FDA released an ambitious Draft Strategic Plan for 2012-2016 to guide the activities of its Foods and Veterinary Medicine ("FVM") Program (meaning the activities of CFSAN and CVM, as well as ORA’s food-related activities).  The Plan articulates priorities organized around the following eight goals:

• “Improve effectiveness and efficiency across all levels of the FVM Programs” – among other things, FDA plans to address the thorny problem of developing public health metrics.
• “Establish science-based preventive control standards across the farm-to-table continuum,” largely through regulations and guidance issued under the authorities granted under the FSMA.
• “Achieve high rates of compliance with preventive control standards domestically and internationally” through inspections, enforcement, and increased collaboration with state officials.
• “Strengthen scientific leadership, capacity, and partnership to support public health and animal health decision making,” with a focus on “mission-critical science capabilities.”
• “Provide accurate and useful information so consumers can choose a healthier diet and reduce the risk of chronic disease and obesity” – menu/vending machine labeling and an update of the nutrition facts panel are on the agenda.
• “Encourage food product reformulation and safe production of dietary supplements” – sodium and trans fat are targeted for reduction.  As for dietary supplements, FDA intends to enhance post-market surveillance and to finalize and implement the new dietary ingredient guidance.
  “Improve detection of and response to foodborne outbreaks and contamination incidents.”
• “Advance animal drug safety and effectiveness,” with attention to encouraging the “judicious use of medically important antibiotics.”

Comments on the plan should be submitted by November 1, 2011.