By Jennifer D. Newberger –

To finish out a year in which the Center for Devices and Radiological Health ("CDRH") issued what appeared to be an unprecedented number of draft guidance documents, CDRH issued two more on December 27, 2011.  This blog post discusses one such draft guidance, titled “The 510(k) Program:  Evaluating Substantial Equivalence in Premarket Notifications [510(k)].”  A primary purpose of the draft guidance is to clarify certain critical points in the substantial equivalence decision-making process, and to do so, the draft guidance proposes a new decision-making flowchart.  It also updates the approaches to the Special 510(k) and the Abbreviated 510(k) programs.  If finalized, this draft guidance document could potentially have a more significant impact on the 510(k) notification process than any of the other draft guidance documents issued this year, since it addresses the heart of the 510(k) program:  how FDA determines substantial equivalence. 

Perhaps most interesting is CDRH’s attempt to do away with its longstanding acceptance of “split predicates,” with nothing more than a conclusory statement in a footnote.  A split predicate refers to a situation in which a manufacturer is attempting to “split” the 510(k) decision-making process by demonstrating that a new device has the same “intended use” as one marketed device and the same “technological characteristics” as a second marketed device.  In its 510(k) Working Group Preliminary Report and Recommendations (Preliminary Report), CDRH stated that it should “explore the possibility of explicitly disallowing the use of ‘split predicates.’”  Rather than “exploring” this possibility, the draft guidance document states in footnote 15 that the use of a split predicate “is inconsistent with the 510(k) regulatory standard.”  It does not explain how it reached this conclusion.  Perhaps by changing its longstanding approach to split predicates in a footnote, CDRH hoped the change would go unnoticed.  We hope that, by pointing it out, this policy reversal can at least be “explored” before being finalized.

While the draft guidance officially does away with split predicates, it introduces a new concept called “reference devices,” stating that, in certain circumstances, “a manufacturer may refer to legally marketed devices that have a different intended use or different technological characteristics that raise different questions of safety and effectiveness, to address specific scientific questions for a new device.”  In other words, reference devices may be used “to address certain performance characteristics of the new device.” 

The draft guidance is clear that a reference device is not a predicate device, which raises the question:  if it is not a predicate device, what is it, and why is it permitted?  The statute allows comparison to a predicate device, not to a reference device.  The draft guidance states that the reference device scenario is “very complicated,” and therefore FDA “will need to rely on its scientific and regulatory expertise to determine when this scenario may be applied.”  While the draft guidance provides one illustrative example, it is not clear when a reference device may be appropriate, or what factors FDA will consider in making this determination, giving FDA broad leeway to accept—or, perhaps more importantly to industry, reject—a reference device at its discretion.

Although the draft guidance indicates that FDA will continue to permit multiple predicates, “FDA recommends that the manufacturer identify the primary predicate device to which a substantial equivalence claim is being made” (emphasis added).  Perhaps in exchange for requiring that of the 510(k) submitter, FDA will require itself to “clearly cite the predicate device relied upon in determining substantial equivalence.”  Additionally, the submitter “should identify each device and explain why more than one predicate or a reference device” is necessary and appropriate to support substantial equivalence.  Of course, because the draft guidance does not describe the circumstances in which either multiple predicates or a reference device may be appropriate, such justification may be difficult.

The draft guidance also attempts to clarify the distinction between “intended use” and “indications for use,” and states that the intended use “encompasses the indications for use.”  It also describes how CDRH determines intended use, and seems to take an approach slightly different from that described in the statute.  Section 513(i)(1)(E)(i) of the Federal Food, Drug, and Cosmetic Act ("FDCA") states that a determination of the intended use of a device “shall be based upon the proposed labeling submitted in a report for the device under section 510(k).”  The statute does not allow for consideration of information outside the proposed labeling in determining the intended use of a device.  Nevertheless, the draft guidance states that “FDA may rely upon publicly-available scientific information or Agency knowledge about how a disease progresses to determine whether indications for use to treat a certain disease or anatomical site constitute a new intended use.”   Not only does this go beyond FDA’s statutory authority, but allowing FDA to use “Agency knowledge” to determine the intended use of a device without providing scientific support will only further hinder the transparency and predictability of FDA’s decisions.

Finally, the draft guidance addresses whether differences in technological characteristics raise different questions of safety and effectiveness, stating: “A ‘different question of safety or effectiveness’ is a question raised by the technological characteristics of the new device that was not applicable in the 510(k) for the predicate device, and poses an important safety or effectiveness concern for the new device.”  The draft guidance includes examples of differences in technological characteristics that it believes raise different questions of safety and effectiveness.  It seems, however, that whether the questions are “different” just depends on how the question is phrased.  For example, FDA states that there are different questions of safety and effectiveness for a new device made of “significantly different materials and processes” than the predicate.  In explaining why the questions of safety and effectiveness are different, the draft guidance asks questions very specific to the new material, rather than more a more general question about whether the material might negatively interact with the body.  It seems like the latter question could lead to a conclusion that there are not different questions of safety effectiveness, while the former will.  If FDA poses the questions such that they are too specific to the new technology, it seems that there will nearly always be different questions of safety and effectiveness.  By virtue of having new technological characteristics, there will be specific questions not raised by the predicate.  This should not necessarily preclude a finding of substantial equivalence.

As with all the draft guidance documents issued this year, it remains to be seen whether FDA gives any weight to the comments submitted, what the guidance will look like when finalized, and how FDA will implement it.

By Jamie K. Wolszon & Alan M. Kirschenbaum –

FDA has issued two important documents bearing on communications regarding off-label uses and (in one of the documents) not-yet-approved products.  The first, which was posted on FDA’s web site earlier this week, was a draft guidance on how a drug, biologics, or device manufacturer should respond to unsolicited requests for off-label information.  The draft guidance addresses both private requests and requests made in public forums, including emerging electronic media such as product websites, discussion boards, or web chat-rooms.  Although FDA’s policy permitting companies to respond to unsolicited requests dates back at least to 1982, this guidance is the most detailed exposition of the policy to date, and, of course, the only one that addresses emerging electronic media.  FDA explains that, if a manufacturer responds to an unsolicited request in the manner set forth in the guidance, FDA will not use the response as evidence of the firm’s intent that the product be used for an unapproved or uncleared use, and the response also will not be regulated as promotional labeling or advertising.

The draft guidance applies to all approved or cleared prescription human and animal drugs (including biologics) and medical devices for humans.  FDA explains that cleared or approved devices include, not only those subject to 510(k) notification or PMA approval, but also “devices that are legally marketed for a specific intended use without an individual product approval or substantial equivalence determination”, e.g. class I and II devices marketed for a use exempt from the PMA or 510(k) processes.  For those devices, the draft guidance defines a request for off-label information as “any request for information regarding a new use for which approval or clearance would be required.”  The draft guidance does not cover medical products that are not currently approved or cleared for any purpose.

The draft guidance defines an unsolicited request as one that is not prompted in any way by a manufacturer or its representatives and that is initiated by persons or entities that are completely independent of the relevant firm, including health care professionals, health care organizations, members of the academic community, formulary committees, patients, and caregivers.  By contrast, a solicited request is one that is “prompted in any way by a manufacturer or its representatives . . .”  A number of examples of solicited requests are provided.

The draft guidance distinguishes between public and non-public unsolicited requests.  A non-public unsolicited request is one made “directly to a firm using a one-on-one communication approach” such as an individual who calls or emails the medical information staff at a firm.  A public unsolicited request is one “made in a public forum, whether directed to a firm specifically or to a forum at large,” such as a question posed to a firm representative during a live presentation and heard by other attendees, or a question about an off-label use of a specific product posted on a firm-controlled website or a third-party discussion forum visible to a broad audience. 

The guidance on non-public unsolicited requests is generally consistent with FDA’s historical policy on such requests:  responses should be provided only to the requestor as a one-on-one communication.  They should be scientific and non-promotional in tone and presentation; generated by medical or scientific personnel independent from sales or marketing; tailored to answer only the specific question asked; and truthful, non-misleading, accurate, and balanced.  The response should be accompanied by a copy of the FDA-approved labeling, a statement that FDA has not approved or cleared the product for the use(s) described in the response, a statement of the approved or cleared indication, all important safety information, and a list of references.  Records should be kept of the request, the response, and any follow-up inquiries.

The section of the draft guidance on public unsolicited requests ventures into new areas that have not heretofore been addressed in FDA policy statements.  FDA explains that it has two concerns with providing off-label information in a public forum in response to an unsolicited public request.  First, by answering the question in public, the manufacturer exposes those who did not make the request to the off-label information.  Moreover, due to the enduring nature of websites, the information may remain available in the public domain even after it becomes outdated.  Accordingly, the draft guidance provides that a company’s public response to a public request cannot provide any of the requested off-label information.  Instead, the company representative must note that the information requested is off-label and then provide the contact information of the company’s medical/scientific personnel.  Also, a company should only respond to a request that specifically references the company’s own named product.  Note that these restrictions apply, not only to requests made on electronic forums, but also those made by attendees at a live meeting. 

If the individual making the request follows up with the company, the guidelines for responding are the same as those for responding to a non-public unsolicited request, described above. 

In a separate but related development, the December 28th Federal Register contained an FDA notice announcing the opening of a docket to receive comments on scientific exchange involving off-label uses of approved/cleared products or products for which there is not yet any approval or clearance.  FDA opened this docket in response to a Citizen Petition filed by several pharmaceutical companies requesting that FDA clarify its policies regarding communications related to off-label uses and pre-approval communications (see our previous post here).  The notice specifically requests comments on “scientific exchange.”  Under FDA’s drug and device regulations and Agency policy, the “exchange of scientific information” concerning an investigational drug or device is not subject to restrictions on promotion, but FDA has not yet attempted to define the scope of “scientific exchange.”  The Agency is seeking comments and information on scientific exchange to assist it in evaluating FDA policies on off-label and pre-approval communications.  FDA asks for responses to a number of specific questions, including how scientific exchange should be defined, what kinds of activities are included, how it should be distinguished from promotion, and whether off-label communications should be treated differently from pre-approval communications.  Comments may be submitted through March 27, 2012.

By Ricardo Carvajal –

Earlier this month, the HHS Office of Inspector General ("OIG") issued a report that identifies a number of “significant weaknesses” in FDA’s oversight of food facility inspections conducted by state agencies under contract with FDA.  OIG found that FDA:

• “failed to ensure that the required number of inspections was completed"
• “paid for many inspections that were incomplete”
• “did not ensure that all State inspections were properly classified and that all violations were remedied”
• “failed to complete the required number of audits for one-third of the States and did not always follow up on systemic problems”

According to OIG, “[t]he most common systemic problem was the inspectors’ failure to identify violations.”  It appears that approximately 16% of inspectors reportedly had this type of deficiency.  OIG’s findings are significant because, as of 2009, the majority of FDA’s food inspections were conducted by state inspectors. 

The OIG report could lend further ammunition to those who question the reliability of non-FDA inspections and audits.  Third-party auditors have repeatedly come under fire in the wake of recent outbreaks of foodborne illness, and are now being targeted in personal injury lawsuits. 

Overall confidence in third-party audits could be bolstered by FDA’s implementation of the third-party auditor accreditation system authorized by FSMA.  Although that system is expected to focus on imports, FDA has previously indicated that it might move toward recognition of third-party certification programs more generally (see our previous posting here).  However, the OIG report suggests that the success of such efforts could turn on FDA’s own capacity as an auditor of auditors.

By Alan M. Kirschenbaum & Nisha P. Shah –

In the December 19, 2011 Federal Register, CMS published a long-awaited proposed regulation to implement the transparency report requirements of the Patient Protection and Affordable Care Act.  Hyman, Phelps & McNamara, P.C. has prepared a summary of the proposed rule, which is available here.  The CMS proposal is unusual in the number of issues on which CMS is considering alternative approaches and soliciting comments.

 Among the more noteworthy features of the proposed rule are the following:

• Although the statute requires reporting by March 31, 2013 of payments and other transfers of value made in calendar year 2012, CMS has decided not to require manufacturers to begin collecting required information until 90 days after publication of the final rule.  This means that the initial report due on March 31, 2013 would cover only a portion of CY 2012.

• The reporting requirement would apply to foreign entities that market covered products in the U.S., as well as to entities that do not manufacture covered products themselves, but instead hold FDA approval, licensure, or clearance and contract out the actual manufacturing.

• The marketing of a single covered (i.e. federally reimbursable) product is sufficient to subject a manufacturer to the requirement to report all of its payments, even if it primarily manufacturers non-covered products.

• For purposes of determining whether an entity manufacturers covered products and is thus subject to the reporting requirement, covered products include prescription – not OTC – drugs and biologicals, and only devices requiring PMA approval on 510(k) clearance – not 510(k)-exempt devices.

• An activity associated with several purposes would need to be broken down into each segregable purpose and reported separately rather than as a single lump sum.  For example, if a payment to a consultant covered a service fee, travel expenses, and meals, the value of the fee, travel, and meals would have to be broken out and reported separately.

• An exemption for “educational materials that directly benefit patients or are intended for patient use” would not cover educational materials given to physicians for their own education.  This could mean that educational and promotional materials provided to physicians for their own education would have to be reported if they exceeded the de minimis threshold.

• Manufacturers who provide research funding to institutions would not have to report on the exact amount received by each principal investigator.  However, manufacturers who provide grants to third parties for CME would have to report on the amounts received by each physician faculty member if the identities of the faculty are publicly available.

• Provisions for a delay in CMS publication of payments to clinical investigators would apply to clinical investigations of new products, but not of new indications for currently marked products.

• Under an expansive definition of GPOs that are subject to a requirement to report physician ownership interests, a GPO could be interpreted to include a distributor.

These and other features of the CMS proposal that are described in our memorandum warrant comment by manufacturers.  CMS is accepting comments through February 17, 2012.

By JP Ellison –

We have previously posted both on FDA’s renewed focus on misdemeanor prosecutions of “responsible corporate officers” under the Park doctrine generally, and on the use of that doctrine against four Synthes executives (see here, here, here, here, and here).  Two recent opinions (here and here)
imposing nine (9) month terms of imprisonment for those executives, warrant renewed attention to these cases because they suggest a government approach to misdemeanor prosecutions  that may change the risk analysis of a defendant charged solely with an FDC Act misdemeanor. 

As readers may recall, Synthes and the four executives all pled guilty in 2009.  The four executives each pled guilty to a single misdemeanor count, the only charge against them in the indictment.  The corporate defendants entered into so called “C” pleas, pleas in which the parties agree to a particular sentence that the judge can accept or reject, but not revise.  In contrast, the plea agreements for the individual defendants did not agree on a sentence.  Instead, there was a contested sentencing, during which each side presented its arguments for the appropriate sentence, subject to the statutory limitation that the sentence could not exceed one year.  At the conclusion of the contested sentencing proceeding, the court imposed the sentence it considered appropriate.  In the case of these two executives, that sentence was 9 months in prison. 

Notwithstanding the fact that the government charged each executive only with a single misdemeanor and accepted a plea to that charge; during the sentencing, it presented evidence that the executives personally participated in “false[],” “fraudulent,” “deceptive,” and “intentionally deceiving” conduct.  This evidence convinced the judge that there was an “unparalleled” “pattern of deception," which in turn affected the sentence he imposed.  Indeed, while acknowledging that the pleas before him were based upon Park and the responsible corporate officer doctrine, the judge declared in one case that “[n]o similar set of facts can be located in the universe of Park doctrine cases,” and in the other that although the “Court well understands and respects historical sentencing practices for responsible corporate officers under the Park doctrine . . . This case stands alone.” 

This scenario was not necessarily what the regulated industry expected when discussions of a revitalized Park doctrine first surfaced several years ago.   Much of the renewed interest in the Supreme Court’s 36 year old Park decision had focused on the prospect of the government prosecuting a responsible corporate officer who was unaware of an FDC Act violation, but allegedly had the authority and responsibility to detect and remedy the violation.  Such attention on the unaware executive has been understandable because when a person commits an FDC Act violation with the intent to defraud or mislead, he can be prosecuted for a felony violation of the FDC Act.  Accordingly, there was some expectation that the government’s new wave of Park prosecutions would be those where the government did not believe that the defendant engaged in fraudulent conduct or was even aware of the alleged criminal conduct.  Thus, it followed that such prosecutions would not involve allegations that there was evidence of the defendant’s intent to defraud and mislead.

If the cases against the Synthes executives are a sign of things to come, the government’s use of misdemeanor remedy may not be so limited, however.  Instead, Park may be used by the government to charge defendants with misdemeanors, but nevertheless, the government may plan to present evidence of fraud regardless of whether the defendant pleads guilty.  

For a responsible corporate officer threatened with a felony violation of the FDC Act and offered an opportunity to plead guilty to a misdemeanor, the prospect of a contested sentencing at which the government presents its “fraud” evidence may or may not affect that officer’s decision.  For a responsible corporate officer facing only a misdemeanor charge, the calculus post –Synthes may be different.  Certainly the 2 level downward adjustment for acceptance of responsibility under the Sentencing Guidelines, which was applied in the cases against the Synthes executives, must be considered, but if months of jail time is a realistic possibility based on a misdemeanor plea, a rational responsible corporate officer may elect to take his chances at trial realizing that his upside risk is statutorily capped at a 12 month prison term.

By Jennifer D. Newberger –

The Government Accountability Office (“GAO”) recently issued a report on pediatric device development.  The report “(1) describes barriers to developing pediatric devices, (2) describes how pediatric device consortia have contributed to the development of pediatric devices, and (3) examines FDA data on the number of pediatric devices approved since FDAAA was enacted.” 

The GAO was required to issue a report of this type pursuant to the FDA Amendments Act of 2007 (“FDAAA”).  FDAAA had a suite of incentives to develop devices for children, particularly devices that receive a humanitarian device exemption (“HDE”).  FDAAA also authorized “demonstration grants” for nonprofit consortia to facilitate pediatric device development, and required FDA to provide annual reports to Congress on the number of approved pediatric devices.  Finally, FDAAA also required GAO to issue a report on pediatric device development.

Perhaps the most interesting finding is that FDA does not actually maintain or track its data regarding device approvals in such a way as to allow it to provide the required information regarding pediatric device approvals to Congress.  Although FDA established an “electronic flag” for its reviewers to use to identify the devices labeled for pediatric indications, “FDA officials reported that these electronic flags are not consistently applied, and that the agency does not provide formal training or guidance to its device reviewers regarding proper implementation of the pediatric flags.  Therefore, information from FDA’s tracking system is not sufficiently reliable to identify PMA and HDE devices labeled for use in pediatric patients.”  It is certainly difficult to evaluate whether FDAAA’s provisions have increased the number of pediatric devices when FDA does not provide reliable approval data. 

GAO also spoke with stakeholders to assess the barriers to pediatric device development and whether the incentives under FDAAA helped in overcoming those barriers.  The stakeholders indicated that, while helpful, the incentives are insufficient, especially because of the small market for pediatric devices involving orphan diseases, and the outsized costs necessary to study them.   

With regard to the pediatric consortia, GAO found that the pediatric device consortia created under FDAAA assisted 107 pediatric device projects in the first two years of the grant program.  FDA awarded approximately $5 million in grants to four pediatric device consortia in fiscal years 2009 and 2010.  The support provided by the consortia varied depending on the device’s phase of development. 

Overall, while GAO was disappointed with the data maintained by FDA regarding approval of pediatric devices, it believes that the FDAAA provisions “show potential for more pediatric devices in future years.”

In a new Legal Backgrounder published by the Washington Legal Foundation, Hyman, Phelps & McNamara, P.C.’s Karla L. Palmer and Jeffrey N. Gibbs write that a recent Florida federal district court ruling in United States v. Franck’s Lab, Inc., if upheld on appeal, will have implications that extend broadly to other areas of FDA law, particularly as it relates to FDA’s increasing use of guidance documents to expand regulatory requirements. 

As we previously reported, the U.S. District Court for the Middle District of Florida (Ocala Division) ruled in September 2011 that FDA did not have authority to enjoin the “long-standing, widespread, state-regulated practice of pharmacists filling a veterinarian’s prescription for a non-food producing animal by compounding from bulk substances.”  The court reached its decision after wading through the various guidance documents FDA had issued through the years laying out the Agency’s criteria for when it would decline to exercise “enforcement discretion,” and instead initiate enforcement action against a compounding pharmacy.  In early November, the government appealed that decision to the U.S. Court of Appeals for the Eleventh Circuit.

Ms. Palmer and Mr. Gibbs write that if the Eleventh Circuit upholds the district court decision, the decision “will be invoked by interested parties seeking to constrain FDA’s use of non-binding guidance documents to define prohibitions against which FDA may take enforcement action or impose new requirements on applicants, and to attack FDA assertions that it is entitled to Chevron deference.”  Although FDA’s desire to use guidance in lieu of rulemaking is understandable, say the authors, as guidance documents take less work to promulgate, go through less review, and can be revised more readily, “ease of use does not excuse FDA from the need to comply with the Administrative Procedure Act.”

By Riëtte van Laack –

In a December 12, 2011 decision, Judge R. Leon of the District Court for the District of Columbia granted Defendants’ Motion to Dismiss an action by Physicians Committee for Responsible Medicine (Plaintiff) requiring that Defendants FDA and USDA withdraw the “MyPyramid” food diagram and dietary guidelines, and adopt Plaintiff’s proposed “Power Plate” food diagram and dietary guidelines instead.  Plaintiff alleged that certain portions of the Dietary Guidelines do not reflect the preponderance of current and scientific medical knowledge because, among others, they only identify foods that should be eaten more frequently and do not identify which foods should be eaten less frequently.

Judge Leon dismissed the case on the grounds that Plaintiff failed to demonstrate that it had standing because it did not present evidence that it (or its members) had suffered an actual or imminent concrete and particularized injury.  As required by the National Nutrition Monitoring & Related Research Act (“Nutrition Act”), Defendants published a report of nutritional and dietary information and the Dietary Guidelines.  Plaintiff failed to present evidence as to how these Dietary Guidelines affected or interfered Plaintiff’s efforts to improve the health and well-being of Americans.  In addition, Defendants’ report and Dietary Guidelines, published every five years as required by the Nutrition Act, does not constitute an agency action.  In fact, the Nutrition Act specifically states that the Dietary Guidelines do not constitute a rule or regulation issued by a Federal agency.  Thus, they are not subject to judicial review under the APA and Plaintiff failed to state a claim upon which relief could be granted.

By Jennifer M. Thomas –

A Government Accountability Office (“GAO”) Report released on December 15, 2011, the same day as a Senate Committee hearing, finds that FDA needs increased authority in order to address the growing problem of drug shortages.  In her statement before the Senate Committee on Health, Education, Labor, and Pensions, GAO Director of Health Marcia Crosse stated that according to the Report, FDA is currently “constrained in its ability to protect the public health from the impact of [drug] shortages.” 

We first posted about the serious public health problem presented by drug shortages, and the government’s search for a solution to that problem, after President Obama issued an Executive Order in early November.  Since that time, both the executive and legislative branches have focused on addressing drug shortages.  Moreover, industry appears to be taking steps to address the problem independently.  While the “Preserving Access to Life-Saving Medications Act of 2011” (S. 296, H.R. 2245) remains pending in committee, FDA announced the December 19th publication of an interim final rule to make better use of its existing shortage-related authority under the Federal Food, Drug, and Cosmetic Act (“FDCA”).  Also, the Generic Pharmaceutical Association (“GPhA”) announced its own Accelerated Recovery Initiative to “reverse current drug shortages and prevent further ones. . . .” (see here and here)

GAO Report

In its Report, the GAO confirmed much of what on-lookers, industry, and FDA already knew or suspected.  The Report cites a 200 percent increase in drug shortages between 2006 and 2011.  The 196 shortages reported in 2010 represented a record number for one year, and 2011 is on-pace to surpass that record, with 146 shortages reported as of June, 2011.  GAO reports that the average duration of a drug shortage between 2006 and 2011 has been 286 days, or approximately 9 months.  The GAO Report then goes on to analyze the causes of fifteen drug shortages that had a significant impact on public health in-depth, using information reported to FDA and obtained from four of the manufacturers involved in those shortages. Twelve out of the fifteen shortages GAO analyzed were caused primarily by manufacturing problems with other exacerbating factors such as lengthy facility improvements, etc.  The remaining shortages GAO analyzed were caused by disruptions in the supply of Active Pharmaceutical Ingredients (“APIs”). 

Sterile injectable drugs can be difficult to manufacturer and, according to FDA officials surveyed by the GAO, are currently being produced by a few aging facilities.  These factors contribute to the increase in manufacturing problems for these drugs.  The fact that very few manufacturers are producing certain drugs also means that if one manufacturer experiences manufacturing problems or supply chain issues, the others are not able to readily increase production in order to prevent a drug shortage.

According to the GAO, FDA has demonstrated that it can prevent most drug shortages if it learns of potential supply or manufacturing disruptions in advance.  However, FDA lacks statutory authority to require manufacturers to provide the agency with advance information about shortages, or to require manufacturers to take actions to prevent, mitigate, or end shortages.  As we noted in our previous discussion of this topic, FDA’s only authority with regard to drug shortages relates to life-supporting, life-sustaining medications, or those for use in preventing a debilitating disease or condition, and only when such drugs are produced by a single manufacturer.  21 U.S.C. § 356c; 21 C.F.R. § 314.81(b)(3)(iii).  Without additional authority, FDA’s ability to prevent drug shortages is very limited.

FDA Interim Final Rule

Nevertheless, FDA announced an interim final rule (Docket No. FDA-2011-N-0898) that seeks to make the most of its current FDCA authorities.  Specifically, FDA’s interim final rule modifies the agency’s interpretation of the term “discontinuance” and clarifies the term “sole manufacturer” with respect to the FDCA’s requirement that sole manufacturers notify FDA at least 6 months in advance of discontinuing certain products. 

Under the new interim rule, FDA defines “discontinuance” to “include both permanent and temporary interruptions in the manufacturing of a drug product, if the interruption could lead to a disruption in supply of the product.”  FDA states that the following circumstances, among others, would trigger “discontinuance” reporting under the agency’s new definition of that term: (1) delay in acquiring APIs or inactive ingredients that could lead to a temporary interruption in manufacturing; or (2) manufacturing shut-downs for maintenance or other routine matters, if the shut-down extends for longer than anticipated.

Further, the interim rule seeks to clarify any confusion about the definition of a “sole manufacturer” by defining that term as “an applicant that is the only entity currently manufacturing a drug product . . . whether the product is manufactured by the applicant or for the applicant under contract with one or more different entities.”  A “sole manufacturer” is such regardless of whether there are other NDA or ANDA holders for the same drug, if those other NDA or ANDA holders are not manufacturing the drug in the United States.  

FDA’s modified definition of “discontinuance” in the interim rule, in particular, may significantly increase the instances in which sole manufacturers are required to notify FDA of an impending production disturbance.  However, without action by Congress FDA will not be able expand the shortage reporting requirements much further and will remain, as the GAO report indicates, “constrained” with regard to drug shortages. 

By Jennifer D. Newberger –

On Thursday, December 15, 2011, Senators Chuck Grassley (R-Iowa), Richard Blumenthal (D-Conn.), and Herb Kohl (D-Wis.) introduced the “Medical Device Patient Safety Act.”  This bill contains two distinct proposals:  (1) to give FDA the authority to track and trend device recalls, and (2) to allow FDA to grant conditional clearances for devices that will be subject to post-market requirements.  A summary of the bill is available here. 

Recall Tracking.  While FDA currently has the authority to track and trend recalls, using information submitted to it under section 519 of the Federal Food, Drug, and Cosmetic Act (“FDCA”) and 21 C.F.R. Part 806, it is not required to do so.  This bill would require FDA to routinely assess (1) any information provided to FDA in response to a recall request from FDA under section 518(e) of FDCA, and (2) information required to be reported to FDA under section 519 of the FDCA regarding a correction or removal.  Because a Class III recall would not meet the standard for an FDA-requested recall (“reasonable probability that [the device] . . . would cause serious, adverse health consequences or death”) and information regarding Class III recalls is generally not required to be reported to FDA, the language of the bill essentially means that the program would require FDA to track and trend all Class I and Class II recalls, whether the recalls were requested by FDA or initiated by the manufacturer.  The bill instructs FDA to “use the assessment of information” gathered by the program to “proactively identify strategies for mitigating health risks presented by defective or unsafe devices.”  Importantly, the bill does not give FDA any authority to remove from the market devices cleared through the 510(k) program that FDA determines are “defective or unsafe” based on its tracking and trending of recalls.

The bill also requires FDA to “develop explicit criteria” for assessing whether a company subject to a recall or required to report information regarding a correction or removal “has performed an effective correction or removal action.”  This appears to give FDA very broad latitude in determining what constitutes an “effective” recall, and is not clear whether this language implies a “one size fits all” solution for determining recall effectiveness.  Certainly what may be effective for one type of device may not be effective for another, and there may in fact be differences among devices of the same type.  If Congress enacts this language, hopefully FDA will consult with industry before developing “explicit criteria” that may be impossible to achieve, or that may not be effective for particular devices in unique circumstances.

Conditional Clearance.  The bill proposes amending the FDCA to insert section 510A, Conditional Clearance of Certain Medical Devices.  This would allow FDA to grant conditional clearance for devices cleared through the 510(k) process.  While summaries of the bill indicate that conditional clearances are intended to apply to devices that may have safety concerns, the plain language of the bill does not state when conditional clearance would be appropriate, or any factors FDA must consider in determining whether to grant a conditional, rather than traditional, clearance.

The conditional clearance proposals appear to largely mirror the authority FDA currently has to require conditions of approval for PMA devices.  For example, the bill would give FDA the authority to use the post-market information to evaluate “the safety, effectiveness, and reliability of the device for its intended use.” 

A grant of conditional clearance would also greatly expand FDA’s authority over the labeling and advertising of a 510(k) device.  Currently, FDA has the authority to review the draft labeling of a device undergoing 510(k) review to determine the proposed intended use, and only has authority over the advertising of restricted devices.  Although FDA may condition 510(k) clearances on modifications to the draft language, it does not have specific authority to require certain language in the labeling or advertising of a 510(k) device.  Under the proposed conditional clearance language, however, FDA will have the authority to require conditionally cleared devices to contain “a prominent display in the labeling of the device and in the advertising of warnings, hazards, or precautions important for the device’s safe and effective use, including patient information such as information provided to the patient on alternative modes of therapy and on risks and benefits associated with the use of the device.”  Thus, the bill appears to give FDA authority over conditionally cleared devices similar to the authority it has over PMA devices.  Because the bill does not specify the types of devices that may be appropriate for conditional clearance, FDA could seek to use conditional clearance as a means of exercising expanded authority over the labeling and advertising of 510(k)-cleared devices.

Finally, the bill states that FDA may rescind the conditional clearance of a device if FDA determines that the conditions of clearance have not been met.  This again mirrors FDA’s authority to rescind a conditional PMA approval.

Industry has been encouraging FDA to increase use of its post-marketing authorities for 510(k) devices, with an understanding that this could reduce the burden of pre-market data.  FDA already has sufficient authorities to require manufacturers to conduct post-market studies for devices cleared through the 510(k) process, and it therefore seems unnecessary to provide additional authorities via a conditional clearance process.  Most critically, the bill does not limit when FDA may conditionally clear a device, thus leaving open the possibility that conditions of approval will become a regular part of 510(k) clearances, as they are for PMAs.  Conditions of approval should be specifically reserved for those devices for which FDA has raised a legitimate safety concern, supported by scientific evidence.  It should not become the new standard for clearing devices.

By Susan J. Matthees –

The National Advertising Division (“NAD”) of the Council of Better Business Bureaus recently concluded that claims that Procter & Gamble’s Crest Sensitivity Treatment & Protection Toothpaste could provide relief from sensitive teeth “within minutes” should be discontinued.  Colgate-Palmolive brought the challenge against Procter & Gamble, alleging that Procter & Gamble had no support for the near-immediate relief claims.  The NAD concluded that although Procter & Gamble had robust studies to support the claims for relief from tooth sensitivity, the studies did not show clinically meaningful relief within minutes and thus those claims should be discontinued.  The case is a good reminder that having adequate substantiation requires more than a well-conducted study; the study results must support the actual claims being made. 

Crest Sensitivity & Protection Toothpaste claimed to provide “relief within minutes” for people with sensitive teeth so that users did not “have to wait to enjoy all [their] favorite hot and cold foods.”  The claims were linked by an asterisk to a disclaimer that explained “[f]or sensitivity relief within minutes, first brush sensitive teeth for 30 second each.”  The Crest toothpaste contains stannous fluoride, which Colgate-Palmolive acknowledged can be effective at reducing tooth sensitivity when used for several weeks.  However, Colgate-Palmolive alleged that Procter & Gamble merely repackaged its existing sensitivity product and added the rapid relief claims without conducting any new studies to support the claims.

Procter & Gamble did not have consumer perception evidence on the claims, so the NAD used its expertise to conclude that the advertisements conveyed the message that sensitive teeth suffers who used the product would experience a significant and immediate reduction or elimination of tooth sensitivity.  Procter & Gamble had studies to support that the toothpaste could reduce tooth sensitivity, and the NAD determined that many aspects of Procter & Gamble’s studies were robust – the studies were published, peer-reviewed, used an appropriate design (randomized, blind, parallel study groups), and used appropriate testing periods.  But, the NAD found that the decrease was not clinically meaningful until after at least three days of use.  Thus, the NAD concluded that Procter & Gamble’s claim for relief within minutes was “a far greater benefit to consumers” than the research supported and recommended that the claims be discontinued.  Procter & Gamble agreed to take the NAD’s conclusion into consideration.

By Ricardo Carvajal –

On November 18, the United States District Court for New Jersey granted FTC’s motion for a finding that Lane Labs violated an order agreed to by the parties in 2000.  In part, that order requires Lane Labs’ health-related marketing claims to be substantiated by competent and reliable scientific evidence.  The district court found that Lane Labs’ advertising for its calcium supplement “promised results that were unattainable for large portions of [its] audience,” and that its advertising claim therefore was not substantiated by competent and reliable scientific evidence.  As we discussed in a prior posting, the district court initially denied FTC’s motion in August 2009 after weighing competing testimony and finding that Lane Labs’ marketing claims were adequately substantiated.  FTC appealed, and in October 2010, the Third Circuit Court of Appeals remanded the case to the district court for reconsideration of the substantiation issue.   

Stung by the district court’s initial ruling in 2009, FTC began inserting more specific substantiation provisions into its consent decrees (see, e.g., our prior blog posting regarding FTC’s consent decree with Nestle).  Notwithstanding FTC’s recent victory over Lane Labs at the district court level, the agency can be expected to continue including very specific substantiation provisions in its consent decrees.  As the Lane Labs case shows, the alternative can mean protracted and costly litigation.

By Kurt R. Karst –      

We had hoped that our post from earlier this week, titled Pending DESI Program Proceedings – The List, would stimulate some discussion.  And it did.  One comment in particular that we received from an authoritative source caught our attention and deserves greater airing.  It concerns FDA’s interpretation of the September 19, 2011 iteration of the Agency’s Unapproved Drugs CPG as it applies to products marketed pursuant to FDA’s enforcement discretion under a pending Drug Efficacy Study Implementation (“DESI”) program proceeding. 

As we previously reported, the September 2011 Unapproved Drugs CPG is a line in the sand of sorts.  It says that FDA’s risk-based enforcement approach discussed in the June 2006 version of the CPG continues to apply, but only to unapproved drug products on the market as of September 19, 2011:

The enforcement priorities and potential exercise of enforcement discretion discussed in this guidance apply only to unapproved drug products that are being commercially used or sold as of September 19, 2011.  All unapproved drugs introduced onto the market after that date are subject to immediate enforcement action at any time, without prior notice and without regard to the enforcement priorities set forth below.  In light of the notice provided by this guidance, we believe it is inappropriate to exercise enforcement discretion with respect to unapproved drugs that a company (including a manufacturer or distributor) begins marketing after September 19, 2011.

Since then, FDA has clarified for us that prenatal products are not exempt from the revised CPG, stating generally that “[a]ny unapproved drug that enters the market on or after 9/19/11 is subject to immediate enforcement action without prior notice,” and more specifically, that “prenatal vitamins are not excepted from this CPG.”  FDA is apparently also taking a hard line on the post-September 19, 2011 marketing of drug products subject to a pending DESI proceeding. 

As we noted earlier this week, the September 2011 Unapproved Drugs CPG states that although “any product that is being marketed illegally is subject to FDA enforcement action at any time,” there is a general exception to this policy for marketed unapproved drugs subject to an ongoing DESI proceeding, provided certain conditions are met.  In short, FDA says that “[i]t is the Agency’s longstanding policy that products subject to an ongoing DESI proceeding may remain on the market during the pendency of the proceeding.”  Unapproved Drugs CPG at 10 (emphasis added).   The phrase “may remain on the market” is important here, because FDA’s Office of Compliance is reportedly of the opinion that only those drug products subject to a pending DESI proceeding on the market before September 19, 2011 are subject to the policy.  A drug product that may nevertheless meet the policy parameters that is first marketed after that date will not, we understand, be accorded enforcement discretion. 

But there’s more . . . .

What if a company marketed a drug product subject to a pending DESI proceeding before September 19, 2011, and subsequent to that date contracted with a new distributor to market the same drug product?  That too, we understand, would fall outside of FDA’s ongoing DESI proceeding policy, such that FDA would apparently consider the new distributor’s drug product subject to enforcement action.  And how will FDA know if such a product has been marketed after September 19, 2011?  That’s where the recently revamped National Drug Code Directory will likely come into play.  It includes, among other things, a new “Start Marketing Date” category that would filled in based on registration/listing information submitted to FDA.  FDA will presumably use the information from the “Start Marketing Date” category to target enforcement action. 

By James R. Phelps –

Many seasoned FDA watchers are surprised by the kerfuffle raised when HHS overturned FDA’s plan to allow Plan B emergency contraception available over the counter (see here and here).  This is first time HHS has publicly put its thumb on the scale, and critics cite President Obama’s statement that FDA’s decisions would be based on science, and not politics.  Critics say they fear the precedent means that politics will now have a role in FDA’s processes.  The sober publication, Forbes, headlined its coverage of the Plan B matter this way: “Did the Obama Administration throw FDA under the Bus?” and quoted numerous medical and other personnel concerned about political influences.

The critics of Secretary Sebelius’ action may not like the result, but they are overwrought insofar as they worry about politics entering FDA’s processes.  The fact is, politics has always played a role in FDA’s work.  The Forbes article quotes Ramsey Baghdadi, an editor of the RPM Report, who correctly sees FDA’s Plan B decision at the “intersection of science, politics, and policy.” 

FDA’s leaders emphasize the role of science in the agency’s decisions.  Scientific methodology yields data, but it does not tell us how that information should be used.  Determining how and whether to use the information is a matter of judgment, and the human interactions to make and implement such a judgment inevitably will involve politics. 

Politics is the advocacy of one’s interests.  “Interests” is a broad term; for example, interests can be commercial and they can be ideological.  People inside FDA will push for their interests as regulators.  People outside FDA – in private enterprises and other government organizations, such as HHS – will press to have their interests taken into account.

Politics, from external sources and from within the agency itself, are inevitably given play in FDA’s decisions.  How much influence they will have will depend on many variables; in the Plan B situation, the important variable was that the HHS secretary had statutory authority to do what she did.  Some will cite happy consequences of political actions within and with FDA.  Others will cite examples of what they see as untoward consequences.  But no one should be surprised to see that FDA is subject to political influences.   

Additional Reading:

• FDA Plan B Rx-to-OTC Switch Citizen Petition Denial (FDA Docket No. 2001P-0075; Dec. 12, 2011)
• Press Release – Senators Call on Sec. Sebelius to Explain the Science Behind Plan B Decision

By Larry K. Houck –

The Drug Enforcement Administration (“DEA”) published its long awaited final rule in the Federal Register today (76 Fed. Reg. 77,330 (Dec. 12, 2011)) placing carisoprodol into schedule IV of the federal Controlled Substances Act (“CSA”).  Federal scheduling of carisoprodol follows control of the drug by eighteen states around the country.  Effective January 12, 2012, DEA’s placement pertains to carisoprodol (widely distributed under the trade name of Soma®), and its salts, isomers and salts of isomers. 

DEA’s placement of carisoprodol in schedule IV subjects manufacturers, distributors, dispensers such as pharmacies and physicians, importers, exporters, and anyone in possession of the drug to the applicable provisions of the CSA and its implementing regulations, including administrative, civil and criminal sanctions.

DEA’s final rule establishes the following timetable:

a.  Manufacturers, distributors, dispensers, importers, exporters, researchers, and persons conducting instructional and chemical analysis must submit an application for registration to DEA by January 11, 2012.  Entities currently conducting these activities may continue until DEA has approved or denied their application for registration;

b.  Entities electing not to obtain a DEA registration, or who cannot obtain a registration, must surrender all stocks of carisoprodol pursuant to 21 C.F.R. § 1307.21 on or before January 11, 2012.  Entities may, in the alternative, transfer all carisoprodol to a DEA registrant who is authorized to possess schedule IV controlled substances on or before January 11, 2012;

c.  Carisoprodol will generally be subject to the security requirements applicable to schedule IV controlled substances as of January 11, 2012.  However, certain storage, manufacturing and freight forwarding security requirements under 21 C.F.R. §§ 1301.72(b) and (c), 1301.73 and 1301.77 are not applicable until April 10, 2012;

d.  Commercial containers of carisoprodol packaged on or after April 10, 2012 must be labeled as “C-IV” and packaged in accordance with 21 C.F.R. §§ 1302.03-.07.  Registrants may distribute commercial containers packaged before April 10, 2012 that do not comply with 21 C.F.R. §§ 1302.03-.07 until June 11, 2012.  All commercial containers of carisoprodol must be labeled as “C-IV” and comply with 21 C.F.R. §§ 1302.03-.07 on or after June 11, 2012;

e.  Registrants who possess any quantity of carisoprodol must take an initial inventory of all stocks on-hand on or before January 11, 2012 and then include carisoprodol in its biennial inventory thereafter;

f.  Registrants who possess any quantity of carisoprodol must maintain all records required for schedule IV controlled substances after January 11, 2012;

g.  All prescriptions for carisoprodol or prescriptions containing carisoprodol must comply with DEA’s controlled substance prescription requirements after January 11, 2012;

h.  Carisoprodol is subject to importation and exportation requirements after January 11, 2012; and

i.  Any activity with carisoprodol that is not authorized by, or that is conducted in violation of, the CSA on or after January 12, 2012, is unlawful.

We will discuss DEA’s justification for scheduling carisoprodol in a forthcoming blog post.