GTCbio recently announced that it will be holding the 4th Annual CNS Diseases World Summit from September 18-19, 2014 in San Francisco, California.  The summit consists of two individual conferences that will run in parallel: (1) the 7th CNS Partnering & Deal-Making conference; and (2) the 8th Neurodegenerative Conditions Research & Development conference.   

Sessions and panel discussions for the 7th CNS Partnering & Deal-Making conference include:

• New Approaches to Funding in the CNS
• Private/Public Partnerships in Neuroscience Research
• Joint Session with co-located Neurodegenerative Conditions Research & Development Conference: Rare CNS Diseases
• Partnering & Licensing in the CNS
• Up & Coming Trends and Other Considerations in Neuroscience
• Investment Opportunities with Venture Capital
• Private/Public Partnerships to Advance Research
• Regulatory Considerations and Challenges in the CNS
• New Partnership Structures in CNS R&D

Sessions for the 8th Neurodegenerative Conditions Research & Development conference include:

• Novel Therapeutic Targets and Approaches in Alzheimer's Disease
• Drug Mechanisms and Treatments in Parkinson’s Disease
• New Approaches and Treatments in Neurodegenerative and Neuropsychiatric Conditions
• Joint Session with CNS Partnering & Deal-Making Conference: Rare CNS Diseases
• Biomarkers: Translation from Discovery to Clinical

Hyman, Phelps & McNamara, P.C’s David B. Clissold is scheduled to present at the conference.  As such, we’re able to offer FDA Law Blog readers a special 25% discount off of the regular price.  To obtain the discount, please use colleague code HPMCNS25 when registering for the conference. 

By Jeffrey N. Wasserstein –

As we previously noted, waiting for FDA to issue social media guidances was a little like Waiting for Godot. 

Well, Godot has returned and FDA finally released two long awaited draft guidances relating to social media, one relating to the presentation of risk information and one relating to correcting misinformation.  These are so overdue, that if they were library books, FDA would have had its library card revoked years ago.  FDA initially promised these in 2010.

If I were to tweet a summary of FDA’s recently released draft guidance titled “Guidance for Industry: Internet/Social Media Platforms with Character Space Limitations – Presenting Risk and Benefit Information for Prescription Drugs and Medical Devices” (the “Risk Guidance”) it would be a very brief tweet, well within the maximum 140 characters: “FDA to industry: Nothing’s changed #stuckin20thcentury”.   The Risk Guidance can best be summed up by FDA’s statement:

Regardless of character space constraints that may be present on certain Internet/social media platforms, if a firm chooses to make a product benefit claim, the firm should also incorporate risk information within the same character-space-limited communication. The firm should also provide a mechanism to allow direct access to a more complete discussion of the risks associated with its product.  (Risk Guidance at 5).

In other words, each tweet or sponsored link needs to incorporate whatever claims the company wishes to make (which must be accurate and non-misleading) as well as risk information (including all risk concepts from a boxed warning, all risks known to be fatal or life-threatening, and all contraindications from the approved product labeling.)   Each tweet would also need to include a hyperlink that links to a more complete discussion of risk information.  Note that the link cannot lead to a promotional webpage or even the product labeling, but rather must lead to a page that is (hopelessly) “devoted exclusively to the communication of risk information about the product.”  (Risk Guidance at 10).  FDA encourages companies to use links that make it clear that it leads to risk information, although it will not object to URL shorteners, such as tinyurl or bit.ly.  FDA does permit additional links to be provided, such as to the product homepage or PI, assuming there’s enough room.

Ok, so that’s fine, right?  Still plenty of room to make promotional claims?  Not so fast, sport.  Additionally, FDA requires companies to include both the proprietary and established names for drugs within the tweet or sponsored link.  Then, on the hyperlink to the risk information mentioned above, the communication should include both the brand and established name, as well as at least one dosage form and quantitative ingredient information in conjunction with the brand and established names.  In a nod to teenagers everywhere, FDA acknowledged that commonly recognized linguistic symbols may be substituted for words, such as “&” for “and”, as well as abbreviations, such as HCl for hydrochloride.  However, FDA did not address the use of emoticons or LOL and OMG.  😉

FDA’s example of a permissible tweet is “NoFocus (rememberine HCl) for mild to moderate memory loss-May cause seizures in patients with a seizure disorder www.nofocus.com/risk”.  (Risk Guidance at 14).  Six characters to spare!  And this is a drug that has very few risks, apparently.  Similarly, for an example of a Google sponsored link, three of the six links in the ad that lead to specific parts of the promotional website deal with risk and safety information.  The real takeaway from this Draft Guidance comes early on, when FDA states:  “If an accurate and balanced presentation of both risks and benefits of a specific product is not possible within the constraints of the platform, then the firm should reconsider using that platform for the intended promotional message (other than for permitted reminder promotion).”

Leaving the snark aside (temporarily, we still have another draft guidance to get through!), what FDA is saying is that each space-limited communication needs to adhere to the rules relating to promotional labeling.  This is no real surprise.  While those of us who watch the issue closely would have liked to have seen some out of the box thinking and creativity, this draft guidance is consistent with advice that most regulatory attorneys and consultants have given (see Wasserstein, The Regulation of Social Media: Whither FDA? at 7-9 in Using Social Media in FDA-Regulated Industries:  The Essential Guide (FDLI 2010).  The Risk Guidance doesn’t open any doors, but it might make companies that have drug or medical device products with relatively simple risk profiles more comfortable in tweeting very basic product related tweets.  Alternatively, the benefits claims can be broken up into multiple tweets, provided each is accompanied by the appropriate balancing information, product names, and hyperlinks.

Turning now to the draft guidance titled “Guidance for Industry:  Internet/Social Media Platforms: Correcting Independent Third-Party Misinformation About Prescription Drugs and Medical Devices” (we’ll call this one the “Misinformation Guidance”), we encounter a little more flexibility from FDA.  In the Misinformation Guidance, FDA makes clear that companies do not have obligations to correct misinformation created by third parties, often called User Generated Content, or UGC.  However, if a company voluntarily corrects misinformation in a truthful and not misleading manner, FDA will not object if the corrective information does not satisfy other regulatory requirements regarding labeling and advertising.  (Misinformation Guidance at 3).  In other words, if a firm corrects misinformation about the indication or efficacy, but does not include any safety or risk information, FDA will not take regulatory or enforcement action.

The first question addressed is whether the draft guidance applies to the correction of misinformation.  FDA makes clear that the draft guidance does not apply to corrections of misinformation made by the company itself or to UGC on a company-moderated and controlled discussion group, such as where the company removes or edits negative posts about its products and adds positive commentary.  The company, by doing so, has exerted control over the UGC.  However, FDA clarified that companies are not responsible for correcting misinformation found in UGC about their products when the UGC is truly independent of the firm.  When FDA made a similar statement in a prior draft guidance relating to submission to FDA of real time social media interactions, we noted that “this does not address the issue of whether a regulated company would need to correct misinformation or off label discussions placed on site or platform controlled by the company.”  Either we are more widely read by FDA than we thought, or FDA had already been thinking along the same lines, so that issue has now been laid to rest.

So, what can companies do to correct misinformation in a way that need not comply with promotional labeling and advertising regulatory requirements?  In brief, they should address the misinformation and not use it as a springboard to engage in promotional messaging.  The correction should be posted in the same area or forum or should reference the area where the misinformation is found.  Companies can either post directly (if permitted) or notify the site owner of the misinformation.  In all cases, the company should disclose that the person making the communication is a company employee.  Although risk and other information about the product isn’t required to be included in the correction if not relevant, the approved PI should be included either via PDF or a link to the approved labeling.  The correction should be limited to the scope of the misinformation.

Companies have often been reluctant to monitor third party sites lest they be held responsible for all the content on the site.  FDA stated that if the company is correcting misinformation in part of the forum or site, it should identify the section of the forum or site it is addressing and correct all the misinformation (both positive and negative) within that section.  The company is not responsible for the site other than the clearly defined portion it identifies.  (Misinformation Guidance at 7). 

Another concern companies previously had was that once it tried to correct misinformation, would they be responsible for continuing to monitor the site?  (I’ve heard that stated by FDA’ers at public meetings in the past.)  The Misinformation Guidance makes clear that FDA does not expect companies to continue to monitor the website or forum.  (Misinformation Guidance at 8).

Finally, FDA does not expect companies to submit corrections of misinformation to FDA, but does recommend that companies keep records in case FDA has questions.  The records should include the content of the misinformation, where it appeared, the date it appeared, what corrective information was provided and when the corrective information was provided.

Companies have 90 days from the date of publication of in the Federal Register to provide comments to the draft guidances (written or electronic submissions are both permitted, but not tweets).  So, if you don’t have any exciting summer plans, this summer might be a good time to submit comments on these draft guidances!  

By James E. Valentine –

On June 11, 2014, a panel before the House Energy and Commerce Committee’s Subcommittee on Health hosted its second hearing on the 21st Century Cures Initiative.  The Subcommittee sought input on whether current economic and regulatory incentives are sufficient to encourage robust investment in the research and development of innovative medical products, particularly for those patients with unmet medical needs.  The Subcommittee has cited that only 500 of 7,000 known diseases have effective treatments, and legislators are interested in closing this “innovation gap.”  While there was agreement with respect to the unmet medical need by patients, there was little consensus among hearing witnesses as to how to appropriately incentivize medical product development.

The primary policy recommendation presented at the hearing was the Modernizing Our Drug & Diagnostics Evaluation and Regulatory Network Cures Act of 2013, or MODDERN Cures Act of 2013 (H.R. 3116) (“Cures Act”), raised by Marc Boutin, Executive Vice President and Chief Operating Officer of the National Health Council.  As described by Mr. Boutin, current legal and market failures have led to a category of products for diseases that meet FDA’s definition of unmet medical need, but have insufficient patent protection.  This class of products is referred to as “dormant therapies.”  The Cures Act would provide designated therapies, if approved, 15 years of marketing exclusivity.  Mr. Boutin argued that because incentives for rare disease development under the Orphan Drug Act have been largely successful, more common diseases, such ALS and Alzheimer’s disease, would be prime candidates for dormant therapy development.

Dr. Samuel Gandy, on behalf of Dr. Kenneth Davis, President and CEO of Mt. Sinai Health System, seconded Mr. Boutin’s call for additional statutory exclusivity.  He proposed as an alternative that Congress create categories of exclusivity for specific areas with unmet medical need.  Citing the need for drugs to reduce the rate of disease progression in Alzheimer’s disease, Dr. Gandy recommended additional exclusivity for oral drugs for this indication.

Other witnesses were not optimistic about a statutory exclusivity program, such as the Cures Act, being able to foster innovation in drug development.  Dr. Steven Miller, Senior Vice President and Chief Medical Officer for Express Scripts Holding Company, stated that the burden of increased costs created by a wide range of products qualifying for long term exclusivity would fall to health plans and employers.  This concern was echoed by members of Congress who were concerned with creating monopolies in a time where the rising costs of health care are already creating barriers for access.  Dr. Miller presented the concern that statutory exclusivity would pervert the commercial market and actually inhibit innovation, while artificially restricting competition.  He even went on to suggest that the tax code ought to support the burden of additional exclusivity as a public good, rather than putting it solely on the backs of payers of health care.

There was also concern about the breadth of the statutory inclusion criteria for a “dormant therapy” designation under the Cures Act.  Mr. C. Scott Hemphill, a Professor of Law at the Columbia University Law School, argued that, under FDA’s definition of an “unmet medical need,” many products that would otherwise have sufficient market forces, and would otherwise be approved by the Agency, would prevent generic competition.  He instead recommended a narrowly tailored approach, like that of the Hatch-Waxman Act and Orphan Drug Act. 
 
Both Dr. Miller and Mr. Hemphill advocated for a targeted statutory exclusivity program that would reward truly innovative products.   Alternatively, Dr. Fred Ledley, Professor of Natural and Applied Sciences at Bentley University and Management Director of the Center for Integration of Science and Industry, expressed that, because innovation in medical product development is directly tied to innovation in basic science, a patent protection-based approach would support new discoveries.  Dr. Ledley did concede that statutory exclusivity could be useful when there is an unmet medical need based on true market failures.

There was consensus among the witnesses with respect to the need for greater certainty and consistency across in the application of regulatory standards, including in the use of expedited approval pathways from one review division to the next.  Expedited programs, such as breakthrough therapy and accelerated approval, were recognized as useful regulatory mechanisms to expedite the drug development process.  While not a direct incentive, if successful, these programs result in approvals with greater length of patent protection remaining. 

Each witness’s written testimony, as well as a transcript and recording of the hearing, can be found here.  See our previous post on HP&M Director Frank Sasinowski’s testimony at the first 21st Century Cures hearing on PCAST Report on Drug Innovation.

By Allyson B. Mullen –

As part of the Medical Device User Fee Act of 2012 ("MDUFA III") Commitment Letter, FDA and the medical device industry agreed to participate in a comprehensive outside assessment of the medical device review process.  The assessment was performed by Booz Allen Hamilton ("Booz Allen").  On December 11, 2013, Booz Allen released its initial report with the following priority recommendations:

• Develop criteria and establish mechanisms to improve consistency in decision making throughout the review process;
• Provide mandatory full staff training for the three primary IT systems that support MDUFA III reviews;
• Identify metrics and incorporate methods to better assess review process training satisfaction, learning, and staff behavior changes; and
• Adopt a holistic, multi-pronged approach to address five quality component areas to standardize process lifecycle management activities and improve consistency of reviews.

See our earlier post here.
 
On June 11, 2014, Booz Allen issued its final report and CDRH issued its Plan of Action ("the Plan").  The final report makes 11 recommendations, including, among other things, that CDRH conduct a retrospective review of withdrawn premarket submissions to identify the cause of the withdrawal.  The report cites a fifty percent increase in 510(k) withdrawals from fiscal year 2012 to fiscal year 2013.

While the final report issues 11 recommendations, several with subparts, the CDRH Plan focused on the four priority recommendations from Booz Allen’s December 2013 report.  It is unclear whether CDRH will update the Plan to address the remaining recommendations in the final report.

The CDRH Plan of Action, which reads somewhat like a FDA Form 483 response by a device manufacturer, outlines actions with respect to each of the four priority recommendations.  With regard to the first recommendation, “develop criteria and establish mechanisms to improve consistency in decision making throughout the review process,” the Plan indicates that CDRH will inventory and perform a gap assessment of its existing processes, procedures, policies and metrics relating to premarket applications (510(k)s, PMAs, 510(k) requests for Additional Information, PMA Major Deficiencies, and IDE approval decisions).   Once complete, CDRH plans to identify lessons learned and best practices for decision making from other organizations and then develop new premarket application review processes, procedures, and policies with the intent of streamlining the process.  One hopes that these new processes, procedures, and policies will speed up the review process.  However, at least one recent attempt to improve the quality of 510(k)s has, in some cases, slowed down the process with a rigid and formalistic process (see our earlier post here).  Although unaddressed in the CDRH Plan, the Booz Allen final report acknowledges that the greater than 50% refusal rate during the first round of RTA reviews for 510(k)s is problematic for the overall review process, and optimization of the RTA process is one of the 11 recommendations in the final report. 

As to the second recommendation, “provide mandatory full staff training for the three primary IT systems that support MDUFA III reviews,” the Plan indicates that after completing a review of the current IT systems, CDRH will incorporate training on these systems into the CDRH Reviewer Certification Program (RCP).  Following this implementation, CDRH plans to create a group of experts on the systems, which presumably will be available to reviewers in need of assistance.  In a second stage of this part of the Plan, CDRH intends to broaden its efforts in reviewing and identifying gaps with regard to training on other IT processes.

The Plan for the third recommendation, “identify metrics and incorporate methods to better assess review process training satisfaction, learning, and staff behavior changes,” is short and simple.  CDRH will research best practices for training evaluation, determine evaluation requirements for premarket training, develop metrics and evaluation plan, and implement the same. 

The portion of the Plan for the final recommendation, “adopt a holistic, multi-pronged approach to address five quality component areas to standardize process lifecycle management activities and improve consistency of reviews,” is by far the most significant, in both length and potential impact to the effectiveness of the CDRH premarket review process.  There are four parts of this section of the Plan: (1) Senior Management, Corrective and Preventative Action and Continuous Process Improvement; (2) Resource Management; (3) Document Management; and (4) System Evaluation.  Sections 1 and 3 address the need to assess and identify gaps in current processes related to the relevant areas, and revise and implement new processes related to the same.  The Resource Management Section indicates that these recommendations are addressed in other areas of the Plan.  Finally, the System Evaluation section indicates that CDRH will review and evaluate the processes for monitoring review of 510(k) sub-processes. 

While there no hard deadlines for any of the actions set out in the Plan, in a blog post from Jeffrey Shuren, Director of CDRH, he said that the immediate actions related to the four priority recommendations, outlined both above and in the Plan, will be complete by the end of 2016.  Jeffrey Shuren, FDA Voice, Report: CDRH on Track to Improve Device Submission Review Process, June 11, 2014.

No timeline was given for the remaining actions in the Plan, which Dr. Shuren described as covering “longer-term actions to further enhance the efficiency of [CDRH’s] processes beyond what [Booz Allen] recommended.”  We look forward to seeing the implementation of all of the actions in the Plan and hope there is a positive affect on device premarket reviews.

Hyman, Phelps & McNamara, P.C. (HP&M) is seeking a junior associate.  The ideal candidate will have two to three years experience dealing with regulatory issues relating to food and drug law at the U.S. Food and Drug Administration (FDA), a law firm, or an FDA-regulated company.  Candidates must have excellent academic credentials and strong communication and writing skills.  Candidates should send their curriculum vitae, transcript, and a writing sample to Jeffrey N. Wasserstein (jwasserstein@hpm.com).  HP&M is an equal opportunity employer. 

By Ricardo Carvajal –

In a prior posting, we reported on a lawsuit  brought by Jensen Farms (Jensen) against its auditor Primus Labs (Primus) alleging that Primus had been negligent in the conduct of its audit – negligence that allegedly contributed to the 2011 outbreak of listeriosis associated with cantaloupes produced by Jensen.  Related litigation initiated by victims of the outbreak has begun winding its way through courts in multiple states, and early decisions in those cases suggest that food companies may want to start giving careful consideration to their conduct and use of audits – be they first, second, or third party audits – and how the results of those audits could come back to haunt them in the event of an outbreak.

As a refresher, we begin with a brief recap of events leading up to the 2011 outbreak.  In May 2011, Jensen made changes to its processing, purportedly based in part on recommendations made by Bio Food Safety, a Primus contractee.  Those changes purportedly resulted in the discontinuance of a chlorine wash.   A subsequent audit by Bio Food Safety did not identify the lack of a chlorine wash as a deficiency, and yielded a score of 96%.  Around that time, an outbreak was unfolding that would eventually claim an estimated 33 lives and result in 147 hospitalizations.  Epidemiological and traceback investigations conducted in the wake of the outbreak led FDA to Jensen in September of that year, and the subsequent investigation resulted in a criminal prosecution and misdemeanor plea (see our previous post here).

Perhaps predictably, Jensen sued Primus for negligence.  Also, victims of the outbreak sued Jensen, Primus, Bio Food Safety, and Frontera Produce (the distributor of the cantaloupes), alleging wrongful death based on negligence.  That litigation is proceeding in multiple states, including Colorado, Louisiana, and Oklahoma.  A threshold question in those cases is whether an auditor owes a duty to consumers (as opposed to owing a duty only to the company being audited).  Early decisions are split on that question.  One court granted defendants’ motion to dismiss, holding that a third party auditor of an agricultural producer does not owe a duty to consumers, as that would stretch concepts of foreseeability and duty too far.  The court found that Primus supplied its audit report to Jensen alone, and there was no evidence of plaintiff’s reliance on the audit report.  Further the court found that there was no contract or regulatory requirement that imposed a duty to undergo an audit, and that there was no factual basis indicating what the audit was intended to accomplish.   However, a different court denied defendants’ motion to dismiss, holding that consumer injuries are within the scope of an auditor’s duties, and that a negligent audit can foreseeably result in contamination before products enter commerce.  That court found that Jensen would not have distributed the cantaloupes if it had failed the audit.

Although preliminary in nature, these decisions suggest that the underlying purpose of an audit could have significant implications for any potential liability that could arise from the conduct of that audit.  That could be a noteworthy development, given the potential use of audits to meet obligations arising under the preventive controls and supplier verification provisions of the Food Safety Modernization Act (FSMA).  Although it is too soon to know whether or how audit requirements will be incorporated into the final rules implementing those provisions, the Primus litigation suggests that it’s not too soon to be thinking about the purpose of an audit, and whether or how that purpose should be captured in contracts or other documents.  It’s also worth considering how the results of an audit might be relied on by the audited company and other parties that might have a stake in the outcome of the audit.  These thorny issues could get even thornier as FSMA implementation proceeds.

By Jennifer M. Thomas –

In another confirmation of the Lanham Act’s reach following on the heels of the Lexmark decision, the U.S. Supreme Court ruled today that POM Wonderful LLC’s (“POM’s”) Lanham Act suit against Coca-Cola Co. (“Coke”) over juice product labeling is not precluded by the FDC Act (Docket No. 12-761).  We previously posted here, here, and here about the case, and about the positions of various amici curiae – including the U.S. Solicitor General – on the proper interaction between the FDC Act and Lanham Act. 

Stated briefly, the issue in this case was whether POM’s Lanham Act false and misleading advertising claims challenging the labeling of Coke’s Minute Maid Blueberry Pomegranate juice product were barred by the FDC Act and FDA regulations governing the labeling of juices.  POM argued, among other things, that Coca-Cola’s prominent placement of the words “Pomegranate” and “Blueberry” on the product label, as well as a vignette depicting pomegranates and blueberries among the other fruits that contributed (much more substantially) to the product composition, was false and misleading. 

Before getting into the details of this short and sweet Supreme Court opinion, it is worth noting a few limitations on its scope.  Importantly, the Court in POM expressly denies any intended impact on issues of federal-state preemption under the FDC Act:

[T]his is not a pre-emption case.  In pre-emption cases, the question is whether state law is pre-empted by a federal statute, or in some instances, a federal agency action. . . .   This case, however, concerns the alleged preclusion of a cause of action under one federal statute by the provisions of another federal statute.  So the state-federal balance does not frame the inquiry.

Slip. Op. at 7.  Further, the opinion appears to be restricted to Lanham Act claims regarding products for which FDA does not approve or actually mandate the labeling:  “FDA does not preapprove food and beverage labels under its regulations . . . [and] does not necessarily pursue enforcement measures regarding all objectionable labels.”  Id. at 11.  Time will tell if the principles expressed here are subsequently applied to FDA-regulated products more broadly.

The Court took a nuts-and-bolts approach to evaluating the intersection of the FDC and Lanham Acts, starting from the plain language of both Acts.  It first determined that neither statute evidenced an express legislative intent to preclude operation of the Lanham Act with respect to the labeling of FDA-regulated products, a point which it considered particularly salient given the fact that the acts have “coexisted since . . . 1946 [and] . . . [i]f Congress had concluded, in light of experience, that Lanham Act suits could interfere with the FDCA, it might well have enacted a provision addressing the issue during these 70 years.”  Slip. Op. at 9.  Moreover, the Court found further evidence of legislative intent not to preclude Lanham Act claims in the fact that Congress did choose to preempt state law labeling claims but failed to even mention potentially competing federal laws in that preemption provision.  Id. at 10.  Finally, the Court described the Lanham Act and FDC Act essentially as good buddies — complementing each other with respect to both coverage and remedies, each compensating for the potential failings of the other, and together creating “synergies among multiple methods of regulation.”  Id. at 12. 

The Court was most emphatically not swayed by the Government’s view, expressed in an amicus brief, that Lanham Act claims should be precluded only “to the extent the FDCA or FDA regulations specifically require or authorize the challenged aspects of [the] label.”  Id. at 15 (quoting Brief for United States as Amicus Curiae 11).  In fact, the Court rejected the premise on which the Government’s position was based, namely that the FDC Act and implementing regulations “are at least in some circumstances a ceiling on the regulation of food and beverage labeling,” because it viewed that position as conflicting with legislative intent that the Lanham Act and FDC Act “complement each other with respect to food and beverage labeling.”  Id.  The Court appeared to take umbrage at the Government’s presumption that private parties could be precluded “from availing themselves of a well-established federal remedy because an agency enacted regulations that touch on similar subject matter but do not purport to displace that remedy or even implement the statute that is its source.”  Id. at 17.

By Kurt R. Karst –      

Although this blogger didn’t catch the episodes of The Six Million Dollar Man that originally aired in the mid-1970s, I did see them once they were syndicated.   As I remember it, the opening theme and narration to the popular television show starring Lee Majors as Steve Austin was gripping – at least to a young child in the early 1980s.  (The same can be said for the opening theme and narration to The Incredible Hulk television series starring Bill Bixby as Dr. David Banner and Lou Ferrigno as the Hulk.)   The premise of The Six Million Dollar Man is that after a terrible crash, austronaut Steve Austin had to be rebuilt with bionic implants to assist a government organization fight crime (and even Bigfoot).  As the opening narration states:  “Steve Austin, astronaut.  A man barely alive.  Gentlemen, we can rebuild him.  We have the technology.  We have the capability to build the world’s first bionic man.  Steve Austin will be that man.  Better than he was before. Better, stronger, faster.”

The opening narration to The Six Million Dollar Man played on a mind loop while this blogger read FDA’s recent guidance offering to ANDA sponsors: “ANDA Submissions — Content and Format of Abbreviated New Drug Applications.”  The guidance, which is accompanied by a webcast providing an overview of the document, is part of a broader initiative by FDA and the Office of Generic Drugs (“OGD”) to rebuild the generic drug program in the U.S.  It also comes as folks gear up for the full implementation of the Generic Drug User Fee Amendments (“GDUFA”) later this year.  The draft guidance complements other OGD efforts aimed at improving ANDA quality, incuding guidance on enhanced refuse-to-receive standards, the establishment of a public docket (Docket No. FDA-2014-N-0032) to receive input and suggestions on ways to improve ANDA quality and on how to best communicate those suggestions to the generic drug industry (see our previous post here), and other offerings on OGD’s website.

The ANDA quality guidance doesn’t break any new ground.  Of course, that’s not what it is intended to do.  Rather, the value of the draft guidance is that it consolidates a lot (but not all) of OGD’s best advice and cross references to other policy documents on point in one organized document for easy reference and clarity.  As FDA states in the notice announcing the draft guidance:

The guidance document is intended to assist applicants in preparing complete and high-quality original [ANDAs] for submission to FDA under the [FDC Act].  The guidance summarizes the statutory and regulatory requirements for ANDAs, references existing guidance documents, and incorporates additional recommendations on the content and format of ANDA submissions.  This guidance describes the Common Technical Document format for human pharmaceutical product applications and specifies the information to be submitted in each section of the application.

The focus on quality is important if, in this post-GDUFA world, there are to be significant numbers of first-cycle approvals.  Under the GDUFA Performance Goals and Procedures, FDA agreed to review and act on 60% of original ANDA submissions within 15 months from the date of submission for the year 3 cohort (Fiscal Year 2015); 75% of original ANDA submissions within 15 months from the date of submission for the year 4 cohort (Fiscal Year 2016); and 90% of original ANDA submissions within 10 months from the date of submission for the year 5 cohort (Fiscal Year 2017).  Acting on an application includes issuance of a complete response letter, an approval letter, a tentative approval letter, or a refuse-to-receive action. 

Higher quality ANDAs should minimize the number of complete response letters and refuse-to-receive actions, and increase the number of tentative and final approvals.  Clearly, we’re not yet at that point.  According to the most recent GDUFA statistics published by FDA, the number of complete responses and refuse-to-receive actions significantly outnumber the number of tentative and final approvals.

We doubt that the generic drug industry will tolerate such statistics as we move deeper into GDUFA – and begin thinking about GDUFA II – however, we recognize that GDUFA is a two-way street.  FDA has to have a better, stronger, and faster generic drug program under GDUFA, but help make that happen, the generic drug industry needs to submit applications of the highest quality. 

By William T. Koustas –

FDA has issued a new draft guidance titled “Drug Supply Chain Security Act Implementation:  Identification of Suspect Product and Notification” (Draft Guidance).  This Draft Guidance is the first of many to come in FDA’s implementation of the Drug Supply Chain Security Act (DSCSA).  As was apparent at the recent DSCSA public workshop (as we posted here), industry has been anxiously awaiting more information from FDA as DSCSA provisions, including provisions regarding suspect and illegitimate products, begin to take effect the first of the year.

One of the initial requirements is to notify FDA and trading partners of product that is identified as “illegitimate.”  FDC Act §§ 582(b)(4), (c)(4), (d)(4), (e)(4).  Under the DSCSA, if a trading partner identifies a product that is suspect, it must quarantine the product and conduct an investigation to determine whether the product is illegitimate.  Id.  Upon determining that the suspect product is in fact illegitimate, the product must remain quarantined, be appropriately disposed of, and a notification must be made to FDA and trading partners.  Id.
 
The DSCSA tasked FDA with addressing three issues in this guidance: (1) identifying scenarios that could increase the risk of suspect product entering the supply chain; (2) recommending ways trading partners can identify and determine whether product is suspect; and (3) creating a process for trading partners to terminate illegitimate product notifications.  FDC Act § 582(h)(2).  The Draft Guidance addressed each of these three issues as follows:

(1)  Potential scenarios that increase the risk of finding suspect products:  FDA identified a number of potential scenarios that could lead to vulnerabilities in the supply chain.  FDA groups the scenarios into three categories:  (1) trading partners and product sourcing (e.g., purchasing from a new trading partner); (2) supply, demand, history, and product value (e.g., product is in high demand in the U.S.); and (3) product appearance (e.g., product packaging appears different from the usual packaging).

(2)  Recommendations for identifying and determining if product is suspect:  FDA also took a three-part approach here, and identified three areas in which products might be suspect:  (1) pricing (e.g., sold at very low prices); (2) package and transport containers (e.g., compromised packaging); and (3) labeling on individual saleable units (e.g., missing information on the label).

(3)  Notification of illegitimate product and termination:  The DSCSA requires trading partners to notify FDA and other trading partners once they determine that a suspect product is illegitimate.  The Draft Guidance sets forth a process for trading partners to make such notifications via a new form (attachment A to the Draft Guidance) and a new website.  The DSCSA also requires trading partners to consult with FDA in order to terminate an illegitimate product notification, but the Draft Guidance appears to take that a step further.  FDA views this requirement under the DSCSA as requiring “trading partners [to] provide FDA with an opportunity to provide its expert views and advice on proposed terminations of notifications.”  FDA committed itself to responding to requests for termination within 10 business days (with the caveat that, if it would take longer, FDA would notify the trading partner). 

Also of note, as FDA makes clear throughout the Draft Guidance, it views the portions of the guidance related to termination of illegitimate product notifications as binding upon finalization.  Generally, guidance documents are non-binding. 

While FDA fulfilled all the requirements that the DSCSA set forth for this guidance, and even arguably went a step beyond with respect to termination of notifications (i.e. new form, website, FDA 10 day response time), the Draft Guidance leaves at least one significant gap that we expect trading partners will want FDA to eventually fill.  As the DSCSA is written, a suspect product must be determined to be “illegitimate” to warrant a notification to FDA.  While the Draft Guidance discusses scenarios regarding whether a product is suspect, it does not bridge the gap and articulate when a suspect product becomes an illegitimate product as defined under the DSCSA.   

As FDA acknowledged, this guidance does not address all suspect and illegitimate product-related issues, but it is a start.  Interested parties should submit comments on the Draft Guidance within 60 days of its publication in the Federal Register (79 Fed. Reg. 33,564 (June 11, 2014)). 

By Kurt R. Karst –      

In what might very well be the first decision in a case involving a counterclaim seeking an order to correct or delete patent information from the Orange Book (and not concerning a patent use code), last week the U.S. District Court for the Southern District of California denied a Motion for Summary Judgment filed by Fresenius Kabi USA, LLC (“Fresenius”) to remove a patent – U.S. Patent No. 6,992,218 (“the ‘218 patent”) – from the Orange Book listed by Cadence Pharmaceuticals (“Cadence”) for OFIRMEV (acetaminophen) Injection.  FDA approved OFIRMEV on November 2, 2010 under NDA No. 022450 for the management of mild-to-moderate pain, for the management of moderate-to-severe pain with adjunctive opioid analgesics, and for the reduction of fever.  In 2012, Fresenius submitted a 505(b)(2) application – NDA No. 204767 – to FDA containing Paragraph IV certifications to the ‘218 patent and to U.S Patent No. 6,028,222, both of which are listed in the Orange Book as drug product patents.

Before we get into the specifics of the OFIRMEV case, some background is necessary for those who don’t necessarily get into every nook and cranny of the Hatch-Waxman Amendments. . . .

The 2003 Medicare Modernization Act (“MMA”) added provisions to the FDC Act to give 505(b)(2) and ANDA applicants the ability to challenge the listing of a patent in the Orange Book for a brand-name reference listed drug.  Prior to the enactment of the MMA, courts had ruled that there was no private right of action to delist an allegedly improperly listed patent (see, e.g., Mylan Pharmaceuticals, Inc. v. Thompson, 268 F.3d 1323, 60 USPQ2d 1576 (Fed. Cir. 2001); Andrx Pharmaceuticals, Inc. v. Biovail Corp., 276 F.3d 1368, 61 USPQ2d 1414 (Fed.Cir.2002)).  As a result of these decisions, as well as a July 2002 report from the Federal Trade Commission – “Generic Drug Entry Prior to Patent Expiration: An FTC Study” – that highlighted the problem of, among other things, the submission of inaccurate patent information, Congress added the patent delisting counterclaim provisions to the statute. 

The patent delisting counterclaim provisions at FDC Act §505(c)(3)(D)(ii)(I) applicable to 505(b)(2) applications state:

If an owner of the patent or the holder of the approved application under [FDC Act § 505(b)] for the drug that is claimed by the patent or a use of which is claimed by the patent brings a patent infringement action against the applicant, the applicant may assert a counterclaim seeking an order requiring the holder to correct or delete the patent information submitted by the holder under FDC Act § 505(b) or (c)] on the ground that the patent does not claim either – (aa) the drug for which the application was approved; or (bb) an approved method of using the drug.

The MMA also added almost identical counterclaim provisions at FDC Act §505(j)(5)(C)(ii)(I) applicable to ANDA sponsors. 

The patent delisting counterclaim provision was most famously the topic of the U.S. Supreme Court’s decision in Caraco Pharm. Labs, Ltd. v. Novo Nordisk A/S, __ U.S. __; 132 S. Ct. 1670 (2012) (see our previous post here); however, that case concerned the scope of the counterclaim provision.  That is, whether challengeable patent information includes patent use code narratives.  While there have been some cases in which the delisting counterclaim provisions have been asserted by 505(b)(2) and ANDA applicants (see our previous posts here and here), the cases were ultimately resolved without a merits decision on the counterclaim.

The OFIRMEV case caught our attention last year when the district court decided Cadence’s Motion to Dismiss the Amended Counterclaim for “Improper Patent Listing” (Count V, ¶¶ 25-45) of the ‘218 patent filed by Fresenius (opposition and reply briefs here and here).  According to Fresenius, the ‘218 patent is improperly listed in the Orange Book for OFIRMEV because it “only consists of process claims and a single product-by-process claim directed to a non-novel product.”  Under regulations promulgated by FDA in 2003, process patents are not eligible for Orange Book listing (21 C.F.R. § 314.53(b)(1)); however, product-by-process patents can be listed if the product claimed is novel (21 C.F.R. § 314.53(c)(2)(i)(L)).  Cadence argued that Fresenius’ counterclaim does not fit into either of the categories identified in the FDC Act and should be dismissed.  Finding that Fresenius “can state a delisting counterclaim by alleging that the ‘218 patent, a product-by-process patent, does not claim a novel product,” the district court denied Cadence’s Motion to Dismiss and allowed the counterclaim challenge to proceed.

Following the court’s decision to let the counterclaim challenge proceed, Fresenius ultimately filed a Motion for Summary Judgment to delist the ‘218 patent from the Orange Book (opposition and reply briefs here and here).  According to Fresenius:

While the ‘218 patent contains 19 claims, the first 18 claims are “process” claims that do not support Orange Book listing.  Claim 19 is the only claim of the ‘218 patent that could provide the basis for listing the ‘218 patent because it is a product-by-process claim, and product-by-process patents are listable if the claimed product of the process is “novel.”  But the product of claim 19, an injectable aqueous solution of acetaminophen, is not novel. . . .  Because the product of product-by-process claim 19 is not novel, the ‘218 patent should be delisted from the Orange Book pursuant to the counterclaim provisions of the Hatch-Waxman Act.

Put another way, Fresenius argued that a product-by-process claim directed to a non-novel product is substantively no different than a process claim; thus ‘218 patent is a process patent that may not be listed in the Orange Book.  The district court, however, did not agree.

In a June 5th decision, the district court sided with Cadence, saying that the issue of novelty ultimately bears on the validity of the ‘218 patent:

Fresenius asks the Court to decide in the delisting context whether Cadence’s representation of novelty is correct. Whether the product claimed is novel also bears on the validity of claim 19.  A product-by-process claim which claims a non-novel product is invalid. . . .  Fresenius’ attack on the novelty of the product claimed in claim 19 is therefore also an attack on the claim’s validity.

According to Fresenius, in analyzing the novelty issue in the delisting context, the Court should disregard the presumption of patent validity and the accompanying heavier burden of proof to overcome the presumption. . . .  Fresenius has cited no authority in support of this argument, and the Court is aware of none.  On the other hand, Fresenius has asserted a separate invalidity counterclaim contending that claim 19 is invalid because the claimed product is obvious, i.e., not novel.  The invalidity counterclaim is not the subject of Fresenius’ pending summary judgment motion.  In light of the foregoing, the Court declines to determine solely in the delisting context whether the product of claim 19 is not novel. The novelty issue is better addressed at trial in the context of Fresenius’ invalidity counterclaim.

The court also noted that following Fresenius’ logic could mean an odd outcome: “a discordant finding that a product which is found novel in light of the validity presumption for purposes of patent validity, is not novel for listing purposes, and that the product-by-process patent claiming it is therefore not entitled to listing, thus requiring delisting of a valid product-by-process patent.”

Whether an appeal of the district court’s decision will ensue remains to be seen.  Perhaps the issue of novelty will ultimately be decided, leading Fresenius to revisit Orange Book listing of the ‘218 patent.   Regardless, there is now more jurisprudence to consider when challenging the listing of a patent.  

By Riëtte van Laack –

In Quesada v. Herb Thyme Farms, Inc., Plaintiff Quesada alleged that Herb Thyme Farms, Inc. (Herb Thyme) lied about the nature of its “Fresh Organic” line of herbs.  According to Plaintiff, Herb Thyme misrepresented its “Fresh Organic” products as 100% percent organic products when they were not.  Plaintiff claimed that “to increase profits and to keep pace with growing demand, Herb Thyme devised and carried out a scheme to take advantage of the popularity of the organic food movement by labeling and selling its non-organic products under its ‘100% Organic’ label.”  Allegedly, Herb Thyme mixed organic and conventional herbs and labeled the final product as 100% “Fresh Organic” products.  Ms. Quesada brought claims for (1) unfair and deceptive trade practices in violation of the Consumers Legal Remedies Act (CLRA); (2) violation of the false advertising law; (3) unlawful conduct in violation of the unfair competition law (UCL); and (4) unfair and fraudulent conduct in violation of the UCL.  (Apparently, the original complaint did not cite the California Organic Products Act of 2003 (COPA) or the Organic Food Production Act (OFPA)). 

Herb Thyme moved for a judgment on the pleadings, arguing that Ms. Quesada’s state law claims were preempted.  The trial court agreed that the OFPA expressly and impliedly preempted Plaintiff’s claim, and entered judgment against Plaintiff.

On appeal, Ms. Quesada argued that her action was based solely on the COPA, not on the OFPA, contending that Farm Raised Salmon Cases is controlling.  In that case, the California Supreme Court held that states are free to provide for private remedies under state law so long as state law requirements are identical to federal law requirements (see our previous post here). 

The Court of Appeal affirmed the trial court’s ruling concluding that a state consumer lawsuit based on violations of COPA, or violations of the OFPA, would “frustrate the congressional purpose of exclusive federal and state government prosecution and erode the enforcement methods by which the [OFPA] was designed to create a national organic standard.”  It held that the doctrine of implied preemption foreclosed such claims.  According to the Court of Appeal, “a private right of action under the unfair competition law based on violations of COPA would conflict with the clear congressional intent to preclude private enforcement of national organic standards.”  The Court of Appeal distinguished this case from the Farm Raised Salmon Cases; Congress permitted states to enact a state organic certification program if it met the requirements of the Act, and was federally approved.  Accordingly, California, through COPA, essentially administers and enforces OFPA rather than its own state law.

Plaintiff petitioned the California Supreme Court for review.  On April 30, 2014, that Court granted the petition narrowing the question to “Whether the Organic Foods Production Act of 1990 . . . preempts state consumer lawsuits alleging that a food product was falsely labeled ‘100% Organic’ when it contained ingredients that were not certified organic under [COPA].”

By Anne K. Walsh –

Late last Friday afternoon, FDA issued a new guidance document describing FDA’s recommended practices for distributing reprints that convey new risk information for approved drug and biologic products.  The guidance defines “new risk information” as information that becomes available after a drug is marketed that rebuts or mitigates information about a risk already identified in the approved labeling.  This term does not include information about a newly identified risk that was not previously included in the approved labeling, or new information that indicates that a risk is more serious than reflected in labeling.  FDA acknowledges the value of quickly disseminating this type of information to health care professionals:  “FDA recognizes that the safety profile of a drug evolves throughout its lifecycle as the extent of exposure to the product increases and that it can be helpful for health care practitioners to receive significant new risk information about an approved product in a timely manner.” 

In the guidance, FDA emphasizes that the dissemination of new risk information for approved uses of drugs is distinct from the dissemination of information concerning new uses of products, addressed in the February 2014 draft guidance discussed here.  FDA differentiates new risk information from new use information in two ways:

• Because “there are differences in the purpose, nature, and reliability of the evidence used to determine the effectiveness of a drug (e.g., to support a new intended use) and the evidence that is the basis for the product’s risk assessment,” guidance is needed to address the spectrum of appropriate data sources for new risk information; and
• Because health care practitioners may be confused by new risk information that contradicts the information in approved labeling, guidance is needed to ensure new risk information “meets appropriate standards for reliability and is presented with appropriate disclosure of its limitations.”

Therefore, FDA claims that it will not object to the distribution of new risk information if it is distributed in the form of a reprint (or digital copy) of a published study, and if the manufacturer follows certain principles related to the data source and the distribution methods of the reprint.  It should be noted that, unlike the earlier reprint guidance document on new uses, FDA excludes medical devices from the scope of this guidance.  FDA drops this reference in a footnote without further explanation.

The guidance describes a distribution scheme for reprints containing new risk information that is very similar to the distribution of reprints related to unapproved uses.  For example, the reprint must be accompanied by a cover sheet disclosing that FDA has not reviewed the data and any financial interests between the study author and the manufacturer.  The reprint also must be accompanied by the approved product labeling, and cannot be distributed with any promotional material.

But unlike the earlier draft guidance on new uses, the new guidance describes the types of studies or analyses necessary to be assure the reliability and persuasiveness of the data.  For example, FDA will consider whether the conclusions of the study give appropriate weight and consideration to all relevant information in the safety database; whether the study is sufficiently well-designed and informative to merit consideration in assessing the implications of a risk; and whether the study is at least as persuasive as the data sources that underlie the existing risk assessment in the approved labeling.  These criteria appear to introduce a level of subjectivity to the adequacy of the data source.

If a manufacturer meets the requirements of the guidance, FDA claims that distribution of new risk information will not render the labeling false or misleading under 21 U.S.C. § 352(a).

Comments are due within 75 days of publication of the Federal Register notice announcing the draft guidance.

By John R. Fleder –

The National Advertising Division (“NAD”) of the Council of Better Business Bureaus has administered an industry sponsored, self-regulatory program for many years in which national advertisers can complain about their competitors’ advertising.   NAD reviews the advertising and issues public decisions regarding the challenged advertising.  The program relieves the parties involved of the costs of a lawsuit.   The Federal Trade Commission has encouraged advertisers to participate in the NAD process.  In that connection, the Commission has demonstrated that, when a company “loses” an NAD case but will not change its advertising practices, the FTC will be inclined to take enforcement action against that advertiser.

Although the NAD lacks legal remedial powers, when a company refuses to participate in the NAD process after an advertisement is challenged or when a company does not alter its practices as a result of an adverse NAD decision, the NAD will typically refer the matter to the Federal Trade Commission to consider an enforcement action against the advertiser.  The FTC has encouraged advertisers to participate in the NAD process.  In that connection, the agency has publicly stated that, when a company” loses” an NAD case but will not change its advertising practices, the FTC will be inclined to take enforcement action against that advertiser.  Historically, the FTC has frequently taken such an action after receiving a referral from the NAD.

Nevertheless, we have seen a number of instances over the past few years where the FTC has informed the NAD that the Commission has declined to take an enforcement action after an NAD referral.  That has typically happened when the alleged violator ceased the practices in question after the NAD referral was made to the FTC.  However, it is extremely rare for the FTC to disagree on the merits with an NAD decision.

It was somewhat stunning to read the FTC’s May 13, 2014 letter to the NAD concerning a challenge by Pfizer Consumer Healthcare to advertisements being run by a competitor, Hisamitsu Pharmaceutical, Inc. regarding the Salonpas pain relief patch.  Hisamitsu refused to participate in the NAD process and the NAD issued a short decision simply forwarding the matter to the FTC.  Nevertheless, the FTC decided not to take an enforcement action against Hisamitsu.

Given the company’s refusal to participate in the NAD process, the FTC’s decision to decline an enforcement action was noteworthy on that ground alone.  More interesting was the FTC’s other reasons for declining to bring an enforcement action.  The Commission openly disagreed with Pfizer, concluding that, based on the evidence presented, the FTC did not believe “that the overall net impression of Hisamitsu’s advertisement is misleading.”

One of the main reasons that many companies participate in the NAD process when one of their advertisement is challenged is their fear that, if they do not participate and/or if the NAD rules against their advertisements, they will almost surely be sued by the FTC.  This recent decision may alter the thinking of certain companies.

Nevertheless, an adverse NAD decision poses real business concerns for many national advertisers, and an FTC enforcement action and class action lawsuits remain real dangers when a company decides to ignore an adverse NAD ruling.

By Kurt R. Karst –      

FDA’s Pre-Launch Activities Importation Request (“PLAIR”) program got a lot of attention last July when the Agency finally announced the issuance of a draft guidance document (Docket No. FDA-2013-D-0836) describing the program.  Briefly, the PLAIR program allows, on a case-by-case basis and subject to FDA’s discretion, the importation and warehousing of finished drug and biological products where an application for approval (i.e., an NDA, ANDA, or BLA) is pending and where the import and warehousing will expedite the commercial launch of the product once FDA approves a marketing application.

We started talking about FDA’s PLAIR program years before the Agency issued formal guidance (see our previous post here).  In a later post (May 2012), we discussed a case – Sanofi-Synthelabo v. Apotex, Inc. – clearly showing some tension between FDA’s PLAIR program and Hatch-Waxman.  We won’t get into the specifics of the case here, as readers can refer to our previous post for the details.  However, in a nutshell, ANDA sponsor Apotex (the only company to have thus far commented on FDA’s draft PLAIR guidance) was, pursuant to an Order issued under 35 U.S.C. § 271(e)(4), permanently enjoined from “engaging in the commercial manufacture, use, offer to sell or sale within the United States, or importation into the United States” of its generic version of PLAVIX (clopidogrel bisulfate) Tablets until the expiration of a particular patent (and any associated pediatric exclusivity).  As Apotex was gearing up for ANDA approval, the company asked for an amended Order permitting importation of its drug product into the U.S. as a result of a PLAIR request submitted to FDA.  The request for an amended Order was denied by both a district court and the Federal Circuit. 

A new article published in the Hastings Science & Technology Law Journal authored by Alex Cheng and Matthew Avery, titled “The Conflict Between the FDA's Pre-Launch Activities Importation Request Program and the Hatch-Waxman Act,” further explores FDA’s PLAIR program.  It takes a close look at the tension between PLAIRs and the Hatch-Waxman Amendments, and, in particular, in the context of the Sanofi case.

Noting that “[i]f a district court issues a permanent injunction pursuant to section 271(e)(4) of the Patent Act to prohibit the generic company from importing its infringing drug product before the date that the patent expires, then the generic should not be able to take advantage of PLAIR to import its generic drug into the United States ahead of anticipated ANDA approval,” the authors suggest both an amendment to FDA’s PLAIR guidance and to 35 U.S.C. § 271(e)(4).  First, write the authors:

To ensure that the FDA does not approve PLAIR requests during the term of a patent injunction, the FDA should amend the PLAIR process so that an applicant is required to submit information identifying any injunctions that may prohibit importation of its product.  For example, the FDA could amend the PLAIR Draft Guidance to require the following be included with all PLAIR requests:

(j) A letter signed by an authorized representative of the applicant certifying under 18 U.S.C. § 1001 that the applicant is not a party to a court order subject to an injunction prohibiting importation of the drug product.

This requirement will save both the FDA and the courts resources. Such a requirement would allow the FDA to reject PLAIR requests that seek to illegally import products during the term of an injunction (or to summarily deny such requests if they fail to submit this required information). In turn, this would prevent courts from having to weigh in on whether importation under the PLAIR request is proper.

Although ANDA (and 505(b)(2)) applicants are currently required to notify FDA of court actions (see 21 C.F.R. § 314.107(e)), it seems unlikely that the FDA components to which these notifications are sent (i.e., the Office of Generic Drugs or a particular Division in the Office of New Drugs) would, as a matter of course, apprise the Agency’s PLAIR team in the event a PLAIR has been (or will be requested).  As such, this proposed additional element to a PLAIR request seems to make sense.

Second, the authors suggest a revision to 35 U.S.C. § 271(e)(4), as reflected in the bolded and italicized typeface below: 

For an act of infringement [caused by filing an ANDA with a Paragraph IV certification] – (A) the court shall order the effective date of any approval of the drug . . . to be a date which is not earlier than the date of the expiration of the patent which has been infringed, (B) injunctive relief may be granted against an infringer to prevent the commercial manufacture, use, offer to sell, or sale within the United States or importation into the United States of an approved drug, veterinary biological product, or biological product, except importation into the United States shall be allowable to the extent that such importation is permitted by the Food and Drug Administration pursuant to a Pre-launch Activities Importation Request, . . . .

This amendment, say the authors, “would allow generic companies to import their products during the term of an injunction, while still prohibiting them from actually marketing their products until the brand-name manufacturer’s patent expires, thereby protecting the pioneer’s patent rights.”  In addition, the authors state that 35 U.S.C. § 271(e)(4) could be “further amended to only allow importation if the PLAIR applicant submits a letter signed by an authorized representative certifying under 18 U.S.C. § 1001 that it will not sell, offer to sell, or distribute its product prior to receiving final marketing approval from the FDA.”   Such amendments to the statute would appear to be a sufficient way to both protect patent rights and place all ANDA sponsors (both domestic and foreign) in a similar marketing position.   

By Alexander J. Varond –

On May 29, FDA issued its final guidance on “Expedited Programs for Serious Conditions – Drugs and Biologics.”  We blogged previously on the draft guidance and each of FDA’s four expedited programs (fast track designation, accelerated approval, priority review, and breakthrough therapy designation). 

FDA’s final guidance retains much of the contents of the draft version and reflects changes in FDA’s thinking about the breakthrough therapy program based on its review of approximately 186 requests for designation to date, 48 of which have been granted.  The guidance also provides new details related to accelerated approval.

Overarching themes in the final version of the guidance include explicit references to flexibility related to rare disease; the incorporation of the benefit-risk paradigm, which takes into account the severity of the disease or condition; and clearer statements that products “prevent[ing] a serious condition or reduc[ing] the likelihood that the condition will progress to a more serious condition or a more advanced stage of disease” should be eligible for these expedited programs.

Breakthrough therapy designations

FDA’s changes to the breakthrough therapy designation portion of the guidance amount to a fine-tuning of the program rather than a major overhaul.  The following are some of the important clarifications made:

• A grant of breakthrough therapy designation does not guarantee approval. 
• A drug that has its breakthrough therapy designation rescinded “may still have sufficient evidence after completion of the drug development program to support marketing approval.”
• A suggestion by the Agency that a sponsor consider submitting a request for breakthrough therapy designation is “advisory and should not be interpreted as guaranteeing breakthrough designation.”
• Although demonstrating substantial improvement over existing therapies is traditionally done by analyzing preliminary comparative data against available therapies, other types of clinical data may also be persuasive, including data collected in single-arm studies comparing a new treatment with well-documented historical experience.  Examples of single-arm trials that may be persuasive include:
• Study data showing that a new drug significantly increases lung function in cases where lung function decline is a major manifestation of a disease, and where there is no available therapy that increases lung function; and
• Data demonstrating that a cancer drug substantially increases overall response rate compared with historical controls, with consideration of duration of the response.
• The definition of “available therapy” has been modified to include a drug that is “granted accelerated approval because of restricted distribution and the study population for the new drug under development is eligible to receive the approved drug under the restricted distribution program.”
• The final guidance also elucidates the evidence needed to demonstrate that a pharmacodynamic (PD) biomarker is a clinically significant endpoint.  This includes the extent of understanding of the disease pathophysiology; whether the biomarker is on a causal pathway of the disease process; and the time course of the drug’s effect on the biomarker (i.e., a showing that the biomarker can be measured earlier than a surrogate endpoint).
• An explicit reference to a rolling review feature has been added, although this was implied in the draft guidance.

Accelerated approval

The accelerated approval section of the guidance also makes several clarifications and expresses FDA’s priorities.  The final guidance:

• Strengthens FDA’s focus on requirements for postmarketing confirmatory trials.
• Restates the Agency’s “longstanding commitment to regulatory flexibility regarding the evidence required to support product approval for the treatment of serious or life-threatening diseases with limited therapeutic options.”
• Stresses that manufacturers seeking approval for drugs that may be approved via the accelerated pathway should be prepared for a rapid pace of drug development (e.g., manufacturing and development of companion diagnostics).
• Slightly modifies the definition of intermediate clinical endpoint (“ICE”) to mean “a therapeutic effect that can be measured earlier than an effect on [irreversible morbidity or mortality (“IMM”)] and is considered reasonably likely to predict the drug’s effect on IMM or other clinical benefit.”
• States that an important consideration in the use of ICEs is whether the demonstrated therapeutic effect alone would be a basis for traditional approval.  Approvals for products for serious conditions based on clinical endpoints other than IMM will usually be considered under traditional approval procedures. 
• Provides additional examples of surrogate endpoints and ICEs that can be used to support an accelerated approval.
• Provides additional clarity related to the due diligence requirement for confirmatory trials for drugs approved via the accelerated approval pathway.