ACI is holding its 3rd Annual Legal, Regulatory, and Compliance Forum on Cosmetics & Personal Care Products on March 7-9, 2016 at the Carlton Hotel in New York City. This is the first year ACI is partnering with the Independent Cosmetic Manufacturers and Distributors and the Professional Beauty Association on the Cosmetics and Personal Care Products Forum.  The program provides “a comprehensive guide to the latest developments affecting ‘articles intended for cleansing, beautifying, promoting attractiveness, or altering the appearance’.” 

Among other topics, there will be a panel entitled: “Is it a Cosmetic, a Drug, Or Something Else?  Exploring Regulatory Lines for ‘Cosmetic-Type’ Products Which Affect the Structure or Function of the Body.”  Hyman, Phelps & McNamara, P.C.'s Paul M. Hyman will appear on this panel, speaking on “Fundamentals of the Cosmetic/Drug (and Device) Distinction.” 

You can still register for the program (and receive a discount) at www.AmericanConference.com/Cosmetics, or contact Bolam Kim (B.Kim@americanconference.com) directly to attend.  Please be sure to use discount code S10-866-866L16.S to register and receive 10% off the tuition fee. 

DIA is holding its 27th annual Marketing Pharmaceuticals conference on Thursday and Friday, March 3-4, 2016, at the Bethesda North Marriott Hotel and Conference Center in Bethesda, MD. DIA is a not-for-profit, global organization dedicated to bringing health care product development professionals together in a neutral environment to improve health and well-being throughout the world.  The conference focuses on the complexities of regulatory and compliance challenges within the marketing and promotion of pharmaceuticals, biologics, and medical devices in an evolving environment.

Featured topics include:

• FDA updates on recent enforcement actions and guidances
• Litigation and compliance updates
• Safety labeling changes: real world execution into packaging, advertising, and promotion
• Engaging payors, nontraditional, and emerging customer markets
• Advocacy groups: when & how should they be engaged?
• How to remain compliant in a global environment
• Scientific exchange
• Social media: using new and emerging technologies compliantly
• Global advertising and promotion processes and standards

Hyman, Phelps & McNamara, P.C.’s John R. Fleder will be speaking about recent developments and legal issues in off label marketing and the practical consequences of those developments, Dara Katcher Levy will be moderating a luncheon round table discussion, and James E. Valentine will be moderating a session about when and how to engage advocacy groups.

You can still register for the conference online here. DIA is offering FDA Law Blog readers the option for a single day registration rate.  To take advantage of the single day registration rate, please call DIA’s Customer Service Team directly at 1.888.257.6457, reference the Marketing Pharmaceuticals conference and the FDA Law Blog, and which day you would like to attend.  Please note, this rate is not available online. 

Over the past few years, the Food and Drug Administration has dramatically increased its inspections of foreign manufacturing facilities for Active Pharmaceutical Ingredients (APIs) and finished dosage form drugs, with potentially cataclysmic consequences for U.S. parent companies, distributors, and manufacturers relying on foreign APIs or contract manufacturing. Additionally, the Justice Department and the Securities and Exchange Commission have brought multiple enforcement actions under the anti-bribery and record-keeping provisions of the Foreign Corrupt Practices Act (FCPA) for inappropriate inducements provided to foreign physicians and others deemed to be “foreign officials” because they are in the business of providing health care.  Sharing information with U.S. agencies and among themselves, anti-corruption authorities in other countries (especially China) have also been flexing their enforcement muscles against pharma companies.

Learning how to protect vital overseas supplies of APIs and pharmaceuticals can prevent or alleviate serious hardship. Dechert LLP and Hyman, Phelps & McNamara P.C., are proud to sponsor a free joint conference on these topics April 5, 2016, from 2:30 to 5:15 p.m., in Dechert’s New York City law offices.  The conference (with cocktails to follow) will feature two panels of experts who will address the current enforcement climate for corrupt practices and for FDA inspections that can block imports of pharmaceuticals to the United States.  Speakers will recommend measures that pharmaceutical companies and their investors can take to avert or alleviate harm.

FDA Inspections outside the United States, and their disastrous consequences 

Many of FDA’s foreign inspections are taking place in China and India, and they have led to the discovery of an increasing number of serious current good manufacturing practice (cGMP) violations, along with a commensurate increase in Warning Letters threatening enforcement action (15 Warning Letters to Chinese and Indian firms in 2015 versus four in 2012). Furthermore, a disturbingly large number of those Warning Letters have raised concerns about the pharmaceutical firms’ “data integrity” (13 Warning Letters to Chinese and Indian firms in 2015 versus two in 2012).

In addition to Warning Letters, adverse regulatory consequences resulting from bad foreign inspections include seizures, injunctions, criminal prosecutions, the refusals to approve New Drug Applications (NDAs) and applications to market generic drugs, and, just as significant, import detentions. Indeed, imports of products, including APIs, can be refused admission into the United States “…if it appears…that such article is adulterated [or] misbranded…” as defined in the Federal Food, Drug, and Cosmetic Act (emphasis supplied).  

These foreign facilities may be just an inspection away from disrupting the supply chain of countless U.S. drug manufacturers. Case in point, on March 2, 2015, FDA investigators walked into Zhejiang Hisun Pharmaceutical Co., Ltd. (Hisun), in China and immediately discovered a number of serious cGMP deficiencies, including data integrity problems.  At one point, according to FDA, the investigators walked into a lab and noticed an employee pull a memory stick from a computer and place it in his pocket.  When they asked what he had taken, the man ran away (see here). The agency issued a warning letter to Hisun, and at least 15 of the firm’s products have been barred from entering the U.S., creating a significant disruption in the pharmaceutical supply chain.  

At the April 5 conference, two experts from the internationally recognized pharmaceutical/medical device law firm Hyman, Phelps & McNamara P.C., Douglas B. Farquhar and Mark I. Schwartz, will discuss what can be done to prevent adverse FDA inspectional findings at foreign plants, and how to cope with the bad inspection when it happens.

We will be joined at the seminar by Lewis Ho of Dechert LLP, who will discuss the impact of the enforcement effort on companies in China, and Carmen M. Shepard, Senior Vice President of Global Policy and Regulatory Counsel at Mylan Inc., who will provide industry perspective on these issues. Ms. Shepard will also be interested in hearing from other industry attendees to develop an action plan urging FDA to streamline the process for lifting Official Action Indicated status from plants with poor inspections, and for closing out Warning Letters.

Threats posed by bribery and corruption

For many years, pharmaceutical companies with overseas activities have faced compliance challenges in multiple jurisdictions. The Justice Department and the SEC have brought multiple enforcement actions under the FCPA.  Anti-corruption authorities in other countries also have been active.  Most prominently, Chinese authorities have been actively investigating and taking enforcement actions against pharma companies, and their local business partners and agents, for such conduct.  These enforcement actions and the increasing cooperation and information-sharing among government authorities globally are subjecting global pharma companies to the threat of simultaneous enforcement actions in multiple jurisdictions.  Pharma companies as a consequence are redoubling their efforts to preach and practice ethical compliance worldwide.

But compliance problems need not be limited to one’s own activities. Increasingly, pharma companies with global operations face potential liability for the corrupt behaviors of their third-party partners, including joint ventures, representatives and agents, and contract manufacturers.

And, in the wake of significant negative publicity about the ramp-up of inspections of non-U.S. pharmaceutical facilities by U.S. and local regulatory agencies, pressure may build to “make problems go away” via inappropriate payments. This threat may be acute in countries where both the local regulator and the regulated firm simply expect issues to be resolved in this manner.

Corrupt acts of this sort by local partners could cause global pharma companies significant reputational harm as well as supply chain disruption.    

Two experts on foreign corruption and compliance from Dechert, Jeremy Zucker (Washington, DC) and Kareena Teh (Hong Kong), will discuss these anti-corruption compliance issues from U.S. and Asian perspectives and share “war stories” from recent investigations.

Please click on this link to register to attend the event.

BIOGRAPHIES:

DOUGLAS B. FARQUHAR, Director at Hyman, Phelps & McNamara P.C., has more than 30 years of experience as a prosecutor and defense and regulatory attorney. Since joining the firm in 1997, he has advised pharmaceutical and medical device manufacturers and wholesalers, compounding pharmacies, and individuals on a wide range of enforcement activities, including consent decrees, criminal investigations, debarment issues, arbitration proceedings, civil seizures, FDA inspectional issues, and injunctions.

LEWIS HO, a Dechert partner in its Hong Kong office, leads the life sciences practice in Asia. He helps life sciences and technology companies and their financial sponsors to capture, manage, risk assess, evaluate and monetize their intellectual property assets.  He has extensive experience advising on both inbound and outbound technology transfer transactions, and has negotiated more than 60 collaboration, outsourcing, joint venture and licensing deals with various life sciences companies, academic institutes, hospitals and contract research organizations.  He also assists Chinese companies acquiring IP assets and manufacturing facilities overseas.

MARK I. SCHWARTZ, Of Counsel at Hyman, Phelps & McNamara P.C., advises clients on biologic, drug, and device compliance, as well as on regulatory issues. He joined the firm after spending close to 13 years at the Food and Drug Administration in various capacities. Most recently, Mr. Schwartz was CBER’s Deputy Director in the Office of Compliance and Biologics Quality, an office with approximately 140 staff members.

CARMEN M. SHEPARD, is the Senior Vice President, Global Policy and Regulatory Counsel at Mylan.  She is an expert in the area of generic drug approvals, both for finished dosage form drugs and APIs. Ms. Shepard is responsible for handling legal regulatory issues arising from the company’s generic drug business in over 140 countries. She is also responsible for the company’s policy efforts globally.

KAREENA TEH, a Dechert partner based in its Hong Kong office, advises multinational, PRC, and Hong Kong clients on governance, regulatory and compliance matters, as well as general corporate and commercial litigation matters. Ms. Teh’s experience in these areas includes representing multinational companies and individuals in cross-border fraud, corruption, money laundering and market misconduct investigations.

JEREMY ZUCKER, a Dechert partner based in its Washington, D.C. offices, is co-chair of the firm’s International Trade and Government Regulation practice. He advises clients on international trade regulatory compliance matters, including in relation to the FCPA, the Export Administration Regulations, the International Traffic in Arms Regulations, economic sanctions programs administered by the Office of Foreign Assets Control and the anti-money laundering provisions of the USA Patriot Act.  Mr. Zucker assists clients in all phases of their compliance and risk mitigation programs, including evaluating existing programs, developing and drafting new policies and procedures and providing training, as well as conducting risk assessments, compliance audits and complex internal investigations.

By Allyson B. Mullen –

By In early February, Booz Allen Hamilton (“Booz Allen”) issued its Final Implementation Report assessing the actions taken by CDRH to address the firm’s earlier recommendations to improve the Center’s premarket review activities. We previously blogged on Booz Allen’s recommendations and CDRH’s plan of action here and here.

Booz Allen’s report summarizes a number of key projects completed by the Center in an effort to promote predictable, efficient, and consistent premarket reviews. These projects address all 11 of Booz Allen’s recommendations from its earlier reports. A few of the most notable actions taken by CDRH are:

• Identification of short- and long-term review process to track and monitor for quality. These metrics include Refuse to Accept (RTA) decisions and final decisions.
• Rolling out the SMART template, “a self-guided tool for reviewers based on standardized operating procedures to handle similar issues encountered on different submissions.”
• Revised the 510(k) RTA guidance and checklist. We saw several improvements in the revised guidance, which we blogged on here.
• Implementing internal work instructions for withdrawal decisions and interactive review communications with sponsors.
• Revised the eCopy guidance to emphasize the importance of the use of features that facilitate searching and navigation.

While FDA has completed all of the above projects, there was insufficient time for Booz Allen to assess the implementation and effectiveness for the majority of these projects. Therefore, the report was unable to do more than speculate as to whether these actions will ultimately address the underlying concerns that prompted Booz Allen’s original review and whether additional actions may be necessary.

It is also too soon to know if these efforts will translate into shorter or more predictable review times for industry. In the report’s discussion of CDRH’s actions leading to the steps above, there are a few interesting points/statistics:

• Based on a review of 510(k) submissions from calendar year 2013, it was found that 510(k)s that were refused during the RTA process were associated with overall longer review times.
• An audit of 731 submissions, received over a three month period, showed that:
• on average sponsors missed eight (8) criteria in the checklist, with more than 75% of submissions missing more than 4 criteria,
• 66% of submissions did not include an RTA checklist completed by the sponsor instructing FDA as to where and how each element was addressed in the submission,
• The top four (4) most frequently missed criteria were: (i) shelf life methods (element 28); (ii) prior submissions (element 9); (iii) substantial equivalence rationale (element 16); and (iv) performance data – full test reports provided (element 36),
• Substantive review occurred in only a small number of RTA reviews (11%) and substantive review was not generally the sole cause for a refusal, and
• When substantive review did occur, it most frequently occurred in the reviewer’s assessment of the device description.
• ODE reviewers were trained not to interact with submitters during the RTA review process whereas OIR reviewers worked interactively with submitters during RTA review. The report states that “CDRH subsequently concluded that [interactive review] during RTA may reduce the rate of RTA elements requiring clarification.” It appears this conclusion was reflected in the revised RTA process. We hope that based on the revised guidance, ODE reviews will follow the lead of OIR reviewers with regard to RTA reviews.
• A survey of CDRH review staff regarding eCopy issues identified that:
• Nearly 80% of reviewers were reviewing non-searchable eCopy submissions, which led to an increase in review time, and
• Almost 90% of reviewers reported reviewing submissions that did not include bookmarks or hyperlinks, and this could add to the review time.

Sponsors taking note of some of these points could improve their odds of a successful premarket review. Providing a completed RTA checklist and a searchable eCopy are two small steps that industry could take on its end to facilitate smoother 510(k) reviews.

By Jennifer D. Newberger –

Judge Royce Lamberth, a Senior Judge in the United States District Court for the District of Columbia and sitting by designation in the United States District Court for the Western District of Texas, is no stranger to First Amendment cases involving FDA. See Washington Legal Foundation v. Henney, 56 F. Supp. 2d 81 (1999). More than 15 years have passed since he ruled that the restrictions in the FDA Modernization Act of 1997 (FDAMA) and FDA’s implementing regulations regarding distribution of off-label materials were unconstitutional.

On February 25, 2016, upon conclusion of the evidence in a criminal case styled United States v. Vascular Solutions, Inc., on which we previously posted here, Judge Lamberth charged the jury by instructing them on the relevant law. The case involves allegations that the defendants, a medical device company and its president, engaged in an unlawful off-label marketing campaign. The government’s superseding indictment alleged that the defendants engaged in a criminal conspiracy to violate the Federal Food, Drug, and Cosmetic Act (FDC Act), and committed four counts of selling misbranded medical devices.

After deliberating for one day, the jury came back with a verdict of “not guilty” on all counts for both the company and its CEO, Howard Root. Though we cannot know why the jury reached this verdict, Judge Lamberth instructed the jury by, in effect, reminding the jury that FDA’s ability to restrict speech that is truthful and not misleading is limited:

It is also not a crime for a device company or its representative to give doctors wholly truthful and non-misleading information about the unapproved use of a device. If you find that VSI’s promotional speech to doctors was solely truthful and not misleading, then you must find the Defendants not guilty of the misbranding offense.

The first of the two sentences above was included in the government’s proposed jury instructions, provided to the court on January 7, 2016. Whether such a statement represents a change in position for the government depends largely on the context in which the government is speaking and the circumstances in which such information is distributed.

FDA has long stated that the dissemination of information about unapproved uses can be important for medical professionals, and so long as the information is distributed according to certain guidelines provided by FDA, FDA would not consider the information to be evidence of a new intended use. See FDA, Guidance for Industry, Distributing Scientific and Medical Publications on Unapproved New Uses — Recommended Practices (Feb. 2014).

Importantly, however, FDA has stated that publications about unapproved uses must “[b]e distributed separately from the delivery of information that is promotional in nature” in order to fit within the “safe harbor” of the above-mentioned guidance document. Consistent with this position, FDA has traditionally taken the position that off-label promotion of a drug or device for a use that has not been cleared or approved by FDA is a violation of the FDC Act. In contrast, the Department of Justice (DOJ) has made a number of statements in other cases indicating that the law is not so clearly a black and white situation. See, e.g., United States v. Stryker Biotech, LLC, No. 09-cr-10330 (D. Mass. 2012), in which DOJ stated in a brief that “not all off-label promotion is a crime” and that “there is some off-label promotion that is not illegal.”

Judge Lamberth’s instructions to the jury seem more consistent with DOJ’s position in Stryker than FDA’s traditional view of off-label promotion. In the jury instructions, Judge Lamberth indicated that promotional speech itself would not be evidence of misbranding so long as the speech was solely truthful and not misleading. This position is consistent with a growing trend among courts to find that truthful and not misleading promotional materials may be distributed by a company without violating the misbranding provisions of the FDC Act. See, e.g., United States v. Caronia, 703 F.3d 149 (2d Cir. 2012); Op. and Order, Amarin Pharma, Inc. v. FDA, No. 1:15-cv-03588-PAE (S.D.N.Y. Aug. 7, 2015) (see our previous posts here and here). It is notable that the jury instruction states that in order to avoid violating the misbranding provisions, the speech must be solely truthful and not misleading. This suggests that if any portion of the company’s “speech” is not truthful or is misleading, it may result in a product being deemed to be misbranded.

In reading Judge Lamberth’s jury instruction, it is important to keep in mind that the court is not necessarily making a statement about charges the government could have brought but chose not to. For example, the court charged the jury based on the superseding indictment of December 2, 2015. That indictment did not contain an adulteration charge involving selling devices without an approved PMA (unlike the original indictment of November 13, 2014). Nevertheless, given the growing willingness of companies to challenge FDA’s regulation of off-label promotion, their success in doing so, and court decisions indicating that the distribution of truthful, non-misleading information about an unapproved use does not violate the misbranding provisions of the FDCA, DOJ and FDA must carefully consider how to proceed in bringing charges of off-label promotion.

Reminder: Register now for the May 3, 2016 Virginia Tech and HP&M Conference on Effective Documentation.  Information on the conference is available here.

By Kurt R. Karst –  

Earlier this week at the Generic Pharmaceutical Association’s (“GPhA”) annual meeting in Orlando, Florida, Dr. Kathleen (“Cook”) Uhl, Director of the Office of Generic Drugs (“OGD”), gave the keynote address, providing the generic drug industry with a much-anticipated lowdown on FDA’s progress in implementing the Generic Drug User Fee Amendments of 2012 (“GDUFA”). According to Dr. Uhl’s facts and figures (there’s no fiction in them, she noted to the packed audience), OGD has made significant headway on improving communication and increasing productivity.  (According to Dr. Uhl, this is  due primarily to OGD’s improved IT system for the generic drug program that was put in place in October 2014.) 

Dr. Uhl’s presentation covered five topics: (1) GDUFA Update; (2) Output & Productivity; (3) Quality of ANDA Submissions; (4) Update on Pre-Year 3 Cohort; and (5) Opportunities for Improvement & Challenges.  We’ll focus on topics (2)-(4) as they tend to be of the greatest interest to ANDA applicants.  For a point of reference, and as background, we refer folks to the GDUFA I Program Performance Goals and Procedures. (GDUFA II is currently being negotiated.  FDA has already held several negotiation sessions and stakeholder meetings.)

Output & Productivity

Output is really where the rubber meets the road under GDUFA. After all, that’s what the generic drug industry is paying user fees for in the first place: to increase generic drug availability with a greater number of ANDA approvals must faster than in the pre-GDUFA era.  Of course, high output depends on high quality input (we’ll get to that topic a little later).  By the end of GDUFA Year 5 (Fiscal Year 2017), when OGD is expected to review and act on 90% of original ANDAs within 10 months from the date of submission, OGD anticipates that a typical 10-month review cycle will follow the timeline below. 

But we’re not quite at this timeline yet! So where are we?

After an initial two years of high volume submission numbers (GDUFA Years 1 and 2; FYs 2013 and 2014), ANDA submissions tapered off in FY 2015, as shown in the tables below. (Although the second table below reflects submissions through September 2015, there was an increase in submissions in the first quarter of FY 2016 (GDUFA Year 3), with 180 ANDA submissions in December 2015 alone.)

FDA’s various actions on ANDAs – final approvals, tentative approvals, and complete responses – have been pretty consistent over the first three FYs of GDUFA, though the number of Complete Response Letters has increased dramatically compared to FY 2012. The increase is due to a large number of Complete Response Letters for pre-GDUFA backlog ANDAs, as shown in the second table below.  As shown in the third table below, FY 2016 has gotten off to a tremendous start, with 99 final and tentative approval actions in December 2015.  That’s the highest number of final and tentative approvals ever issued in a single month. 

In other good news, Dr. Uhl reported that OGD has eliminated the Office’s backlog of ANDAs requiring a filing decision, which stood at two ANDAs in December 2015. Today, ANDA filing (receipt) decisions are being made in about 31 days. 

Quality of ANDA Submissions

Dr. Uhl laid out various metrics for ANDA quality, including the first peek at GDUFA Year 3 (FY 2015) ANDA actions. ANDA Refuse-to-Receive (“RTR”) continue to be a problem, with hundreds of ANDAs being issued RTR letters each fiscal year, as shown in the table below. In fact, of the 180 ANDA submissions made in December 2015, approximately 30% of them were issued RTR letters, primarily for insufficient stability information and/or insufficient dissolution information).  Although the RTR numbers provided by Dr. Uhl are generally in line with the Refuse-to-File numbers for applications submitted to FDA during the first few years of PDUFA implementation, the ANDA RTR numbers should be lower.  Many of the RTR letters could have been avoided with closer scrutiny of the submission.

In addition, the number of ANDA review cycles – and, in particular, CMC review cycles – remains high. Very few applications are approved after the initial review cycle. 

Moving on to the first numbers provided by FDA for ANDAs submitted in FY 2014 (GDUFA Year 3), only 12% of the 51 ANDAs with a 15-month action date that fell in January 2016 received a first cycle approval (or tentative approval).  Most of the submissions were the subject of a Complete Response Letter.  Of course, that’s only 1 month of data, so folks should not be overly concerned . . . . yet.  By way of comparison, 36% of applications were approved under the first cycle in the first year of PDUFA (FY 1993). 

Update on Pre-Year 3 Cohort

With respect to pre-year 3 GDUFA ANDAs, the details are a little sketchy. Although we know generally where things stand with pre-Year 3 applications, thanks in large part to  FDA’s recent launch of the Generic Drug Review Dashboard, we don’t have much insight into FDA’s ability to meet internal goals set for those applications.  Those internal (and aspirational) goals, known as Target Action Dates (“TADs”), were created by FDA to give industry comfort that review of their applications would not suffer as a result of OGD’s need to meet goals for applications submitted post-year 2. TADs also serve as a sort of dry run for OGD to meet the true goals under GDUFA.  The TADs established by FDA are shown in the slide below.  Although knowing the various TADs OGD has established are nice, it would be helpful to know OGD’s success rate. 

Reminder: Register now for the May 3, 2016 Virginia Tech and HP&M Conference on Effective Documentation.  Information on the conference is available here.

By Melisa M. Moonan –

After more than 600 comments and four and a half years since the draft guidance (“Applying Human Factors and Usability Engineering to Optimize Medical Device Design” (June 21, 2011)) was published, FDA has released the final device human factors guidance, “Applying Human Factors and Usability Engineering to Medical Devices, Guidance for Industry and Food and Drug Administration Staff” (Feb. 3, 2016) (final HFE guidance). FDA considers the terms human factors engineering and usability engineering to be synonyms; we utilize the acronym HFE here for convenience.

The final HFE guidance provides a detailed framework for consideration and testing of user interface design and potential use error. FDA delayed effectiveness of the final HFE guidance until April 3, 2016, perhaps to provide industry some time to understand whether the numerous language and organization changes made since the 2011 draft guidance was published are just fine-tuning or represent significant changes in agency expectations. With some exceptions, we do not believe the final version represents significant overall change from the draft. Many changes appear to be clarification of terminology and addition of detail. Some changes (including the revision to the title to drop the words “optimize” and “design”) appear to emphasize an agency message that the goal of the guidance is the establishment of safety and effectiveness of devices for their intended users, uses, and use environments, not merely design optimization that may enhance safety and effectiveness. In short, human factors design and validation are critical components of a device’s safety and effectiveness, not merely an added bonus.

As we previously blogged, here, the agency simultaneously issued a complementary draft guidance, “List of Highest Priority Devices for Human Factors Review, Draft Guidance for Industry and Food and Drug Administration Staff” (Feb. 3, 2016) (draft List guidance). The draft List guidance addresses one issue raised by the draft HFE guidance, i.e., when will the agency expect or request HFE data in premarket submissions. In the draft List guidance, FDA provides a list of 16 classified device types and the corresponding product codes for which FDA will expect human factors data to be included in premarket submissions in an “HFE/UE Report”, as outlined in Appendix A of the final HFE guidance. As we discussed in our blog, FDA also sets out certain circumstances under which ODE reviewers will be empowered to ask for such data on a case by case basis for devices not on the list.

Comments and Changes

In the Federal Register announcement for the final HFE guidance, FDA stated that comments on the draft HFE guidance most frequently requested changes to the guidance’s language and structure, and clarification of the following topics: risk mitigation and human factors testing methods; user populations for testing; training of test participants; sample size determination; reporting for premarket submissions; and collecting human factors data as part of a clinical study. Considering the complexity of this topic, the significant impact on industry and the extraordinarily high level of interest, we believe this guidance topic may have been better served by notice and comment rulemaking. FDA conducted a webinar on the guidance on February 19, 2016, which can be found here: http://www.fda.gov/Training/CDRHLearn/. In addition, we believe an agency FAQ document may be beneficial for enhanced understanding of FDA’s thinking and its responses to industry concerns.

One of the changes made was to add definitions of some important terms. One of the new definitions is for the term “critical task,” and that term receives additional focus in the final HFE guidance. A critical task is “[a]user task, which if performed incorrectly, or not performed at all, would or could cause serious harm to the patient or user, where harm is defined to include compromised medical care.” Devices with identified critical tasks would therefore seem to qualify for submission of their HFE data to FDA in premarket submissions. Related changes to the guidance’s section on Preliminary Analyses and Evaluations provide additional detail on methods of identifying critical tasks, and an expanded section specific to critical task assessment methods and findings was added to the final “HFE/UE Report” outline provided in Appendix A.

Another difference from the draft guidance is found in the Conclusion section of the final guidance’s HFE/UE Report outline. The draft Report outline’s Conclusion section requested a statement from the applicant that the product had been found “reasonably” or adequately” safe and effective for the intended users, uses, and use environments, i.e., language akin to the PMA approval standard of “of a reasonable assurance of safety and effectiveness.” However, the final Report outline’s Conclusion section requests a statement that dispenses with the modifiers; a submitter’s HFE/UE Report conclusion now should be that the device “has been found to be safe and effective for the intended users, uses, and use environments.” The recommended conclusion language thus exceeds that of the PMA approval standard. We are curious how FDA will implement review of the HFE/UE Report in the context of a PMA approval, and are particularly interested in how the Report fits into 510(k) review and clearance, where the overall standard is substantial equivalence, and predicates may not have HFE data on file with FDA for comparison. We believe it would be helpful if FDA utilizes an FAQ document or the draft List guidance to clarify how review of HFE/UE Reports will affect premarket programs and processes.

We noted a similar shift in language by FDA in the final guidance’s Scope section. The draft guidance recommended implementing HFE testing where there was a “moderate to high risk” of use error. In the final guidance, FDA states that use errors are not easily anticipated and suggests that potential severity alone, i.e., without giving much, if any, weight to likelihood of occurrence of the harm, should drive HFE design activities and decisions whether a hazard (a “potential source of harm”) must be designed out to eliminate the risk. This is paralleled in the risk mitigation section (now section 7) where the title has changed from “Mitigation and Control of Use –Related Hazards” to “Elimination or Reduction of Use –Related Hazards.”

HFE Validation Testing and Residual Risk Analysis

In addition to critical tasks, another major emphasis in the final guidance is on HFE validation testing (now section 8). FDA encourages seeking review of draft validation testing protocols under the CDRH pre-submission program to ensure the methods used will be acceptable. There is also guidance provided on HFE validation testing for product modifications and/or corrections, and a new Appendix (Appendix C) that provides information on and examples of test results analysis.

The four key factors identified for HFE validation testing design are:

• the test participants represent the intended (actual) users of the device;
• all critical tasks are performed during the test;
• the device user interface represents the final design; and
• the test conditions are sufficiently realistic to represent actual conditions of use.

The recommended sample size remains a minimum of 15 from each distinct user population, and could be higher for certain device types. The final guidance also reiterates that subjects should be U.S. residents and should not be employees of the manufacturer, and training should approximate what would be given to actual users, including that it should be allowed to elapse somewhat before testing.

An area that the final guidance fails to clarify fully are the differences between HFE simulated use testing, HFE actual use testing, and HFE actual use testing that is considered clinical testing requiring an IDE or exemption. With regard to the latter, the final guidance states that when “actual use testing is needed to determine safety and effectiveness of the proposed device and the requirements of § 812 apply,” an IDE or IDE exemption would be needed. This is an unhelpful tautology. We believe examples of actual use HFE studies that do and do not require IDE or IDE Exemption would be helpful. This is particularly important for planning modifications to 510(k) devices, where the need to do a clinical trial to support equivalent safety and effectiveness may trigger a 510(k) submission requirement.

Like the draft, the final guidance states that testing results indicating that use errors that could cause harm persist in the design are not acceptable in submissions, unless there is a strong rationale demonstrating that “further reduction of the errors’ likelihood is not possible or practical” and the benefits of device use outweigh the residual risk of harm. A promise to address the use errors in subsequent versions will not suffice, and may invite further scrutiny of the HFE processes used.

Looking Forward

We recommend that device manufacturers prioritize review of the final HFE guidance and the draft List guidance. With the publication of the final HFE guidance, manufacturers can expect increased FDA scrutiny of HFE design processes during inspections focusing on design controls. FDA will expect to see medical device user interfaces thoroughly considered in product risk assessments, and will look for HFE processes for user interface evaluation, risk mitigation, and validation testing to have been implemented wherever a use error could result in serious harm. With regard to premarket submissions, agency expectations should remain status quo ante until the draft List and accompanying criteria for requests for such data are finalized. Nonetheless, manufacturers should conduct human factors risk assessment and consider the final HFE guidance’s recommendations for devices in development.

This 1-day conference, scheduled for Tuesday, May 3, 2016 in Arlington, Virginia, is for individuals who draft or review documentation relating to the quality of products regulated by FDA. Effective documentation (written communications/company records) is critical to the success of any company, most especially any doing business in a regulated industry. Documents speak for the company and the writer. Documents are subject to misinterpretation by third parties and can subject a firm to unnecessary regulatory action or litigation. Conversely, effective documentation can demonstrate that a company’s quality system and actions are properly functioning to prevent a health risk to consumers from the company’s products. This conference will provide advice on how to create accurate and complete documentation to meet FDA requirements and avoid common pitfalls that can harm the company. Speakers include Stewart Crumpler from Quintiles, and Brian Donato, Jeffrey Shapiro and Roger Thies from Hyman, Phelps & McNamara, P.C. Attendance will be limited to 60 attendees to facilitate interaction with the program faculty.

For more information and to register please visit the conference website and click on the Educational Programs tab. A link to the registration form is available in the course announcement. Payment can be made by check or credit card.

UPDATE:  THIS 1-DAY CONFERENCE HAS BEEN CANCELLED.

By Mark I. Schwartz –

Unlike solid oral dosage form drugs that don’t require sterilization, generally, parenteral drug products must be sterilized and, due to their nature, many parenteral drug products cannot be terminally sterilized. This leaves aseptic manufacturing. In the aseptic process, the drug product and the container/closure are first subjected to sterilization methods separately, and then are brought together. Given that, in these circumstances, there is no process to sterilize the drug product in its final container, the final product must be filled and sealed in an exceedingly high quality environment. See FDA, Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice (Sept. 2004), at 2.

As an example of what can go wrong in an aseptic environment, at a recent FDA Team Biologics inspection at a facility in Europe, investigators noted in the 483 a wide variety of what they concluded were microbiological-based manufacturing issues, including: a viral contamination event; mold-like material in the fermentation and purification areas; inadequate CAPAs related to contamination events involving a spore-forming microorganism and one from the species Methylobacterium; as well as a CAPA from a contamination event related to a soil bacteria (Bacillus thurengiensis); cleaning and cleaning validation issues; and inadequate environmental and microbial controls. (The 483 also contained three purportedly significant labeling observations, which we won’t dwell on here, given the subject matter of the posting.)

Theoretically, any one of these events, assuming they actually occurred as suggested by the FDA investigators, could have resulted in product contamination and recall, though it is not even clear that the products manufactured during this timeframe were ever released from the facility.

Given that much can go wrong in an aseptic manufacturing process, and microorganisms are ubiquitous in our environment, many firms find that significant microbiological contamination issues occur at facilities engaged in such manufacturing. Indeed, FDA has stated that the vast majority of drugs recalled due to nonsterility or a lack of sterility assurance in the U.S. have been produced via aseptic processing. Id. at 3.

And certainly much is alleged to have gone wrong at the European site inspected by FDA’s Team Biologics late last year. However, our ability to understand precisely what transpired is hampered by the liberal redactions that FDA made to the 483 before it was cleared for release by the agency. Nevertheless, the following has been alleged: first, the purported inadequate microbial control supposedly consisted of a failure to perform bioburden and endotoxin testing at certain steps in the manufacturing process.

Regarding the corrective and preventative actions that “…were found to be inadequate…”, 21 CFR Part 211 does not even speak of corrective and preventative actions (i.e., CAPAs). So, the investigators’ conclusion that they were inadequate is somewhat of a red herring. Rather, 21 CFR 211.192 requires that “…[a]ny unexplained discrepancy…or failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated. . . . ” So a more appropriate observation by FDA would have been that these investigations had allegedly not been thoroughly investigated.

One of the purportedly inadequate investigations involved a water breach from a cooling system that leaked into the adjacent holding tank due to an improper weld. The cooling liquid was analyzed as part of the investigation and the soil bug, Bacillus thurengiensis, was recovered. Yet, FDA investigators claimed that no CAPAs had been initiated “…to clean, disinfect, sanitize, or sterilize the cooling system.”

Another purportedly inadequate investigation was opened as a result of a contact sample which allegedly grew 96 colony forming units (presumably well exceeding the action level), including a species of Methylobacterium and certain spore forming rods.

The viral contamination event is not well described by FDA in the 483 but, to the extent that it actually occurred, it likely contaminated the cell line, and apparently the firm was allegedly unable to detect where the virus had allegedly entered the manufacturing process. In addition, the FDA investigators criticized the firm because, allegedly, “…[a]dditional samples are not tested from the previous harvests in an effort to verify that virus is not present in low concentrations or non-uniformly throughout the fermenter.”

Next, cleaning and cleaning validation are significant programs at aseptic processing facilities. When either is inadequate the result is likely to provide evidence of microbiological contamination, because dirt and residue can be vehicles for, and oftentimes nutrition for, microbes. In this case, regarding cleaning validation, there was allegedly no procedure or requirement to repeat it or to re-evaluate it, even when circumstances may have warranted. Allegedly, a non-conformance was opened after two valves on a tank holding sterile product were observed to have a residue (believed to be an aggregated protein). Yet, allegedly, no samples were taken of the residue for definitive identification or for microbiological testing.

Regarding the cleaning operations, FDA concluded that equipment which had been previously cleaned, and verified as cleaned by an operator, was observed to allegedly contain a dried white residue. There was also allegedly inadequate cleaning of the fermentation and purification areas of the facility, where investigators noted “…[t]he trench next to the steam condenser in fermentation contained growth-like blobbed material as well as black mold-like material. One leg for the tank was observed to have black mold-like material on it.”

Finally, there were several alleged instances where equipment appeared to be wet and where the residual moisture was not evaluated for microbial contamination. Specifically, a tank was “…observed to contain a significant amount of residual liquid which covered more than 80% of the bottom of the vessel…” and in another situation, “…residual water was observed inside piping for tanks…and rouge was observed…[yet]…[t]here were no swabs taken inside the tanks or piping for microbiological testing. There was no bioburden or bacterial endotoxin testing of the remaining liquid. . . .”

Industry practice dictates, and FDA strongly recommends, that sterile drugs be manufactured using aseptic processing only when terminal sterilization is not feasible. Id. In other words, aseptic manufacturing is fraught with problems that are absent when manufacturing products that can be terminally sterilized. These inspectional observations would purport to buttress this proposition. Of course, biological products, like the drugs manufactured at this facility in Europe, cannot be terminally sterilized.

We’ll have to wait and see whether CBER determines that the observations in this 483 meet the threshold of regulatory significance to warrant a Warning Letter. Rest assured, you will be kept posted on all developments.  

By Ricardo Carvajal –

The prompt was an invitation to speak at the 21st Annual Tulane Environmental Law and Policy Summit on the pros and cons of genetically engineered food animals, in the wake of FDA’s approval of AquAdvantage salmon as a new animal drug (a topic we’ve addressed here, here, here, here, and here).  The panel featured a lively exploration of the issue from multiple perspectives, yielding perhaps only one point of agreement: the debate will continue, and is one to which any developer of such products had better be attuned.

A more traditional approach to food production was the subject of a panel on urban farming, a movement that has blossomed in a number of cities throughout the U.S. in response to demand for locally produced foods.  For the moment, the scale of production appears too small to face significant hurdles under Federal regulation, particularly requirements scheduled to take effect under FSMA.  That could change as investors start to ply the sector and finance development of larger scale production.  State and local requirements are another matter, especially those that govern zoning, land use, and product liability.  Solutions to those challenges have been found in a number of municipalities, and the movement can be expected to continue to grow in response to locavore demand.

Three detours were well worth any food and drug lawyer’s time.  The first was to the Audubon Butterfly Garden and Insectarium, which features a stunning collection of insects and related critters – many of importance in agricultural production.  When hunger strikes, the Insectarium houses Bug Appétit, a forward-looking snack bar that features culinary creations made from a variety of insects, and is in tune with the developing market for commercially produced insect-derived foods. 

The second detour was to the New Orleans Pharmacy Museum, which is devoted to the early history of pharmacology.  The site belonged to Louis Dufilho, reportedly America's first licensed pharmacist, and includes exhibits on a wide range of products and practices common in 19^th century – some of which helped to set the stage for passage and enactment of the 1906 Pure Food and Drug Law.

Finally, there’s the music – food and medicine for the soul?  One of its finest purveyors is Johnny Vidacovich, a New Orleans institution who maintains a performing schedule that would make many-a-youngster wilt – and who provided a fine cap to a very worthwhile 48 hours.

By Ricardo Carvajal & Jay W. Cormier –

In response to a Congressional directive buried in the 2016 Consolidated Appropriations Act (“the Appropriations Act”), FDA issued an Import Alert targeting “[a]ny shipment of suspected or known GE salmon or product composed in whole or in part of GE salmon” for further evaluation.  The Appropriations Act, at section 761, purports to prohibit FDA from admitting such products during fiscal year 2016 “until FDA publishes final labeling guidelines for informing consumers of such content,” and further directs FDA to “develop labeling guidelines and implement a program to disclose to consumers whether salmon offered for sale to consumers is a genetically engineered variety.”

Ominous as it may sound for a would-be importer of GE salmon, the immediate impact of FDA’s Import Alert is negligible.  As well known to all the participants in this long-running drama, AquaBounty Technologies, Inc. – the unstated target of the Congressional directive and the Import Alert – won’t have any GE salmon ready for market during fiscal year 2016. 

As to the Congressional directive to publish “final labeling guidelines,” FDA previously issued draft guidance providing for voluntary labeling of GE salmon, consistent with the agency’s conclusion that there is no material difference between food derived from AquAdvantage salmon and its conventional counterpart (see our prior posting here).  To the extent that Congress is directing FDA to require such labeling, FDA could do so only by changing its conclusion regarding materiality, or changing its longstanding interpretation of that concept as embedded in § 201(n) of the FDC Act.  The first course of action would appear to lack a scientific basis, and the second would have significant implications that go beyond food labeling and extend to labeling of other FDA-regulated product categories, including drugs and medical devices. 

Given the wording of the Appropriations Act, it appears that FDA could finalize the draft GE salmon labeling guidance in its current form.  The Appropriations Act does not explicitly direct that labeling be mandatory, nor does it provide a statutory basis for FDA to impose such a requirement.  Congress knows how to write legislation to that effect; to wit, Congress has attempted and failed no less than eight times since 2010 to pass such legislation (here, here, here, here, here, here, here, and here).

In summary, this is but one more play in a playbook evidently intended to derail the domestic marketing of GE salmon by any means – even means that are highly implausible.  The signal sent to a company that is considering developing a food derived from a GE animal can hardly be encouraging.  Simply put, meeting the rigorous scientific and regulatory criteria established by FDA might not be the most significant or unpredictable barrier to success.   

By Kurt R. Karst –      

Whether notice of commercial marketing given before FDA approval can be effective and whether, in any event, treating [Public Health Service Act (“PHS Act”) § 351(l)(8)(A) (42 U.S.C. § 262(l)(8)(A))] as a standalone requirement and creating an injunctive remedy that delays all biosimilars by 180 days after approval is improper.

Those are the questions presented by Sandoz Inc. (“Sandoz’s”) in a Petition for Writ of Certiorari submitted to the U.S. Supreme Court earlier this week on the last possible day permitted for such a petition.  The highly anticipated petition is the first time – but certainly won’t be the last time – the Supreme Court has been asked to take up an issue raised by the text of the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).  The Sandoz Petition appeals one aspect of a highly fractured July 21, 2015 opinion handed down by the U.S. Court of Appeals for the Federal Circuit in a dispute between Amgen Inc. (“Amgen’s”) and Sandoz over Sandoz’s ZARXIO (filgrastim-sndz), a biosimilar version of Amgen’s NEUPOGEN (filgrastim) (see our previous post here).  FDA licensed ZARXIO on March 6, 2015 under BLA 125553. 

The provision at issue – PHS Act § 351(l)(8)(A) – states that a biosimilar (or subsection (k) “applicant shall provide notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the biological product licensed under subsection (k).”  A 2-1 panel majority of the Federal Circuit ruled that licensure of a biosimilar application is required before an “operative notice” of commercial marketing can be given.  Specifically, in overturning a lower court decision on this issue, the Federal Circuit stated:

We believe that Congress intended the notice to follow licensure, at which time the product, its therapeutic uses, and its manufacturing processes are fixed. When a subsection (k) applicant files its aBLA, it likely does not know for certain when, or if, it will obtain FDA licensure.  The FDA could request changes to the product during the review process, or it could approve some but not all sought-for uses.  Giving notice after FDA licensure, once the scope of the approved license is known and the marketing of the proposed biosimilar product is imminent, allows the RPS to effectively determine whether, and on which patents, to seek a preliminary injunction from the court. . . .  We therefore conclude that, under paragraph (l)(8)(A), a subsection (k) applicant may only give effective notice of commercial marketing after the FDA has licensed its product.

In a dissenting opinion, Judge Chen found the 180-day notice of commercial marketing provision to be optional, just like the BPCIA’s so-called “patent dance” provisions (which were also ruled on in the Federal Circuit’s opinion). 

The importance of final resolution of the meaning of the BPCIA’s 180-day notice of commercial marketing provision – either in the context of Sandoz’s Petition, if it is granted, or in another case that could ultimately reach the Supreme Court (there are at least three similar lawsuits pending around the country, including this one) – cannot be understated.  The Federal Circuit's ruling on the notice of commercial marketing provision, if it is upheld, could have everlasting effect on the biosimilars industry (more so that the Court's ruling on the optional nature of the statute’s patent dance provisions).  And reference product sponsors may find (and argue for) new ways to apply it, perhaps in the context of supplemental applications submitted to FDA seeking changes to a licensed Section 351(k) biosimilar product.  Such supplemental applications may seek changes to the manufacturing process of a biosimilar product, or to add into labeling an indication previously omitted because of unexpired patent or non-patent exclusivity (e.g., orphan drug exclusivity) protections on the reference product.  Why not argue for a 180-day notice in those situations as well?

Sandoz rolls through many of these concerns in the company’s Petition, so we’ll just let the company do the talking here:

In a fragmented decision, the Federal Circuit has disrupted the careful balance struck by Congress between competition and innovation.  If not reversed, the Federal Circuit’s ruling will delay access by patients to all biosimilars for six months longer than Congress intended.  The Federal Circuit reached that result by adding an extra-textual limitation to the BPCIA’s “Notice of commercial marketing” provision.  That provision calls for “notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the biological product licensed under subsection (k),” i.e., the abbreviated biosimilar pathway. 42 U.S.C. § 262(l)(8)(A) (emphasis added).  The Federal Circuit held that an applicant “may only give effective notice of commercial marketing after the FDA has licensed its product.”  App., infra, 20a (emphasis added).

A majority of the Federal Circuit panel then enforced that erroneous reading by divorcing that provision from the BPCIA’s patent resolution regime and replacing the remedies expressly provided in the BPCIA with a new remedy: “a 180-day injunction beyond the express twelve-year statutory exclusivity period.”  App., infra, 43a-44a (Chen, J., dissenting).  As Judge Chen recognized in dissent, the majority effectively awarded sponsors “an extra-statutory exclusivity windfall” of 180 days more than Congress expressly granted.  App., infra, 44a (Chen, J., dissenting).  The Federal Circuit’s decision cannot be squared with the BPCIA’s text and purpose, and it conflicts with this Court’s precedents. As the district court observed, if Congress had wanted to add six months to the statutory exclusivity period, “it could not have chosen a more convoluted method of doing so.”  App., infra, 76a.

By its plain terms, the notice of commercial marketing provision simply calls for 180 days’ notice before a biosimilar is marketed. Regardless of whether notice is given before or after FDA approval of the biosimilar, the notice would serve the statute’s purpose of giving the reference product sponsor at least 180 days to initiate suit.  But special notice after FDA approval would be superfluous, as FDA licensure is a public act.  The Federal Circuit reached its erroneous conclusion by reading too much into the word “licensed” in subsection (l)(8)(A).  That adjective merely refers to the biosimilar product that will be marketed, which will be licensed by the time of marketing.  Nothing in the text provides that an applicant must wait until the FDA publicly approves its biosimilar, then provide “notice” of its self-evident intent to market that approved biosimilar, and then wait six months more before marketing its product.

The Federal Circuit compounded this error by disconnecting Section 262(l)(8)(A) from the BPCIA’s patent resolution regime and by creating a new remedy nowhere provided by the BPCIA: an injunction against commercial marketing until 180 days after post-approval notice is given. If Congress had so intended, it knew how to stay FDA approval for 180 days; it also knew how to authorize injunctions to enforce the notice provision.  It did neither.  Instead, it provided sponsors with a powerful remedy: a patent suit for artificial infringement that could be brought even before FDA approval.  42 U.S.C. § 262(l)(9)(B), (C); 35 U.S.C. § 271(e)(2)(C).  Although Amgen brought such a suit, it made no attempt (and still has not) to seek an injunction based on any alleged patent infringement by Sandoz.

Without any such patent showing by Amgen, the plain terms of the BPCIA authorized Sandoz to make its biosimilar filgrastim product Zarxio® immediately available to cancer patients upon FDA approval: (1) Sandoz already had provided Amgen more than 180 days’ notice of its intent to market, giving Amgen time to bring suit (which it did) and seek a patent-based injunction (which it did not), and (2) any statutory exclusivity period had expired, as Amgen already had enjoyed 24 years of exclusivity.  See App., infra, 8a-9a.  Instead, due to the Federal Circuit’s erroneous interpretation of the notice of commercial marketing provision, competition was excluded from the market well beyond the exclusivity period granted by Congress, and cancer patients had to wait many months after FDA approval of Sandoz’s product for access to more affordable medicine.

Sandoz’s petition does not address one aspect of Judge Lourie’s opinion that has long intrigued us: his suggestion that an additional 180 days of marketing exclusivity is not necessarily a consequence of the Federal Circuit decision.  In that opinion Judge Lourie stated:

Furthermore, requiring FDA licensure before notice of commercial marketing does not necessarily conflict with the twelve-year exclusivity period of § 262(k)(7)(A).  It is true that in this case, as we decide infra, Amgen will have an additional 180 days of market exclusion after Sandoz’s effective notice date; that is because Sandoz only filed its aBLA 23 years after Amgen obtained FDA approval of its Neupogen product.  Amgen had more than an “extra” 180 days, but that is apparently the way the law, business, and the science evolved.  That extra 180 days will not likely be the usual case, as aBLAs will often be filed during the 12-year exclusivity period for other products.

It’s possible that Judge Lourie envisioned that FDA will provide tentatively or conditionally approve biosimilars during the reference product’s exclusivity period and that this tentative or conditional approval would then allow a notice of first commercial marketing to be provided under the statute.  It’s not clear that this is an interpretation of the statute that would withstand judicial review.  And absent FDA following up on Judge Lourie’s suggestion, we may not have an answer to that issue in the near-term.

What are the chances that the Supreme Court will take up the Sandoz Petition?  That’s difficult to say, of course.  And the recent passing of Justice Antonin Scalia adds more unknowns to the mix.

By James E. Valentine –

Last month, the U.S. Government Accountability Office (GAO), the independent, nonpartisan agency that provides auditing, evaluation, and investigative services to Congress, publicly released the findings of a report on FDA’s handling of drug postmarket safety oversight.  As reflected in the title of the report, “FDA Expedites Many Applications, But Data for Postapproval Oversight Need Improvement,” the focus was on the safety of drugs brought to the market more quickly through use of FDA’s expedited programs (breakthrough therapy, accelerated approval, fast track, and priority review).  The GAO report was commissioned by Congresswoman Rosa DeLaura, D-Conn., following the release of another GAO report in October 2015 that implicated the safety oversight of medical devices approved by FDA. 

The report sought to examine the status of postmarket safety oversight of drugs approved using one or more of FDA’s expedited programs, which are programs to facilitate and expedite the development and review of new drugs.  This would have allowed GAO to determine the validity of Congresswoman DeLaura and consumer advocates’ concern that the use of expedited programs increases the risk of unforeseen safety issues once marketed (e.g., because there is less information due to fewer, smaller, or shorter clinical trials).  However, because “FDA lacks reliable, readily accessible data on tracked safety issues and postmarket studies needed to…conduct systematic oversight,” there was not reliable data to allow GAO to test this hypothesis.

In the absence of information on postmarket safety reporting and oversight, the GAO report instead independently examined the use of certain expedited programs. Here are some highlights of GAO’s findings:

Expedited Program Requests: Fast Track and Breakthrough Therapy Designation

• Of the 772 requests for fast track designation FDA received from October 1, 2006, through December 31, 2014, FDA granted about two-thirds (or 525) of them.
• FDA denied one-fourth (or 207) of the request for fast track designation, and the remaining 40 requests were either withdrawn by the sponsor or the drug application was inactivated, terminated, or cancelled before FDA could make a decision on the request.
• Since fiscal year 2011, the number of requests FDA has granted fast track designation has increased, from 54 requested granted in fiscal year 2011, to 89 granted in fiscal year 2014.
• In contrast, FDA denied more than half (or 120) of the 225 requests for breakthrough therapy designation that the agency received since that expedited program was established in July 2012 through the end of December 2014.

Expedited Program Requests: By Product Category

• Of the 525 requests for fast track designation that FDA granted from fiscal year 2007 through the first quarter of fiscal year 2015, the most common product categories to be granted fast track were:
  • Antiviral with 112;
  • Oncology with 81;
  • Neurology with 74;
  • Anti-infectives with 55;
  • Gastroenterology and inborn errors with 46;
  • Hematology with 34; and
  • Cardiovascular disease and renal with 32.
• The most common product categories among the 71 requests for which FDA granted breakthrough therapy designation from July 9, 2012, through December 31, 2014, were:
  • Oncology with 15;
  • Antiviral with 14; and
  • Hematology with 14.

Approvals Using Expedited Programs

• About a quarter of the 1,717 drug applications that FDA approved from October 1, 2006, through December 31, 2014, used at least one expedited program.
• Of 444 approved drug applications that used one or more expedited programs, 344 (77%) used one expedited program, 78 used 2 programs, 20 used 3 programs, and 2 used all four programs.
• Priority review was the most used program, with 408 of the 444 drug applications (92%) receiving priority review.
• FDA review time was an average of 8.6 months for marketing applications for drugs that used at least one expedited program compared with 12.1 months for marketing applications for drugs that did not.
• The most common product category for drug applications approved by FDA from October 1, 2006, through December 31, 2014, that used at least one expedited program was:
  • Oncology with 19% of applications;
  • Antivirals with 17% of applications; and
  • Hematology with 12 % of applications.

GAO Recommendations

While GAO confirmed that expedited programs play a significant role in the development and review of drugs (as demonstrated by the findings described above), GAO made two recommendations to FDA that would facilitate the future assessment of whether these programs pose additional postmarket safety risks to patients once they are on the market:

• Develop comprehensive plans, with goals and time frames, to help ensure that identified problems with the completeness, timeliness, and accuracy of information in its database on tracked safety issues and postmarket studies are corrected, and
• Work with stakeholders within FDA to identify additional improvements that could be made to FDA’s current database or future information technology investments to capture information in a form that can be easily and systematically used by staff for oversight purposes.

While, in FDA’s comments to the GAO recommendations, the Agency concurred with these recommendations, FDA clarified that FDA-approved drugs that used an expedited program do not necessarily require different postmarket safety monitoring than other drugs, noting that tracked safety issues and postmarket studies are utilized to monitor all drugs after they are approved by FDA. Therefore, it is unclear, even once it has implemented these recommendations, whether FDA will increase scrutiny of postmarket safety risks for those drugs approved using an expedited program.

In collaboration with KPMG’s government pricing leaders, Hyman, Phelps & McNamara, P.C. (“HP&M”) will conduct a free webinar on the recently published Medicaid Rebate Final Rule (see our previous post here).  The webinar, titled “A Practical Guide the Medicaid Rebate Final Rule,” will be held on Friday, February 19 from 1:00 to 3:00 pm EST.  For information about the webinar and how to register for it, click here.  Speakers are HP&M’s Michelle Butler and Alan Kirschenbaum, and KPMG’s Jennifer Lospinoso and Timothy Nugent.

By Kurt R. Karst –      

Question: When was the first time FDA approved an ANDA containing a Paragraph IV certification to a patent listed in the Orange Book for DIPRIVAN (propofol) Injection, 10 mg/mL, approved under NDA 019627, and granted a period of 180-day exclusivity?

Buehler, Buehler?

If your guess is when Gary Buehler, R.Ph., was Director of FDA’s Office of Generic Drugs (“OGD”), you’re wrong. It was actually before Mr. Buehler was appointed Director of OGD in July 2001 (and perhaps while he was serving as OGD‘s Deputy Director in 1999).  When FDA first (and, to our knowledge, the last time, until recently) approved and ANDA for generic DIPRIVAN and granted a period of 180-day exclusivity, Roger L. Williams, M.D., then-Deputy Center Director for Pharmaceutical Science in CDER at FDA, signed the letter approving GensiaSicor ANDA 075102 (approved on January 4, 1999).  That exclusivity seems to have been triggered by commercial marketing, and expired on October 17, 1999.  That was a long time ago.  Bill Clinton was still President. 

Why all the history about the world of ANDA 180-day exclusivity as it existed prior to the December 2003 enactment of the Medicare Modernzation Act (“MMA”), when exclusivity was patent-by-patent and was triggered by the earlier of first commercial marketing or a final court decision of patent invalidity or non-infringement? After all, we now live in a post-MMA Hatch-Waxman world – and we have for some time now – where 180-day exclusivity is largely product-based, and where exclusivity, if eligibility for it is not forfeited, is triggered only through commercial marketing of the drug product. 

That’s all true . . . mostly.

As we noted in our “Bad Penny” post back in February 2014, pre-MMA 180-day exclusivity was not deleted from the law in 2003. Rather, it was put into hibernation for a set number of drugs (a list of which we provide in our previous post).  These days, pre-MMA 180-day exclusivity only comes out of hibernation every once in a while.  One day, it will make an appearance about as frequently as Brood X cicadas, a type of 17- year cicada.  And after that, it will be see about as often as a critically endangered animal.  Finally, pre-MMA 180-day exclusivity may one day become a mythological Hatch-Waxman creature, along the likes of Bigfoot or the Loch Ness Monster.

But we’re not quite there yet . . . .

Last week, after the January 2016 Orange Book Cumulative Supplement was published on FDA’s Orange Book website, we took a look at some of the new entries in the “Patent and Exclusivity Drug Product List.” One addition in particular stuck out like a sore thumb: a period of “PC” exclusivity (i.e., “Patent Challenge,” or 180-day exclusivity) for ANDA 205307 for Propofol Injection, 10 mg/mL, expiring on February 24, 2016. That period of 180-day exclusivity was not triggered by commercial marketing (ANDA 205307 was not even approved until December 22, 2015), but rather by an earlier final court decision with a holding on the merits on the exclusivity-bearing patent: U.S. Patent No. 8,476,010 (“the ‘010 patent”). That’s right!  We have a sighting of a relatively rare pre-MMA period of 180-day exclusivity.  And with a gap of about 17 years since the first period of 180-day exclusivity was granted for generic DIPRIVAN, it’s at least noteworthy. 

The exclusivity was triggered after Dr. Reddy’s Laboratories, Inc., a subsequent Paragraph IV filer to the ‘010 patent (ANDA 205067), filed a Complaint for Declaratory Judgment (after some previous patent infringement court proceeding) and obtained a Final Judgment on August 28, 2015 that the company’s proposed Propofol Injection drug product does not infringe the ‘010 patent. Add 180 days to that August 28, 2015 date and you come up with February 24, 2016.  That’s the date listed in the January 2016 Orange Book Cumulative Supplement for the expiration of 180-day exclusivity associated with ANDA 205307 (and the ‘010 patent).

So keep your eyes peeled folks. Pre-MMA exclusivity is still – or could be –lurking out there in the shadows of a number of old drug products.  When it does come up in the form of a newly listed patent, you have to be quick on the draw to get your certification in to FDA first.