By Robert W. Pollock* & Kurt R. Karst –      

If there’s something strange in your neighborhood; Who you gonna call? If there’s something weird, and it don't look good; Who you gonna call? Unfortunately, FDA doesn’t have a Ghostbusters-type unit to call when there’s something strange or weird compliance-wise going on in your neighborhood that’s holding up final ANDA (or 505(b)(2) NDA) approval. (Oh, and you’re welcome for the earworm!)

The GDUFA program has spurred an increase in the number of inspections for generic drug applicants and the establishments identified in those applications. With the increasing number of inspections, comes an increase in Establishment Inspection Reports (“EIRs”) that need to be written by FDA investigators, cleared by their supervisors, and then reviewed and cleared by the Center for Drug Evaluation and Research’s Office of Compliance. As was noted in a recent post on the Lachman Consultants Blog, there appears to be a growing problem in getting timely resolution of compliance-related issues from the time the EIR leaves the field and up until FDA’s computer systems are updated to provide an acceptable finding.

Our firms (Hyman, Phelps & McNamara, P.C. and Lachman Consultant Services, Inc.) have been hearing a rising chorus of complaints about being stuck in what one applicant called the “Compliance Black Hole.” Another company referred to it as the “Endless Summer,” because that company has been trying to figure out when their compliance status will change in the FDA computers after having received no 483 observations on reinspection since March of this year.

Firms note that calls to FDA Regulatory Project Managers (“RMPs”) or Regulatory Business Project Managers yield the same response: “There is nothing we can do until the computer system is updated.” Many of these responses come after the issuance of a Complete Response Letter (“CRL”) stating that the only outstanding issue is resolution of the status of a facility’s compliance. So the firm is stuck in a waiting mode.   Simply calling the Office of Compliance has yielded basically the same result. Clients are telling us that they do not receive return calls (or that they are simply told to sit tight and wait).

Trying to find a sympathetic ear at FDA is also difficult, particularly when a firm is ready to launch but for the final compliance clearance and approval action. In addition, we have heard from firms with potential date-certain launch dates (either day-181 dates or settlement dates) that they were informed by FDA officials that the compliance status of their application remains unresolved in the Agency’s computer system, notwithstanding the fact that the sponsor was informed by an FDA field investigator that there were either no 483 observations following inspection, that a completed EIR was forwarded to CDER finding satisfactory the firm’s responses to inspectional observations, or that an approval recommendation had gone forward. While we recognize we don’t always have the full picture when we hear these types of observations from sponsors, the frequency of occurrence of such complaints is increasing in dramatic fashion. Last week alone, Lachman Consultants received four inquiries about such issues. Each company expressed exasperation in not being able to get an answer other than “You just have to wait!”, and asked the same question: “Who can I call at FDA to discuss the issues?”

There’s no easy answer to that question. Depending on your level of exasperation, you might start at the top of the FDA Office of Compliance food chain, or perhaps at the Office of Process and Facilities, which is in the Office of Pharmaceutical Quality. (Here’s the CDER List of Key Officials in case you need it.)  It’s unclear how many applications are being delayed because they are stuck in the “Compliance Black Hole” . . . probably dozens, and perhaps several score. But, as noted above, a simple call to FDA is unlikely to do the trick in removing a compliance status block on approval. Instead, a sponsor might consider escalating the issue by requesting a meeting with the relevant FDA officials. After all, he who screams the loudest might be more likely to get FDA’s attention.      

* Mr. Pollock is Senior Advisor, Outside Director to the Board, Lachman Consultant Services, Inc., and is an author of the Lachman Consultants Blog.

For almost 40 years FDA has allowed device firms to promote their device while a 510(k) submission is still pending.  Yet, questions about how to apply this policy still remain.  In an article newly published in MedTech Insight, titled "Promoting Your 510(k)-Pending Device: 5 Questions About FDA's Policy," Hyman, Phelps & McNamara, P.C.'s Jeffrey K. Shapiro answers some of the most frequently asked questions.   

By Riëtte van Laack –

A couple of weeks ago, the Food Safety Inspection Service of the USDA (FSIS) announced the availability of an updated compliance guideline regarding animal-raising claims. The previous guideline dated from 2002.

Traditionally, the FSIS has interpreted the Federal Meat Inspection Act (“FMIA”) and Poultry Products Inspection Act (“PPIA”) to require that labels for federally inspected meat and poultry products be approved before the meat and poultry products are marketed, except when the label is generically approved. Labels with animal-raising claims are not eligible for generic label review and must be submitted to FSIS. Examples of claims include: “Raised Without Antibiotics,” “Organic,” “Grass-Fed,” “Free-Range,” “Raised without the use of hormones.” FSIS allows such claims only if the company submits documentation to support the claim(s). Moreover, FSIS determines whether a claim will be false or misleading. For example, since under U.S. law, chickens may not be treated with hormones, FSIS will not approve a claim “no hormones administered” unless the claim includes the statement: “Federal regulations prohibit the use of hormones in poultry.”

Depending on the claim, the documentation needed to support the animal-raising claim generally includes:

• A detailed written description explaining the controls used for ensuring that the raising claim is valid from birth to harvest or the period of raising being referenced by the claim;
• A signed and dated document describing how the animals are raised (e.g., vegetarian-fed, raised without antibiotics, grass-fed) to support that the specific claim made is truthful and not misleading;
• A written description of the product-tracing and segregation mechanism from time of slaughter or further processing through packaging and wholesale or retail distribution;
• A written description for the identification, control, and segregation of non-conforming animals or products; and
• A current copy of the certificate if the claim is certified by a third party, e.g., organic certification or non-GMO verified project.

The updated guideline provides a number of examples of animal-raising claims and the documentation required for the sample claims. It also addresses what, if any, documentation is required when an establishment wants to “duplicate” animal-raising claims from purchased products/ingredients incorporated into the establishment’s product.

FSIS issued the updated guideline in response to questions it received about animal-raising claims. Much of the information likely already was available in some other format such as on askFSIS, and in policy statements. Although comments may be submitted until December 5, 2016, FSIS advises establishments that wish to use animal-raising claims to use the guideline immediately.

By James E. Valentine –

In what can only be described as a success story, FDA’s Patient-Focused Drug Development (“PFDD”) initiative has opened the doors to hundreds of patients, caregivers, and other patient representatives to share their experiences with their diseases and conditions with FDA. This series of disease-specific meetings has helped set what FDA refers to as the “therapeutic context” for its regulatory decision-making for drugs and biologics.  PFDD gives patients an opportunity to help CDER and CBER review staff better understand the burden and impacts of their condition and their experiences with treatment options.  This amplification of the patient perspective allows for the evaluation and inclusion of information that is not conveyed by reading the medical literature and textbooks.  This input is not limited to the day of the meeting itself, but is memorialized in a “Voice of the Patient” report that is in turn made available to FDA review staff.  This report importantly includes a draft benefit-risk assessment framework, which provides patient input in a format that can be used during drug approval decisions.

Four years into what FDA refers to as its “pilot,” the Agency announced a milestone for the program: it held its 20th PFDD meeting – the number of meetings FDA committed to host under the fifth authorization of the Prescription Drug User Fee Act (“PDUFA V”).  While that was the minimum required number, FDA will hold four more PFDD meetings by the end of FY2017, which is when PDUFA V expires. 

While the PFDD meetings were underway, FDA negotiated a draft commitment letter for PDUFA VI.  As proposed, FDA will not be committing to host any additional PFDD meetings.  This begs the question: what is the future of PFDD?

(This is not a new question; see one of our previous discussions here.)

The Future: Externally-Led PFDD Meetings?

The most obvious answer is that PFDD meetings are not going to stop, but will instead be carried on by patient organizations instead. Because there are many more disease areas than can be covered by the 20+ FDA meetings under PDUFA V, in December 2015 FDA invited patient organizations to host their own PFDD meetings.  This parallel effort involves patient organizations submitting a Letter of Intent (“LOI”) to FDA, after which point they may proceed with planning and hosting an externally-led PFDD meeting. 

While this program is still getting off the ground, early examples have demonstrated that well-planned and executed externally-hosted meetings can be a successful alternative to FDA-hosted meetings:

• On November 16, 2015, the Amyloidosis Research Consortium (ARC) in collaboration with the Amyloidosis Foundation and Amyloidosis Support Groups hosted an “Amyloidosis Patient Forum with FDA.” Although this meeting occurred before FDA formally announced a process for hosting externally-led PFDD meetings, the agenda mirrored that of FDA’s PFDD meetings. As a result of the meeting, on June 7, 2016, ARC submitted a “Voice of the Patient” report to FDA, which follows the same format as the FDA reports (the report can be found here).
• On September 15, 2016, the Myotonic Dystrophy Foundation (MDF) hosted the first official externally-led PFDD meeting, which also had an agenda that followed the format of FDA’s PFDD meeting. MDF has committed to develop a “Voice of the Patient” report to submit to FDA.

Both the amyloidosis and myotonic dystrophy meetings had the key elements that made the FDA meetings so successful: large turnouts by their patient communities; a well-constructed agenda that included a mixture of patient panels, polling questions, and moderated audience discussion; webcast/livestream participation; and, attendance by key FDA officials, including remarks from some. In addition, the externally-drafted “Voice of the Patient” report will serve as an important resource to FDA review staff. 

So do Externally-Led PFDD Meetings Fit Within PDUFA VI?

While PDUFA VI does not explicitly address whether FDA will continue to accept LOIs for externally-led PFDD meetings, there are a number of activities under the “Enhancing the Incorporation of the Patient’s Voice in Drug Development and Decision-Making” commitment that could accommodate the program. Alternatively, the draft commitment letter indicates that FDA may be moving away from the PFDD meeting model:

FDA will develop a series of guidance documents to focus on approaches and methods to bridge from initial patient-focused drug development meetings, like those piloted under PDUFA V, to fit-for-purpose tools to collect meaningful patient and caregiver input for ultimate use in regulatory decision making.

This could include more qualitative methodological approaches, such as surveys of patient communities and other technologies to capture patient experiences (e.g., Patient-Reported Outcome measures).

Could PFDD Meetings Reemerge Under FDASIA Section 1137?

On February 19, 2016, FDA published a report on publicly-submitted stakeholder views on potential “strategies to solicit the views of patients during the medical product development process and consider the perspectives of patients during regulatory discussions,” which the Agency is required to develop and implement under the Food and Drug Administration Safety and Innovation Act (“FDASIA”) Section 1137, “Patient Participation in Medical Product Discussions.”  The report states that several comments recommended the facilitation of more systematic patient engagement by the Office of the Commissioner across FDA Centers responsible for human medical product regulation.  If there is a demand by patient stakeholders for the initiative to continue, one plausible possibility would be for PFDD to transition to the Office of the Commissioner where patients could share their experiences with CDER, CBER, and CDRH. 

If that happens, I guess the initiative would have to be renamed Patient-Focused Medical Product Development or PFMPD. Or just keep it as PFDD…

By Jeffrey K. Shapiro –

In 1976, FDA first began comprehensive regulation of medical devices. Among the new statutory provisions, there was one requiring persons registering with FDA to list all marketed devices.  Each device on the list was to be accompanied by a copy of the label and package insert (see Section 510(j) of the Federal Food, Drug, and Cosmetic Act).

Within two years, FDA had decided that requiring a copy of the label and package insert was not going to be practical or useful. FDA said that it might not need the information when submitted and, unless consistently updated, it might be out of date when needed.  Also, there was no practical way to compile, update or access the information, much less provide routine public access.  Typically, the device listings were submitted on paper and manually transcribed into data storage on reels of magnetic tape and floppy disks.  Therefore, in lieu of requiring compliance with the actual statutory requirement, FDA required device firms to maintain a historical file of labels and labeling available upon FDA’s request.

Fast forward almost 40 years. The Internet is now pervasive and electronic storage is robust and easily searchable.  Taking advantage of the now-established technology, FDA is proposing to give new life to the requirement in Section 510(j).  As it happens, Section 510(j) has remained on the books the entire time even though not enforced for all of these years.

The foregoing history is recounted in the preamble to FDA’s new proposed rule. What are the features of the proposed rule?  Those who are interested will, of course, want to read the entire proposal.  The most important features can be summarized as follows:

• The new rule would be limited to Class II and Class III devices intended for home use. It would not apply to devices intended for use in professional health care facilities, such as hospitals, nursing homes, clinical laboratories, or physician offices.
• The label and package insert would be electronically submitted each time device listing is electronically submitted or updated, which is required at least annually. The information could be in a PDF format, which may some day transition to FDA’s Structured Product Labeling (SPL) format.
• The statutory term “package insert” would be defined by regulation (for the first time ever) to cover the information that is delivered to the lay home user with the device. It would not include information for device installers, servicers, or health care professionals. This limitation arises from the chief aim of the rule, which is to help lay home users find device instructions.
• FDA would archive the information in an easily searchable database. One particular advantage would be keeping information on file for older devices even after a manufacturer discontinues marketing (and may have stopped posting the package insert on its web site).

FDA gives two primary reasons for the limited reach of the new rule. The first is the agency’s belief that Class II and Class III home use devices have a higher risk of misuse due to lost or misplaced labeling and operating instructions.  The second is that FDA would like to gain experience maintaining this type of database before applying it more broadly.  Presumably, the program could be expanded if it proves beneficial.  (One quibble with the proposed definition of package insert is that the definition is appropriate for this rule but would have to be revised if the rule were expanded.  It would be better to define it properly and then limit the type of package insert required under this rule.)

The preamble to the proposed rule supplies little hard data to back up the supposed benefits. It does indicate that in-home device cause a significant number of serious adverse events (based on 2014 data) and also FDA has received reports of lost labeling for high risk in-home devices.  But the preamble does not provide data to establish that lost or missing instructions actually cause or contribute to a significant percentage of serious adverse events.

Even so, the proposed rule still seems generally like a good idea. FDA’s core function is regulating labeling and so the notion that device manufacturers would submit current labeling to FDA makes sense.  Indeed, it was part of the original statutory design in 1976 for all manufacturers to do so, even though FDA found it impractical for many decades.  In 1976, moreover, Congress probably was more concerned about giving FDA access for regulatory purposes.  Nonetheless, perhaps the best part of the proposed rule is enabling FDA to provide the public with reliable access to current labeling.  Intuitively, the availability of easy-to-find instructions for use is likely to contribute to safe and effective device usage, even if supporting data for this proposition are currently scarce.

FDA also proposes over time to add links to relevant information for affected devices, such as recalls and manufacturer notifications. It is easy to imagine that FDA might eventually be able to build out a very robust public database with full device life cycle information, one that is easily accessible to the agency and device users, whether in the home or in professional healthcare facilities.  The painful UDI adoption process now underway may help make this database even more granular.  If that is the future, and one hopes that it is, then this proposed rule is a useful step in that direction.

By Karla L. Palmer –

In a move unprecedented in recent memory, on October 13, 2016, DEA published a Withdrawal of Notice of Intent to Temporarily Place Mitragynine and 7- Hydroxymitragynine (i.e., kratom) in schedule I of the Controlled Substances Act.

As background, a little over a month ago, on August 31, 2016, DEA’s Administrator issued a notice of intent to temporarily schedule in schedule I of the Controlled Substances Act (CSA) the opioids mitragynine and 7-hydroxymitragynine. These opioids are the main active constituents of the plant kratom.  DEA took this action based on the Administrator’s finding that placement of these opioids into CSA’s schedule I was “necessary to avoid an imminent hazard to the public safety.”  Thus, any final order would impose administrative, civil, and criminal sanctions and regulatory controls applicable to schedule I controlled substances on the manufacture, distribution, possession, importation, and exportation of, and research and conduct of instructional activities of these substances

As DEA’s August 31st Notice of Intent stated, 21 U.S.C. § 811(h)(4), requires the Administrator to notify the Secretary of HHS of his intention to temporarily place a substance into schedule I of the CSA. The Administrator transmitted notice of his intent to place mitragynine and 7-hydroxymitragynine in schedule I on a temporary basis to the Assistant Secretary on May 6, 2016.  The Assistant Secretary responded on May 18, 2016, advising that, based on FDA’s review, there are “currently no investigational new drug applications or approved new drug applications” for mitragynine and 7-hydroxymitragynine. The Assistant Secretary also stated that HHS did not object to the temporary placement of mitragynine and 7-hydroxymitragynine in schedule I of the CSA.   DEA noted neither substance is currently listed in any CSA schedule, and there were no approved new drug applications or investigational new drug applications for the substances.

Importantly, to temporarily schedule a substance in schedule I, because of its “imminent hazard to the public safety,” the Administrator must consider only three of the eight statutory factors typically required for scheduling a controlled substance under 21 U.S.C. § 811(c): the substance's history and current pattern of abuse; the scope, duration and significance of abuse; and what, if any, risk there is to the public health. 21 U.S.C. §

811(h)(3)

. Consideration of these factors includes actual abuse, diversion from legitimate channels, and clandestine importation, manufacture, or distribution. Id. § 811(h)(3). Temporary scheduling is only permitted for schedule I substances: those that have a high potential for abuse, no currently accepted medical use in treatment in the United States, and a lack of accepted safety for use under medical supervision. Id. § 812(b)(1).  Thus, considering the history and current pattern of abuse, the scope, duration and significance of abuse; and risk to the public health, as addressed in the Notice, DEA published its Notice of Intent concerning the substances, stating that after 30 days it could publish a final rule temporarily scheduling the substances for a period of up to two years.  DEA noted also that, although it believed the Notice was not subject to APA notice and comment requirements, the Administrator would “take into consideration any comments submitted by the Assistant Secretary with regard to the proposed temporary scheduling order.”

Although we are unsure yet whether the Assistant Secretary submitted comments, DEA stated in its October 13th Notice of Withdrawal of Intent that it had “received numerous comments from members of the public challenging the scheduling action and requesting the  Agency consider those comments and accompanying information before taking further action.  A check of the docket (DEA-442) did not reveal that any comments had been publicly posted, although DEA stated in its withdrawal notice it is reviewing comments it received by email and mail, and those comments do not need to be resubmitted.  

A simple Google search of “Kratom,” however, shows a glimpse of the widespread and significant public outcry resulting from DEA’s emergency scheduling attempt. Others reported last week that DEA faced pressure from industry and Capitol Hill, including letters to DEA signed by several members of Congress requesting DEA to permit adequate time for stakeholders to comment or otherwise weigh in on the propriety of DEA’s temporary scheduling decision.  

DEA’s Notice of Intent to Withdraw states the Agency will now receive from FDA its scientific and medical evaluation, and scheduling recommendation for the substances. See 21 U.S.C. § 811(b).  (DEA noted it previously requested FDA’s evaluation (which FDA is required to provide within a reasonable time under § 811)).  Not only do we look forward to reading FDA’s scientific and medical evaluation, and scheduling recommendation, but we also assume the public will file numerous comments addressing both the propriety of DEA’s decision and of kratom use generally.  DEA has established a comment period for docket number DEA-442, which will remain open until December 1, 2016. 

By Serra J. Schlanger & Alan M. Kirschenbaum –

We previously reported (here and here) on two opinions handed down by Judge Rya Zobel of the Federal District Court for the District of Massachusetts construing the discount safe harbor under the Federal health care program antikickback statute (AKS).  In both cases, Judge Zobel held that the buyer’s discount disclosure requirement under the safe harbor cannot be met unless the government requests the disclosure.  In other words, government action is a necessary condition of protection under the safe harbor, despite the fact that the government typically does not request such documentation.  There have been noteworthy developments in both of these cases.

In one of the cases, United States ex rel. Herman v. Coloplast Corp., et al. (Case 1:11-cv-12131-RWZ), the United States filed a Statement of Interest on October 6 that includes a footnote directly refuting Judge Zobel’s interpretation.  In footnote 2, the government states “if the Secretary or a State agency requests disclosure, the buyer must provide the requested information to retain protection under the safe harbor. If, however, the Secretary or a State agency has not requested disclosure, safe harbor protection remains available if all other requirements are met. . . .” (emphasis added).  The DOJ’s view is consistent with that expressed by PhRMA in its amicus brief, and is also consistent with the long standing position of the OIG.  One can only hope that the DOJ and PhRMA will succeed in enlightening the Court on the proper interpretation of the discount safe harbor’s disclosure requirement.

Less helpfully, the DOJ reiterated the position set forth in its previous Statement of Interest in this case that, “if a reduction in price is conditioned on more than a simple purchase, it is not a mere discount” and therefore is not eligible for protection under the discount safe harbor. According to the DOJ, “[n]othing in the AKS or HHS-OIG regulations suggests that a manufacturer and a distributor can hide a personal services contract within a discount, particularly a discount based on volume or market share.” 

We wonder how the DOJ’s interpretation applies to manufacturer formulary rebates that are ubiquitous in both commercial and Medicare Part D plans, under which manufacturer rebates are conditioned not simply on purchases but also on the payor providing certain services – i.e., maintaining a specified formulary status for the drug and enforcing the plan formulary. Under the DOJ’s restrictive view, these rebates presumably would not be eligible for protection under the discount safe harbor.  The DOJ’s interpretation might also exclude many value-based purchasing arrangements that are gaining momentum in the marketplace as cost-saving measures, such as performance-based rebates triggered by specified clinical outcomes, rather than simply purchases.  Indeed, CMS is proposing to initiate value based purchasing models under Medicare Part B.  It is uncertain whether the DOJ’s restrictive interpretation of the discount safe harbor could subject these arrangements to liability under the AKS. 

In the second case before Judge Zobel, United States ex rel. Banigan v. Organon USA, Inc., et al. (Case 1:07-cv-12153-RWZ), defendant Omnicare filed a reply brief on October 7 in further support of its motion for reconsideration or interlocutory appeal.  Omnicare is challenging Judge Zobel’s interpretation of the disclosure requirement of the discount safe harbor, discussed above.  Omnicare’s brief correctly notes that the ability of manufacturers and their customers to enter into discounts and rebate arrangements depends on the availability of the discount safe harbor.  Citing to our September 14 blog post, Omnicare adds that “the Court’s interpretation of the [discount safe harbor’s] second prong ‘eviscerates the safe harbor, rendering it virtually useless’ to charge-based providers.”  We will continue to closely follow the Organon and Coloplast cases in this blog.

By Riëtte van Laack –

The Sunscreen Innovation Act (SIA) was enacted in 2014. It amended the FDC Act to provide specific deadlines for FDA’s review of time and extent applications (TEAs ) for sunscreen active ingredients.  Thus far, FDA has proposed sunscreen orders for all eight pending requests, all of which tentatively determined that the active ingredients are not GRASE and that more data are necessary to allow FDA to determine otherwise.

Pursuant to mandate of the SIA, about 11 months ago, FDA issued four draft guidances related to sunscreen time and extent applications (see our previous post here). On Friday, October 7, 2016, FDA issued the final versions of two of the four guidances, the guidance on withdrawal of sunscreen TEAs, and the guidance on requesting advisory committee review.

The final guidance on withdrawal of a sunscreen TEA is virtually identical to the draft guidance. Only two comments were submitted.  Both commenters asserted that FDA has no authority to publish a non-GRASE decision when the sponsor withdraws the TEA after a proposed sunscreen order has been published.  FDA disagreed and maintains its position that because the information was submitted as part of a public process, the information remains part of the public record.   In April, 2016, FDA issued a proposal regarding withdrawal of TEAs, consistent with this position.  Since FDA has issued proposed orders for all eight pending requests, unless the sponsors submit supplemental data supporting GRASE status, sponsors cannot prevent FDA from publishing non-GRASE decisions for all eight ingredients.  

The final guidance on requesting advisory committee review also contains no surprises and is largely identical to the draft guidance. Again, only two comments were submitted.  The final guidance provides additional detail regarding the timing of the request for a meeting.  FDA recommends that the sponsors request the meeting “at the time they submit their initial data package, or no later than at the time of the filing determination” and for sponsors of pending requests are recommended to submit their request at the time they submit their supplemental data package. 

By James E. Valentine & David C. Clissold –

Nearly two years after releasing its Notice of Proposed Rulemaking (“NPRM”), and with about 900 comments from the public to consider, the National Institutes of Health (“NIH”) has published its Final Rule on clinical trials registration and results reporting.  These regulations provide specificity and expand upon the self-implementing requirements that have been in effect since the Food and Drug Administration Amendments Act (FDAAA) was passed in 2007.  The Final Rule largely maintains the proposed rule’s requirements for submitting registration and summary results information, including adverse event information, for specified clinical trials for drugs, biological, and device products to ClinicalTrials.gov (for a detailed overview of these requirements, see our previous coverage here). 

However, FDAAA Section 801 delegated decision-making on several key issues to NIH’s rulemaking, including expansion of results reporting for unapproved drugs and the submission of summary narratives and trial protocols (see our previous discussion of deferred topics here).  While there is much to digest in the 177-page Final Rule, this blog post will highlight how the Final Rule addresses these previously unanswered questions, as well as other key changes from the NPRM.

Submission of Results Information for Products Unapproved, Unlicensed, or Uncleared for Any Use

FDAAA Section 801 requires the submission and posting of registration information and results information for applicable clinical trials of approved, licensed, or cleared products (“approved products”), as well as the submission of registration information and posting requirements for an applicable clinical trials of unapproved, unlicensed, or uncleared products (“unapproved products”). In addition, the statute deferred to NIH as to whether to require the submission of results information from applicable clinical trials of unapproved products, whether or not approval was sought.  The Final Rule maintains the NPRM’s proposal to require the submission of results information for applicable clinical trials of products unapproved for any use (i.e., any indication), regardless of whether FDA approval is or will be sought or obtained. 

The Final Rule does make a change to the NPRM regarding the applicability of this requirement to applicable clinical trials of unapproved products with a primary completion date before the effective date (January 18, 2017) that are subsequently approved for the use studied in the applicable clinical trial. Under the proposed rule, results reporting was required if the results submission deadline due to FDA approval was after the effective date of the rule.  This proposal was scaled back so that, now, such trials are not subject to the new results reporting requirements.

Submission of Technical and Non-Technical Results Summaries Not Required

FDAAA Section 801 required NIH to determine whether a summary of the clinical trial and its results in a technical or non-technical summary could be included as part of required results reporting on ClinicalTrials.gov “without being misleading or promotional.” In response to public comments expressing concerns regarding the difficulty of trial sponsors to write accurate, non-promotional, and non-misleading summaries,  NIH decided to not require either type of narrative summary of results in the Final Rule.  NIH notes that future rulemaking may be warranted if additional research can determine a way for such summaries to be produced reliably and consistently. 

Submission of Protocols and Statistical Analysis Plans

FDAAA Section 801 instructed NIH to require a full protocol or information on the protocol for the trial to the degree it “may be necessary” to help evaluate the results of the trial. While the NPRM laid out several ways this could be achieved, NIH was compelled by public comments arguing that protocols provide information to better contextualize the reported results information.  For example, protocols provide more detail about methods of participant selection, randomization, masking, and assignment to arms; methods of collecting data; specific information about clinical trial interventions, such as other elements of care provided; and assessment of adverse events.  Thus, the Final Rule requires submission of the full protocol and the statistical analysis plan (“SAP”), if it is a separate document, as part of the results reporting, and both will be posted with the results. 

NIH also recognized some concerns raised in public comments about protecting personally identifiable information about individuals participating in or involved in conducting the clinical trials. To address these, the Final Rule allows the responsible party to redact information about individual clinical trial participants.  In addition, the trial allows redaction of identifying information about individuals involved in conducting the trial, as long as it is not otherwise required to be submitted as part of the clinical trial information.

Potential Legal Consequences of Non-Compliance

While not addressed in the NPRM, the Final Rule includes a new section that addresses the legal consequences of non-compliance. This new section describes potential civil or criminal actions, civil monetary penalties, grant funding actions, and judicial remedies that may be pursued as a result of a responsible party’s failure to comply with the regulations.  In addition, this section describes certain non-compliant activities that will be considered prohibited acts under the Federal Food, Drug, and Cosmetic Act that can result in certain of the various types of enforcement action against the responsible party. 

Although not included in the text of the regulation, the preamble to the Final Rule specifies that, under the statute, NIH will include notices on ClinicalTrials.gov denoting non-compliance. These notices include: failure to submit required information; submission of false or misleading information; penalties imposed, if any; whether the information has been corrected; and, failure to register the primary and secondary outcomes.

Effective Date, Compliance Date, and Applicability Determinations

The Final Rule extends the effective date proposed in the NPRM from 45 calendar days to 120 calendar days from the date the Final Rule was filed for public inspection in the Federal Register, or January 18, 2017. However, the compliance date remains the same in the Final Rule, at 90 calendar days after the effective date, or April 18, 2017. 

To aid in determining the applicability of the requirements set out in the Final Rule, the process for making this determination was clarified. Specifically, the registration requirements that apply to an applicable clinical trial are determined by the date on which the trial is initiated (i.e., the actual start date).  Meanwhile, the results reporting requirements that apply to an applicable clinical trial are determined by the date on which the trial reaches its actual primary completion date.  Lastly, the marketing status of a product will be determined based on its marketing status on the primary completion date. 

NIH-Funded Research

NIH also announced, in conjunction with the Final Rule, a final policy that would extend similar registration and reporting requirements to all clinical trials funded by NIH, regardless of whether they are subject to FDAAA.

By Andrew J. Hull –

There has been an interesting development in the ongoing prosecution of a slew of former officers and employees of the New England Compounding Center (NECC). As you may recall, the NECC was responsible for shipping allegedly contaminated compounded steroid epidural products nationwide, allegedly resulting in widespread sickness and death (see our previous post here).

Last week, the federal district court in Massachusetts (Stearns, J.) dismissed the indictment as it pertained to two former NECC employees, Kathy Chin and Michelle Thomas. The indictment charged them with felony counts of dispensing drugs into interstate commerce without a valid prescription.  Under 21 U.S.C. § 353(b)(1), a drug is deemed misbranded while held for sale if it is dispensed by a pharmacist without a valid prescription.  The felony charge requires an intent to defraud or mislead.

The controversial aspect of indicting Chin and Thomas is that they were not pharmacists dispensing prescriptions in the way most people would understand that description. Rather, they were actually in charge of the final check of prescription drug packages for accuracy as to name, address, and contents. 

The indictment alleged that Chin and Thomas had to know these prescriptions were phony because the patient names were so unlikely, including celebrities, famous athletes, and fictional characters (e.g., “David Letterman,” “Jay Leno,” “Dale Earnhardt,” “Tony Tiger,” “L.L. Bean,” and “Filet O’fish”). The government took the position that their incidental role in checking the packages for the phony prescriptions made them just as guilty of the crime as the pharmacists who dispensed the drugs without a valid prescription.

The court, however, held that the FDC Act did not provide fair notice to the defendants that their activities would constitute “dispensing.” The court noted that the FDC Act does not define the word “dispensing,” and held that the word should be given its meaning in common parlance within the statutory context:

In the world of pharmacology, a pharmacist engages in the act of dispensing when she “fill[s] a medical prescription.” Stedman’s Medical Dictionary (28th ed. 2014).  In other words, a pharmacist dispenses a drug when she acts in her role as a licensed professional authorized to fill (put together) a medical prescription for delivery to a patient.

Order at 8.

Absent the constitutional due process that fair notice provides to defendants informing them that their activities are covered under a criminal statute, the court ruled that the indictment, as it pertained to Chin and Thomas, failed. Specifically, the court held that because the defendants’ conduct was only “incidental” to the activity of dispensing, the FDC Act did not provide them with fair notice that their conduct violated the FDC Act:

Returning to basics, the issue in this case is one of fair notice. Would a reasonable person, even a reasonable pharmacist, understand from the indictment that by matching orders to packages prior to their being shipped, she was criminally liable for participating in the filling of a prescription that she had never approved (or is even alleged to have seen), and as a result was guilty of dispensing (misbranding) the prescribed drug with the intent to defraud?  The answer, as best as I can determine, is that she would not.  Absent allegations of conduct amounting to fair notice of a crime under the [FDC Act], the indictment fails.

Id. at 11-12.

Criminal cases entertaining constitutional due process challenges of fair notice under the FDC Act are rare. See, e.g., Kordel v. United States, 335 U.S. 345, 348-49 (1948); United States v. Zenker, No. 94-50616, 1996 WL 468614 (9th Cir. Aug. 16, 1996).  We could only locate a single case in the long history of the FDC Act that actually dismissed criminal charges under a “fair notice” due process theory. United States v. Geborde, 278 F.3d 926, 932 (9th Cir. 2002) (holding that the FDC Act’s “held for sale” provision did not provide fair notice to a doctor that his conduct of providing friends with homemade (i.e., misbranded) drugs for free was covered under the FDC Act).  

Recent Supreme Court case law has expanded the “fair notice” concept as a check against government regulation and prosecution of people in the regulatory context. See generally FCC v. Fox Television Stations, Inc., 132 S. Ct. 2307 (2012).  We anticipate there may be other challenges to FDA enforcement cases on this ground.

By James E. Valentine & Karla L. Palmer –

On October 6, 2016, the Food and Drug Administration (FDA or the Agency) amended its regulations to update the list of drugs that may not used in compounding under the exceptions set forth in sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act (FDCA).  This list reflects those drugs that have been withdrawn or removed from the market because the drugs or components of such drugs have been found to be unsafe or not effective. See 21 C.F.R. § 216.24.  FDA originally published its withdrawn or removed list back in 1999.  FDA states its primary focus since the 1999 final rule (and the 2014 proposed rule) has been on whether the drug products are unsafe.  FDA notes that it may add to the list to include products that are not effective, or update the list to include additional products that are unsafe.  These updates will continue to occur through notice and comment rulemaking; FDA will also (typically) only add to or modify the list after consultation with the Pharmacy Compounding Advisory Committee (PCAC).  FDA also states it will create and maintain a web page about proposed drugs that it is considering adding to the list.   A single list will apply to both sections 503A and 503B.

Revisions to the Withdrawn or Removed List

Consistent with the July 2, 2014 proposed rule (which we covered here), public comment thereon, and after soliciting input from FDA’s PCAC, the final rule adds the following  24 drugs to the withdrawn or removed list, which is codified at 21 C.F.R. § 216.24:

In addition, the rule creates an exception for ophthalmic solutions of bromfenac. No drugs previously listed were removed from the list. 

Exceptions to the List  

While most drugs on the list may not be compounded in any form, in FDA’s preamble to the rule, the Agency clarifies two exceptions. First, when FDA provides an exclusion for a particular formulation, indication, dosage form, or route of administration for a drug on the list (e.g., ophthalmic solutions of bromfenac), this indicates that there is an approved drug containing the same active ingredients that has not been withdrawn or removed from the market because it has been found to be unsafe or not effective.  As such, that particular formulation, indication, dosage form, or route of administration that is expressly excluded from the list may still be compounded under sections 503A and 503B.  

Second, some drugs are listed only with regard to certain formulations, concentrations, indications, routes of administration, or dosage forms because they have been found to be unsafe or not effective (e.g., oral and parenteral diethylstilbestrol containing 25 mg or more per unit dose).  As such, other formulations, concentrations, indications, routes of administration, and dosage forms not on the list may still be compounded.  

In addition, the preamble notes that just because a drug is on the withdrawn or removed list “does not mean it is banned completely and absolutely from compounding.” If warranted, FDA states that drugs on this list could be made available under an expanded access program under 21 C.F.R. part 312, subpart I. 

By Jennifer M. Thomas –

You might have read in our blog post two weeks ago that Quality Egg, LLC executives Austin (Jack) and Peter DeCoster had petitioned for panel rehearing and rehearing en banc of the Eight Circuit opinion affirming their three-month prison sentences.  Last Friday, the Eighth Circuit denied the DeCosters’ petitions.  Three judges voted to rehear the case en banc, but they were a minority of the ten active judges on the Eighth Circuit.

From the Eighth Circuit’s perspective, the case is over.  However, the DeCosters have the right to seek a writ of certiorari from the Supreme Court, and we expect they will.  We will keep you updated on any further developments in the case.

By Anne K. Walsh & Robert A. Dormer –

As we predicted it might, FDA effectively shut down a drug facility based solely on its conduct during an FDA inspection, without any observed GMP or safety concern related to the company’s products or procedures.  In a September 15, 2016 Warning Letter issued to Nippon Fine Chemical Co., Ltd., FDA cited the provision deeming drugs adulterated based on an owner or operator limiting or refusing inspection, 21 U.S.C. § 351(j), and tersely identified three ways in which the company violated this provision:

1. Barring access to areas – the quality control manager allegedly directed employees to “stand shoulder-to-shoulder” to bar access to portions of the laboratory and equipment.
2. Refusal to provide copies of documents – although the FDA investigator appears to have reviewed complaint records, the firm allegedly refused to provide take-home copies of these records for the investigator.
3. Limiting photography – the quality assurance manager allegedly prevented the investigator from taking photographs of a piece of equipment used to manufacture drugs; it is not clear from the Warning Letter how exactly the manager prevented pictures from being taken.

FDA has used this adulteration provision only a handful of times since it was added to the Federal Food, Drug, and Cosmetic Act (FDC Act) in 2012. In earlier Warning Letters, the refusal was an add-on violation to other GMP violations.  Here, FDA bases the entire Warning Letter solely on the firm’s refusals, without alleging any other issues.  Notably, the company’s refusal to allow photographs is identified as evidence of refusal.  As discussed in earlier posts (here and here), FDA’s authority to take pictures has never been tested by the courts, yet FDA asserts it has this power in its guidance and in Warning Letters as if it that authority is accepted in FDC Act jurisprudence.

Also, because the recipient of the instant Warning Letter is a foreign firm, the company’s refusal during the inspection results in a ban of that company’s products into the United States. As referenced in the Warning Letter, FDA placed the company on Import Alert 99-32 for the same reasons underlying the Warning Letter.  The Import Alert means that FDA can detain, without physical examination, products imported to the United States, and can continue to detain these products until it completes an inspection.  The Import Alert further states that inspection reports from third parties may help FDA prioritize inspection requests, but it is clear FDA will not permit product to enter the United States without conducting its own inspection.  Given the limited availability of foreign investigators, timing for relief of a firm placed on this list is unknown.  

One observation about Import Alert 99-32: although it includes companies from seven different countries (Canada, China, Hong Kong, Hungary, India, Italy, and Japan), the breakdown of countries placed on the list due to import refusals skews heavily to Chinese and Indian firms. We can only speculate as to why these countries have more targets, and note that companies in these highly scrutinized countries should be made aware of this provision and its dire implications.

Lastly, this is not an issue limited to foreign inspections. A domestic firm also received a Warning Letter in 2014 for, among other things, refusing to allow photographs of its medicated feed storage conditions.   That Warning Letter was closed out after eight months, which is lightning speed for any close-out letter.  This timing would be near impossible for a foreign firm, which would require a scheduled reinspection to be prioritized above the queue of other foreign establishment inspections.

By Kurt R. Karst –    

A mere 1 year and 8 months after FDA’s February 6, 2015 publication of a Proposed Rule to implement certain provisions of the December 8, 2003 Medicare Modernization Act (“MMA”), Pub. L. No. 108-173, 117 Stat. 2066, and 12 years and about 10 months after the MMA’s enactment, we finally have new Hatch-Waxman regulations. On October 6, 2016, FDA published in the Federal Register a Final Rule, titled “Abbreviated New Drug Applications and 505(b)(2) Applications,” that will forever alter the Hatch-Waxman landscape, and that will likely fuel controversies and provide fodder for litigation for years to come. The Final Rule is the latest – and most significant – in a series of actions intended by FDA to preserve the balance struck with the September 24, 1984 enactment of the Hatch-Waxman Amendments between benefits from the availability of low-cost and high quality generic drugs and the need to reward those manufacturers who bring innovative (i.e., brand-name) drug products to market.

While the focus of the Final Rule is only about 10 pages of MMA statutory text, the document spans 79 triple-column pages in the Federal Register, including about 22 pages of regulations that will be codified in the Code of Federal Regulations as of December 5, 2016.  Several proposals FDA made in February 2015 (see our previous post here) are retained in the Final Rule, while a few have been dropped (either because of court decisions, or because FDA decided to move in a different direction). Perhaps most significant is FDA’s decision to drop (at least for now) a proposal to defer to a 505(b)(2) or ANDA applicant’s interpretation of the scope of a patent that it does not own (and, in particular, for a method-of-use patent that is identified in the Orange Book with a patent use code and narrative).  Instead, FDA will institute a patent listing dispute mechanism whereby the “NDA holder must provide a narrative description (no more than 250 words) of the NDA holder’s interpretation of the scope of the patent that explains why the existing or amended ‘use code’ describes only the specific approved method of use claimed by the patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product.”

As you can imagine, we’re still poring over the Final Rule. We’ll probably put together a Summary and Analysis. But for now, below are some highlights (courtesy of FDA) of the changes compared to the Proposed Rule (including references to the relevant section in the Final Rule). Also, we’ve put together a 100-page Regulation-by-Regulation Redline of the new regulations compared to FDA’s existing regulations. We hope you find it helpful in navigating the vast waters of FDA’s Final Rule.   

Final Rule Description of Change From Proposed Rule

21 C.F.R. § 314.3

Definitions (§ 314.3(b))

• Revises the definition of 505(b) applications to clarify that it is an NDA for which “at least some of” the investigations relied upon by the applicant for approval were not conducted by or for the applicant and for which the applicant has not obtained a right o f reference or use (see section V.P. 3). 
• Revises the definition of “acknowledgment letter” to delete the reference to 505(b)(F) applications and limit the applicability of this term to ANDAs (see section V.A.1).
• Revises the definition of “commercial marketing” to clarify that it includes the introduction or delivery for introduction into interstate commerce of the reference listed drug by the ANDA applicant (see section V.A.2).
• Revises the definition of “date of approval” to incorporate section 505(x) of the FD&C Act (see section V.A.3).
• Revises the definition of “listed drug” to clarify that a drug product is deemed to be a listed drug on the “date of approval” of the NDA or ANDA (see section V.A.3).
• Revises the definition of “substantially complete application”- to describe an ANDA that on its face is sufficiently complete to permit a substantive review and clarify that “sufficiently complete” means that the ANDA contains all the information required under section 505(j)(2)(A) of the FD&C Act and does not contain a deficiency described in § 314.101(d) and (e) (see section V.A.5).
• Revises the definition of “tentative approval” to include a notification that an NDA or ANDA otherwise meets the requirements for approval under the FD&C Act but cannot be approved because there is a period of exclusivity under section 505E of the FD&C Act (see section V.A.7).

21 C.F.R. § 314.50 

Patent claiming drug substance, drug product or method of use (§ 314.50(f)(1)(i)(C))

• Clarifies that the requirement for a 505(b)(2) applicant to provide an appropriate certification or statement for each patent listed in the Orange Book: for a pharmaceutically equivalent drug product applies to one such pharmaceutically equivalent drug product approved in an NDA before the date of submission of the original 505(b)(2) application and not a resubmission or a supplement (see section V.H).

Method-of-use patent (§ 314.50(i)(l)(iii)(A))

• Clarifies that a 505(b)(2) applicant may submit a statement under section 505(b)(2)(B) of the FD&C Act if the applicant is not seeking approval for an “indication or other condition of use claimed by a method-of-use patent rather than “any” indications or other conditions of use claimed by the method-of-use patent (see section V.C.1).

Untimely filing of patent information (§ 314.50(i)(4))

• Provides that an amendment to the description of the approved method(s) of use claimed by the patent will not be considered timely filing of patent information if the amendment is submitted within 30 days of a decision by the USPTO or a Federal court that is specific to the patent and alters the construction of a method-of-use claim(s) of the patent, and the amendment contains a copy of the decision (see section V.B.2.b).

21 C.F.R. §  314.52 

Sending the notice of paragraph IV certification (§ 314.52(b))

• Requires that a 505(b)(2) applicant send a notice of a paragraph IV certification on or after the date of filing described in § 314.101(a)(2) or (3), but not later than 20 days after the date of the postmark on the “paragraph IV acknowledgement letter” (see section V. D.1.a).
• Removes the requirement for a 505(b)(2) applicant to submit an amendment at the time it sends notice of a paragraph IV certification and permits submission of a single amendment that contains all required information within 30 days of the date on which the last notice is received (see section V.D.3.b).

Content of a notice of paragraph IV certification (§ 314.32(c))

• Omits the proposed requirement that notice of a paragraph IV certification must contain a statement that the 5O5(b)(2) applicant has received the paragraph IV acknowledgement letter (see section V.D.1.a).

Amendment or supplement to a 505(b)(2) application (§  314.52(d))

• Requires that after the date of filing of a 505(b)(2) application the applicant must send notice of a paragraph IV certification included in an amendment or supplement at the same time that the amendment or supplement is submitted to FDA (see section V.D.1.b).

21 C.F.R. § 314.53 

General requirements and  Reporting Requirements  (§ 314.53(b)(1) and (c)(2))

• Clarifies that if the method(s) of use claimed by the patent does not cover an indication or other approved condition of use in its entirety, the NDA holder’s use code must describe only the specific approved condition of use claimed by the patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use or sale of the drug product (see section V.B.1.c).
• Clarifies that the NDA ho1der submitting information on the method-of-use patent must identify with specificity the section(s) and subsection(s) of the approved labeling that describes the method(s) of use claimed by the patent submitted (see section V.B.1.c).

Other Reporting Requirements (§ 314.53(r)(2))

• Omits the proposed requirement for an NDA holder to include information on whether a patent is a reissued patent of a patent previously submitted for listing (see section V.B.1.e.).
• Maintains the current requirement for an NIDA holder to include information on whether the patent has been submitted previously for the NDA (see section V.B.1.d).
• Adds the requirement for an NDA holder to identify, for a patent that has been submitted previously  for listing, all changes from the previously submitted patent information and specify whether the change is related to the patent or related to an FDA action (see section V.B.2.b).

Supplements (§ 314.53(d)(2))

• Omits the proposal to require an NDA holder to submit a statement with an NDA supplement if the NDA holder is not received to resubmit patent information pursuant to § 314 53(d)(2)(ii)(A) (see section V.B.2.a).

Where to send submissions of Forms FDA 3542a and 3542 (§ 314.53(d)(4)

• Designate the CDER Central Document Room, rather than the OGD Document Room, as the official repository for submission of Form FDA 3542 and clarifies that Form FDA 3542 can be submitted electronically (see section V.B.2.c).

Submission date of patent information (§ 314.53(d)(5))

• Establishes that the submission date of patent information is the earlier of the date on which Form FDA 3542 is date-stamped by the CDER Central Document Room or officially received by FDA in an electronic format submission that complies with § 314.50(1)(5) (see section V.B.2.d).

Requests by persons other than the NDA holder (§ 314.53(f)(1))

• Requires that a person submitting a patent listing dispute for a method-of-use patent include a statement of dispute that is only a narrative description (no more than 250 words) of the person’s interpretation of the scope of the patent (see section V.B.4.a).
• Requires that a person submitting a patent listing dispute directed to a drug substance, drug product, or method-of use patent only include information in the statement of dispute for which the person consents to disclosure because FDA will send the text of the statement to the applicable NDA holder without prior review or redaction.
• Requires that the NDA holder’s response to a patent listing dispute directed to a drug substance, drug product, or method-of-use patent include a signed verification of the accuracy and completeness of the response (see section V.B.4.a).
• Requires that the NDA holder’s response to a patent listing dispute for a method of use patent also include a narrative description (no more than 250 words) of the NDA holder’s interpretation of the scope of the patent that explains why the existing or amended “use code” describes only the specific method of use claimed by the patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product.  Requires that the narrative description only contain information for which the NDA holder consents to disclosure because FDA will send the text of the statement to the person who submitted the patent listing dispute without review or redaction (see section V.B.4.a).
• Provides that FDA will promptly post information on its Web site regarding whether a patent listing dispute has been submitted for a published description of a patented method of use for a drug product and whether the NDA holder has timely responded to the patent listing dispute (see section V.B.4.a).
• Omits the proposal to review a proposed labeling carve-out with deference to the 505(b)(2) and/or ANDA applicant(s)’ interpretation of the scope of the patent in certain circumstances, which is not being finalized at this time (see section V.B.4.a). 

21 C.F.R. § 314.54 

Procedure for submission of a 505(b)(2) application  requiring investigations for approval of a new indication for, or other change from, a listed drug (§  314.54(a)(l))

• Clarifies that the requirement for a 505(b)(2) applicant to identify one pharmaceutically equivalent drug product approved in an NDA as a listed drug (or an additional listed drug) relied upon applies before the date of submission of the original 505(b)(2) application and not a resubmission or a supplement (see section V.H.).

21 C.F.R. § 314.60 

Patent certification requirements (§ 314.60(f))

• Requires that if an amendment the 505(b)(2) application does not contain a patent certification or statement, the applicant must verify that the proposed change described in the amendment is not: (1) A new indication or other condition of use; (2) a new strength. (3) an other-than-minor change in product formulation; or (4) a change to the physical form or crystalline structure of the active ingredient (see section VF.1).

21 C.F.R. § 314.70 

Patent certification requirements (§ 314.70(i))

• Omits proposed § 314 70(i) on patent certification requirements for 505(b)(2) supplements, which is not being finalized at this time (see section V.F.2).

21 C.F.R. § 314.90 

Waivers (§ 314.90)

• No substantive changes from the proposed rule (see section V.L.).

21 C.F.R. § 314.93 

Petition to request a change from a listed drug (§ 314.93)

• No substantive changes from the proposed rule (see section V.I).

21 C.F.R. § 314.94 

Method-of-use patent (§ 314.94(a)(12)(iii)(A))

• Clarifies that an ANDA applicant may submit a statement under section 505(j)(2)(A)(viii) of the FD&C Act if the applicant is not seeking approval for “an” indication or other condition of use claimed by a method-of-use patent rather than “any” indications or other conditions of use claimed by the method-of-use patent (see section V.C.1).

Untimely filing of patent information (§ 314.94(a)(12)(vi))

• Provides that an amendment to the description of the approved method(s) of use claimed by the patent will not be considered untimely filing of patent information if the amendment is submitted within 30 days of a decision by the USPTO or a Federal court that is specific to the patent and alters the construction of a method-of-use claim(s) o f the patent, and the amendment contains a copy of the decision (see section V.B.2.b).
• After request to remove a patent or patent information from the list (§ 314.94(a)(12)(viii)(B)).
• Omits the proposed requirement for a first applicant to lawfully maintain a paragraph IV certification to an original patent that has been reissued, which is not being finalized (see section V.B.1.e and V.E.3).

21 C.F.R. § 314.95 

Sending the notice of paragraph IV certification (§ 314.95(b))

• Deletes the reference to an “acknowledgment letter” in § 314.95(b)(1) and (b)(2) because an ANDA applicant will now receive a “paragraph IV acknowledgment letter” if the ANDA contains a paragraph IV certification  before the ANDA is received (see section V.D.1 a).
• Removes the requirement for an ANDA applicant to submit an amendment at the time it sends notice of a paragraph IV certification and permits submission of a single amendment that contains all required information within 30 days of the date on which the last notice is received (see section V.D.3.b).

21 C.F.R. § 314.96 

Patent certification requirements (§ 314.95(d))

• Clarifies that a paragraph VI certification to a patent or patent claim for which an ANDA applicant previously submitted a paragraph IV certification is a “recertification” rather than an “amendment” of the paragraph IV certification (see section V.F.3).
• Requires that if an amendment to the ANDA does not contain a patent certification or statement, the applicant must verify that the proposed change described in the amendment is not:  (1) a new indication or other condition of use; (2) a new strength; (3) an other-than-minor change in product formulation; or (4) a change to the physical form or crystalline structure of the active ingredient (see section V.F.1).

21 C.F.R. § 314.97 

Patent certification requirements (§ 314.97(c))

• Omits proposed § 314.97(c) on patent certification requirements for ANDA supplements, which is not being finalized at this time (see section V.F.2).

21 C.F.R. § 314.99 

Other responsibilities of an applicant of an ANDA (§ 314.99)

• No substantive changes from the proposed rule (see section V.L.).

21 C.F.R. § 314.101 

Receiving an ANDA (§ 314.101(b))

• Clarifies current Agency practice that following a refuse-to-receive decision, an ANDA applicant may:  Withdraw the ANDA under § 314.99; correct the deficiencies and resubmit the ANDA; or take no action, in which case FDA may consider the ANDA withdrawn after 1 year (see section V.J.2).
• Omits the proposed administrative consequence for ANDA applicants who fail to send notice of paragraph IV certification within the statutory timeframe (see section V.J.3).

NDA or ANDA deficiencies (§  314.101(d))

• Clarifies that FDA will consider the nature (e.g., major or minor) of the deficiencies, including the number of deficiencies in the ANDA in determining whether an ANDA is incomplete on Its face (see section V.J.2).
  Regulatory Deficiencies (§ 314.101(e))
• Clarifies that FDA will refuse to file a 505(bX2) application or refuse to receive an ANDA if submission is not permitted under sections 505(c)(3)(E)(ii), 505(j)(5)(F)(ii), 505A(b)(1)(A)(i)(I), 505A(c)(1)(A)(i)(I), or 505E(a) of the FD&C Act (see section V.A.7).

21 C.F.R. § 314.105 

Approval of an NDA and an ANDA (§  314.105)

• Removes the proposed statement that an NDA is approved on the date of the issuance of the approval letter, and clarifies that a new drug product may not be marketed until the “date of approval,” rather than the “date of the approval letter” (see section V.A.3).
• Clarifies that approval of a 505(b)(2) application or ANDA also may be delayed by a period of  exclusivity for the listed drug under section 505E of the FD&C Act (see section V.A.7)

21 C.F.R. § 314.107 

Disposition of patent litigation (§ 314.107(b)(3))

• Revises § 314.107(b)(3)(v) to more dearly describe the timing of approval o f a 505(b)(2) application or ANDA when a preliminary injunction is entered by a Federal district court before the expiration of a 30-month stay (or 7-1/2 years where applicable) (see section V.M.2.g).
• Clarifies that the 30-month period (or 7-1/2 years where applicable) will be terminated if the court(s) enter(s) an order of dismissal without a finding of infringement in each pending suit for patent infringement brought within 45 days of receipt of the notice of paragraph IV certification sent by the 505(b)(2) or ANDA applicant (see section V.M.2.j).
  Delay due to exclusivity (§ 314.107(d)).
• Clarifies that approval of a 505(b)(2) application or ANDA also may be delayed by a period of exclusivity for the listed drug under section 505E of the FD&C Act (see section V.M.4).

Notification of court actions or written consent to approval (§ 314.107(e))

• Requires submission of a copy of any “written consent to approval” by the patent owner or exclusive patent licensee, rather than any “.documented agreement,” and clarifies that a copy of any order entered by the court terminating the 30-month or 7-1/2.-y ear period includes an order described in § 314.107(b)(3)(vii) and (vii) (see section V.M.5).
• Provides that all information required by § 314 107(e)(1) must be sent to the applicant's NDA or ANDA rather than to OGD or the appropriate division in OND (see section V 3.1.5).

21 C.F.R. § 314.108 

New drug product exclusivity(§ 314.108)

• No substantive changes from the proposed rule.

21 C.F.R. § 314.125 

Refusal to approve an NDA (§ 314.125)

• Clarifies that FDA may refuse to approve a 505(6)(2) application if it does not contain a patent certification or statement pith respect to each listed patent for a drug product approved in an NDA that is pharmaceutically equivalent to the drug product for which the original 505(b)(2) application is submitted and that was approved before the original 505(b)(2) application was submitted (see section V.H).

21 C.F.R. § 314.127 

Refusal to approve an ANDA (§ 314.127)

• No substantive changes from the proposed rule (see section V.L.).

21 C.F.R. § 320.1 

Definitions (§ 320.1)

• No substantive changes from the proposed rule (see section V.A).

21 C.F.R. § 320.23 

Basis for measuring in vivo bioavailability or demonstrating bioequivalence (§ 320.23)

• No substantive changes from the proposed rule (see section V.N).

By Alexander J. Varond –

One day before the program’s sunset, President Obama signed a bill to temporarily reauthorize the rare pediatric disease priority review voucher program for 3 months.  The program has had significant interest from industry, and the program’s extension on September 30 was the product of substantial efforts on the part of stakeholders, including rare disease advocates. 

This is the second short-term reauthorization of the program, which was originally slated to end in March 2016. Unlike the first reauthorization (which we discussed here), the Advancing Hope Act (S. 1878) was a more ambitious undertaking.  As such, it amended the definition of “pediatric rare disease,” likely expanding eligibility for the program.  We discussed the law’s impact on the program’s scope in a post last week.

The law makes several other key changes. First, the Advancing Hope Act now requires Sponsors to notify FDA of the Sponsor’s intent to request a pediatric voucher upon the submission of a rare pediatric disease product application.  This requirement comes into effect 90 days after the enactment of the Advancing Hope Act, which incidentally is just a few days prior to the program’s December 31, 2016 sunset.  Second, Sponsors are now expressly prohibited from receiving more than one priority review voucher per drug.

Reading the law makes it abundantly clear that the September 30, 2016 reauthorization is a stop-gap measure. Congress’s effort to quickly pass the bill and avoid creating a gap in the program, meant making a last-minute amendment to the program’s end date of at least September 2022 to December 31, 2016.  As a result of the last-minute amendment, some parts of the bill are fairly nonsensical.  For example, by 2022, GAO will be required to issue another report on the program, similar to the one it issued in March 2016.  It would be odd if the pediatric voucher program was not reauthorized past 2016 and yet the GAO was required to report on the program in 2022 (more than 5 years after the end of the program).

Members of Congress have expressed a strong desire to address FDA-related legislation (including the 21st Century Cures Act, which we discussed here) during the lame duck session of Congress after the November elections.  Part of this attention will go towards discussing the pediatric voucher program and its long term or permanent reauthorization.

Voucher User Fees for FY2017

FDA also recently released its user fees for redeeming tropical disease and pediatric vouchers.  Effective from October 1, 2016 to September 30, 2017, the Fiscal Year 2017 user fee is $2,706,000.  This is $21,000 less than the fee in FY2016.  We discussed how FDA calculates the user fee here.