Attorney East Hampton

By Sara W. Koblitz —

Over the last few years, FDA has clearly prioritized efficient generic development (see, for example, the Drug Competition Action Plan).  While FDA hosted public meetings, published MAPP revisions, and compiled lists of off-patent/off-exclusivity drugs, Congress reauthorized the Generic Drug User Fee Act in 2017 and included a provision requiring GAO to study issues regarding approval of a generic drug applications in the first review cycle.  Further, as part of GDUFA II, FDA committed make changes in an effort to minimize the number of review cycles necessary for applicants to attain approval.    This month, the GAO released its report commenting on both the first review cycle statistics and FDA’s efforts to minimize review cycles thus far.

The GAO Report looked at generic drug approvals between FY 2015 and 2017 – before implementation of the GDUFA II commitments – as well as documentation from the first review cycle for 35 applications from FY 2017 and 2018.  GAO identified several factors that may impact approval in the first cycle, including the sufficiency of the application, deficiencies in drug quality, the type of drug reviewed, and the application’s priority status.  Ultimately, GAO made two recommendations: FDA should improve consistency in communication between reviewers and sponsors, and FDA should assess the effect of brand-name labeling changes on approval of generic drugs.

Given the timeframe of the approvals reviewed, the Report tells us little about FDA’s success in achieving its GDUFA II commitment with respect to first cycle reviews.  The Report also relies on a small sample size of detailed application review (35) and interviewees (15).  But the Report is nonetheless enlightening.  Notably, of the 2030 generic drug applications reviewed by FDA from FY 2015 through 2017, only 12 percent (or approximately 244) applications were approved in a first review cycle.  That means that 1786 ANDAs went through subsequent review cycles to obtain approval, potentially delaying approval for years.  On average, from 2013 through 2017, it took three review cycles for ANDAs to attain approval.

Some of the GAO’s findings were neither surprising nor attributable to FDA:  some applications, particularly those of unsophisticated sponsors, simply were not sufficient.  Either the application was not complete or the applicants did not fully understand and fulfill application requirements, directly impacting the likelihood of receiving approval during the first review cycle.  Applications that FDA initially Refused to Receive were slightly less likely to be approved in the first review cycle.  All of this makes sense if one assumes that the RTRs and insufficient applications were filed by relatively inexperienced filers.  An inexperienced filer is more likely to get tripped up than a sponsor that has been through the process before.  Additionally, drug complexity factored into likelihood of approval during the review cycle.  Again, this makes sense: route of administration, formulation, combination drugs, complex APIs, and like factors impact the sufficiency and complexity of the data needed for approval.   Drug quality deficiencies, like the drug manufacturing facilities, were also responsible for large share of failure to attain approval during the first review cycle.

Interestingly, the GAO also noted that the type of Priority Review designation a product receives may be correlated with first cycle failures.  According to the GAO analysis, rates of approval in the first cycle were lower for first generics than for applications with no priority designation.  Meanwhile, first-cycle approval rates for other types of priority designations (i.e. drug shortages or public health emergencies) were higher than for applications with no priority designation.  The GAO report hypothesized that rushing to submit applications to get first generic status may result in lower quality applications.

The Report does highlight some of the changes that FDA has adopted since 2013 to enhance communication with applicants and improve reviewer consistency.  FDA has issued 993 new and revised product-specific guidance documents since 2013, in addition to other regulatory guidance to facilitate approval and reduce deficiencies.  378 of the product-specific guidances have been focused on complex drugs.  At the GAO’s suggestion, FDA now publicly announces its plans for issuing new and revised product-specific guidances.  Additionally, FDA now encourages reviewers to communicate with applicants about issues and issue discipline review letters at the mid-point of the review cycle rather than at the end of the cycle to provide applicants with an opportunity to address issues before issuing a Complete Response Letter.  FDA has also taken steps to enhance consistency from FDA reviewers, including review templates and adopting common phrases for communicating deficiencies.

The GAO Report notes that, even with FDA’s enhancements, inconsistency among generic drug application reviewers persists.  These inconsistencies may play a big role in approval during the first review cycle because reviewers may provide substantively different assessments of similar generic applications.  Some reviewers provide suggestions on how to remedy a deficiency while others do not even specify what further information may be required.  This inconsistency could mean the difference between addressing deficiencies in a timely manner during the first review cycle and a Complete Response Letter.  As such, inconsistency in reviewer communication is a major focus of the GAO’s recommendations to FDA.

Further, based on interviews, the Report posits that brand-name drug labeling changes occurring mid-cycle may impact first review cycle approvals.  Because the generic sponsor must change the labeling to match the Reference Listed Drug, such a change midway through the review cycle may require the ANDA sponsor to revise its labeling.  FDA thought that gamesmanship in labeling changes to delay generic competition would be challenging to coordinate but acknowledged that such a scenario was a possibility.  However, because the Office of Generic Drugs does not coordinate on timing of approval of brand-name drug label changes with the Office of New Drugs, the Agency could not speak to this directly.  As such, GAO recommended that FDA assess the extent to which brand-name label changes impact first review cycle approval of generic drugs.

On the whole, the Report was not too critical of FDA considering the statistics.  With a paltry 12 percent of ANDAs approved in the first review cycle, one would think that GAO would have a myriad of recommendations.  But it didn’t, which may indicate that FDA’s changes are helping ANDA review trend in the right direction.  But for now, as FDA further implements these changes to meets its GDUFA II goals, those ANDA sponsors who don’t attain that elusive first review cycle approval must continue to try.  In the words of the late Aaliyah: If at first you don’t succeed (first you don’t succeed), dust yourself off, and try again.

By Serra J. Schlanger —

California

Last week, U.S. District Court Judge Morrison C. England Jr. denied the state of California’s motion to dismiss PhRMA’s lawsuit challenging SB 17, which was signed into law in October 2017 and became effective on January 1, 2018.  (Our summary of SB 17 is available here.)  As we previously reported (see here, here, and here), PhRmA challenged the implementation and enforcement of SB 17 on the grounds that the law’s notice, reporting and justification obligations are unconstitutional.  More specifically, PhRMA has argued that SB 17 violates the First Amendment, the Commerce Clause, and the Fourteenth Amendment’s Due Process Clause.  The state sought to dismiss the lawsuit, but Judge England found that PhRMA’s “non-conclusory” allegations could proceed.

Colorado

As we previously reported (here), Colorado recently enacted HB 19-1131, which requires drug manufacturers to provide prescribers with a drug’s wholesale acquisition cost (WAC) during marketing activities.  Drug manufacturers must also provide prescribers with the names of at least three generic prescription drugs from the same therapeutic class.  Although the state has not yet issued regulations or guidance regarding these “Prescription Drug Cost Education” requirements, the new law took effect on Friday, August 2, as no referendum petition was filed with the Colorado Secretary of State.

We will continue to monitor and report on state price reporting and transparency efforts.

Hyman, Phelps & McNamara, P.C. is pleased to publish this second issue of the FDA Law Alert, a newsletter highlighting key postings from our nationally acclaimed FDA Law Blog.  Please subscribe to the FDA Law Blog to receive contemporaneous posts on government regulatory and enforcement activities affecting the broad cross-section of FDA-regulated industry.   As the largest dedicated FDA law firm, we are happy to help you or your clients navigate the nuances of the laws and regulations affecting the industry.

Cross-Cutting Issues

• Disclosure of Confidential Information
  • A recent Supreme Court decision lowers the standard for the government to withhold from disclosure confidential commercial or financial information it receives from regulated industry.  In their post, Anne Walsh and Ricardo Carvajal describe the impact that the Court decision will have on FDA-regulated entities who routinely submit this type of information to FDA.
• Enforcement Discretion
  • Douglas Farquhar discusses FDA’s power to exercise enforcement discretion.  His post focuses on a recent court decision holding that FDA cannot delay or relax enforcement requirements mandated by the Tobacco Control Act, and must require manufacturers of tobacco and other nicotine products to submit applications to market those products.

Drugs

• Drug Development
  • In this post by Frank Sasinowski and James Valentine, they highlight the approval of the first systemically administered somatic gene replacement therapy. The approval of Avexis’s Zolgensma (onasemnogene abeparvovec-xioi), for treatment of spinal muscular atrophy (SMA), is a milestone for personalized medicine that targets the root causes of genetic diseases using gene replacement.
• Biosimilars
  • FDA finalized its guidance to assist biosimilar manufacturers to demonstrate interchangeability with a reference product.  Sara Koblitz writes about activities since the draft guidance was issued in 2017 and the potential impact the final guidance will have on drug manufacturers seeking to establish interchangeability.

Devices

• PMA Panels
  • Jeff Gibbs and McKenzie Cato take a close look at the relationship between the outcomes of FDA advisory panels to review pre-market applications (PMAs) and the ultimate outcomes and time to resolution of PMAs.  Their post discusses why the relationship may not be clear cut.
• Unique Device Identification (UDI)
  • FDA finalized its guidance for industry on UDI labeling requirements applicable to convenience kits (two or more medical devices packaged together for the convenience of the user).  Rachael Hunt compares the draft guidance with the final version and describes scenarios to illustrate its application.
• Off-Label Promotion and Reporting Violations
  • Anne K. Walsh and Adrienne Lenz describe the woes of a device manufacturer held accountable for civil and criminal violations related to its wound dressing product.  Not only does this case highlight the steep penalties associated with reporting violations — a $3 million criminal fine in this case – but it also shows that off-label promotion remains a targeted area of interest for the government.

Hatch-Waxman

• 180-Day Exclusivity
  • Kurt R. Karst continues his coverage of the BLOCKING Act, legislation that could make 180-day exclusivity eligibility unpredictable for ANDA applicants.  In this latest post, Karst details two alternative versions of the bill that could maintain the 180-day incentive, but would address FDA’s concerns about competition and pricing for drugs.

Healthcare

• Fraud and Abuse
  • In response to objections that the restrictions were too prohibitive, New Jersey amended its rules regarding the acceptance of remuneration by prescribers from pharmaceutical manufacturers.  Alan Kirschenbaum summarizes the significant changes from the original rule in his post.

Foods and Dietary Supplements

• Product Labels
  • Riёtte van Laack writes in her post about FDA’s letter to industry supporting the inclusion of a “Best if Used by” statement on food products, but notes that FDA cannot enforce this requirement on foods.
• DMHA Regulation
  • Hi-Tech Pharmaceuticals, Inc. recently sued FDA to stop enforcement activities around DMHA-containing products, arguing FDA has not undergone formal rulemaking as required by the Administrative Procedure Act.  Ricardo Carvajal and JP Ellison are following this litigation here.

DEA and Cannabis

• Medical Cannabis  
  • John Gilbert and Larry Houck describe proposed legislation that would compel DEA to issue more marijuana manufacturer registrations for research.  Their post walks through federal regulation of studies involving the potential medical utility of marijuana and the current requirements for these manufacturers.

The American Conference Institute’s (“ACI’s”) popular “Paragraph IV Disputes Master Symposium” is coming up again! The conference will take place from October 3-4, 2019 at the W Chicago in City Center, Chicago, IL.

ACI has put together an excellent program for conference attendees that include presentations from esteemed Judges and key representatives from the PTO, and FTC. In addition, attendees will get to hear from a virtual “who’s who” of Hatch-Waxman litigators and industry decision makers.  Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst, will be speaking at a “Regulatory Think Tank” session titled “Analyzing The Effect of the Latest FDA Initiatives on Generic Drug Access and ANDA Litigation.”

FDA Law Blog is a conference media partner. As such, we can offer our readers a 10% discount off the current price tier.  The discount code is: D10-815-815AX01.  You can access the conference brochure and sign up for the event here.

We look forward to seeing you at the conference

By Karla L. Palmer —

In a much-anticipated decision for those that have been following the saga of whether FDA has appropriately set the test for determining how it may include bulk substances on its list of substances that may be used in compounding under Section 503B of the Federal Food, Drug, and Cosmetic Act, the D.C. District Court provided its answer in a decision handed down late last week.  The closely watched matter involves a fierce battle between big pharma and compounders that started in the summer of 2017  and has been documented on this blog here and here.  Recall briefly that, back in 2017, FDA approved Vasostrict®; certain outsourcing facilities had nominated – and FDA approved – the addition of the bulk active pharmaceutical ingredient vasopressin to its interim list of bulk drug substances that may be used in compounding.  After a flurry of litigation activity in the fall of 2017 and early 2018, FDA resolved to revise its process for reviewing nominations to its bulk substances list, which effectively stayed the pending litigation against the Agency brought by Endo Pharmaceuticals, maker of Vasostrict®.  In early 2019, FDA announced its revised process for determining whether to include substances on its bulks list. FDA’s new process, described here, ultimately resulted in FDA’s determination to remove vasopressin from the bulks list, and, unsurprisingly brought about more litigation.

All of this leads us to the United States District Court for the District of Columbia’s recent decision.  Recall that Athenex sued FDA over the Agency’s interpretation of the bulks nomination process and subsequent removal of vasopressin from the bulks list.  See Athenex, et al. v. Alex M. Azar II, et al., Civ. No. 19-cv-00603 (APM) (D.D.C. 2019), here.  In a detailed 31-page memorandum opinion, the District Court ruled in favor of FDA, considering the text, structure and legislative history of Section 503B.  While the ultimate outcome may not be all that surprising given the deference shown to federal agencies under the Supreme Court’s landmark Chevron administrative deference standard, Chevron U.S.A., Inc. v. Natural Resources Defense Council, Inc., 467 U.S. 837 (1984), what is somewhat surprising to those that have been following the matter is that the Court decided the issue based on the first prong of Chevron.  This means that the Court found unambiguous the underlying statutory text, structure, and legislative history of Section 503B;  thus, FDA’s interpretation of the same gave effect to the “unambiguously expressed intent of Congress.” The Court also determined that FDA’s exclusion of vasopressin from the bulks list was not arbitrary and capricious.

The Court reviewed the new test for nominations that FDA first published in March 2018 and finalized a year later.  The new guidance considers, as a threshold matter, whether the bulk substance is a component of an FDA-approved drug produc.  It also considers whether that FDA-approved product has an attribute that makes it medically unsuitable to treat certain patients, which attribute the proposed compounded formulation will address.  FDA then considers whether there is a basis to conclude that the proposed compounded drug product must be produced from a bulk substance rather than an FDA-approved drug.

Reviewing the “plain meaning” of the statute, the Court disagreed with Athenex’s interpretation of “clinical need” for use of a bulk substance.  Athenex argued that the Agency’s framing of “clinical need” improperly replaces “bulk drug substances” as the term appears in Section 503B(a)(2)(A), with the term “compounded drug product,” thus making FDA’s nomination process a review of approved products and not the bulk substances in those products.  Not buying Athenex’s reason, the Court held Athenex’s interpretation would produce an unreasonable result –– as there is a “clinical need” for every bulk substance because, by definition, a bulk drug substance is one “intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease….”  Mem. Op.  at 14.  The Court noted that Athenex’s interpretation draws “no actual distinction among bulks substances- there is a ‘clinical need’ for all.”  Id.  The Court further found (among other reasons for ruing against Athenex under Chevron’s first prong) that Congress knew how to permit compounding with FDA-approved drug products, because that provision is included in Section 503A’s provision permitting compounding with components of FDA-approved drug products.  A similar provision is non-existent in Section 503B.

Athenex also pointed to the statute’s “essentially copies” provision, arguing that FDA’s interpretation of “clinical need” makes that provision redundant.  Specifically, the “essentially copies” provision ensures that compounders “will not compound drug products that rival FDA-approved drugs, so the clinical need provision cannot fulfill the same purpose.”  Mem. Op. at 23.  Refusing to take Plaintiff’s bait, the Court stated that Section 503B’s redundancies reflect the broader purpose of creating a clear market advantage for approved drugs, and that compounded drug products are used essentially to fill the gaps left by FDA-approved drug products.  Specifically, the Court held that both the “essentially a copy” provision and the “clinical need” inquiry are directed at identifying “whether the compounded product is one that fills a therapeutic purpose unmet by the approved drug.”  Notwithstanding the sparse legislative record reflecting the passage of the Drug Quality and Security Act, the Court also found that FDA’s method of determining “clinical need” comports with Congress’s mission of protecting the public health in the wake of the 2012 New England Compounding Center tragedy.

As if the Court’s Chevron step one reasoning was not clear enough, in the “interest of completeness” Judge Mehta also held that FDA would prevail at Chevron step two.  In brief, the Court held that FDA offered a “reasoned explanation” for its interpretation of Section 503B.  Lastly, the Court found that FDA’s decision to exclude vasopressin from the bulk substances list was not arbitrary and capricious.  Noting that its review of the Agency’s decision making was “narrow,” the Court found that the Agency’s rejection of Plaintiff’s “clinical need” arguments – namely its “advantageous” ready-to-use and chlorobutanol-free formulation – were not arbitrary.

It remains to be seen what effect if any, the Court’s decision will have on the Section 503B bulks list generally, especially for those listed substances that are components of approved drug products.

By Adrienne R. Lenz, Senior Medical Device Regulation Expert —

FDA recently finalized the guidance document, Postmarketing Safety Reporting for Combination Products (“PMSR Guidance”).  The PMSR Guidance addresses compliance with the final rule on postmarketing safety reporting (PMSR) requirements, 21 C.F.R. Part 4, Subpart B (“PMSR final rule”), for combination products.  This is a complicated area, so the guidance is welcome.

The PMSR Guidance begins with discussion of the different types of combination products because PMSR requirements vary depending on the combination product type.  A “single-entity” combination product is a product composed of two or more regulated components.  A “co-packaged” combination product includes two or more separate products packaged together.  A “cross-labeled” combination product is a drug, device or biological product packaged separately from other constituents and, according to its investigational plan or proposed labeling, is “intended for use only with an approved individually specified drug, device or biological product where both are required to achieve the intended use, indication or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed.” PMSR Guidance at 3.

The PMSR final rule applies to two types of applicants:  Combination Product Applicants and Constituent Part Applicants.  When there is a single marketing authorization for a combination product, or multiple authorizations held by the same entity, the applicant of the marketing authorization(s) is a Combination Product Applicant.  In the case of cross-labeled combination products where different applicants hold marketing authorizations for the different constituent parts, these applicants are Constituent Part Applicants.  It is important to note that a company is a Constituent Part Applicant “only if that entity holds an application to market that product as a constituent part of a combination product.” Id. at 6.

Both Combination Product Applicants and Constituent Part Applicants are required to submit application type-based reports.  Additionally, constituent part-based reporting requirements are applicable to Combination Product Applicants and information sharing is required for Constituent Part Applicants.  For Combination Product Applicants, additional reporting requirements are based on the constituent types.  For example, a single-entity or co-packaged combination product approved in an NDA that includes a drug and device constituent is subject to safety reporting requirements described in 21 C.F.R. Part 314 for the drug and also to five-day reporting requirements, malfunction reporting requirements and correction and removal reporting requirements described in 21 C.F.R. Part 803 and 21 C.F.R. Part 806 for the device.  The guidance uses the term “Individual Case Safety Reports” (ICSR) to describe a “report of an event experienced by an individual user of a combination product, including adverse events and malfunctions.” Id. at 10.

The PMSR Final Rule and PMSR Guidance describe an approach for streamlined reporting.  Where reports can be submitted in the same manner and satisfy all applicable requirements, including submission timelines, a single report may be used to comply with more than one reporting requirement.  The PMSR Guidance clarifies that “in the same manner” means that a report is “submitted in the same way (e.g., electronic, paper submission) and to the same recipient group within FDA (e.g., via a common electronic gateway).” Id. at 23.

There are not many substantive changes in the final PMSR Guidance compared to the draft.  Expanded discussions are provided for five-day reports, malfunction reports and combination product ICSRs for foreign events or experiences to offer greater clarity.

The final rule was published in December 2016, establishing an effective compliance date for application type-based PMSR requirements as January 19, 2017.  The final rule also established a compliance date of July 19, 2018 for constituent part-based PMSR requirements and associated recordkeeping.   However, FDA has issued Immediately in Effect Guidance, Compliance Policy for Combination Product Postmarketing Safety Reporting, first in March 2018 and subsequently in April 2019, but is delaying enforcement.  FDA does not intend to enforce requirements for constituent part-based PMSR requirements, the submission process for constituent part-based ICSRs or recordkeeping requirements until the following dates:

• July 31, 2020, for Combination Product Applicants using the FDA Adverse Event Reporting System (FAERS) and Electronic Medical Device Reporting System (eMDR) to report ICSRs
• January 31, 2021, for Combination Product Applicants using the Vaccine Adverse Event Reporting System (VAERS) to report ICSRs

The delayed enforcement should give Combination Product Applicants time to update procedures and infrastructure to allow for the increased reporting requirements.

Overall, the PMSR Guidance provides detailed explanations and numerous helpful examples for navigating the complex requirements for postmarketing safety reporting for the various combination product types for both Combination Product and Constituent Part Applicants.

By James E. Valentine & Larry J. Bauer, Senior Regulatory Drug Expert —

Developing drugs for kids with rare diseases is important work. If you would like to hear from one of these kids, check out this video: “My Philosophy for a Happy Life,” by the late Sam Berns.

Offering priority review vouchers to sponsors that develop new drugs for children with rare diseases is an important incentive program that has wide support.  This week, FDA published a revised draft guidance of the original November 2014 draft guidance titled, “Rare Pediatric Disease Priority Review Vouchers, Guidance for Industry” (hereinafter “revised guidance”).  This revision was primarily intended to reflect more recent legislative changes from the Advancing Hope Act of 2016, as well as clarify several other aspects of the program.

New Requirements and Changes

The revised guidance is updated to reflect a number of post-2014 statutory updates.  First, the Advancing Hope Act created a requirement for sponsors seeking a rare pediatric disease priority review voucher (RPD PRV) to request the voucher upon submission of the rare pediatric disease product application.  This change clarifies that the voucher must actually be requested in the original NDA or BLA application.  Prior to this, even if the sponsor had not requested it, the FDA felt obligated to review an application and award an RPD PRV if it appeared to meet the requirements of the program.  This shifted the burden and responsibility from the Agency to the sponsor.

A second change from the Advancing Hope Act was the clarification that no sponsor of a rare pediatric disease product application may receive more than one priority review voucher issued under any section of the Federal Food, Drug, and Cosmetic Act for the same drug. This prevents a product for a rare disease that also happens to be a neglected tropical disease or medical countermeasure from getting two priority review vouchers for the same application.

The revised guidance also reflects that the 21st Century Cures Act of 2016 provides a sunset for the RPD PRV program so that FDA may not award any RPD PRVs after September 30, 2020, unless the rare pediatric disease product was designated by September 30, 2020 and subsequently approved by September 30, 2022.  After September 30, 2022, FDA may not award any RPD PRVs.  The program could possibly be extended in the future but that will require legislative action.

Re-Defining a “Rare Pediatric Disease”

Perhaps the greatest change in this revision is its incorporation of the new statutory definition of a “rare pediatric disease.”  The original definition stated that the disease had to “primarily affect individuals from birth to 18 years of age.”  FDA interpreted this to mean that sponsors were required to submit substantiating data that greater than 50% of the affected U.S. population with the disease were aged 0-18 years.  This original definition, not only being challenging to demonstrate, had unintended consequences.  The standard of care for certain rare diseases, e.g., sickle cell disease, has gradually improved the life expectancy of people with the disease. Currently, for some rare diseases, more than 50% of the people living with the disease are surviving into adulthood.  Children with the disease continue to be seriously affected but are living longer.  Under the old definition, these diseases would be excluded from being eligible for a voucher, contrary to the intent of legislators.  The new definition corrected this problem by stating that a rare pediatric disease is one where “the serious or life-threatening manifestations (of the disease) primarily affect individuals from birth to 18 years of age.”  Under this definition, a larger range of rare diseases that would not have qualified previously may now be eligible for vouchers.

What are Serious or Life-Threatening Manifestations?

This new statutory definition of rare pediatric disease hinges on the interpretation of the word “manifestations.”  The revised guidance states that manifestations are “expressions” or “symptoms” that are serious or life-threatening that occur during childhood (i.e., 0-18 years old) given current standard of care for pediatric patients.  Importantly, the guidance states that onset of a symptom is not enough, but it must progress to be serious or life-threatening while patients are children.  Then, to determine whether these manifestations “primarily affect children,” the guidance provides the following factors:

1. Timing and rate of disease progression (e.g., end-stage organ disease occurs in childhood);
2. Manifestations of abnormal growth or development; and
3. Whether the proportion of children is greater than the proportion of adults with the given manifestation.

These factors are consistent with our experience with qualifying rare pediatric diseases as such under this new statutory definition.

Needing to Show A Drug Is “For” Prevention or Treatment of a Rare Pediatric Disease

Given that rare pediatric diseases are now defined by their manifestations, FDA included a new section on what it means for a drug to be “for” the treatment or prevention of the disease.  The revised guidance does not require a drug to be studied in or approved for treatment of the manifestations that “primarily affect children,” but instead merely requires the drug to be approved for an indication that is clinically meaningful to pediatric patients with the disease (e.g., for treatment of some other serious or life-threatening manifestation, or if it treats the underlying cause of the disease generally).  Importantly, the guidance states that applications should include in their priority review voucher requests scientific justification for how the approved indication will be clinically meaningful to pediatric patients.

Clarifying the Requirement to Rely on Clinical Data from Studies in the Pediatric Population

The revised guidance also interprets and clarifies the requirement that the application “relies on clinical data derived from studies examining a pediatric population and dosages of the drug intended for that population.”  It shifts in its language, from saying that the application “must” have certain information, to stating that it “should” have it:

1. It should have been studied in a clinically meaningful pediatric population with the rare disease (although the studies may include adults in appropriate circumstances)
2. The pediatric data should have been critical to obtaining adequate labeling for the pediatric population in terms of safety, effectiveness, and dosage information (although data from studies including adults may also have supported the pediatric labeling in appropriate circumstances).

In addition, the revised guidance walks back in requiring labeling of the drug be for use by the full range of affected pediatric patients in all cases, now acknowledging there are reasonable exceptions.  For example, the guidance states that there may be instances where it is not reasonable to include all pediatric age ranges affected by the disease without causing undue delays in completing the studies and submitting the application.  FDA appears to be most interested in preventing sponsors from submitting data from a “token pediatric population” to try and justify meeting the requirements for a voucher.

The revised guidance also added the statement reminding sponsors that after getting an RPD PRV, they may still further develop the same drug for additional indications, including different adult indications, without losing the voucher.

Providing FDA Comments on the Revised Guidance

FDA is accepting comments on the revised draft guidance by September 30, 2019 here.

By Serra J. Schlanger & Alan M. Kirschenbaum —

As we have previously reported (see here, here, and here) four states (Vermont, Colorado, Florida, and Maine) have passed laws to establish drug importation programs.  Reversing long-standing policy, the U.S. Department of Health and Human Services (HHS) announced on Wednesday, July 31, 2019 that HHS and the U.S. Food and Drug Administration (FDA) have developed a federal “Safe Importation Action Plan” proposing two pathways to allow for the importation of drugs from foreign countries.

Pathway 1 will allow States, wholesalers, and pharmacists to submit plans to HHS for demonstration projects that allow for the importation of certain drugs from Canada.  The demonstration projects must be designed to comply with the federal drug importation laws outlined in Section 804 of the Federal Food, Drug, and Cosmetic Act (FDC Act), 21 U.S.C. § 384.  As outlined in the Safe Importation Action Plan, HHS and FDA will publish a Notice of Proposed Rulemaking (NPRM) to address Section 804’s requirements, including those related to drug quality, record keeping, and product testing.  States, wholesalers, and pharmacists that participate in the demonstration projects will be required to certify that the drug importation poses no additional risk to the public’s health and safety and will result in significant cost reductions for covered products.  Drugs eligible for importation will be limited to drugs for sale in Canada that are versions of FDA-approved prescription drugs; such drugs must be manufactured with active pharmaceutical ingredients (API) manufactured at facilities that also manufacture API for the FDA-approved version.  Under the federal drug importation laws, controlled substances, biological products, infused drugs, intravenously injected drugs, drugs inhaled during surgery, and certain parenteral drugs are excluded from importation.  HHS and FDA also plan to exclude any drug with a REMS from the importation demonstration project programs.

The future NPRM will seek feedback on how States, wholesalers, and pharmacists can demonstrate that the drug importation programs will result in significant cost reduction for the covered drug products.  As we previously reported (see here), when faced with this same question, Vermont found that the costs of implementing a compliant drug importation program may outweigh any savings the state could hope to realize from importing lower cost drugs.  The Safe Importation Action Plan says that HHS and FDA will seek feedback on “the best way to identify the expected acquisition cost of the imported drug, the cost of assuring the drug is safely imported, and the mechanism for delivering those savings to the consumer (as opposed to the savings being absorbed by the supply chain).”

Pathway 2 will allow drug manufacturers to import versions of their FDA-approved drugs that are sold in foreign countries, “potentially allowing them to offer a lower price than what their current distribution  contracts require.”  In order to take advantage of this pathway, manufacturers will need to establish that the foreign version is the same as the U.S. version.  A manufacturer who meets the requirements of the pathway will be able to sell a foreign version of a drug product in the U.S. under a different NDC number than the U.S. version.  Importation of foreign versions is expected to occur using conventional supply channels, so the pathway will rely on applicable existing safeguards to ensure supply chain integrity.

Pathway 1 will be subject to notice and comment rulemaking, so the timeframe for when interested States, wholesalers, and pharmacists will be able to submit proposals for demonstration projects to HHS is currently unknown.  Further, once the rulemaking process is complete, HHS will need to approve any demonstration projects and importation programs before drugs can be imported from Canada.  HHS and FDA plan to implement Pathway 2 through guidance, so it is possible that manufacturers may be able to take advantage of this pathway more quickly.

The Safe Importation Action Plan is significant because Pathway 1 appears to reverse decades of opposition to the importation of drugs from foreign countries by pharmacies and distributors.  Since the enactment of FDC Act Section 804 in 2003, no administration, Democrat or Republican, has been willing to provide the necessary certification that importation under that section “will pose no additional risk to the public’s health and safety; and will … result in a significant reduction in the cost of covered products to the American consumer.”  This Administration is laying the groundwork for such a certification for individual demonstration projects if compliance with the statutory requirements and upcoming regulatory requirements can be demonstrated.

Pathway 2 is also significant because it would establish a new vehicle for the importation of drugs.  The Safe Importation Action Plan states that Pathway 2 will offer a way for manufacturers to offer lower cost versions of their drugs where they otherwise could not readily do so because they are locked into contracts with other parties in the supply chain.  Certain manufacturers have recently begun to market lower cost versions of their drugs under different NDCs, as an alternative to the existing higher-priced version but unaccompanied by rebates.  It is uncertain whether manufacturers who wish to offer lower cost versions of their existing drugs in the U.S. would find Pathway 2 more advantageous than simply introducing a new, lower cost version to the U.S. market (under a new NDC) without importing it.

We will continue to monitor and report on federal and state efforts to address drug pricing issues.

The American Conference Institute’s (“ACI’s”) popular “FDA Boot Camp” – now in its 34th iteration – is scheduled to take place from September 18-19, 2019 at The Bostonian Hotel, Boston, MA. The conference is billed as the premier event to provide folks with a roadmap to navigate the difficult terrain of FDA regulatory law.

ACI’s FDA Boot Camp will provide you not only with the essential background in FDA regulatory law to help you in your practice, but also key sessions that show you how this regulatory knowledge can be applied to situations you encounter in real life. A distinguished cast of presenters will share their knowledge and provide critical insights on a host of topics, including:

• The organization, jurisdiction, functions, and operations of FDA
• The essentials of the approval process for drugs and biologics, including: INDs, NDAs, BLAs, OTC Approval, the PMA process and the Expedited Approval Process
• Clinical trials for drugs and biologics
• Unique Considerations in the approval of combination products, companion diagnostics, and stem cell therapies
• The role of the Hatch-Waxman Amendments in the patenting of drugs and biologics
• Labeling in the drug and biologics approval process
• cGMPs, adverse events monitoring, risk management and recalls

In addition—and new for 2019—are special focus sessions on:

• FDA’s Digital Health Initiative
• Opioid and Other Controlled Substances Classifications
• The Impact of the FDA Reauthorization Act on Drug Approvals

Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will co-chair the conference and will present in a session titled “Navigating the Approval Process for Drugs and Biologics.”

FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount. The discount code is: D10-815-815AX01.  You can access the conference brochure and sign up for the event here.  We look forward to seeing you at the conference.

Telemedicine platforms provide consumers and patients with convenient access to healthcare services. For this reason, the interest in and use of telemedicine services has increased significantly in recent years. While many discussions of the risks related to telemedicine focus on state laws and fraud and abuse concerns, FDA has begun to exercise its enforcement authority over telemedicine-related activities.

In this month’s issue of Compliance Today, Hyman, Phelps & McNamara, P.C. associates Serra Schlanger and Rachael Hunt provide an overview of FDA’s enforcement authority and discuss examples of its application in two recent cases.   Click here to read the article, Telemedicine: Understanding the FDA’s role in recent regulatory and enforcement actions.