ACI’s 13th Annual Paragraph IV Disputes Conference

ACI’s 13th Annual Paragraph IV Disputes Conference

Spring is here!  How do we know?  Is it the cherry blossoms starting to bloom in Washington, DC?  Is it the daffodils emerging from hibernation?  No – we know it’s Spring because the annual American Conference Institute (“ACI”) “Paragraph IV Disputes” conference is right around the corner.

That’s right, ACI will be holding its 13th annual “Paragraph IV Disputes” conference from April 29-30, 2019 at the Conrad New York in New York City.  The 2019 conference is a special one with the 35th Anniversary of the Hatch-Waxman Amendments later this year (September 24, 2019).  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 moderating a panel titled “Latest FDA Initiatives Affecting Generic Drug Access and Pricing.”  The panel speakers are FDA’s Grail Sipes, Deputy Center Director, Regulatory Policy, CDER, and Maryll Toufanian, Director Office of Generic Drug Policy, CDER.  We’ll be delving into the latest and greatest FDA policy and legal initiatives, including the Drug Competition Action Plan and Competitive Generic Therapies.

FDA Law Blog is a conference media partner.  As such, we can offer our readers a special discount off the current price tier.  The discount code is: D10-896-896AX01.  You can access the conference brochure and sign up here.

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FDA Publishes Notice to Remove Substances from its Bulks List I for Section 503B Outsourcing Facilities … and Let’s Watch What Happens Next

FDA Publishes Notice to Remove Substances from its Bulks List I for Section 503B Outsourcing Facilities … and Let’s Watch What Happens Next

By Karla L. Palmer

We posted last year about the dispute over FDA’s determination to include certain nominated substances on its Bulk Substances List 1 for Section 503B outsourcing facilities.  Recall that in 2017, after FDA approved Endo/Par’s Vasostrict® finished drug product, several entities nominated active pharmaceutical ingredient vasopressin for inclusion on FDA’s Section 503B Bulk Substances List 1.  After review of the nominations, FDA added vasopressin to Bulks List 1 in mid-2017.  Next, FDA’s nomination and listing process (already the subject of two Agency revisions and “redos” since 2014, blogged about here) ground to a halt.  The nominations process and the list itself was (and remains) the subject of contentious litigation involving FDA, Endo Pharmaceuticals and its subsidiary Par Sterile Products, and outsourcing facility Athenex Pharma Solutions.

After proposing to change the nomination process in March 2018 (here), which continued a stay in the litigation against FDA brought by Endo/Par, FDA received approximately 60 industry comments.  It published its final guidance for the section 503B nomination process on March 4, 2019 (here).  In response to those 60 comments “or on its own,” FDA stated it made certain changes in the final guidance document; however, those changes do not change the process in which FDA intends to engage to review a nominated substance.  Instead, FDA’s final guidance on the nomination process explains in more detail

how Congress’ limitation on bulk drug substances that can be used in compounding under section 530B helps preserve the integrity of the new drug approval process, and identifie[s] the process to request that FDA identify or remove a bulk drug substance from that list after the Agency has made a final determination with respect to that substance….

At the same time FDA published final guidance on the nomination process, FDA issued another final guidance document, this time removing two bulk substances from FDA’s interim Bulks List 1: vasopressin and nicardipine hydrochloride (here).

Addressing the more controversial subject of compounding using vasopressin, FDA stated among other reasons that nominations and comments it received did not identify an attribute of commercially available Vasostrict® that makes it “medically unsuitable for patients,” and that the compounded products “are intended to address” that attribute.  FDA also stated that the proposal for compounders to compound a “ready-to-use” formulation versus the commercially available Vasostrict® product for improved efficiency for prescribers or healthcare providers, or to address the possibility that the approved drug may be mishandled by a medical professional, is not a “clinical need to compound a drug product” using a bulk substance.

Not surprisingly, outsourcing facility Athenex Pharmacy Solutions LLC filed a lawsuit pursuant to the Administrative Procedures Act against FDA and others challenging FDA’s bulks determination (on the same day as FDA’s Federal Register notice announcing its vasopressin decision).  Although Athenex originally sought immediate injunctive relief from the D.C. District Court barring FDA from enforcing its vasopressin determination, FDA has agreed not to engage in an enforcement action against Athenex based solely on use of vasopressin until after the district court issues a decision on the merits concerning whether FDA’s actions removing vasopressin from its Bulks List 1 were appropriate.

In its Memorandum in Support of its Motion for Summary Judgment on the merits of the lawsuit, filed on March 18, 2019, Athenex notes that vasopressin has been used in medical care for almost a century to treat life threatening and emergency conditions.  Athenex argues that FDA made the decision to exclude the ingredient from its Bulks List because “a pharmaceutical company is using it to make a branded drug product … that FDA thinks that doctors should choose to use instead of Athenex’s compounded vasopressin drug product.”

Athenex argues that FDA has misinterpreted Congress’ “plain language” instruction concerning whether there is a “clinical need” for substances as “directing FDA to decide whether doctors should always choose an existing branded product over any compounded product made with that substance.”  Among other problems, FDA’s vasopressin determination wrongfully invades the practice of medicine.  In addition, because vasopressin is indeed a component of an approved drug product, FDA has “officially acknowledged” vasopressin is an active pharmaceutical ingredient that meets patients’ “clinical needs.”  Athenex also argues that the plain language of the statutory definition of “bulk drug substance” confirms the subject of the clinical need inquiry required under section 503B is for the active pharmaceutical ingredient and not the finished drug product.      

Athenex next argues that its vasopressin compounded formulation is different from Vasostrict® in clinically significant ways that FDA wrongfully and arbitrarily ignores.  First, unlike the commercially available drug, Athenex’s vasopressin formulation is provided in a ready-to-use formulation and thus avoids Vasostrict’s® 16-step administration process.  Furthermore, Vasostrict®, as stated on its own label, is contraindicated in patients with a known allergy to chlorobutanol and Athenex’s vasopressin is not.  Athenex argues that FDA arbitrarily disregarded these clinically significant differences when it determined to remove vasopressin from section 503B’s Bulks List 1.

We look forward to reviewing FDA’s opposition to Athenex’s Memorandum, and watching what happens next in this long-running “David versus Goliath” saga.

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HP&M Attorney Pens the Case for Use of Patient and Caregiver Perception of Change Assessments in Rare Disease Clinical Trials

HP&M Attorney Pens the Case for Use of Patient and Caregiver Perception of Change Assessments in Rare Disease Clinical Trials

By James E. Valentine

On March 16, 2019, Advances in Therapy published a commentary authored by HP&M Attorney James E. Valentine along with co-authors Marielle Contesse, Tracy Wall, and Mindy Leffler.  The paper sets forth the case, and provides a methodologic overview, for incorporating qualitative patient and caregiver video interviews into clinical trials as one method for rigorously capturing patient experiences and caregiver observations (referred to as PPC and CPC Assessments).  This paper comes on the heels of a recent National Academies of Sciences workshop report on the Science of Patient Input that cited James Valentine’s recommendation for this type of methodology as a novel way to solicit patient experiences in clinical trials (see previous coverage here).

James Valentine and his co-authors propose the novel PPC and CPC Assessments to help overcome the many methodological challenges to measuring treatment effect in rare diseases.  Because of the small number of patients and the nature of rare diseases, study design often involves a tension between properly powering a study and minimizing heterogeneity of the study population.   Broadening the inclusion criteria to power the study can result in increased heterogeneity, which then makes it difficult to select outcome measures with sensitivity across the study population.  This diversity, combined with the novelty of the drug being assessed, may mean that it is not always possible to predict the different ways treatment benefit might manifest across patients, further complicating the selection of outcome measures.  Lastly, there is often a lack of validated, disease-specific outcome measures, which leads to borrowing outcome measures that were used in other diseases, which lack sensitivity.  These methodological challenges in rare disease clinical trials can lead to uncertainty about whether some trials fail as a result of failed measurement of the drug effect rather than failed treatment.

In an effort to:

(1) create a bulwark against type 2 errors as a result of these challenges to assessing treatment effect in rare diseases,

(2) maximize the contribution to the scientific data by each and every rare disease patient volunteering to participate in studies, and

(3) embrace the principle of “patient-focused drug development” to ensure that the breadth and depth of patient insight into their experience is considered in FDA approval decisions,

the PPC and CPC Assessments can be employed to capture patients’ and caregivers’ perceptions of change using semi-structured video interviews that can be implemented before, during, and after a clinical trial.  Furthermore, these qualitative interviews can be done in the clinic, over the phone (via a mobile application), or with a web conferencing system.  The paper provides an in-depth discussion of how to design and implement the PPC and CPC Assessment methodology based on the experiences of each of the authors who come to this as regulatory experts, patient advocates, clinical researchers, and/or drug developers.

The paper concludes that seeing the patients and caregivers on video and hearing directly from them about their experiences can be important information for regulators, payers, and prescribers.  Among other things, this kind of patient experience report may provide context to the meaningfulness of clinical trial endpoints, where patients and their caregivers voice how changes experienced during a trial impacted how they felt or functioned in daily life.  Or it may encourage regulators and payers to consider an impact on patient quality of life that may not have been documented in the study’s more conventional outcome measures.  Finally, the 21st Century Cures Act requests FDA to include a description of how patient experience data was obtained and reviewed by FDA, and this new methodology would provide a means tailor-made to this purpose.

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A Doggone Shame for Vanda: DC District Court Grants FDA’s Remand Motion on Dog Study/IND Clinical Hold Challenge

A Doggone Shame for Vanda: DC District Court Grants FDA’s Remand Motion on Dog Study/IND Clinical Hold Challenge

By Sara W. Koblitz

About 6 weeks after Vanda filed its complaint, the company’s lawsuit has joined its clinical trial: on hold.  Last week, the District Court of D.C. granted FDA’s motion for a voluntary remand of the case challenging FDA’s requirement to perform 9-month large animal studies prior to commencing studies in humans staying the case for 45 days from the Court’s Order while FDA reevaluates its position.  While Vanda supported a voluntary remand, it strongly advocated that the Court stay the case while vacating the clinical hold on its 52-week human study.

FDA requested a voluntary remand to “address certain procedural issues Vanda noted in its Complaint, including the allegations about the agency’s response to scientific arguments submitted by Vanda and the treatment of a guidance document as a binding rule.”  Notwithstanding all the usual pre-litigation negotiations about the issue that were discussed in Vanda’s Complaint, only now will FDA “provide a full written explanation of the agency’s analysis and ultimate position.”  FDA does not, however, seem willing to reexamine its fidelity to guidance – stating that it intends to address on remand “the legal import of the guidance document and fully setting out the scientific basis for its actions here.”   From this statement, it is unclear whether FDA is actually planning to re-review the scientific merits of Vanda’s arguments or merely provide more explanation upon remand.  Importantly, FDA also requested that the Court remand without vacatur of the original agency decision if the court agrees to FDA’s remand request, meaning that the the Partial Clinical Hold should remain in place until FDA provides its new analysis.

Because Vanda agreed to the voluntary remand, the only issues remaining for the Court decide with respect to this motion are the questions of remand without vacatur and length of a stay.  Vanda argued that the Clinical Hold has no valid legal basis because FDA was required to analyze these issues before issuing the Clinical Hold.  Vanda hypothesized that FDA is “merely stalling in an attempt to make superficial changes to a legally deficient hold—in effect ‘putting lipstick on a pig’” and shouldn’t be given additional time to make procedural corrections while further delaying Vanda’s clinical trial program.  Because “unsupported agency action normally warrants vacatur” and because remand without vacatur is fundamentally inconsistent with the APA, Vanda argued that only remand with vacatur is appropriate.  Vanda also argued against the 75 day stay that FDA requested, arguing that a 30 day stay – the amount of time that FDA would normally have to consider an entirely new IND – is more appropriate.

The Court agreed to the voluntary remand to give FDA the opportunity to “cure its mistakes,” but declined to vacate the Clinical Hold.  The Court actually questioned whether it has authority to vacate an agency action in the absence of a request for emergency relief.  This is especially true because FDA’s filing did not concede that the Clinical Hold order is invalid.  But the Court emphasized that even if it could, it would not vacate the Clinical Hold because it has not been determined deficient and the procedural defects are likely to be corrected on remand.  Questions of patient safety risks further supported the Court’s decision.  In an act of compromise, the Court decided to stay the case for 45 days (75 days from FDA’s motion) – until April 28, 2019 – rather than the 75 days (from the Court’s decision) FDA requested.

Given that Vanda has been fighting its battle with FDA on this issue since May 2018, it’s interesting that it took litigation to compel FDA to address Vanda’s procedural and scientific complaints with any sort of gravity.  The government notes that Vanda did not “invoke the appeal procedures,” but Vanda explained in its Complaint that its attempt to do so through the Formal Dispute Resolution process was met with additional procedural roadblocks.  FDA’s remand request is especially considering in that FDA essentially admits that it did not fully comply with the procedural requirements for imposing a Clinical Hold.  Many small companies are before FDA every day and may encounter similar issues but don’t have the resources to fight FDA in court.  The Agency fully admits that it did not comply with its own requirements, and it is now asking for the opportunity to do so only after Vanda filed a lawsuit.  Even if FDA is just going to “put lipstick on a pig” here and redraft its Clinical Hold Letter to include a reasoned explanation, all interested parties should agree that it shouldn’t take litigation to pry such an explanation from FDA.

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To Ask, or Not to Ask, That is the Question: FDA Guidance on Nonbinding Feedback After Certain Inspections of Device Establishments

To Ask, or Not to Ask, That is the Question: FDA Guidance on Nonbinding Feedback After Certain Inspections of Device Establishments

By Rachael E. Hunt

FDA recently issued a draft guidance document, Nonbinding Feedback After Certain FDA Inspections of Device Establishments, which outlines the process for obtaining FDA feedback on proposed remedial actions in response to observations issued on a Form 483, the Agency’s Inspectional Observations Form, following an inspection.

Background

Section 702 of the FDA Reauthorization Act of 2017 (FDARA) amended the Federal Food, Drug, and Cosmetic Act (FDCA) to require FDA to provide nonbinding feedback in certain circumstances after an FDA inspection of a device establishment.  Specifically, FDCA section 704(h)(2) states:

(A) The Secretary shall, with respect to a request described in subparagraph (B), provide nonbinding feedback with respect to such request not later than 45 days after the Secretary receives such request.

(B) A request described in this subparagraph is a request for feedback—

(i) that is made by the owner, operator, or agent in charge of such establishment in a timely manner; and

(ii) with respect to actions proposed to be taken by a device establishment in a response to a report received by such establishment pursuant to subsection (b) that involve a public health priority, that implicate systemic or major actions, or relate to emerging safety issues (as determined by the Secretary).

Statutory Eligibility and Justification

In the draft guidance, FDA reiterates the statutory criteria for nonbinding feedback: the request must describe how one or more observations “involve a public health priority,” “implicate systemic or major actions,” or “relate to emerging safety issues (as determined by [FDA]).”  The request must, therefore, include a justification as to why one of the eligibility criteria is met.  FDA provides the following examples of observations that would likely meet the statutory criteria for nonbinding feedback:

  • An observation regarding conditions that, if unaddressed, are likely to result in the release of a violative product that may cause death or serious injury.
  • An observation regarding quality system or subsystem deficiencies which have or are likely to result in a nonconforming, violative and/or defective device.
  • An observation relating to an emerging safety issue that, if unresolved, is likely to result in the release of devices likely to cause death or serious injury.

Request for Feedback

Eligible requests should be submitted no later than 15 business days after a Form 483 is issued and should be addressed to the same FDA contact responsible for receiving any response to the Form FDA 483.  Any response to a Form 483 should be distinct from a request for nonbinding feedback, although the two submissions can be sent together.

The request should state the inspectional observation for which feedback is being requested as well as the proposed remedial actions, including a proposed timeline.

FDA’s Response

Upon receiving a request, FDA will first determine whether the eligibility criteria are met.  If not, FDA will notify the requestor within 45 days that the request is ineligible. If the request does meet one of the criteria, FDA is required to provide nonbinding feedback within 45 calendar days.  This feedback will indicate whether the proposed actions appear adequate, partially adequate, or inadequate.  Where FDA’s feedback is that a proposed action is partially adequate or inadequate, FDA will provide an explanation and a recommendation as to what may be needed for FDA to consider the proposed actions adequate.

Limitations of Feedback

The draft guidance articulates the limitations of the feedback provided by FDA, watering down most of the utility of this program.  Specifically, the guidance notes that FDA’s feedback “may not adequately address the cause of the problems that led to the inspectional observations, and additional action may be warranted.”  The guidance also notes that FDA’s feedback does not prevent additional observations or regulatory action.  Any response from FDA would, therefore, provide little comfort to a sponsor who had already admitted that a Form 483 observation “involve[s] a public health priority,” “implicate[s] systemic or major actions,” or “relate[s] to emerging safety issues (as determined by [FDA]).”  The process, therefore, puts sponsors in a lose-lose situation.  While the admissions could be used in an enforcement action or a products liability lawsuit to demonstrate knowledge of a problem, a failure to request available feedback could be used to show negligence or willful ignorance of the same.

We encourage stakeholders to review the draft guidance and provide comments under docket number FDA-2018-D-4711.  The comment period closes on April 22, 2019.

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Three’s Finally a Crowd: DEA Proposes Replacing Triplicate DEA-222 Order Forms with Single-Sheet Form

Three’s Finally a Crowd: DEA Proposes Replacing Triplicate DEA-222 Order Forms with Single-Sheet Form

By Larry K. Houck

After years of talk about replacing the antiquated, carbon-leaved triplicate Official Order Form (“DEA Form 222” or “DEA-222s”) required for schedule I and II controlled substance transfers, the Drug Enforcement Administration (“DEA”) is proposing to implement a single-sheet order form.  New Single-Sheet Format for U.S. Official Order Form for Schedule I and II Controlled Substances (DEA Form 222), 84 Fed. Reg. 5395 (Feb. 21, 2019).  In addition, DEA is proposing to expand who can issue powers of attorney (“POAs”) authorizing employees to execute DEA-222s.

The Federal Controlled Substances Act (“CSA”) requires written orders made by a purchaser to be documented on a DEA Form 222 or its electronic equivalent through DEA’s Controlled Substance Ordering System (“CSOS”) for the transfer of schedule I and II controlled substances.  DEA currently issues serially numbered DEA-222s with the registrant’s name, address, and registration number, their authorized activity, and the drug schedules they are authorized to handle.  Current DEA-222s are triplicate forms with carbon sheets sandwiched in-between.  The DEA-222s allow DEA to track schedule I and II transactions.

Registrants fill out the DEA-222, adding the name and address of the DEA-registered supplier, the date, the number of controlled substance packages ordered, package size, and the controlled substances they wish to order.  The purchaser retains Copy 3 of the form and sends Copy 1 and Copy 2 to the supplier.  The supplier documents the number of controlled substance packages shipped and the date shipped.  The supplier retains Copy 1 of the form and sends Copy 2 to the DEA Special Agent in Charge where the supplier is located.  The purchaser documents the quantity of packages received and the date on Copy 3.  The purchaser and the supplier must maintain their DEA-222 copies for two years.

DEA is proposing to preprint the new forms on security paper, with each bearing a unique number and enhanced security features “to ensure the identity of the original while making it difficult to copy for counterfeit purposes.”  DEA believes the single-sheet form will be more convenient for registrants, noting that technology now exists with laser printers, scanners, and photocopiers that were not available when the triplicate form was initiated.  DEA also observed that a single vendor produces the triplicate forms and that process has become costly.

Registrants ordering schedule I and II substances with the new DEA-222s would complete and retain a copy of the form and send the original to the supplier.  The supplier would record information related to filling the order on the original form and retain it.  Suppliers, such as pharmacies and practitioners, who are not required to report transactions to DEA’s Automation of Reports and Consolidated Orders System (“ARCOS”) would submit a copy of the original DEA-222 to the DEA Registration Section/DRR by mail or email.  The purchaser will record information related to the items received on its copy of the form.  Purchasers and suppliers would continue to preserve order forms for two years.

DEA will permit registrants to exhaust their supply of triplicate DEA-222s for up to two years after the rule becomes effective.  DEA would issue the new forms to registrants when they deplete their supply of triplicate forms.

DEA is also proposing to expand who may issue POAs to execute the new DEA-222s.  Registrants may authorize individuals to order schedule I and II substances by executing a POA for each such individual.  The POA must be retained with executed DEA-222s for the same period as any order form bearing the signature of the employee authorized by the POA, and must be available for inspection by DEA investigators.

Currently, only the person who signed the most recent DEA application can execute POAs for authorizing persons to execute DEA-222s on behalf of the registrant.  DEA is proposing to expand the number of individuals who can issue a POA similar to who can sign an application for a DEA registration.  DEA is proposing that a POA for executing the new DEA-222s be issued by the registrant if an individual, by a partner if the registrant is a partnership, or by an officer if the registrant is a corporation, corporate division, association, trust, or other entity, any corporate officer may sign the POA.

Replacing triplicate DEA-222s is overdue.  Sophisticated technology is available that allows registrants to order schedule I and II substances with enhanced security that minimizes the risk of diversion through ordering.  DEA could have required all registrants to order schedule I and II substances electronically through the CSOS system, which would have created a burden on those registrants who lack access to the Internet or required technology.  And why not relieve ARCOS-reporting suppliers from having to file copies of order forms when they already submit the sales data to DEA?  The new flexibility for who may issue a POA to execute the new DEA-222s will help resolve the current conundrum faced by registrants when the individual who signed the prior DEA registration is not available or has left the company.

Electronic comments must be submitted, and written comments must be postmarked, on or before April 22, 2019.

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Emerging Technology: Implanted Brain Computer Interface Devices for Patients with Paralysis or Amputation

Emerging Technology: Implanted Brain Computer Interface Devices for Patients with Paralysis or Amputation

By Adrienne R. Lenz, Senior Medical Device Regulation Expert

An Implanted Brain Computer Interface (BCI) device may sound like something out of science fiction, but FDA apparently believes these devices are on their way to becoming a reality.  FDA recently released a draft guidance document that provides recommendations on how to gain approval to conduct clinical studies of these devices in support of eventual marketing clearance.  The new draft guidance, Implanted Brain-Computer Interface (BCI) Devices for Patients with Paralysis or Amputation – Non-clinical Testing and Clinical Considerations (Guidance), provides recommendations for non-clinical testing and clinical study design information that should be included in pre-submissions or Investigational Device Exemptions (IDE) for BCI devices, which are defined as  “neuroprostheses that interface with the central or peripheral nervous system to restore lost motor and/or sensory capabilities in patients with paralysis or amputation.”  Guidance at 1.   Designated a “leapfrog guidance,” it serves as a “mechanism by which the Agency can share initial thoughts regarding emerging technologies that are likely to be of public health importance early in product development.”  Id. at 2.

Though the scope of the guidance is limited to pre-submissions and IDEs for implanted BCI devices, the presentation of information is likely to be a useful reference for other devices and submission types.  The guidance provides detailed recommendations on descriptive information to be provided for the system and its key components, many of which are used in other device types, including leads, electrodes, connectors, processing hardware, stimulation hardware, assistive components, programmers, control units, algorithms, and batteries.  The guidance then walks through the types of information and testing that should be included in an IDE application, including software, biocompatibility, sterility, pyrogenicity, shelf life and packaging, electrical safety and electromagnetic compatibility, wireless technology, magnetic resonance (MR) compatibility, non-clinical bench testing, animal testing and clinical performance testing.  Throughout these sections, reference is given to many existing topic-specific FDA guidance documents and FDA recognized standards.

As is to be expected for an implanted device, FDA emphasizes the need to demonstrate the safety and reliability of implanted BCI devices.  While much work is needed to bring an implantable BCI device to clinical trials, they are clearly emerging from the realm of science fiction, which is great news for patients with paralysis or amputation who would be the ultimate beneficiaries.

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Let’s Play Name That Biosimilar!

Let’s Play Name That Biosimilar!

By Sara W. Koblitz

Ok, Tom, I think I can name that biosimilar in four letters!  Added on to the suffix!  And let’s make it interesting: it’s an interchangeable.

As a follow-up to its 2017 Guidance for Industry: Nonproprietary Naming of Biological Products, FDA issued a new draft guidance filling in the gap that it left with respect to the naming of interchangeable products.  This draft guidance is an “Update” that is not intended to be finalized, but it merely announces FDA’s current thinking on naming interchangeable products, transition products, and already-approved biologics in an effort to solicit comments and eventually revise its 2017 guidance.

While FDA punted on the appropriate format for interchangeable suffixes in 2015 and again in 2017, this guidance provides FDA’s long-awaited proposal.  FDA considered two approaches to interchangeable naming, and both required use of a suffix: a unique suffix or a suffix shared with the reference product.  As with biosimilars, FDA ultimately settled on a unique suffix for interchangeable products, stating that “a distinguishing suffix is necessary to achieve adequate pharmacovigilance for these products.”  This will also avoid the need to change the nonproprietary name of a biological product that is first licensed as a biosimilar and later meets the requirements for interchangeability.

Importantly, this guidance also announces FDA’s about-face on the topic of already-approved biosimilars.  The 2017 Naming Guidance posited that both newly licensed and previously licensed originator biological products and biosimilar products would need a distinguishing suffix, but the Update reversed this position.  The Update states that FDA “no longer intends to modify the proper names of biological products that were licensed under the PHS Act without an FDA-designated suffix in their proper names.”  Further, the Update also exempts “transition” products from suffix requirements.  FDA is continuing to evaluate its approach to vaccines, which requires a unique suffix under the 2017 guidance.

FDA explains that it has determined that the objectives of the suffix naming convention – pharmacovigilance and safe use – can be accomplished without retroactively adding a suffix to previously licensed products.  This decision was “intended to minimize the potential burden for sponsors and the healthcare systems, and to avoid potential confusion for healthcare providers and patients, given that the nonproprietary names of drugs seldom change postapproval.”  FDA reasoned that most biological products that share the same core name will have distinct nonproprietary names.  The Update provided very little information on the impetus for its change in position with respect to previously licensed products, but Commissioner Gottlieb’s statement announcing the Update did raise concerns about the costs on the healthcare system passed on to consumers that might arise from the retroactive application of these suffixes.

The naming issue has been contentious since the passage of the BPCIA, with one camp arguing that unique names are necessary for safety and accurate adverse event reporting and the other arguing that different names will be a major barrier to marketplace acceptance of biosimilars by undermining the “sameness” of biosimilars and interchangeable products and preclude their widespread adoption.  In keeping with its mission, FDA clearly and expressly opted for safety with Commissioner Gottlieb stating that “I do not believe that the naming convention should be used to advance [biosimilar competition] goals if it could come at the expense of the ability to ensure patient safety.”  Regardless, he emphasizes that FDA does not see the addition of these suffixes as a hurdle to biosimilar competition and adoption.

Along with guidance, FDA also published a Policy and Procedure (MAPP 6720.5)  detailing the internal procedures relating to the selection of four-letter suffixes.  FDA will review up to 10 proposed suffixes to identify a viable suffix candidate and will then evaluate whether a suffix would be false or misleading.  The Office of Surveillance and Epidemiology will be responsible for evaluating the suffix with input from the Office of Prescription Drug Promotion.

Comments on the Update draft guidance should be submitted to FDA within 60 days of publication (around May 7, 2019).

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USDA and FDA Publish the Terms of Their Joint Regulation of Human Food, Derived from Cell Lines of USDA-Amenable Species

USDA and FDA Publish the Terms of Their Joint Regulation of Human Food, Derived from Cell Lines of USDA-Amenable Species

By Riëtte van Laack

As readers of this blog may recall, the issue of the regulation of meat and poultry derived from cell lines, identified by such terms as cultured meat, clean meat, and cell-based meat, became front cover news a little more than a year ago when the U.S. National Cattlemen’s Association (USCA) filed a Petition with FSIS to define the term meat (and beef) to exclude these types of food prepared from cells from cattle.

Subsequently, the question as to who has jurisdiction, FDA or USDA, became a hotly debated topic.  On November 16, 2018 in a joint press release, USDA and FDA announced that they had come to an agreement on a joint regulatory framework under which FDA would oversee cell collection, cell banks, and cell growth and differentiation, and USDA oversight would start during the cell harvest stage and extend through the production and labeling of food products derived from the cells of USDA amenable species, i.e., livestock and poultry.  Details were said to be forthcoming.

On March 7, 2019, USDA and FDA announced the “Formal Agreement Between FDA and USDA Regarding Oversight of Human Food Produced Using Animal Cell Technology Derived from Cell Lines of USDA-amenable Species” providing further information about the agreed framework.  Consistent with the press release from Nov. 2018, FDA will oversee the production of the cells and then jurisdiction will transition to USDA during the cell harvest stage.  The agreement is general and the exact parameters of the regulation of these products still need to be developed.  Some noteworthy aspects:

  • The Agencies contemplate a premarket consultation process “to evaluate production materials/processes and manufacturing controls, to include oversight of tissue collection, cell lines and banks, and all components and inputs.”
  • The facilities where the cells will be grown and harvested will be dual jurisdiction facilities.
  • While in Nov. 2018 the Agencies asserted that no additional legislation would be necessary, the formal agreement includes a provision that FDA and USDA “will undertake a joint process to identify any changes needed to statutory or regulatory authorities to effectuate” the agreement.
  • The agreement refers to the product category as “food, derived from cell-lines of USDA-amenable species” or similar terms, thereby leaving the issue of naming these products for another day.
  • FDA explains the basis for its jurisdiction over these products; USDA does not. The agreement refers to meat and poultry products that bear the mark of inspection and in the press release USDA Deputy Under Secretary mentions that “Consumers trust the USDA mark of inspection to ensure safe, wholesome and accurately labeled products.”  This suggests a loss for USCA, as its Petition requested to not allow products derived from cell lines to bear the mark of inspection.

In light of the various States proposing (e.g. Nebraska) or passing laws (e.g., Missouri) prohibiting the term meat on foods derived from cell lines, the agreement between FDA and USDA may not be the end of the debate.

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After Several Attempts to Get it Right: FDA Releases Final Guidance on Evaluation of Bulk Substances for Use in Section 503B Outsourcing Facilities

After Several Attempts to Get it Right: FDA Releases Final Guidance on Evaluation of Bulk Substances for Use in Section 503B Outsourcing Facilities

By Karla L. Palmer

On Monday, March 4, 2019,  FDA released its Final Guidance , titled “Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act.”  We blogged about FDA’s draft guidance here, which FDA published about a year ago in March 2018.  As noted in that prior blog post, FDA’s impetus for re-doing – for a third time – the process for its evaluation of bulk substances was largely driven by a lawsuit filed against the Agency after it determined in the summer of 2017 to include the bulk substance vasopressin on the list – vasopressin bulk products likely would compete with Endo/Par’s FDA-approved Vasostrict.  (See the Complaint filed by Endo International and Par Sterile Products against FDA and blogged about here).  More to follow soon on the exciting saga of vasopressin, Athenex, Endo/Par, and FDA ….

FDA’s Federal Register Notice on the final bulks evaluation guidance states that it received about 60 comments on the revamped evaluation process.  Although FDA did not address specifically in its Notice any of those comments, it did (in response to comments received and “on its own”), for example, further explain how “Congress’ limitation on bulk drug substances that can be used in compounding … helps to preserve the integrity of the new drug approval process and identified the process to request that FDA add or remove a bulk drug substance from the 503B Bulks List after the Agency has made a final determination” concerning the substance.  The evaluation process itself that FDA sets forth in the Final Guidance remains unchanged from FDA’s March 2018 draft evaluation process, as shown in this comparison of the draft and the final guidances.   The first consideration FDA makes in its evaluation process is whether the bulk substances is a component of an FDA-approved drug product.

What is somewhat disconcerting is that FDA undertook this third and final review of its bulks nomination process based on the Endo/Par challenge under the Administrative Procedure Act.  FDA states its changes to the Final Guidance underscore the importance of protecting the integrity of the drug approval process, securing a safe drug supply and enhancing innovation.  Notwithstanding, vasopressin, which has been used in hospitals and on crash carts for decades, was approved as part of FDA’s unapproved drugs initiative, and to our knowledge has likely resulted in a dramatically increased price for the FDA-approved drug product, which leaves a complicated issue for consumers of drug products – and FDA.

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