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.

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.

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.

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.

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.

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).

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.

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.

The American Conference Institute’s (“ACI’s”) popular “FDA Boot Camp” – now in its 33rd iteration – is scheduled to take place from March 25-27, 2019, at the Park Lane Hotel in New York, NY. 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
• A session on “How FDARA and the 21st Century Cures Act Are Impacting Drug Approvals through New Evidentiary Requirements”

Hyman, Phelps & McNamara, P.C.’s Jeffrey K. Shapiro will present in a session titled “Medical Devices, Combination Products, and Companion Boot Camp: A Review of FDA Guidelines and Regulations.”

FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount. The discount code is: D10-874-874BX01.  You can access the conference brochure and sign up for the event here.  We look forward to seeing you at the conference.

On March 5, Scott Gottlieb, M.D., announced he will be stepping down as Commissioner of FDA.  His resignation will become effective in about one month.  His two-year tenure, since May 2017, has been very productive.  Gottlieb spearheaded initiatives on a variety of complex issues, including generic drug pricing, electronic cigarettes, drug compounding, and the 510(k) program.  Secretary of HHS, Alex Azar, stated that Dr. Gottlieb “has been an exemplary public health leader, aggressive advocate for American patients, and passionate promoter of innovation.”

Dr. Gottlieb has also been a prolific tweeter throughout his time as Commissioner, frequently engaging directly with the public about the Agency’s actions.  At the FDA Law Blog, we have been particularly grateful for his tweets expressing appreciation of our article titles.

Though we do not yet know what the future holds for FDA in the post-Gottlieb era, we decided to look back at some of his noteworthy actions and accomplishments as described in our blog posts:

1. FDA Announces Various Initiatives to Increase Oversight of the Dietary Supplement Industry – February 15, 2019
2. Commissioner Gottlieb and CBER Director Marks Deliver “State of Cell and Gene Therapy” Joint Statement – January 30, 2019
3. C. Escher By Way of Generic Drug Pricing – January 18, 2019
4. International Plan of Mystery: ICH Guidelines for Generic Drugs – November 28, 2018
5. Possible Major Changes to 510(k) Program Ahead – November 26, 2018
6. Gottlieb to E-Cigarette Manufacturers: Reduce Youth Use or I Will END You – September 18, 2018
7. FDA Commissioner Gottlieb Indicates Modification of Requirement for “Added Sugar” Declaration on Pure Maple Syrup and Honey; Details are Forthcoming – Sweet! – September 17, 2018
8. Industry Submits Comments (Nearly 3000) and the Agency Listens: Revised Draft Standard MOU Addressing Section 503A’s Limits on Interstate Shipments of Compounded Medications – September 10, 2018
9. It Feels Like the First Time: FDA’s First Competitive Generic Therapy Approval – August 9, 2018
10. FDA Commissioner Gottlieb Emerges as a Champion for Patient Engagement in 2018; Patient-Centric Guidance Development, Rare Disease Listening Sessions, and the Benefit-Risk Framework – April 11, 2018
11. FDA Opens A Door For Consumer Genetic Tests – December 4, 2017
12. Commissioner Gottlieb’s Statement: “We Want You”… Seeking Able-Bodied Compounders to Register as Outsourcing Facilities Pursuant to FDCA Section 503B – October 4, 2017
13. FDA’s Hatch-Waxman Public Meeting and Progression of the Agency’s Drug Competition Action Plan – July 19, 2017
14. A Few More Steps in FDA’s Drug Competition Action Plan – June 27, 2017
15. FDA, Under New Leadership, Seeks More Comments on Rules Affecting Off-Label Communications – May 19, 2017

On October 24, 2018, the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (“SUPPORT”) for Patients and Communities Act was signed into law (the Act’s text is available here).  The SUPPORT Act includes a number of provisions to address the ongoing opioid crisis, such as expanding the use of telehealth services for the treatment of Medicare beneficiaries with substance abuse disorders and increasing the number of health care providers that can prescribe or dispense medications that treat opioid use disorders.

Buried within the 250 page SUPPORT Act is Section 8122, the “Eliminating Kickback in Recovery Act of 2018” (“EKRA”) (codified as 18 U.S.C. § 220).  Although there is limited legislative history for this section, it appears that EKRA was initially intended to prohibit recovery homes and clinical treatment facilities from engaging in “patient brokering,” a practice where third parties recruit individuals with substance abuse disorders for these facilities in exchange for kickbacks.  However, the addition of laboratories to EKRA, seemingly at the last minute, makes this section of the SUPPORT Act much more expansive.

Under EKRA, it is a federal crime to knowingly and willfully:

1. solicit or receive any remuneration (including any kickback, bribe, or rebate) directly or indirectly, overtly or covertly, in cash or in kind, in return for referring a patient or patronage to a recovery home, clinical treatment facility, or laboratory; or
2. pay or offer any remuneration (including any kickback, bribe, or rebate) directly or indirectly, overtly or covertly, in cash or in kind–
   • to induce a referral of an individual to a recovery home, clinical treatment facility, or laboratory; or
   • in exchange for an individual using the services of that recovery home, clinical treatment facility, or laboratory.

Violations of EKRA may result in fines of no more than $200,000, imprisonment of no more than 10 years, or both, for each occurrence.

Although the language used in EKRA is similar to the language in the Federal Health Care Program Anti-Kickback Statute (the “Federal AKS”) (42 U.S.C. § 1320a-7b(b)), there are some important differences to be aware of.

First, EKRA applies to all health care benefit program business, including private payors, while the Federal AKS applies only to items and services paid for by federal health care programs.

Second, even though the SUPPORT Act focuses on substance abuse treatment, EKRA applies to all laboratory testing, regardless of whether the laboratory tests are related to substance abuse.

Third, like the Federal AKS, EKRA includes exceptions for certain arrangements (e.g., discounts, personal services and management contracts).  However, some of EKRA’s exceptions are different than the Federal AKS exceptions.  For example, EKRA includes an exception for patient copay and coinsurance waivers and discounts that differs from Federal AKS guidance regarding such waivers and discounts.  More importantly, EKRA’s exception for remuneration paid to employees is narrower than that the Federal AKS employment exception.  The Federal AKS employment safe harbor (42 C.F.R. § 1001.952(i)), protects payments, including volume-based commissions, paid to bona fide employees.  EKRA protects payments made to bona fide employees and independent contractors as long as the payment is not based on the number of individuals referred, the number of tests performed, or the amount billed to or received from a health care benefit program from the individuals referred.  In other words, even though volume-based commissions may be paid to employees under the Federal AKS, under EKRA, a laboratory that pays volume-based commissions to its employees risks enforcement.

EKRA became effective when the SUPPORT Act was signed into law on October 24, 2018, but federal regulations and guidance have not yet been issued, so there are still outstanding questions about EKRA’s impact.  One significant question is the extent to which certain aspects of EKRA are preempted by other laws, including the Federal AKS.  As drafted, EKRA says that it does “not apply to conduct that is prohibited under [the Federal AKS].”  This somewhat confusing language seems to prevent prosecution of conduct involving federal health care programs under both EKRA and the Federal AKS.  However, conversely, this appears to permit prosecution under EKRA of conduct permitted under the Federal AKS (e.g., a laboratory that provides volume-based commissions protected by the Federal AKS to employees, could be prosecuted under EKRA for providing those commissions).

We will continue to monitor developments related to EKRA but encourage laboratories to evaluate how this new law impacts their current business practices.

On February 21, the U.S. Court of Appeals for the Second Circuit issued a summary order reversing the dismissal by the District Court of the Southern District Court of New York of an action by FTC and New York State (“FTC”) action challenging the marketing claims for Prevagen.

As we reported previously, the marketers of Prevagen claimed that a “landmark double-blind and placebo controlled trial demonstrated” that Prevagen improved short-term memory, learning, and delayed recall over 90 days.  However, although the company did in fact perform the claims study, according to the FTC the study did not support the claims; in fact, the study failed to show a statistically significant improvement in the experimental group over the placebo group.  Only after Defendants conducted more than 30 post-hoc analyses of the results did they find some statistically significant differences.  Nevertheless, the lower court dismissed the action, finding that the FTC challenge to the study “never proceed[ed] beyond the theoretical” because the complaint only showed that there were “possibilities that the study’s results do not support its conclusion.”  The Second Circuit disagreed.  Without going into detail on the statistical (mis)understanding by the lower court, the Court of Appeals concluded that the complaint adequately alleges that the results of the study contradict representations made in the marketing materials, and therefore, the lower court erred in dismissing the action.

On Tuesday, February 19, 2019, FDA released its first Final Rule (of many likely to follow…) identifying six substances that FDA has determined are appropriate for use in compounding by Section 503A pharmacies.  The Final Rule relates back to FDA’s 2016 Proposed Rule nominating certain bulk substances and setting forth proposed criteria for bulk substance evaluation by FDA and its Pharmacy Compounding Advisory Committee.  The Final Rule also identifies four substances that FDA has determined may not be used in compounding, and provides information on factors that FDA will consider when it reviews bulk substance nominations submitted under Section 503A.  Lastly, the Federal Register notice announcing the rule addresses in its preamble the dozens of comments submitted to the docket announcing the proposed rule.

First, concerning substances: FDA added the following to Bulks List 1:

• In addressing one comment, FDA Brilliant Blue G—otherwise known as Coomassie Brilliant Blue G-250
• Cantharidin (for topical use only)
• Diphenylcyclopropenone (for topical use only)
• N-acetyl-D-glucosamine (for topical use only)
• Squaric acid dibutyl ester (for topical use only)
• Thymol iodide (for topical use only).

The following will not be added to FDA’s Bulks List 1:

• Oxitriptan
• Piracetam
• Silver Protein Mild
• Tranilast

Concerning comments filed after publication of the proposed rule, a few highlights:

FDA acknowledges (at page 4701) that unless otherwise indicated, “inclusion of a substance on the 503A Bulks List is not limited to a specific use.”  But, for purposes of evaluation of a substance for inclusion, FDA does find it necessary to examine a substance in the context of a specific or proposed use, noting it would not be possible for FDA to consider all uses for all nominated substances.

FDA also addresses (in response to several comments) whether USP dietary supplement monographs should be considered an “applicable USP or NF monograph” under Section 503A, and thus permitted for use in compounding human drug products.  As set forth in Section 503A(b)(1)(A)(i), a bulk substance may be used in compounding if it meets one of the following criteria; (1) complies with the standards of an applicable USP or NF monograph if one exists, and the USP chapter on drug compounding; (2) if such a monograph does not exist, it is a component of an FDA-approved drug; or (3) if such a monograph does not exist and it is not a component of an approved drug, then it is on a list of bulk drug substances that may be used in compounding, to be developed by FDA through regulation (which is the point of the Final Rule).  FDA’s 2016 Proposed Rule on use of bulk substances under Section 503A, advises that the “applicable USP or NF monograph” must be a USP or NF “drug “ monograph, and not a USP dietary substance monograph.  Further elaborating on this issue, FDA states that its interpretation is both “legally supportable and in the best interest of the public health.”  This is because, among other stated reasons, dietary supplements and drug substances have different regulatory schemes, and pharmacy compounding involves the compounding of drug products and not dietary supplements.  FDA further states its interpretation is in the best interest of the public health because USP dietary supplement monographs can differ significantly from drug monographs due to the “differences between dietary supplements and drug products.“  Noting that dietary supplements are for ingestion, those standards are not necessarily appropriate for compounding drug products that may be used for different routes of administration such as injection, topical, or intramuscular use.  FDA further states that USP limits for impurities are different for these two types of products; specifically, the bioburden allowable for dietary supplements is considerably higher than allowed for drug substances.  Reliance on dietary supplement standards, although “USP” could also put patients at risk, FDA states.  FDA notes, however,  that the availability of a substance as a dietary supplement is not a criterion that FDA considered when evaluating a substance for inclusion on 503A’s Bulks List. Concerning a comment on the applicability of the Homeopathic Pharmacopeia of the United States or other types of monographs as also “applicable” monographs for use in compounding under Section 503A, FDA states that it declines to consider such a compendium an “applicable monograph” under Section 503A.

We are sure more Bulks Lists — proposed and final rules — for both Sections 503A and B will follow in the coming months and years.  This one is effective as of March 21, 2019.

After months of ever expanding drug recalls, and multiple investigative reports by different media outlets calling into question the safety of the U.S. generic drug supply (see, for example, “America’s Love Affair with Cheap Drugs has a Hidden Cost,” “How a Tainted Heart Drug Made in China Slipped Past the FDA,” and “Culture of ‘Bending Rules’ in India Challenges U.S. Drug Agency” all published earlier this year by Bloomberg, as well as “When Medicine Makes Patients Sicker” published earlier this year by Kaiser Health News) Commissioner Gottlieb and Center Director Woodcock took the unusual step of issuing a press release to refute some of the allegations in these reports.

Recently, there have been reports in the press calling into question the quality of our nation’s drug supply and specifically, asserting that certain generic drugs are of a lesser quality than brand drugs. Some of these reports claim to be based on data analysis. We believe these interpretations are seriously flawed and do not account for the full picture of our global vigilance over generic drug manufacturing.

Apart from the standard statements that we’ve previously heard from FDA, such as the fact that generic drugs are just as safe and effective as their brand drug counterparts, and that FDA continuously analyzes data to ensure the quality and safety of both generic and brand drugs throughout the products’ lifecycle, the press release included some new information.

For example, the agency stated that pharmacovigilance data regarding Atorvastatin (the generic name for Lipitor), which has been in the news lately, indicates that there is no evidence that any single generic version of this drug was more likely to be associated with adverse events than any other, and also that there is no evidence that any Atorvastatin generic drug was more likely to be associated with adverse events than the innovator product.  It is instructive that the agency did not make similarly specific assertions regarding any of the other drugs referenced in the recent media reports cited at the top of this posting.

Also, to rebut suggestions in the media that the perceived problems with generics were due to the diminished number of surveillance inspections, the press release seemed to acknowledge the reduced number of inspections while at the same time dismissing its significance due to the agency’s improved targeting of inspections where they are most needed:

“While the numbers of inspections have varied over the past few years, compliance actions, including warning letters, have increased. Warning Letters to human drug manufacturers regulated by the FDA’s Center for Drug Evaluation and Research (CDER) have steadily increased over the past four years. In fact, in FY 2018, CDER issued nearly five times as many warning letters to human drug manufacturers as it did in FY 2015.

19 in FY 2015;

43 in FY 2016;

67 in FY 2017; and

94 in FY 2018.

But it’s important to note that we don’t believe this reflects a growing problem in drug quality. On the contrary, the FDA’s improvements to targeting inspections and in evaluating recommendations for enforcement action mean more attention is being given to higher risk facilities than ever before. By better focusing our inspectional resources on higher risk facilities, we can identify potential quality problems that have the most impact on consumers. Then, we can take appropriate action to address our public health concerns.”

Another FDA statement that we are all familiar with, and that was repeated in the press release, is that drugs manufactured outside the U.S. are required to meet the same standards as drugs made domestically.  In addition, the agency added that: “…the FDA labs tested 323 products from around the world – including more than 100 from India – to determine if foreign manufacturers had a higher incidence of product failure. All 323 samples met U.S. market quality standards using testing standards set by the United States Pharmacopeia (USP) or submitted in marketing applications.”

However, what the press release fails to mention is whether the samples from India had, on average, exceeded pharmacopeial standards by as much, or more, as the products manufactured in the U.S. and other first world countries.  What also remains unanswered is whether the FDA disagrees with the implication from these recent media reports that, on average, there are more frequent and more significant quality problems with drugs emanating from developing countries than with drugs emanating from the developed world and, if so, what more will FDA be doing to deal with these issues?

Back in 2014, The Sunscreen Innovation Act (“SIA”) amended the Federal Food, Drug, and Cosmetic Act with the goal of accelerating the review of sunscreen ingredients that had been proposed for addition to the sunscreen monograph.  Although the original focus of the SIA was on ingredients that sought to be added via the time and extent application (“TEA”) process (see our blog post here), it also included a host of directives to FDA to issue guidances, certain procedural rules, and by November 26, 2019, a final rule on nonprescription sunscreens (the legislation did not include a deadline for a proposed rule).  To date, FDA has met the deadlines for these various guidances and other actions (some are discussed here, here, and here).  The only remaining significant item on the SIA “to-do” list is the final rule mandate.

On February 26, FDA issued the proposed rule which covers overall safety and effectiveness standards, and addresses the status of the active ingredients already covered by the stayed final rule (but not the TEA ingredients).  Although safety of the various active ingredients is the main issue, the proposed rule also addresses a host of other issues, such as dosage forms, sun protection factor (“SPF”) limits and labeling requirements.

Safety

The core of the proposal focuses on safety.  At the outset, FDA emphasizes that even though FDA concludes that the safety information for most of the active ingredients from the 1999 stayed monograph is insufficient to meet the standard for Generally Recognized as Safe and Effective (GRASE) Category I, and places the majority of active ingredients in Category III (insufficient evidence for safety), the Agency is not concluding that those sunscreen active ingredients are unsafe; the placement in Category III merely means that additional information is required in light of changed conditions – substantially increased usage and evolving understanding of skin cancer, and the contribution of various UV waves, as well as risks associated with topical products in general.

Since 1999, knowledge about safety for topical drug products for chronic use has evolved. FDA previously discussed the new safety requirements in the 2016 guidance issued pursuant to the SIA.  FDA now considers topical safety issues, such as irritation, sensitization and photo-safety, bioavailability (systemic absorption) and adverse events, as well as carcinogenicity and reproductive toxicity when considering the safety of sunscreen products. The same standard applies for products marketed under a new drug application, or NDA, as well as for monograph products.

Based on the evaluation of available data, FDA concludes that titanium dioxide and zinc oxide (including their nanomaterial forms), are both mineral sunscreens that do not penetrate and are not absorbed through the skin.  Thus, the safety evaluation does not need to consider more than direct effects on the skin.  FDA has sufficient evidence that they are GRASE Category I.  Based on existing data, FDA also has concluded that two active ingredients, amino benzoic and trolamine salicylate, are unsafe and, therefore, are Category II.  Based on information available to FDA, these two active ingredients are not currently used in any sunscreens currently marketed in the United States.

For the remaining 12 active ingredients, cinoxate, dioxybenzone, ensulizole, homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate O, sulisobenzone, oxybenzone, and avobenzone, FDA has not identified safety concerns, but states that existing evidence suggests that these active ingredients are, or may be, absorbed through the skin, and data about the consequences of this absorption are missing.  For each ingredient, FDA discusses the data available and identifies what additional studies are required.  Although more data are available for oxybenzone and avobenzone than for the other 10 Category III ingredients, some data gaps exist.

FDA anticipates that it will require safety testing for final formulations of products containing active ingredients that are absorbed through the skin.  Because, at this time, none of the Category I ingredients are absorbed, it does not propose such testing at this time.

FDA’s requirements regarding safety should not come as a surprise as they are consistent with the individual TEA orders it issued in 2014 and 2015, and with FDA’s 2016 guidance, as well as with the 2018 draft guidance describing recommendations for demonstrating absorption of topical OTC active ingredients for purposes of establishing GRASE status (the so-called “MUsT” guidance).

Dosage Forms

In an ANPR discussing dosage forms, FDA solicited information on spray sunscreens, and in the absence of evidence for the marketing of powder sunscreens before 1972, determined that this dosage form was not eligible for review.  FDA has determined that sunscreens in the spray dosage form may be GRASE provided that the droplets size distribution meets certain requirements, and the label includes specific directions to minimize unintended inhalation and includes a flammability warning.

FDA received information to establish that sunscreen powders were marketed before 1972 and, therefore, are eligible for review.  It requests further data on various issues such as whether the use of this dosage form should be limited to just the face.

Maximum SPF and Broad Spectrum Requirements

FDA discusses at some length new scientific information indicating the importance of broad spectrum protection to protect against UVA wavelength of 370 nm or higher.  Based on this new information it proposes to amend the 2011 rule for sunscreen testing.  Under the new proposal, all sunscreens labeled as SPF 15 or higher must be broad spectrum and must demonstrate protection against irradiation at wavelengths above 370 nm.  These new requirements do not require a change in the testing method; all the required data can be calculated from information acquired by the current method.

FDA has tentatively determined that products with SPF 2-14 are not required to provide broad spectrum protection. Although such products provide no protection against skin cancer, they do reduce the risk of sunburn.  FDA proposes to require prominent label statements to alert consumers to the limited benefit of these low SPF products.  FDA also seeks comments on whether the limited benefits of low SPF sunscreens outweigh the risks (i.e., whether such products which protect only against sunburn are GRASE).

FDA also has reconsidered its position regarding the maximum SPF.  It now proposes to set the maximum label SPF at 60+ and cap the actual SPF for such products at 80.   Because SPF values vary, with increasing variability at higher values, FDA proposes that they be declared in increments of 5 for products with SPF 15-30, increments of 10 for products with SPF 30 to 60, and as 60+ for values in the range of 60-80.

Labeling Revisions

Although FDA’s labeling regulation for sunscreens was finalized only in 2011, the Agency proposes several changes, including a requirement to include on the principal display panel, the names of the active ingredients, a disclosure for products with SPF 2-14, and font size and color requirements for the statement of identity.

Efficacy Testing Final Formulation

Based on experience gathered in inspections and from other sources, FDA is concerned that testing for sunscreen formulations is not always conducted in a way that protects human subjects and produces reliable results.  It proposes to amend the current regulation to clarify the requirements for an IRB and informed consent, use of qualified personnel to conduct the studies, and related requirements for clinical studies.  Failure to observe these best practices will cause the product to be misbranded.  Also, because final formulation testing constitutes the manufacture of a drug, failure to follow proper procedures in clinical tests for the sunscreen would result in an adulterated product. FDA also proposes specific record keeping requirements.

Sunscreen-Insect Repellant Products

FDA has (tentatively) determined that sunscreen-insect repellant products are not GRASE.  FDA bases this determination primarily on the incompatibility of the intended uses and directions for use (sunscreen applied every 2 hours, insect repellant less frequently), and the lack of safety data about possible interaction.

Denial of Three Citizen Petitions

On the day that FDA announced the issuance of the proposed rule, it also responded to three Citizen Petitions related to sunscreen regulations.  All three petitions were denied.  Bare Escentuals Beauty, Inc. had requested that FDA recognize makeup powders as GRASE sunscreens.  As mentioned above, FDA now recognizes powders as a possible dosage form, but FDA denied the petition because, at this time, the Agency has insufficient evidence that sunscreen powders are GRASE.  In 2009, L’Oreal USA Product petitioned requesting that FDA amend FDA’s (stayed) regulation listing GRASE active ingredients to include 5% rather than 3% avobenzone.  FDA denied this petition because, as discussed in the proposed rule, the Agency has insufficient evidence to conclude that avobenzone (at either percentage) is GRASE Category I.  The third petition to which FDA responded was a Citizen Petition by Rapid Precision Testing Laboratories requesting that FDA determine that certain active ingredients included in the stayed monograph are not safe because of their alleged anti-inflammatory effects, thus inflating the SPF value of formulations containing the active ingredients, and that FDA amend the SPF testing method to avoid the alleged effect of anti-inflammatory substances.  FDA concluded that there was insufficient evidence of the alleged effects and denied the Petition.

Effective Date

FDA proposes a comment period of 90 days and an effective date of November 26, 2019, for the final rule.  This date undoubtedly is inspired by the date set in the SIA.  This date would be optimistic in the best of circumstances; 6 months to analyze comments, and internal and administrative reviews, does not appear realistic.  In addition, because of the host of data gaps for the Category III ingredients, we expect to see requests for deferral for many of these ingredients to allow time for collecting of additional data to demonstrate that they are GRASE.  FDA proposes to allow ingredients deferred from the final rulemaking to remain on the market as the data are being generated.

Comments must be submitted by May 27, 2019.