I Hear You Knockin’… Preparing for and Managing DEA Inspections (Part 3)

I Hear You Knockin’… Preparing for and Managing DEA Inspections (Part 3)

By Larry K. Houck

This is the third in a series of posts on what DEA registrants can expect during cyclic and on-site inspections.  Our series focuses on the background of such inspections, how investigators conduct them and how registrants should proactively prepare for and manage them.  Part 1, posted May 3rd, examines the purpose, background and scope of DEA cyclic and on-site inspections.  We posted Part 2 on May 21st, explaining how diversion investigators conduct on-site inspections and what registrants must do before, during and after each inspection to minimize negative findings.

The link to Part 1 is here and Part 2 is here.

Part 3 below lists DEA inspection do’s and don’ts for registrants. They are intended to help DEA registrants be prepared for a DEA inspection.  In our experience, unpreparedness can lead to confusion or misunderstandings during an inspection, and potentially cast a negative light on an  otherwise compliant facility.

Inspection Do’s and Don’ts

Registrants should implement the following to prepare for and manage DEA cyclic inspections:

  1. Designate a specific employee as the contact/liaison for any DEA inquiries or inspections. Also, ensure at least one contact/liaison back-up given that regulatory inspections always seem to occur at the worst time, i.e., the designated employee is on vacation or out that day.  The designated contact/liaison should greet the investigators immediately upon commencement of a DEA inspection, and be available at all times while investigators are on-site.
  2. Ensure DEA registrations and state licenses are current and active and copies maintained in an easily accessible file.
  3. Maintain an updated copy of all controlled substance policies and procedures. These should be routinely reviewed and ensure that they comply with the current federal Controlled Substance Act (“CSA”) and regulatory requirements.  We also suggest that a DEA registrant have a specific protocol or policy that details responsibilities during a DEA inspection.
  4. Conduct periodic random audits and mock DEA inspections comprising accountability audits, and record/report and security reviews. These should be performed by third-parties or independent staff without day-to-day controlled substance responsibilities. Periodic random internal audits disclose losses and deter internal theft. Mock internal inspections help ensure compliance and instill familiarity and confidence in employees during actual DEA inspections. Review prior DEA inspection documents and notes.  Ensure past deficiencies have been remedied.
  5. Compile and maintain an updated inspection binder to provide to investigators comprised of: (a) Copies of current DEA registration and state license certificates; (b) List of controlled substances handled for prior two years; (c) Corporate structure; (d) Hours of operation; (e) Officers, management and responsible employees’ name, home address, date of birth and social security numbers; (f) Employees with access to warehouse, cage and vault; (g) Security system component literature with specifications; (h) Alarm test results; and (i) Central station alarm monitoring contracts.
  6. Consult with Human Resources and employment counsel on requests from DEA for personal employee information.
  7. Maintain all required records and reports in a manner that they can be readily identified, produced or retrieved (in the case of electronic records).  For paper records this means  having them organized and stored in a location that can be easily retrieved.  Be clear on designation of official records that will be produced during any inspection.
  8. Maintain required records and reports for at least two years unless state law requires they be maintained for a longer period of time. Maintain records and reports on-site unless the registrant has notified DEA of off-site storage.
  9. Maintain controlled substances in secure areas at all times except during receiving, processing, packaging, labelling or conveying to the secure loading area. Return controlled substances to secure areas as soon as possible at the end of the activity or workday.
  10. Ensure controlled substances awaiting return or destruction are properly secured and documented. Remember that such products must still be included in any current inventory until they are removed from the facility.
  11. Regularly dispose of expired or unusable controlled substances. Although DEA regulations do not require expired or damage drugs to be disposed of in a certain time, keeping excessive inventories of drugs to be destroyed can be viewed by DEA as a security risk.
  12. Change locks or keycard access, and update lists of authorized employees with access to the warehouse, cage and vault after every relevant personnel change.
  13. Inspect security system components at least quarterly. Repair broken or inoperable components immediately.  (Investigators also appear when a security component is not working properly).  Maintain documentation and literature related to the security system and its components for future reference.
  14. Test every alarm sensor with the central monitoring station at least twice a year.
  15. Evaluate and understand the scope of the DEA inspection. Review each investigator’s credentials and request copies of their business cards.  Understand the differences between a Notice of Inspection, Administrative Inspection Warrant (“AIW”), or Search Warrant.  Corporate counsel should always be notified in the event of an AIW or Search Warrant
  16. Ensure that investigators have an area to work that does not interfere with operations.
  17. Keep accurate notes of all requests for information and/or observations, criticisms or recommendations by DEA investigators. Request clarification from investigators on any areas or requests that are unclear.
  18. Employees should assist investigators with any routine questions about operations or records/reports. However, any requests to interview employees should be referred to senior management and counsel.
  19. Make sure that investigators have all records and reports to conduct their audit and that they understand the registrant’s recordkeeping, reporting and security. Inform the investigators immediately if they do not have accurate counts and inventories of every drug they are auditing, or if they are missing relevant records or reports. Understand the methodology the investigators use to conduct their accountability audit.
  20. For the final audit count, do not overlook drugs in the morgue awaiting destruction or elsewhere on the premises.
  21. Photocopy or set aside in a separate file all records and reports that investigators review, make copies of, take or specifically raise questions about during the investigation.
  22. If the investigators take drugs or original records or reports off-site, obtain a DEA receipt (“DEA Form-12”) listing each item.
  23. Correct deficiencies found by investigators while they are on-site or as soon as possible thereafter.
  24. Provide unavailable information and records or reports requested by the investigators as soon as possible if appropriate to do so.
  25. Do not surrender a DEA registration without consulting an attorney.
  26. Although not required by DEA regulations, request a final discussion or exit interview with the investigators at the conclusion of their on-site activities.
  27. Conduct a post-inspection mirror audit to identify/anticipate any issues DEA may raise in the future and be prepared to address or where necessary take remedial action.

Conclusion

Implementing the recommendations above will help registrants proactively prepare for and manage DEA inspections.  Preparing for and managing successful DEA inspections require preparation, organizing and maintaining complete and accurate records/reports but also employee familiarity with what to expect.  Knowledge of DEA cyclic inspections provided in our three posts will put registrants in the best position to achieve those goals.

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FDA Issues Draft Guidance Distinguishing Remanufacturing from Servicing

FDA Issues Draft Guidance Distinguishing Remanufacturing from Servicing

By McKenzie E. Cato

On June 18th, FDA published a draft guidance document titled Remanufacturing of Medical Devices, which has been several years in the making.  The draft guidance distinguishes between “remanufacturing” and “servicing” of devices.  This distinction can be critical, due to the significantly increased regulatory requirements that apply to a device remanufacturer compared to a device servicer.

In 2016, FDA opened a docket seeking comments on “service, maintenance, refurbishment, and alteration of medical devices” by third parties (see our blog post here).  Two years later, in 2018, FDA issued a Report on the Quality, Safety, and Effectiveness of Servicing of Medical Devices (see our blog post here).  The 2018 report listed several planned actions by the Agency, one of which was to clarify the difference between servicing and remanufacturing.  The new remanufacturing draft guidance appears to be the result of this action item in the 2018 servicing report.

A remanufacturer is defined in FDA’s Quality System Regulation (QSR) as “any person who processes, conditions, renovates, repackages, restores, or does any other act to a finished device that significantly changes the device’s performance or safety specifications, or intended use.”  21 C.F.R. § 820.3(w).  “Remanufacturing” is also included in the definition of “manufacturer” in the regulations.  Id. § 820.3(o).  Because a remanufacturer is defined as a type of manufacturer in the QSR, a remanufacturer must comply with all of the stringent regulatory requirements that apply to a device manufacturer including design controls, production and process controls, complaint handling, and more.

In contrast, a device servicer is not a device manufacturer and, therefore, need not comply with the QSR.  “Service” is defined in the draft guidance as “repair and/or preventive or routine maintenance of one or more parts on a finished device, after distribution, for purposes of returning it to the safety and performance specifications established by the [original equipment manufacturer (OEM)] and to meet its original use.”  According to the draft guidance, servicing excludes activities that significantly change a finished device’s safety or performance specifications or intended use, which would instead fall within the definition of remanufacturing.

Both the 2018 servicing report and the draft guidance note that the majority of complaints and comments received by FDA on inadequate “servicing” that caused or contributed to adverse events or deaths were actually remanufacturing activities.  The draft guidance includes a framework and decision-making flow chart that can be used to distinguish servicing from remanufacturing, and in turn, properly identify the regulatory requirements that apply to the activity.

The draft guidance begins with several “guiding principles” that FDA recommends applying in assessing whether an activity is remanufacturing or servicing:

  1. assessing whether there is a change to the intended use;
  2. determining whether the activities, individually or cumulatively, significantly change the safety or performance specifications of the finished device;
  3. evaluating whether any change to a device would otherwise require a new marketing submission (e.g., in accordance with FDA’s guidance on Deciding When to Submit a 510(k) for a Change to an Existing Device);
  4. assessing changes to dimensional and performance specifications, including to components, parts, or materials;
  5. employing a risk-based approach (e.g., in conformance with ISO 14971) to assess whether an activity is significantly changes performance or safety specifications and therefore should be considered remanufacturing; and
  6. adequately documenting decision-making to help justify decision-making in the event that an inspection is conducted by FDA or the entity’s rationale is otherwise requested by FDA.

FDA defines a “significant change to device performance or safety specifications,” which would be considered remanufacturing, to be a change that, “based on verification and validation testing and/or a risk-based assessment, results in a finished device that is outside the OEM’s performance or safety specifications or introduces new risks or significantly modifies existing risks.”  The draft guidance identifies certain types of activities that FDA believes significantly change the legally marketed device’s performance or safety specifications:  changes to the device’s sterilization methods; changes to the device’s reprocessing instructions; and changes to the device’s control mechanism, operating principle, or energy type.

The draft guidance includes a decision-making flowchart to assess whether a modification to a finished device would be considered remanufacturing.  The flowchart is meant to be used only after an entity has determined that a modification to a device does not significantly change the intended use of a device, because a significant change to the intended use of a finished device would likely be considered remanufacturing.  The flowchart includes questions on adding, removing, or changing a component, part, or material, and assessing whether there are any new or modified risks or significant changes to performance or safety specifications.  If any modification to a finished device is a significant change to a device performance or safety specification, the modification is considered remanufacturing.

While the flowchart provides a helpful framework for assessing device modifications, it is very high-level and lacking in detail, so a close read of the illustrative examples and definitions provided in the draft guidance would be required to adequately assess whether a modification constitutes remanufacturing.

The draft guidance recommends that entities performing servicing activities document their decisions that an activity is not remanufacturing in internal memoranda.  This documentation can be used to justify or explain an entity’s decision-making in the event of an FDA inspection or other request from the Agency.  In an appendix to the draft guidance, FDA provides some helpful examples of the type of information that should be included in such an internal memo.

Now that there is more specific guidance from FDA on what distinguishes servicing from remanufacturing, though only a draft guidance, entities that routinely perform servicing activities should consider implementing a procedure to assess whether an activity significantly changes a device’s intended use or specifications such that it meets the definition of remanufacturing.  Such a procedure could include the decision-making flowchart in FDA’s draft guidance and a template form for documentation of decision-making consistent with the examples in the draft guidance.

Interested parties have until August 23, 2021, to comment on the draft guidance.

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Critics Suggest FDA Approving Aduhelm Will Erode the “Public Trust”: What About Patients’ Trust?

Critics Suggest FDA Approving Aduhelm Will Erode the “Public Trust”: What About Patients’ Trust?

By James E. Valentine

For the last 13 years, this blogger has been at the center of what has now been dubbed “patient-focused drug development.” For 6 years, I served as a patient liaison within FDA in what was then called the Office of Special Health Issues.  This was the office (originally the AIDS Relations Staff) that was established in the 1980’s in response to the HIV/AIDS activism movement, the first function within the Agency with a mission to engage with patient stakeholders.  Over the years, this function expanded to cancer (renamed the Office of AIDS and Special Health Issues) and, ultimately, all serious and life-threatening diseases (dropping the AIDS nomenclature).  As part of this lean and mean team, I worked to incorporate patient viewpoints into study design, results interpretation, and, ultimately, benefit-risk decision-making.  In 2012 we at the Agency, under Dr. Janet Woodcock’s leadership, identified the need for more systematic patient engagement — a way to improve representativeness and be more proactive rather than reactive to interacting with patient communities.  So, we crafted the Patient-Focused Drug Development, or PFDD, a commitment that was agreed to in PDUFA V.  This launched us into a new era where we acknowledged that patients are experts in their lived experience and have important preferences to share. To ignore this wealth of expertise would be a huge missed opportunity to inform drug development and review.  Even since leaving FDA, as the PFDD initiative transitioned to externally-led meetings, my HP&M colleagues and I have helped nearly three dozen patient communities plan externally-led PFDD meetings, and that is only half of the work we do to help facilitate what the 21st Century Cures Act codified as “patient experience data.”

I have been boots on the ground in watching the culture shift both within FDA and in industry, as the value of the patient voice has been recognized as legitimate.  I have witnessed it inform whether clinical trial results are clinically meaningful (or not) as well as the selection and even development of primary endpoints.  Patient stakeholders have become partners in a decision-making process that serves as the gatekeeper to drugs – including both their benefits and their risks – but also will determine whether the status quo will remain (i.e., the morbidity, oftentimes irreversible and progressive, and morality associated with their condition).  As someone who studied in the fields of public health, medical sociology, and biomedical ethics, I was impressed with how quickly the pharmaceutical and biotechnology arena caught up with what took many decades to occur in the context of the physician-patient relationship.  For too long, patients’ perspectives and own preferences we not considered in the provision of care by physicians at the patient level.  The practice of medicine was viewed as paternalistic.  Now there is a whole body of research that supports patients as partners in their own care, and the practice of medicine has largely corrected course.

This is what strikes me as so contradictory about the various critics who are suggesting that FDA violated the public trust when approving Aduhelm (aducanumab-avwa) for Alzheimer’s disease earlier this month (see our previous coverage of the approval here). In the last week, we have seen FDA advisory committee members resign in protest (see coverage here) and consumer advocates call for resignations of FDA officials (see coverage here). These self-proclaimed consumer and public health advocates, all who are physicians, feel they are in a better position to inform and/or judge FDA’s decision than the patients who will ultimately be the ones affected by this regulatory decision.  It harkens to the paternalism in medicine of the past.

As the ultimate stakeholder when it comes to drug approval decisions, shouldn’t we instead consider whether this builds or erodes patients’ trust in FDA?

Patient Input in the Approval of Aduhelm: Setting the Context for Accelerated Approval

While the FDA’s summary basis of approval, including supporting memos from both the Director of the Office of New Drugs (OND) and the Director of the Center for Drug Evaluation and Research (CDER), were just released (as I was writing this very post), FDA previously made clear statements about the role of patient stakeholders. In her closing statement during a press briefing on the date of the approval, CDER Director Dr. Patrizia Cavazzoni stated:

I wanted to thank the patients living with Alzheimer’s, their caregivers and health care professionals who have reached out to us over the past several months regarding the Aduhelm data. While our decisions are based on science and the data in the application, we have listened to and carefully considered the needs of the people who are living with this devastating, debilitating and incurable disease. The data supports patients and caregivers having the choice to use this drug.

What Dr. Cavazzoni lays out is the traditional way in which patients have informed drug benefit-risk decision-making: by setting the “clinical context” of the disease.  This clinical context encompasses two major considerations: 1) an analysis of the disease condition, including the severity of the condition, and 2) the degree of unmet medical need. This frames the assessment of benefits and risks, in a way, calibrating the application of the regulatory framework to the specific condition at hand.  For example, we know that cancer patients have a high tolerance for toxicity when offered a chance at improved survival, a risk tolerance that would not be shared by individuals suffering from the common cold.  We have also learned from patients with progressive conditions, like Pompe disease, that slowing progression of their otherwise universally permanently progressive condition would be of tremendous value to them – they do not need to see reduced symptom burden or improved functioning for a treatment to be meaningful.

However, the scope of patient input goes beyond setting the clinical context.  When a disease is serious or life-threatening and it has an unmet medical need, because there are serious risks associated with not approving a drug (i.e., serious morbidity, oftentimes irreversible and progressive, and risk of mortality), FDA must also balance the risks of making a type 2 error, or false negative conclusion from the data in hand.  Patients also have a role to play in setting the context for how much risk of a type 2 error they are willing to tolerate.  Or, said differently, patients can express their tolerance for less certainty of a treatment benefit.

Because no data set is completely reliable in establishing a drug’s benefit, and because no drug is universally effective for all patients, there is inherent uncertainty in every drug approval.  The question is: how much uncertainty is acceptable?  The Federal Food, Drug, and Cosmetic Act states that the evidence needs to be that “which it could fairly and reasonably be concluded…that the drug will have the effect…” (Section 505(d)).  Patients with different conditions, or even at different stages/severity of the same condition, may have different tolerance for less certainty (similar to the differences in risk tolerance discussed above).  This is why it is important for relevant patient populations to provide input as to what degree of certainty is needed for there to be a fair and reasonable conclusion of drug benefit for their condition.

One regulatory pathway that embodies this concept of “less certainty” is Accelerated Approval. These approvals, like with Aduhelm, may be granted when a benefit is demonstrated on a surrogate endpoint that is merely “reasonably likely…to predict clinical benefit” (i.e., it is not established using a validated surrogate endpoint that would support traditional approval, e.g., FEV1 in asthma or serum LDL in hypercholesterolemia).  Instead, the ultimate clinical benefit must be confirmed in a post-approval study.  If Accelerated Approval works to help expedite drugs to the market as it’s intended, then we should not expect not all drugs approved on these surrogates to have clinical benefit confirmed.  It is in acknowledgement of this inherent uncertainty that FDA has provisions for expedited removal of these drugs if benefit is not confirmed post-approval.

We see that FDA considered Alzheimer’s patients’ input on tolerance for less certainty of treatment benefit for Aduhelm when Dr. Peter Stein, OND Director, shared during the press briefing:

We heard very clearly from patients that they are willing to accept some uncertainty to have access to a drug that could provide meaningful benefit in preventing the progression of this disease which as we all know can have very devastating consequences.

It is clear that this patient input helped inform the Agency’s conclusion that it was appropriate to consider approval based on an unvalidated surrogate (as long as it could conclude the surrogate was “reasonably likely to predict” clinical benefit), even without the ultimate showing of clinical benefit at the time of approval.  Patients expressed a willingness to take on the risks of a drug, even if benefits were less certain, because this uncertain chance of benefit and the associated risks of the drug was worth it to them compared to the alternative: waiting several years for another study, during which time there will be irreversible, progressive neurodegeneration.  Losing one’s identity, or possibly one’s life.  This input was further acknowledged by Dr. Stein in the concluding paragraph of his Concurrence Memorandum (at 9-10):

…approval using this pathway requires a tradeoff: patients and physicians who choose to use the drug must be willing to accept some residual uncertainty regarding clinical benefit – and therefore be willing to take a drug that may ultimately prove ineffective – along with the risks of the drug, in order to gain earlier access to a potentially valuable treatment. FDA staff has heard from patients that many would consider this a reasonable tradeoff and would opt to accept the uncertainty and risks for a drug that is likely, but not confirmed, to provide clinical benefit, potentially slowing the progression of their disease. Based upon this, I agree with the Office of Neuroscience that the benefit-risk balance for aducanumab is positive…

Closing Thoughts: Building Patients’ Trust & Digging into the Aduhelm Summary Basis of Approval

These statements by FDA officials surrounding the approval of Aduhelm, articulating how patient input set the context for their approval decision, should build trust with all patients.  This transparency surrounding one approval decision exemplifies that patient input matters.  This trust, with patients, is the trust that FDA should be most concerned about.

While we made some initial reflections of the merits of the Aduhelm approval in our June 8th blog post, we have not yet fully reviewed the SBA that was just released.  However, in the coming days we hope to do so and may provide our thoughts in subsequent posts.  In our work across many sponsors with many therapeutic modalities for many indications, we see how the many FDA review divisions apply the Accelerated Approval “reasonably likely to predict” standard required of a surrogate endpoint and, even more so, the application of the “substantial evidence of effectiveness” standard required of all new drug approvals, accelerated or traditional.  It is through this lens that we hope to evaluate the Aduhelm approval, to consider whether it “erodes” FDA’s standards.  However, as we collectively review these FDA review documents, we should all consider the patient input that FDA has shared with us and have that serve as our context for review as well.

Further Resources on Patient Input

For those of you who may now be intrigued about the evolution of patient input in drug development and regulatory decision-making, I would point you to some of our FDA Law Blog posts from over the years on this important topic:

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What’s a Sponsor to Do?: The Curious Case of “Disputes” Over Phase 3 Study Design

What’s a Sponsor to Do?: The Curious Case of “Disputes” Over Phase 3 Study Design

By Josephine M. Torrente

End-of-Phase 2 (EOP2) is, in our view, one of the most critical moments in drug development.  It’s the moment at which a drug sponsor selects, and seeks FDA agreement on, its critical Phase 3 study parameters:  dose, eligibility criteria and endpoints, to name a few.  Errors or miscalculations in choosing these design components can send a safe and effective drug to the very expensive graveyard of failed Phase 3 studies.

So, what’s a sponsor to do when, at EOP2 and in subsequent interactions, it cannot reach agreement with the FDA review division on a critical parameter; let’s say the primary endpoint?  Submit a formal dispute resolution to bring the decision to the Office level, you say?  While that seems like a reasonable approach before spending millions of dollars on Phase 3, that option is not available to sponsors.  You see, in 2015, FDA revised its 15-year old FDRR guidance document to exclude EOP2 disagreements from the FDRR process (i.e., “Advice communicated in meeting minutes and other correspondences is not a regulatory action taken by CDER or CBER; therefore, it would not be an appropriate subject for a formal dispute resolution request (FDRR) by a sponsor.”).

In limiting the scope of FDRRs in this way, the Agency comforted itself that meeting minutes and advice letters (regardless of how strongly worded) convey mere “recommendations and/or advice made to a sponsor” and, as such, “[s]ponsors are not bound by such recommendations and/or advice.”  Of course, that’s true – at least as a technical matter.  The practical truth, however, is that failure to follow the Division’s recommendations for Phase 3 design puts the program at significant risk of failure even if the Phase 3 study is successful.  We’ll spare you the countless references to FDA advisory committee briefing documents in which a review division quotes its own earlier minutes or advice, pointing an accusatory finger toward the recalcitrant applicant who didn’t follow that advice.  Suffice it to say that a Phase 3 program that rebuffs FDA advice is a Phase 3 program fraught with peril – which, not surprisingly, is a Phase 3 program that investors will not fund.

We were so alarmed by the predicament created by the 2015 change to the FDRR guidance that we raised the issue in a comment to the docket.  There, we provided a hypothetical test case in which FDA meeting minutes accurately convey the division’s disagreement with the proposed Phase 3 study endpoint: “No, we do not agree. In order for your studies to provide substantial evidence of efficacy, we strongly recommend that you demonstrate an improvement over placebo in [insert FDA-preferred endpoint].” In our hypo (which, for many clients, reflects reality) further discussions with the division suggest that the disagreement cannot be resolved.  Unable to appeal, the sponsor conducts Phase 3 using its preferred endpoint rather than FDA’s and those studies are clinically and statistically successful.  We observed

the sponsor is already on notice that the review division will not consider these studies sufficient to demonstrate efficacy. It will request a pre-NDA meeting at which the division is likely to restate its view and refer back to the EOP2 minutes noting that the sponsor failed to follow previous advice. The sponsor, still unable to avail itself of the FDR process, must spend the resources necessary to prepare and submit a marketing application, and pay a user fee in excess of $2,000,000. FDA may issue a refusal to file (RTF) letter, which will restate that the endpoint is not appropriate. Because the FDRR process is not available for RTF actions, the sponsor must file over protest. Whether the application is voluntarily filed by FDA or filed over protest, the sponsor must wait 10 additional months, and face the prospect of an advisory committee which will consume significant additional resources, prior to receiving a complete response letter (CRL) stating for at least the fourth time that the endpoint was inappropriate. An appeal is still not available. The sponsor must instead request and attend another meeting with the division at which it will, for the fifth time, be told (likely with some warranted frustration by the review division) that the endpoint is not appropriate. Only at this point, three to four years after the original disagreement with the division, can the sponsor appeal under the 2015 Draft Guidance. If the appeal is successful in determining that the alternative endpoint is appropriate, the sponsor must assemble an NDA resubmission and undergo another six month review clock.

Well, despite our comment, FDA chose to finalize the guidance unchanged and since that moment has refused requests for formal appeals of disputes that arise at EOP2.

But why are we rehashing this 5+ year old history today?  In part, it may be that our egos are bruised or that we fester over having been right every time a potential client approaches us with a failed study that would have succeeded had it been able to convince FDA about a particular design element at EOP2, but mostly, it’s because we have identified a very important loophole.  A loophole so large that we’re not sure why we didn’t see it all along.  You see, what is appealable is a Special Protocol Assessment (SPA) No Agreement Letter.  And while conventional wisdom says that one is most likely to submit a SPA if it is possible to achieve  concurrence with FDA on the adequacy of study design, who’s to say that one can’t submit a SPA request in order to confirm a lack of such concurrence, thereby opening up the route to FDRR.

The truth is, we continue to believe that efficient development of novel therapies would be best served by changing the FDRR guidance to permit formal disputes of Phase 3 study design issues.  Since that doesn’t seem likely at this point, sponsors facing division-level disagreement on Phase 3 study design at EOP2 should consider whether to invest the time and resources necessary for the SPA and FDRR processes prior to initiating Phase 3.  While this could delay Phase 3 initiation by 4-5 months, it could accelerate (or make possible) time to ultimate drug approval.

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FDA Disease Specific Workshops: Clinical Trial Designs for Progressive Multifocal Leukoencephalopathy

FDA Disease Specific Workshops: Clinical Trial Designs for Progressive Multifocal Leukoencephalopathy

By Charles Raver & Frank J. Sasinowski

On June 17, 2021, FDA gave notice of an upcoming public workshop focused on clinical trial designs for progressive multifocal leukoencephalopathy (PML).  PML is a rare disease that occurs when the JC virus (JCV), generally thought to lie dormant in the adult population, takes advantage of immunocompromised individuals.  JCV can cause a variety of devastating neurological symptoms primarily through infection of oligodendrocytes and astrocytes, leading to white matter lesions in the central nervous system.  Although this opportunistic virus appears to have no impact on healthy individuals, PML occurs most often in individuals who are immunocompromised, due to diseases like AIDS and leukemia, as well as in individuals taking strong immunosuppressive or immunomodulatory therapies, as may be the case following organ transplant or when managing an autoimmune disorder.  However, this often fatal and debilitating rare disease lacks targeted PML-specific therapies.

With this notice, FDA announced that it aims to engage with the public and private sectors, healthcare providers, academic experts, patients, and industry to discuss – (1) the unmet need for PML therapies and (2) issues of clinical trial design, including feasibility, trial populations, selection of control groups, endpoints, adaptive designs, and master protocols.  Public workshops such as this provide crucial opportunities to exchange ideas and expertise on developing therapeutics, gain insight into FDA thinking on clinical trial design and regulatory approaches, and inform the Agency and other stakeholders about the challenges to developing PML therapies.

The virtual workshop will take place on September 21, 2021, and a public docket seeking comments on the workshop will remain open until November 1, 2021.  Interested parties have until September 3, 2021, to submit requests to present during the workshop.  Our HPM team has extensive experience assisting patient groups, sponsors, and academics with their drug and therapeutic development needs for rare diseases and beyond.  Participation in this workshop is a must for anyone interested in PML, specifically, and an important opportunity to see these workshops in action for those seeking to gain insight into agency thinking around the challenges of rare disease drug development, more generally.

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FDA Publishes OMUFA Arrears List and Answers Fee-Related Questions

FDA Publishes OMUFA Arrears List and Answers Fee-Related Questions

By Deborah L. Livornese

With the new Over-the-Counter (OTC) Monograph Reform came new facility fees (see our blog posts here and here, and FDA’s announcement here), and with new fees comes the new Arrears List. Facility fees under the OTC Monograph User Fee Act (OMUFA) were due for the first time on May 10, 2021, for fiscal year (FY) 2021.  On June 14, 2021, FDA published the OMUFA Facility Arrears List which is a list of registered facilities that are required to pay the FY2021 annual facility fee, but have failed to do so.  The list includes several hundred facilities running over 70 pages.  Given that this is the first year the fees have been assessed, it is not surprising that the list is long.  It likely contains some facilities that ceased operations prior to the applicability of the facility fee, and may also include some facilities that were registered as new manufacturers because they were used solely for the production of hand sanitizer under FDA’s temporary policy for manufacturing hand sanitizers in response to the COVID-19 pandemic.  As FDA explained when it reissued the OMUFA facility fees following the withdrawal of the original publication of fees, these facilities would not be required to pay OMUFA fees.

As with the arrears lists for other user fee programs, (possible) embarrassment is not the only consequence that accompanies appearing on the Arrears List.  Under section 502(ff) of the Food, Drug, and Cosmetic Act, a drug that is manufactured at a facility for which required OMUFA fees have not been paid is deemed misbranded.

On the same day it released the Arrears List, FDA also published on its website a series of Qs & As, “Other OMUFA Fee-Related Questions”.  These cover how to pay an overdue fee, whom to contact to correct an error in the listing, and how to request a refund for a fee paid in error.  They also clarify that, unlike some other user fee programs, there are no waivers or exemptions for OMUFA fees (although FDA is not assessing OMUFA facility fees for the aforementioned hand sanitizer facilities).

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Government Seeks to Dismiss Lawsuit Challenging the Canadian Drug Importation Rule

Government Seeks to Dismiss Lawsuit Challenging the Canadian Drug Importation Rule

By Faraz Siddiqui & Serra J. Schlanger

In October 2020, the Department of Health and Human Services (HHS) and the Food and Drug Administration (FDA) published a Final Rule (which we summarized here) that implemented Section 804 of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 384, to allow states and other entities (Sponsors) to develop a Section 804 Importation Program (SIP) to import certain prescription drugs from Canada into the United States (the “Final Rule”). As we previously reported, the Final Rule and HHS’s certification thereof was swiftly challenged in court by the Pharmaceutical Research and Manufacturers of America (PhRMA), the Partnership for Safe Medicines (PSM), and the Council for Affordable Health Coverage (CAHC).

After receiving a few extensions from the court, on May 28, 2021, the government filed a motion to dismiss the lawsuit for lack for subject matter jurisdiction, and alternatively, for failure to state a claim. According to the government’s memorandum in support of the motion, the complaint “presents ‘abstract hypotheticals or requests for advisory opinions’” and must fail on standing or ripeness. The government contends that the plaintiffs, who filed the lawsuit on behalf of their members seven days before the Final Rule went into effect, have not shown any injury-in-fact and merely allege possible future injury. The government argues that deferring the lawsuit until after a SIP is authorized by FDA would not burden plaintiffs’ members.

The government dedicated a substantial portion of its memorandum to describing the Final Rule in order to “reveal[] how many steps must be taken before [the Final Rule and the Certification’s] impact could be felt by any of Plaintiff’s members, let alone the general public.” This description highlighted many of the same concerns that the plaintiffs raised in their complaint. For example, the government cannot approve a SIP that has potential safety concerns, does not adequately ensure the protection of the public health, and does not result in cost savings to the American consumer. But while the plaintiffs asked the court to enjoin the Final Rule based on these concerns, the government assured the court that it could not even approve a SIP that did not adequately address these concerns.

The government’s motion to dismiss reflects an ambivalent attitude on the part of the Biden Administration toward the Trump-era importation rule. On one hand, the government’s motion to dismiss the lawsuit suggests that the Biden administration is not ready to completely close the door on drug importation as a potential approach to lower drug prices. On the other hand, the government’s memorandum goes into great detail on how difficult it will be to pass the statutory bar and obtain FDA approval to import drugs from Canada. The government emphasized that the onus to satisfy the statutory and regulatory criteria falls squarely on the SIP Sponsors. The government also pointed out that Canada’s Minister of Health has issued an interim order that prohibits would-be Canadian sellers from distributing drugs outside of Canada unless they have “reasonable grounds to believe that the distribution will not cause or exacerbate a shortage of the drug” in Canada. According to the government, the Canadian interim order injects further uncertainty into whether and to what extent the Final Rule could be implemented

It remains to be seen how FDA will evaluate SIPs based on the criteria set forth in the Final Rule. Six states (Vermont, Colorado, Florida, Maine, New Mexico, and New Hampshire) have passed laws allowing for the importation of drugs from Canada. We have reported on several of these laws. Two of these states (Florida and New Mexico) have submitted SIP proposals to FDA. We are watching to see FDA’s response, but do not expect to see these plans approved anytime soon, as the government has made no secret of the fact that FDA is not bound to any statutory timeline to make a decision on SIP proposals that have been submitted.

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Modernizing The Regulation of Laboratory Developed Tests (LDTs): Senator Rand Paul Identifies A Better Way Forward

Modernizing The Regulation of Laboratory Developed Tests (LDTs): Senator Rand Paul Identifies A Better Way Forward

By Jeffrey K. Shapiro

In our last post on Laboratory Developed Tests (LDTs), we suggested that Congress, not FDA, should lead in directing modernization of LDT regulation.  Any change should be made by enacting new law, and not by Food and Drug Administration (FDA) administrative fiat.

Coincidentally, on the same day the post went up, Senator Rand Paul introduced the “Verified Innovative Testing in American Laboratories Act of 2020” or the “VITAL Act of 2020,” a new bill clarifying that the Centers for Medicare and Medicaid Services (CMS), not FDA, is to regulate LDTs.  It would require also that CMS hold a public meeting to solicit recommendations on updating existing Clinical Laboratories Improvement Amendment (CLIA) regulations related to clinical testing laboratories.  This step would help propel forward a public conversation (which CMS has already started) about how to update these regulations in light of technological advances.

FDA argues that technological advances in LDTs necessitate FDA’s regulatory oversight pursuant to the Food, Drug, and Cosmetic Act (FDCA).  Senator Paul’s bill would likewise facilitate regulatory reform to meet technological advances, but it would place the responsibility on CMS and use the vehicle of updating the CLIA regulations.  This approach makes more sense, because the CLIA regulations have always been the main vehicle for regulating clinical laboratory testing.

Indeed, the effort these past few years to apply the FDCA and its implementing regulations to clinical laboratory testing has been a failure.  The outcome was not a surprise, because the FDCA was designed for regulatory oversight of medical device manufacturing and distribution, not clinical laboratory testing.  Applying the FDCA to clinical laboratory testing is akin to putting a square peg in a round hole; it will work for a portion, but there are sharp corners that just do not fit.

The background to this discussion is as follows:  In 1976, Congress amended the FDCA to add a basic regulatory framework for medical devices.  A little more than a decade later, in 1988, Congress amended Public Health Service Act (PHSA) to add the CLIA, which provided a basic regulatory framework for clinical laboratory testing.  The Centers for Medicare and Medicaid Services (CMS) implements CLIA, largely based upon regulations issued in 1992.

Shortly after CLIA was enacted, FDA asserted authority to regulate LDTs under the FDCA.  This conclusion was strange, since CLIA is obviously intended for clinical laboratory testing while the FDCA is obviously intended for medical devices.

Nonetheless, FDA implemented the claimed authority by adopting “enforcement discretion” for all LDTs unless the public health supposedly demanded intervention.  That is, FDA claimed the authority to regulate LDTs while for the most part declining to do so.  Think of a lion watching a gigantic herd of wildebeests thundering past.  Every so often, FDA would charge and pounce, picking off a test here and there for active regulation, while it left the rest alone.

The agency choice of which tests to regulate was not based on factors set forth in a statute or even a regulation.  It was all decided by administrative fiat.  This abuse of enforcement discretion was arbitrary, capricious and likely unconstitutional.  Fortunately, The Department of Health and Human Services (HHS) finally put a stop to it last summer.

With this background, we return to Senator Paul’s bill.  It would require CMS to initiate a public conversation about how best to update the regulations for modern diagnostic technologies.  If there is good follow through, CMS would ultimately issue new regulations reflecting appropriate changes.  In this discussion, we would suggest that CMS also should seek to identify amendments to its statutory authority under CLIA, if any, that are necessary to complete the job of reform.

We predict that the discussion to be initiated by Senator Paul’s bill, focusing on CMS and CLIA, will be much more fruitful than FDA’s attempt (and recent legislative efforts) to apply the FDCA broadly to LDTs.  It is time to recognize that an FDA‑centric approach is not desirable.  That said, because some still argue for FDA oversight of LDTs, at least in part, we will consider in a future blog post whether there exists an appropriate (if limited) role for FDA in oversight of LDTs, even if CMS should take the lead through CLIA, as it has done for three decades or more.

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FDA Flips It and Reverses It: FDA Withdraws HHS Withdrawal of UDI Guidance

FDA Flips It and Reverses It: FDA Withdraws HHS Withdrawal of UDI Guidance

By Sara W. Koblitz

While typically, FDA is responsible for setting forth its own agenda and enforcing compliance with its own regulations, the Trump Administration’s HHS, on its way out the door in late 2020, took the unusual steps of withdrawing an important FDA Compliance Policy Guide, “Marketed Unapproved Drugs – Compliance Policy Guide Sec. 440.100, Marketed New Drugs Without Approved NDAs or ANDAs,” which set forth FDA’s approach to prioritizing enforcement actions and exercising enforcement discretion with respect to marketed unapproved drug products.   As explained in CPG 440.100 and on FDA’s website, FDA adopted the “Unapproved Drug Initiative” (“UDI”) in 2006—later revised in 2011—to remove unapproved drugs from the market using a risk-based approach both to ensure the safety and efficacy of all drug products on the market and the integrity of the drug approval process.  Yet HHS, without input from FDA, “terminated” the UDI, citing increased drug pricing and shortages supposedly arising from the UDI.  HHS further withdrew all FDA materials relating to the UDI to “prevent actors from using Food and Drug Administration (FDA) rules to enjoy artificial monopolies over older drugs.”  While FDA was silent on the withdrawal for about 6 months, FDA finally withdrew HHS’s withdrawal of CPG 440.100 and the UDI on May 27, 2021.

In a somewhat scathing Federal Register Notice, FDA—noting that FDA “did not find any evidence that HHS consulted with, otherwise involved, or even notified FDA before issuing the HHS Notice”—explained that it was withdrawing HHS’s UDI Termination because “the HHS Notice contained multiple legal and factual inaccuracies.”  Specifically, FDA raised concerns with HHS’s misrepresentation of the term “new drug.”  A key term integral to the application of the drug approval requirements to a given product, FDA has always interpreted the term “drug” in the definition of a “new drug” to refer to the “entire drug product” rather than only the active ingredient, and courts consistently have upheld that interpretation.  The November 2020 HHS Notice, however, suggested that FDA previously had defined “new drugs” to mean active ingredient, and, therefore, the Notice reasoned that any active ingredient marketed prior to 1938 should not constitute a “new drug,” could be considered “grandfathered,” and may not require approval prior to marketing.  In this Federal Register Notice, FDA explained that it has never taken that position, as doing so “could result in significant harm to public health by suggesting that unsafe or ineffective drugs could circumvent the drug approval process.” FDA also criticized the implication in the HHS Notice that the CPG changed FDA’s interpretation of “new drug,” “grandfathered,” or “GRASE” status (formally known as drugs that are “Generally Recognized as Safe and Effective”) without required notice and comment.  FDA explained that the CPG changed no interpretations or definitions but merely reflected FDA’s decades-long interpretations and advised the public of FDA’s enforcement priorities.

Further, FDA assiduously defended the success of the UDI program.  Rejecting HHS’s position that the UDI program resulted in the “unintended” and “adverse” consequences of increased drug pricing and shortages, FDA explained that “the HHS Notice is supported by flawed facts,” as the single study relied upon was an observational study of only 26 products without adjustments for inflation, potentially resulting in an overestimation of real price changes.   Contrary to HHS’s assertions, FDA emphasized that the program and related compliance actions have resulted in approval of safe and effective versions of previously unapproved drugs.  FDA also cited carbinoxamine-containing products and quinine as examples of unapproved new drugs that, due to significant adverse events, were ultimately removed from the market as a result of this program.  And FDA refuted the HHS Notice’s association between the UDI and a Daraprim price increase for Daraprim: Daraprim was an approved drug without generic competition, and it was the absence of generic competition—not FDA enforcement under the UDI—that led to the increase in price.

Finally, FDA’s rebuke of the HHS Notice suggested that HHS did not have the statutory authority to withdraw the CPG as only the FDA Commissioner is “responsible for executing” the FDC Act.   FDA concluded its withdrawal notice by stating that “[t]he HHS Notice did not, and legally could not, provide a new pathway for the legal marketing of unapproved new drugs” as “[n]either HHS nor FDA has the authority to exempt a product or class of products that are new drugs under the FD&C Act from the new drug approval requirements of the FD&C Act.”

This is not the first time this year that FDA and HHS have given industry whiplash.  HHS withdrew FDA’s December 29, 2020 Federal Register Notice announcing OTC monograph fees only eight days after publication.  There, HHS threw FDA under the bus, issuing a statement that the imposition of user fees on hand sanitizer manufacturers “was not cleared by HHS leadership, who only learned of it through media reports” and that the HHS Secretary “would never have authorized such an action.”  Similarly, HHS and FDA withdrew HHS-proposed exemptions for 83 medical devices published in the Federal Register by the Trump Administration just days before leaving office.  There, HHS and FDA explained that “the proposed exemptions and bases for them are flawed.”  Once again, the Federal Register Notice explained that FDA “did not find evidence that HHS consulted with or otherwise involved FDA in its proposed exemption or the issuance of the January 15, 2021, Notice” and explained that only FDA ‘‘shall be responsible for executing’’ the FD&C Act.   The Agencies further explained that “it is particularly important that FDA have at least some level of involvement in this type of an action given the expertise needed . . . to assure the safety and effectiveness of a device,” and it’s clear from FDA’s withdrawal of the UDI withdrawal that the same premise applies to drugs.

As we explained back in late 2020 (after calling the HHS’s reasoning “malarkey”), the rescission of the UDI could mark “a return to the Wild West of marketed unapproved drugs instead of companies deciding to seek FDA approval.”  Thankfully, FDA has stepped in to reverse HHS’s thinly-veiled attempt to circumvent statutory drug approval requirements at the expense of safety and efficacy in an effort to control prices.

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FDA’s Accelerated Approval of Biogen’s Aduhelm for Alzheimer’s: A Sign of Applying the Emergency Use Standard Beyond COVID?

FDA’s Accelerated Approval of Biogen’s Aduhelm for Alzheimer’s: A Sign of Applying the Emergency Use Standard Beyond COVID?

By Frank J. Sasinowski & James E. Valentine

Yesterday’s FDA approval of Biogen’s Alzheimer’s drug, Aduhelm (aducanumab-avwa), is historic and is of a magnitude that it may be harbinger for future Agency actions, especially in neuropsychiatric conditions.   This has been a decision we’ve been closely following.  So much so, in November, right after the FDA Peripheral and Central Nervous System Drugs (PCNS) Advisory Committee had met on this therapy, the Pink Sheet quoted HP&M’s Frank Sasinowski in its coverage of the advisory committee as he floated the idea that FDA may turn to consider Accelerated Approval as a path forward on this therapy as the advisory committee had not been asked to nor had offered any opinion on this approval pathway.

Our reading of yesterday’s action is that while this is the direct action of the Director of the Office of Neuroscience, Dr. Billy Dunn, this approval has the full support of the Director of the FDA Center for Drug Evaluation and Research (CDER), Dr. Patrizia Cavazzoni.  This is because, not only did the FDA issue a press release, which is typical of any FDA regulatory action of this consequence but, in addition to the conventional press release which quotes Dr. Cavazzoni, she also issued her own personal, fairly extensive public statement explaining and defending this action.  Moreover, in her statement, Dr. Cavazzoni observes too that the advisory committee had not discussed the possibility of the Accelerated Approval pathway for this therapy.

While we do not yet have the FDA summary basis for approval, which we expect will contain very illuminating review memos, we can turn to the label and other overarching aspects of the approval for insights.  Below we highlight those observations that we believe, in the context of the broader regulatory landscape, set a positive trajectory for future Agency actions.  As you will see, ultimately, this Accelerated Approval may have benefited from FDA’s experience in evaluating products under the Emergency Use Authorization (EUA) regulatory framework.

Key Takeaways from the Aduhelm Label: What’s in It and What Isn’t

First, it was noteworthy what was missing from the label.  What do we mean?  Well, the FDA initially issued draft guidance on how to label drugs approved via the Accelerated Approval (i.e., Subpart H) pathway in 2014, then issued it as final guidance in January 2019.  In this guidance, FDA explains that sometimes “[s]imply reporting the endpoint used may convey sufficient information about uncertainty with regard to the limitations of usefulness drug and of uncertainty about anticipated clinical benefits…” Recent Accelerated Approvals we have been involved with, such as the 2017 approval of benznidazole for Chagas and the 2019 approval of Oxbryta for sickle cell disease, have taken this approach as they do not say anything more than identify the surrogate endpoint that was the basis of the approval and noting “continued approval…may be contingent upon verification and description of clinical benefit in confirmatory trials.”

However, the FDA guidance goes on to say in some cases, additional context is needed by specifically inserting a sentence in the indications statement that: no clinical benefit has been established.  This sentence was included in the 2016 approval of Exondys 51 for Duchenne muscular dystrophy and the 2018 approval of Andexxa for reversal of anticoagulation therapy.

It is noteworthy that this sentence that no clinical benefit has been established was deemed by FDA as unnecessary for Aduhelm to provide additional context beyond that the approval is based on reduction in amyloid beta plaques.  As an aside, we have found this inconsistency between which accelerated approval therapies are saddled with this sentence to be a paradoxical FDA policy as there is but a single standard for surrogate endpoints to be utilized for purposes of every Accelerated Approval (i.e., be “reasonably likely to predict” ultimate clinical benefit).  Moreover, in every Accelerated Approval, the clinical benefit must be confirmed in a post-approval clinical study, just as the labels for all Accelerated Approval drugs state.

Second, it was notable that the trials of Aduhelm were conducted in those with early Alzheimer’s disease, and the indication that FDA approved is for anyone and everyone with Alzheimer’s disease.  In many development programs, there is strong scientific rationale for generalizing the results (e.g., consistencies in the disease process, drug’s overall benefits and risks) and, as a result, indicating a drug for a population broader than those that were studied in clinical trials (see FDA’s indications and usage labeling guidance here).  This approach to labeling encourages sponsors to undertake rationale drug development planning, allowing them to focus on study designs that can most effectively capture treatment benefits (or lack thereof) (e.g., through enrichment – a technique particularly necessary in rare disease settings where numbers are small and heterogeneity is high).

Reflecting on the Use of Accelerated Approval as an Appropriate Tool for Regulatory Flexibility

There is a long and vibrant history of FDA using the Accelerated Approval pathway to help expedite drug development and approval.  This goes back to when Sasinowski was at FDA in the 1980’s, he had a hand in aiding others at FDA, like Dr. Bob Temple, to create on the Agency’s own initiative the Accelerated Approval pathway in order to address the raging AIDS crisis.  Later, in 1993, in private practice Sasinowski advocated for the first use of Accelerated Approval outside of AIDS and cancer, when Dr. Janet Woodcock approved Betaseron as the first drug for multiple sclerosis.  Over the past half of a decade, Sasinowski and Valentine have been involved in more than half of the Accelerated Approvals outside of cancer.  Ever since Sasinowski’s 2012 paper, cataloguing FDA’s exercise of flexibility in its approval of drugs for rare diseases (later followed-up in 2015 with an updated analysis by both HP&M’s Valentine and Sasinowski; both papers available here), the word “flexibility” has been used widely, but what it means or how to apply it is still subjective and largely unknown and unknowable except in hindsight such as in these two papers.

So, it is not surprising there have been questions about the future of Accelerated Approval making their way through the industry in the last year. While historically it seemed that the barrier to use of the pathway was a seemingly high evidentiary bar for demonstrating that a surrogate endpoint is “reasonably likely to predict” ultimate clinical benefit, recent concerns expressed by senior CDER officials indicated the barrier to its use was instead fears of whether the Agency could be sure that post-approval confirmatory studies would be conducted in a timely manner and could be designed in a way that would reliably produce interpretable data.  The basis for this concern materialized in October 2020 when CDER proposed withdrawal of approval for Makena after completion of its confirmatory study.  Then further, in April of this year, when FDA’s Oncologic Drug Advisory Committee met to review several oncology indications granted Accelerated Approval over the last five years in what appeared to be part of a broader evaluation of Accelerated Approvals in oncology.  The question was raised: does FDA still view Accelerated Approval as a realistic tool for expediting drug development?

Yesterday’s approval of Aduhelm helped answer that.  Both Dr. Dunn, in his memo to the PCNS Advisory Committee members, and Dr. Cavazzoni, in her statement, emphasized the utility of Accelerated Approval in devastating conditions where the needs for treatments are urgent.  This is certainly the case in Alzheimer’s disease – and as FDA articulates in its December 2019 draft guidance on substantial evidence of effectiveness, is exactly the context in many rare diseases.

In fact, it is in that document where FDA most extensively describes its flexibility in drug review.  For example, it describes the three major ways in which this substantial evidence of effectiveness standard may be met, the latter two which reflect a demonstration of flexibility via approval based on a single study: (1) two positive adequate and well-controlled studies, (2) one positive adequate and well-controlled study with confirmatory evidence, or (3) one adequate and well-controlled study with statistically very persuasive evidence.  FDA also describes how FDA will apply flexibility in applying this standard to different data sets on a case by case basis where either the condition is rare or is serious or there is a great unmet medical need.  To us, through this approval action, it seems that FDA is showing that the Agency it intends to include the Accelerated Approval pathway in its armamentarium of ways in which to exercise flexibility.  The evidence on the surrogate endpoint would still have to meet the substantial evidence standard by one of those three ways, but the Accelerated Approval pathway is clearly a type of flexibility that FDA has available to it in its discretion.

Closing Thoughts: A Non-COVID-Related Approval Based on Review Experience During the COVID-19 Pandemic 

So how did we get here? There is no question the last year has been unlike any other for all of us, but FDA has been steeped in “new” too.  From PPE to diagnostics, treatments to vaccines, the review staff have been applying a new statutory standard: that which supports Emergency Use Authorization (EUA) of a product for COVID.  While this is not new (see, e.g., EUAs during the Ebola epidemic), the COVID-19 pandemic required all-hands-on-deck.

Yesterday’s action by FDA gives the world a window on one way in which the Agency may be turning to Accelerated Approval; FDA has a regulatory tool, “Accelerated Approval”, that does, in some way, allow reviewers to approach the types of flexibility seen in FDA’s EUA authority where reviewers look to see that “known and potential benefits” outweigh the “known and potential risks”.  FDA always considers protecting against “known and unknown risks” when evaluating every new drug, so the risk evaluation side of this EUA equation would be one familiar to FDA reviewers (see, e.g., the Aduhelm warning for Amyloid-Related Imaging Abnormalities (ARIA)), and is not unique to Accelerated Approval.

Instead, what stands out is the reliance on an unvalidated surrogate that is merely “reasonably likely to predict” clinical benefit (i.e., it is a surrogate that is not so well established that it would support a full, or traditional, approval).  This is, in fact, accounting for “potential benefits”.  So, maybe yesterday’s action is in some way a hidden outgrowth of the Agency’s new experience with and comfort from exercise of its EUA authority in these COVID times.  It may well be that FDA’s COVID experiences have revealed to FDA that it could employ that “potential benefit” part of the EUA standard in the context of Accelerated Approval….such an epiphany could come from being hidden in plain sight all this time.  Perhaps someday we will look back and count today’s action as the harbinger of those unexpected findings and this epiphany that led to a new way to position Accelerated Approval as a finding the potential benefits of a therapy outweighed its known and potential risks.  Onward!

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