One misnomer that has been repeated over the years has been the reference to the “Drug Enforcement Administration” (“DEA”) as the “Drug Enforcement Agency.”  This error has appeared not just in articles and other news publications but in some court documents as well.  The DEA has even made the same mistake.  Default Provisions for Hearing Proceedings Relating to the Revocation, Suspension, or Denial of a Registration; Correction, 87 Fed. Reg. 73246 (Nov. 29, 2022).  Interestingly, this same issue does not appear to have occurred with the Food and Drug Administration, in that, I am not aware of erroneous public references to the “Food and Drug Agency.”

This faux pas may take on new meaning given that recently the Department of Justice (“DOJ”) and DEA have argued that DEA is not an “agency” after all.  In a case involving a challenge to a Freedom of Information Request (“FOIA”) submitted to DEA, the DOJ and DEA appear to now argue that DEA is a “component” of the DOJ and not an agency.  Aims Institute, PLLC, v. Merrick Garland, et. al, Case No. 4:2022-cv-02396 S.D. Tex. (2023).  In an erratum filed to the deposition of an official previously self-identified as the Chief FOIA Officer, the government stated that the individual was in fact, not the Chief FOIA Officer for DEA but Chief of the FOIA/PA Unit at DEA.  The errata further stated that the Chief FOIA Officer was Vanita Gupta, Associate Attorney General of DOJ.  Also, the errata stated that DEA is a “component” of DOJ not an agency.

I refer you to the pleadings in the case and the recent motion filed by the Plaintiff that discusses the merits of the argument as to why DEA is an “agency” and should be held to statutory and regulatory requirements of any administrative agency.  The arguments in this case also highlight a longstanding frustration with obtaining FOIA information from the DEA.  In many cases, it appears DEA does not have the resources or infrastructure to maintain and produce the information to respond to FOIA requests as do other administrative agencies such as FDA.  DEA has always been somewhat unique in that arguably it is primarily a law enforcement agency that has been “burdened” with serving as an administrative agency tasked with regulating manufacturers, distributors, pharmacies and practitioners.

This case may have deeper ramifications on many of DEA’s administrative functions if there is a finding that DEA is not an agency.

More than a decade ago, FDA began systematically to incorporate review of human factors (HF) design validation within 510(k) reviews.  In 2016, the agency issued its definitive HF guidance to guide manufacturers through human factors engineering processes during the development of new medical devices, focusing specifically on the user interface.   All this time, FDA has applied the requirement for HF data to a subset of device types that pose the highest usability‑relate risks, e.g., software controlled devices, some hospital devices, and home use devices.  Accordingly, only a subset of 510(k) submissions have historically included HF validation data.

Now FDA has issued a draft guidance, Content of Human Factors Information in Medical Device Marketing Submissions (Dec. 9, 2022).  This guidance is intended as a complement to the earlier one, focusing on the type of HF data manufacturers should supply in a marketing submission.

In one way, this is good news.  The generation of HF data is a detailed and fairly burdensome process, although certainly short of a full-blown clinical study.  Furthermore, FDA’s HF reviews tend to generate a good percentage of the burdensome additional information (AI) requests in 510(k) reviews.  Many of these AI requests arise because of manufacturer unfamiliarity with the peculiarities in vocabulary and requirements current among FDA’s HF review staff.  And HF‑related AI requests are especially nerve‑racking to manage, because of the ever‑present threat that the study must be repeated to adequately respond.  Industry would certainly welcome guidance intended to smooth the HF aspects of 510(k) reviews.

But there is a very big fly in this ointment.  At least as currently drafted, it appears that the draft HF guidance dramatically expands the number of 510(k) submissions that require HF data.  The threshold is set extremely low:  if there is one “critical task” identified for a new or modified device, HF data must be addressed in some fashion.  (A “critical task” is a “user task which, if performed incorrectly or not performed at all, would or could cause serious harm to the patient or user, where harm is defined to include compromised medical care.”)

To put it another way, according to the draft guidance, the only valid justification for not including human factors data for a new device is that there are no critical tasks.  In the past, FDA made relatively specific determinations as to the HF data requirements (or lack thereof) for various types of device.  This approach is one-size-fits-all.  It will dramatically increases the burden and uncertainty associated with every submission across many device types.

If a single critical task is identified, then human factors validation must be included, regardless of whether such testing was required for the identified predicate.

If the submission is for a modified device which involves a new critical task or which impacts an existing critical task, then a human factors engineering report is required even if usability data were not required for clearance of the original unmodified device/predicate.

The only exception for a modified device is when there were no changes to: the user interface; intended device users; intended device uses; intended use environment(s); training or labeling.  Even in those cases, a high-level summary of the HF evaluation must be included.  FDA could challenge a company’s rationale for concluding that a change did not impact “human factors considerations” and thereby request HF data.  Once again, the uncertainty associated with the submission process will increase.

The draft guidance is at odds with the fundamental purpose of the 510(k) program, to enable an efficient risk-based process for FDA review and clearance of low to moderate risk devices.  A fundamental tenet of the program is that the same testing required for the predicate is generally required for the subject device.  Typically, only changes in technological characteristics from the predicate require use of test methods not required for the predicate.

Consider this scenario:

• A manufacturer files a 510(k) for a Class II device, a surgical mask.
• The subject device is identical to the predicate in all respects.
• Both devices have a single critical task (they must be correctly fitted by the user).
• FDA did not require HF data as a basis for clearance of the predicate.
• The device-specific guidance for surgical masks does not require HF data Surgical Masks – Premarket Notification [510(k)] Submissions | FDA.
• Per this new HF draft guidance FDA would require the highest level, tier 3 HF usability data for 510(k) clearance of the new surgical mask.

As the example shows, this draft guidance departs from the long-standing approach and introduces a new requirement for HF testing, regardless of whether such testing was required for the predicate and regardless of whether alternative methods of addressing differences in technological characteristics are available and less burdensome.  The new policy needs to be justified on a cost/benefit basis, which has not been done, at least as far as can be discerned from the draft guidance.  For example, the agency has not offered how many 510(k) submissions currently require HF data, the adverse effects of not applying an HF requirement more widely, and how many submissions would now present HF validation data after the change goes into effect.

At least to our knowledge, it appears that currently a relatively focused subset of all 510(k)s currently require HF validation.  If so, implementation of the draft guidance will likely cause in dramatic increase in burden on applicants and FDA.  For example, there could be a significant increase in Q‑Subs in order to work out the HF validation protocol or ensure that the agency agrees that HF data is not required.  This issue will increase uncertainty in the 510(k) modification decision making process. For example, if a critical task is introduced or impacted does that trigger the need for a new 510(k)?

The draft guidance can be fixed by simply deferring to existing requirements as to when HF data are required (e.g., as a de novo special control or in a guidance document for a specific device type).  To justify an expansion of the 510(k) burden of this magnitude, FDA needs to provide a clear and detailed accounting of what the problem is, the cost of this change, and why it will improve safety without hindering the development of better devices.

FDA says the primary purpose of this draft guidance is to smooth 510(k) reviews by providing more granular information about how to address the requirement.  It seems like mission creep for FDA to go beyond this primary purpose to impose a dramatic expansion of the requirement.

In short, this draft guidance imposes a major policy change with far-reaching implications.  Simply saying that the approach is “risk-based” is not adequate justification.  The costs and uncertainty of this expansion to HF requirements are significant.  The countervailing need for the change, however, is not well‑documented.  FDA should be careful not to upset the balance inherent in the current 510(k) system, which is used to bring the majority of medical device to market.

Comments on the draft guidance are due on or about March 8, 2023.

Last October, President Joe Biden directed the Secretary of Health and Human Services (“HHS”) and the Attorney General to begin the administrative process of reviewing current marijuana scheduling under federal law.  Then, Congress passed and the President signed the Medical Marijuana and Cannabidiol Research Expansion Act into law in December.  Last month, the Food and Drug Administration (“FDA”) announced in a release that it would not conduct rulemaking that would allow cannabidiol (“CBD”) to be marketed in dietary supplements or conventional foods because “a new regulatory pathway for CBD is needed that balances individuals’ desire for access to CBD products with the regulatory oversight needed to manage risks.”  FDA Statement, FDA Concludes that Existing Regulatory Frameworks for Foods and Supplements are Not Appropriate for Cannabidiol, Will Work with Congress on a New Way Forward.

FDA Principal Deputy Commissioner Janet Woodcock, M.D. issued the release on January 26th stating that she had chaired an FDA “high-level internal working group to explore potential regulatory pathways for CBD products.”  Dr. Woodcock announced that a new regulatory pathway is needed, noting that FDA is prepared to work with Congress on the matter.  She also announced denial of three citizen petitions asking FDA to conduct rulemaking to allow CBD products marketed as dietary supplements.

The release explained that studies have suggested that CBD can potentially harm the liver and male reproductive system and can interact with certain medications.  Exposure to vulnerable populations including children and pregnant women is also a safety concern.

A new regulatory pathway, the statement opines, would provide safeguards and oversight, managing and minimizing risks related to CBD products.  But what would an adequate regulatory pathway require?  What safeguards would it employ?  The statement explains that risk management tools could include clear labeling, prevention of contaminants, CBD content limits, and age restrictions to mitigate the risk of ingestion by children.  A new pathway could also provide access and oversight for animal CBD-containing products.

FDA’s current food and dietary supplement authorities provide limited tools for managing the risks associated with CBD products.  Under current law, the statement warns, any substance, including CBD, must meet specific safety standards to be lawfully marketed as a dietary supplement or food additive.

The working group reviewed studies related to CBD-based Epidiolex, published scientific literature, information submitted to a public docket, and studies conducted and commissioned by FDA.  The working group determined it is not apparent how CBD in dietary supplements and foods could meet safety standards because FDA has “not found adequate evidence to determine how much CBD can be consumed, and for how long, before causing harm.”

The release further noted that CBD also poses risks to animals and humans who could unknowingly be exposed to CBD by consuming meat, milk, and eggs from animals that ingest CBD.  For that reason, FDA also does not intend to pursue rulemaking that would allow CBD in animal food because it is not apparent how CBD products could meet the safety standards for animal food.  As with CBD in dietary supplements and human food, a new regulatory pathway could provide access and oversight for CBD-containing animal products.

The release warned that FDA would continue to take enforcement action, in coordination with state regulators, to protect the public against CBD and other cannabis-derived products.  FDA promised to remain diligent in monitoring the marketplace, identifying products that pose risks and acting within its authorities.  The statement observed that FDA looks forward to working with Congress to develop a cross-agency strategy to regulate CBD-containing products to protect public health and safety.

Meanwhile, dietary supplements and foods containing CBD continue to be marketed and consumed.  Key among questions raised by the release are:

1. What will the new regulatory pathway look like?
2. How will FDA work with Congress on CBD in dietary supplements and foods?
3. Will Congressional Democrats and Republicans work together on these issues or will such efforts be hindered by partisan deadlock?
4. How long will it take to agree upon and establish an acceptable regulatory pathway?

Inquiring minds are waiting.

GoodRx is a digital health platform familiar to many, and a prime example of a single player that operates in several different realms of the evolving and growing digital health marketplace. Among its services are prescription drug discounts, telehealth visits, and other health services.

The Federal Trade Commission (FTC) and its partners at DOJ’s Consumer Protection Branch recently filed a civil complaint against GoodRx for data privacy breaches. The case includes a proposed order that may sharply narrow the company’s ability to traffic in consumer data, often a key part of any digital health company’s business model.

This case was the latest example of government regulators punishing a company that refused to live up to its promises of consumer data protection. It’s also the first enforcement action under the 14-year-old FTC Health Breach Notification Rule. That Rule requires data companies to notify consumers and regulators of unauthorized disclosures of consumers’ personal health information. Unauthorized disclosures can occur either through external hacks or, as we see here, as part of a digital health company’s own internal policies.

FTC and DOJ have for years developed cases under the legal theory that lax data privacy policies amount to unfair and deceptive acts and practices and thus are violations of the FTC Act. Companies holding sensitive data must act as both the Key Masters and the Gate Keepers. Here, the FTC and DOJ allege that GoodRx committed the same sin as many other tech firms before it: the company promised users that their data was safe and inviolate, but according to the complaint, it was not.

GoodRx is alleged to have shared ostensibly protected personal health information with other tech companies, used the data for ad targeting, allowed third-party use of the data, used a HIPAA seal on its site that misrepresented its compliance status, and failed to put other policies in place to protect the data. That’s a good list of the kinds of things that most consumers really do not want their digital medical services provider to do with their sensitive personal information.

The proposed order that resolves the case may take away some of GoodRx’s tools of profitability. It permanently bans the company from trafficking-in patient data on several fronts. These measures include a prohibition on sharing health data for ads, requiring user consent to share data, and implementing a privacy program that a lot of its users probably thought it already had in place.

Perhaps these terms are severe to GoodRx, but the civil penalty was noticeably small compared to other FTC data privacy cases. GoodRx has an estimated market capitalization of over $2 billion dollars. The penalty of $1.5 million is, well, not a lot. Other notable data privacy cases that weren’t first of their kind or that did not include sensitive personal health information include, among many others, Facebook ($90m, $725m and $5b), YouTube ($170m), Capital One ($190m), and Twitter ($150m).

Through our FDA-focused lens, we see a possible roadmap as FDA’s Center for Devices and Radiological Health (CDRH) increases its resources, guidances, and enforcement emphases in the connected digital device space. It may be that cases like this one may affect future FDA data cases.

FDA is building its Digital Health Center of Excellence (DHCE). The catalogue of resources, guidances, and other regulatory materials for the DHCE is growing, as we have noted in prior blog posts. Cybersecurity for connected devices is of key importance to DCHE, as medical devices connected to apps and other portals to the internet offer hackers potential openings to exploit. And, like GoodRx, they may also offer device companies potential profitability through the sharing of valuable data. It’s not a huge leap to imagine a case where hackers get through a connected device’s cybersecurity shields. That kind of event probably triggers the Health Breach Notification Rule, and a civil action against the victim company for poor data privacy practices may not be far behind. And as we see with GoodRx, intentional sharing of data that is advertised as protected may trigger enforcement as well.

But the connected device space must also beware of FDA enforcement under the same scenarios of either voluntary or involuntary breach, and device makers can’t just try to empty their minds and wish for seemingly harmless outcomes that would be, in fact, terrifying. The new Section 3305 of FDORA adds a prohibited Act to Section 331 of the FDCA that relates to this. Failure to comply with new cybersecurity requirements is now a violation that applies to devices that include software, can connect to the internet, and may be vulnerable to cybersecurity threats. Device makers that do not monitor, update, and generally guard against post-market cybersecurity vulnerabilities seemingly face a dual threat of FTC and now, FDA enforcement action, all taken through DOJ.

FDA enforcement might take any number of forms, from a simple inspection, to Form 483, to Warning Letter, to consent decree. But whatever an FDA action might look like, we know that FTC, FDA, and DOJ will view a compromised device as a potentially unsafe device. In one form or another, exposure of consumer patient data may very well have significant regulatory consequences, where the agency streams may all cross to push violators back into a more compliant dimension.

See you on the other side.

Hyman, Phelps & McNamara (“HPM”) Director Larry Houck will present “Prescribing Red Flags, Corresponding Responsibility and DEA Investigations: What’s a Pharmacist To Do?” at this year’s American Pharmacists Association’s (“APhA’s”) Annual Meeting in Phoenix, March 24-27.  Mr. Houck was a diversion investigator with the Drug Enforcement Administration (“DEA”) in the field and at agency headquarters for 15 years before joining HPM in 2001.  Mr. Houck’s session will address pharmacists’ corresponding responsibility to identify and resolve controlled substance prescribing red flags and how to prepare for and manage DEA inspections.

The session will occur Friday, March 24th.  Pharmacists can earn 1 continuing practice education credit for attending this session.

Some of the additional APhA meeting sessions will include:

• Patient counseling
• Veterinary Basics for Community Pharmacists
• The ABCs of 340B
• Federal Regulation Affecting the Practice of Nuclear Pharmacy
• Pharmacy’s Impact on Disparities in Research
• Pharmacists and Patient-Centered Diabetes Care
• Updates in Alzheimer’s Disease
• Unique Patient Case Studies
• Taking the Sick Out of Sickle Cell Disease
• 2023 Immunization Update

Further meeting information, including registration, can be found here.

On February 15, 2023, the Nonprescription Drugs Advisory Committee (NDAC) and the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) held a joint meeting to discuss an application pending before FDA that would switch Narcan (naloxone) Nasal Spray from prescription to over-the-counter (OTC) status.  All 19 members of the joint Advisory Committee agreed that the benefit-risk profile of Narcan Nasal Spray (NNS) is “supportive of its use as a nonprescription opioid overdose reversal agent.”  While this outcome is non-binding, an Advisory Committee’s recommendation—particularly a unanimous recommendation from a joint Advisory Committee meeting—does hold significant weight with FDA.

Background

FDA has faced mounting pressure in recent years to take meaningful action in response to the ongoing opioid crisis.  For the 12-month period ending September 2022, over 100,000 drug overdose deaths were reported.  In August 2022, FDA announced the creation of the Overdose Prevention Framework with the vision to “undertake impactful, creative actions to prevent drug overdoses and reduce deaths.”  We previously blogged on FDA’s September 2022 guidance exempting and excluding specific naloxone transactions (e.g., sales of naloxone from a wholesale distributor to a harm reduction program) from certain requirements under the Drug Supply Chain Security Act.  The Framework also includes an action to support the goal of encouraging harm reduction as expanding availability and access to overdose reversal products, including naloxone, by supporting accelerated product review and “exploring over-the-counter access.”

Many states already have standing orders that allow for the dispensing of naloxone without an individual prescription and other public health initiatives to increase naloxone access.  For example, here in the District of Columbia, residents can access naloxone (free of charge with no identification requirements) at designated pharmacies throughout the District or have naloxone shipped to their address.  While laypeople are already using NNS in a number of states, FDA has cautioned that the current community use differs from OTC use because many of these programs provide patient counseling and instructions for use that go beyond what is included in the current NNS labeling.

The scope of the standing orders varies significantly state-by-state and both harm reduction experts and FDA agree that the prescription status for naloxone continues to pose a barrier to wider access.  However, FDA cannot unilaterally switch a product from prescription to OTC status.  A sponsor must submit a new application or efficacy supplement to an existing application for an Rx-to-OTC switch that includes both efficacy and safety data demonstrating that the drug is safe to use in the nonprescription setting, as well as data that demonstrate consumers can use the drug safely and effectively without the supervision of a healthcare professional.

With the Rx-to-OTC switch objective in mind, FDA took the “unprecedented” step of developing and testing a model drug facts label (DFL) for OTC naloxone and published a label comprehension study and model DFLs for naloxone administered via nasal spray and auto-injector in 2019.  In November 2022, FDA published a preliminary assessment that certain types of naloxone products (nasal spray up to 4 mg, autoinjector up to 2 mg) “may be approvable as safe and effective for nonprescription use.”  Essentially, FDA already prepared a sample DFL and made the preliminary determination that there are sufficient safety and efficacy data to support an Rx-to-OTC switch, but still needed product-specific data on the nonprescription user interface design, including packaging and labeling, to make a conclusive determination.

February 2023 Advisory Committee for NNS Rx-to-OTC Switch

Narcan Nasal Spray was originally approved by FDA in November 2015 (NDA 208411).  In September 2022, the sponsor, Emergent BioSolutions, submitted an efficacy supplement for a full Rx-to-OTC switch of NNS which was the subject of this week’s joint Advisory Committee meeting.  To support their application, the sponsor conducted a human factors validation study (HFVS) designed to verify that participants from all representative user groups could use the proposed DFL to appropriately administer NNS in a simulated overdose setting.  Other than the product-specific administration directions in Step 2, the sponsor’s proposed DFL is adopted verbatim from the FDA model DFL.  The primary endpoints of the HFVS were to evaluate if participants could successfully perform the following product-specific dosing tasks using only the proposed DFL as guidance:

Step 2: Give 1st dose of Narcan OTC Nasal Spray

1. HOLD the Narcan OTC Nasal Spray with your thumb on the bottom of the plunger
2. INSERT the tip of the nozzle into either NOSTRIL
3. PRESS the plunger firmly to give the 1st

The HFVS enrolled a total of 71 participants with an age range of 15-76.  The study results exceeded the pre-defined performance thresholds for Steps 2a and 2b.  Five participants did not adequately demonstrate Step 2c and the lower limit of the 95% confidence interval fell just short of the target, but with an observed proportion of 94.4% of participants with acceptable performance of this step.  As a result of the HFVS, the sponsor changed the layout of the carton panels, and increased the font size, color, and background of the text above the pictograms.

As discussed extensively in the briefing materials and presentation, the sponsor conducted the HFVS without requesting comment and guidance from FDA regarding the methodology or protocol.  FDA flagged five study limitations for the Advisory Committee’s consideration:

1. The HFVS did not include participants in the 10-14 age group.
2. Two user groups did not include at least 30% limited literacy participants.
3. Participants were allowed to review the DFL and packaging for an “unlimited” period which is not representative of a high-risk scenario.
4. Moderators encouraged participants to “think aloud” which is also not reflective of an actual use scenario and may have influenced participant behavior/performance.
5. The “mock” carton labeling tested in the HFVS differs from the intend-to-market carton labeling.

The inclusion of the first limitation was particularly interesting given that FDA’s own label comprehension study also did not include the 10-14 age group.  FDA explained that their Institutional Review Board objected to including children under 15 because participating in response to a simulated overdose situation would potentially be “traumatic” to younger children.  However, as noted by NDAC member Dr. Walker-Harding, seeing a loved one die from an overdose and not being able to do anything is not just potentially traumatic to younger children, but is an unfortunate reality in the current opioid crisis.  Younger children will, tragically, be in situations where they may be the only person available to administer naloxone.

The joint Advisory Committee didn’t disagree that there were certain limitations to the methodology of the HFVS and that the DFL and packaging could be better designed and some members offered suggestions for consideration in making improvements (e.g., including a QR code that links to additional training).  In fact, the DFL and packaging has been redesigned, but the redesign has not been studied in another HFVS.  However, in reaching their unanimous decision, committee members emphasized that (1) naloxone is effective in treating opioid overdoses, (2) there are extensive data that demonstrate naloxone is safe, even when administered in the absence of opioids (i.e., mistakenly administered to a patient who is not experiencing an overdose), and (3) an Rx-to-OTC switch for NNS will save lives.  Several committee members noted that the urgency in increasing access to naloxone—a drug with a well established safety and efficacy profile—is far more significant than perfecting the label.

What’s next?

As noted, the Advisory Committee’s recommendation is important, but is not determinative of FDA’s ultimate decision of whether or not to approve Emergent’s application for an Rx-to-OTC switch.  After completing its review of the application, FDA will approve the drug or may issue a complete response letter outlining the deficiencies that preclude approval.  As was briefly discussed during the Advisory Committee meeting, FDA has no statutory or regulatory mechanism to impose a postmarketing requirement on NNS in this particular context.  FDA could not, for example, approve the NNS Rx-to-OTC switch and also require that the sponsor conduct a new HFVS with the updated DFL and packaging.  The Prescription Drug User Fee Act (PDUFA) goal date by which a decision is expected is March 29, 2023.

FDA is also reviewing an application for OTC naloxone under the trade name RiVive submitted by Harm Reduction Therapeutics last year.  Harm Reduction Therapeutics’ application differs slightly in that it is a new application for a direct-to-OTC approval, rather than an Rx-to-OTC switch of an existing approved application.  The joint NDAC and AADPAC will meet again on March 20 to discuss RiVive and the PDUFA date for that application is April 28, 2023.  FDA could theoretically act on Emergent’s application at any time—before or after the Advisory Committee meets to discuss RiVive.

Sections of the radiological health regulations have been updated with the goal of lessening regulatory burdens. The regulations contain many requirements that are over 30 years old. These regulations apply to radiation emitting products, including not just medical devices but all other radiation emitting products as well.  Thus, these regulations apply to a huge variety of products.

FDA is making these updates in part due to recognition that some of the records and reporting requirements are unnecessary to comply with the Electronic Product Radiation Control (EPRC) program (sections 532, 534(a)(1), and 537(b) of the FD&C Act (21 U.S.C. 360ii, 360kk(a)(1), and 360nn(b))). FDA also noted that some of the recommended protections are outdated and redundant to Federal and State requirements, such as professional guidelines, current radiation guidance documents and industry standards that practitioners and industry rely on to ensure public health and safety.

By amending and repealing certain parts of the regulation, FDA believes that compliance to standards adequately protect public health and provide a reasonable assurance of safety and effectiveness when appropriately used by trained personnel.  Further, radiation emitting products are used in limited circumstances, such as to answer a clinical question or guide disease treatment. It is expected that, during these instances, patient risk from radiation exposure can be mitigated and minimized.

The amendments were announced in the Federal Register last month (here).  As anyone who has submitted a laser report knows, the regulations are not always clear.  It appears that some of the changes may enhance clarity and simplicity while others are more administrative in nature.

One of the most notable changes is that 21 C.F.R. § 1002.1 has been modified so that manufacturers of diagnostic x-ray products no longer need to submit initial (§ 1002.10), supplemental (§§ 1002.11), abbreviated (§ 1002.12) and annual reports (§ 1002.13).  This means that manufacturers of diagnostic x-ray systems no longer need to submit an accession number when importing products.  This should come as a relief to diagnostic x-ray manufacturers which have had to comply with both the device regulatory requirements of submitting 510(k)s, complying with the quality system regulation, and filing MDRs, among other things, as well as the radiation emitting product regulations.

The final rule will be effective February 21, 2023.  This is an ideal time for FDA to make these changes as annual reporting for radiation emitting products are not due until September 1.  Manufacturers, therefore, have ample time to familiarize themselves with the changes.

Chocolate-lovers and hopeless romantics rejoice: FDA has announced that it does not intend to object to the use of certain qualified health claims regarding the relationship between the consumption of cocoa flavanols in high flavanol cocoa powder and a reduced risk of cardiovascular disease.

Though not quite a love letter, FDA’s letter to Petition, Barry Callebaut AG Switzerland, arrived just before Valentine’s Day and announces the Agency’s intention to exercise enforcement discretion for the following qualified health claims:

• “Cocoa flavanols in high flavanol cocoa powder may reduce the risk of cardiovascular disease, although the FDA has concluded that there is very limited scientific evidence for this claim.”
• “Cocoa flavanols in high flavanol cocoa powder may reduce the risk of cardiovascular disease. The FDA has concluded that there is very limited scientific evidence for this claim.”
• “Very limited scientific evidence suggests that consuming cocoa flavanols in high flavanol cocoa powder, which contains at least 4% of naturally conserved cocoa flavanols, may reduce the risk of cardiovascular disease.”
• “Very limited scientific evidence suggests that consuming cocoa flavanols in high flavanol cocoa powder, which contains at least 4% of naturally conserved cocoa flavanols, may reduce the risk of cardiovascular disease. This product contains at least 4% of naturally conserved cocoa flavanols. See nutrition information for_____ and other nutrients.”

FDA’s favorable determination for the petitioner was far from love at first sight.  For all qualified health claims, FDA considers the data and information provided in the petition and available to the Agency, including individual reports of human studies, meta-analyses, review articles, and animal and in vitro studies.  This qualified health petition was submitted in 2018, and after four supplements to the petition (see, e.g., here and here), a public comment period, and a years-long extension to FDA’s response deadline, FDA determined that the current evidence supports the use of the qualified health claims above, provided that the labeling is consistent with its letter of enforcement discretion.  FDA intends to exercise enforcement discretion when the following factors are met:

• The qualified health claim includes a truthful and non-misleading description of the strength of the body of scientific evidence (i.e., “very limited”);
• If high flavanol cocoa powder bears the claim, it has at least 4% of naturally conserved cocoa flavanols and contains at least 200 mg cocoa flavanols per Reference Amount Customarily Consumed (RACC);
• If a food containing high flavanol cocoa powder bears the claim, it includes at least one tablespoon (5-6 grams) of HFCP that includes 200 mg of cocoa flavanols per RACC;
• The high flavanol cocoa powder or food containing high flavanol cocoa powder meets the regulatory definitions for “low fat,” “low saturated fat,” and “low cholesterol” in 21 C.F.R. § 101.62;
• The high flavanol cocoa powder or food containing high flavanol cocoa powder does not exceed disqualifying nutrient levels for total fat, saturated fat, cholesterol, or sodium content under 21 C.F.R. § 101.14; and
• The food containing high flavanol cocoa powder contains at least 10 percent of the Daily Value establishment for vitamin A, vitamin C, iron, calcium, protein, or dietary fiber per RACC.

But before you dig into any heart-shaped boxes of chocolate this Valentine’s Day, note that FDA’s enforcement discretion for these qualified health claims only applies to cocoa flavanols in high flavanol cocoa powder and foods that contain high flavanol cocoa powder—not regular cocoa power, foods containing regular cocoa powder, or other food products made from cacao beans, such as chocolate.  Although the science might not be there, a piece of chocolate on Valentine’s Day may still do you some good.

In November of 2020, plaintiffs representing the pharmaceutical industry sued the U.S. Department of Health and Human Services (HHS) to block a rule that would allow the importation of Canadian prescription drugs (see our blog post on the complaint).  Last week, the D.C. District Court dismissed the suit for lack of standing because plaintiffs could not show any concrete risk of harm.

Despite the apparent green light, it will be a while before we see Canadian drugs on our pharmacy shelves. The final rule does not itself permit any drugs to be imported. Rather than creating its own importation program under Section 804 of the Federal Food, Drug, and Cosmetic Act (FDC Act), the Food and Drug Administration (FDA) used the statute to create a pathway for States and Indian Tribes (“Sponsors”) to develop such programs (called Section 804 Importation Programs, or SIPs).

The final rule’s requirements for SIPs tracked the various statutory criteria of Section 804. Significantly, the final rule also required U.S. manufacturers to authorize the use of their FDA-approved labeling to importers and either test the imported products or give information to importers to test the products so the importers can submit pre-import requests to the FDA. The industry lawsuit challenged the final rule based on constitutional and procedural grounds. It alleged imminent harm because FDA had already received SIP proposals from several states.

As a final check, the statute also required HHS to certify that any Section 804 importation program will produce significant savings for American consumers without risking the public’s safety. Then HHS Secretary Alex Azar issued a “conditional” certification—valid only for SIPs implemented through the final rule, and subject to FDA’s approval of the SIP and pre-import requests. The industry lawsuit also challenged this certification.

Court Found No Imminent Harm and No Associational Standing

Judge Timothy Kelly noted that plaintiffs’ alleged harms did not show that there was “a substantial risk that a future harm will occur” because they failed to show if, when, and how even one of their members would be harmed by an approved SIP or a pre-import request.

According to the court, the plaintiffs could either show that threatened injury is certainly impending, or a substantial risk that a future harm will occur. The court found that plaintiffs’ members’ injuries hinged on, at the very least, the approval of a SIP and the filing of a pre-import request. FDA’s discretion to deny any SIP proposal vitiated any claim that a harm is certainly impending.

The court next focused on whether the plaintiffs showed an increased risk of future harm. The court held that the plaintiffs’ claims are concrete but not imminent because drug importation is still subject to regulatory processes and approvals. The court’s asked three questions to assess the “imminence” of this future harm: will the agency approve the application, when will it do so, and what will the terms of the approval be?  According to the court, “even if the Court assumes an SIP will eventually be approved . . . the Court could only speculate about when such an approval will occur and, more importantly, on what terms.” Decision at 15-16. The final rule specified no timeframe for FDA to act on a SIP proposal. And without knowing the terms of such an approval, the court could not identify which, if any, member of a plaintiff association would suffer the alleged injury. The plaintiffs simply asserted a likelihood that some of their members face a risk of harm.

Plaintiffs Other Alleged Harms Must Also Fail

The judge next discussed plaintiffs’ allegations of past and present “compliance costs.” Twelve members of the plaintiffs submitted declarations of having to expend financial resources for potential pre-import requests. Although the court agreed that these administrative costs were concrete and particularized, it held that the cognizability of such costs “depend[ed] on whether Plaintiffs have met the standard for alleging a ‘substantial increase in the risk of harm’”—which they had not. Decision at 23.

The judge also addressed plaintiffs’ allegations of procedural injury, including an assertion that the HHS Secretary’s certification required an independent opportunity for notice and comment. He dismissed them noting that these kinds of injuries also depend on a showing of “substantial probability of future harm,” which they had not done.

Finally, the judge saw plaintiffs’ allegations of harm to their own organizations (e.g., harm to the shared interest in the safety of U.S. drug supply; being forced to spend additional resources to curtail the circulation of adulterated drugs) as assertions of organizational standings. He dismissed them as “prototypical statements of harm to ‘abstract social interests.’” Decision at 25.

Where Does The Final Rule Go From Here?

Since the Trump Administration issued the final rule, the federal government has been working in earnest on the importation policy. In July 2021, the Biden Administration directed FDA to work with States and Indian tribes to develop SIP proposals. At least six states reportedly submitted SIP proposals to FDA including Colorado, Maine, New Hampshire, New Mexico, Vermont, and Florida, but have not received a decision from the FDA. In March 2022, FDA met with representatives from several states to discuss the development of their SIP proposals.  In August, Ron DeSantis, the governor of Florida, announced a lawsuit against the Biden administration for “reckless delay” of reviewing Florida’s SIP.

Only after FDA approves a SIP will we see how the rest of the pieces of the final rule are implemented—and whether the rule will be challenged again in court.

For medical device start-up companies, understanding and successfully navigating applicable FDA regulations and requirements is an important part of the path to market.  For founders new to the medical device industry, especially with device types that are often considered novel, the learning curve can be steep.

It is common to refer to FDA regulations as either pre-market, meaning they are applied before the device may be marketed, or post-market, meaning that compliance is generally required only after the device is brought to market, with some exceptions.

Pre-market requirements include those for obtaining marketing authorization, including 510(k) clearance (21 C.F.R. Part 807, Subpart E), De Novo authorization (21 C.F.R. Part 860 Subpart D), or PMA approval (21 C.F.R. Part 814), and for conducting clinical trials (21 C.F.R. Part 812).

Post-market requirements cover activities such as registration and listing (21 C.F.R. Part 807), establishing a quality management system (QMS) (21 C.F.R. Part 820), labeling (21 C.F.R. Part 801), unique device identification (21 C.F.R. Part 830), post-market surveillance studies (Section 522 of the FD&C Act), medical device tracking (21 C.F.R. Part 821), medical device reporting (21 C.F.R. Part 803), and reporting corrections and removals (21 C.F.R. Part 806).

It is not surprising that many start-ups focus on the pre-market requirements first, as not achieving marketing authorization makes the need for compliance with other requirements moot.  A question that often comes up is: when is the best time to start preparing for post-market requirements?  For PMA devices, the marketing application contains quality system and manufacturing information, so getting started on the quality system in parallel to device development is important for a timely submission.  For 510(k) devices, sponsors could wait to establish a quality system that covers all post-market requirements until device development is further along.  Waiting too long, however, could lead to delays in being ready to sell and distribute devices if the marketing authorization is received before all necessary procedures are established, so it is important to have a plan that ensures timely development of a full QMS.

There is one section of the QMS, however, that is worth starting early in the product development lifecycle:  Design Controls.  Design controls (21 C.F.R. § 820.30) are described in FDA’s guidance, Design Control Guidance for Medical Device Manufacturers, as “an interrelated set of practices and procedures that are incorporated into the design and development process” (p. 1).  Design controls are applicable to Class III, Class II, and select Class I devices, including those that incorporate software.  Id. § 820.30(a).

In practice, a standard operating procedure for design controls is developed to describe how medical device design will be performed and documented.  Design controls include requirements for:  design and development planning, design input, design output, design review, design verification, design validation, design transfer, and design changes.  There are many resources that provide information and guidance for each of these required elements.

Why should a device start-up company, with limited resources and plenty of work to produce initial prototypes, be thinking about design controls early in development?  There are a number of reasons why it is worthwhile.

First, a design history file includes many documents that must be submitted as part of a 510(k), De Novo, or premarket approval (PMA) application.  For example, FDA generally conducts fairly extensive reviews of software documentation.  It will generally be easier to generate these documents contemporaneously with device development as part of a structured procedure, rather than doing so afterwards.   Or, to put it another way:  We have not yet met an engineer who enjoys remediating the documents for development work that was done in the past.

Second, if clinical data will be needed to support the marketing application, compliance with design controls is required.  The Investigational Device Exemption regulation exempts a device from the requirements for good manufacturing practices except for the requirements for design controls.  21 C.F.R. § 812.1.

Third, establishing and following a process for design controls early in device development may improve the safety, effectiveness, and quality of the device, and the quality of the application for marketing authorization.

Specifically, when following a structured design control process, device requirements and risk mitigations may be more formally discussed cross-functionally, leading to a robust design and decreasing the risk that design changes are needed when design controls are eventually applied, or as part of FDA review.  By following a structured process for identifying requirements and risks, it may be easier to identify issues that could benefit for pre-submission discussions with FDA.

In short, following design controls imposes a certain amount of burden, but the benefits just described usually make it worth the time and expense, even early in development when they may not be strictly required.

In the Spring of 2021, the Health Resources and Services Administration (HRSA) threatened six drug companies with billions of dollars in penalties for not providing 340B discounts to covered entities that sell drugs through vast networks of contract pharmacies (more background on earlier posts).

The drug makers argued that their statutory obligation to provide discounts did not extend to multiple contract pharmacies, who they said often abused the system. HRSA argued that it unambiguously did, and the companies sued. Six district courts presided over these decisions. The outcomes were almost evenly split.

Three of these cases were in the third circuit. AstraZeneca won in the District of Delaware, while Sanofi Aventis and Novo Nordisk lost at the District of New Jersey. Both courts found the statute to be ambiguous, but only the Delaware court vacated HRSA’s penalties; the New Jersey court remanded the issue to HRSA.

Last week, a panel of three judges at the Third Circuit who reviewed these three cases decided in favor of the drug manufacturers. Writing for the court, Judge Bibas said that, while neither Chevron deference nor Skidmore deference applied (because the agency lacks rulemaking authority here), the agency was “entitled to respect”—but only if it had the “power to persuade.” The court decided that it did not, and gave three reasons for its decision.

First, the statute requires manufacturers to offer 340B prices to covered entities but is silent about delivery.  However, according to the court, this silence does not give HHS the authority to read into the statute a requirement to deliver to wherever and whomever the covered entities demand. Second, the court found that neighboring statutory provisions contemplated the drug companies contracting with vendors or commercial entities to distribute discounted drugs. This suggests that Congress’s silence on the issue in the 340B statute was likely intentional. Finally, the court found that legislative history did not necessarily support the government’s view—the most relevant language did not end up in the final statute, and that omission could have supported either party.

The court also reviewed HRSA’s dispute resolution rule and a majority of the judges upheld it. The court refused to give separate legal significance to the fact that HRSA withdrew the proposed rule in 2017 and found a 30-day notice period before the final rule was sufficient under the Administrative Procedures Act.

A lot is at stake here. The 340B program is growing rapidly, and contract pharmacies have been key to that growth. In 2019, covered entities reportedly bought $30 billion worth of prescription drugs (see here; this ballooned to $44 billion in 2021). Compare that to $151 billion for Medicaid, Medicare Part B, and Medicare Part D combined (see here). There is a high likelihood that this case will end up at the Supreme Court, especially if the other cases create a circuit split.

Amongst the many provisions that Congress included in the recent Food and Drug Omnibus Reform Act (“FDORA”) were two subtle changes – one change to the Federal Food, Drug, & Cosmetic Act’s (“FD&C Act”) requirements for advancing an investigational new drug into clinical trials and another change to the Public Health Service Act’s (“PHS Act”) (as amended by the Biologics Price Competition and Innovation Act of 2009) requirements for developing a biosimilar biological product. (For more on FDORA’s other provisions, see HPM’s complete summary here).  Since 1962, the FD&C Act has authorized FDA to require that sponsors of clinical trials submit data from “preclinical tests (including tests on animals)” in order to demonstrate that their drug is safe enough to advance to testing in humans.  FDORA’s change to that key phrase (“preclinical tests…”) has been touted by some as anything but subtle and that it represents a monumental shift in what FDA is empowered to require of sponsors. While this hype may be warranted in some respects—a 60-year old legal provision has now been amended to acknowledge that the science of drug development is advancing—the change is mostly symbolic and is likely to take many years before we see it have a measurable impact.  In effect, the revisions to the FD&C Act and the PHS Act are designed to encourage the use of alternatives to animal testing not eliminate animal testing in drug development.

As noted above, Section 3209 of FDORA amends the statutory language regarding the criteria to obtain an IND.  Previously, the law stated that FDA could condition the opening of an IND upon the submission of reports of “preclinical tests (including tests on animals) . . . adequate to justify the proposed clinical testing.”  21 U.S.C. § 355(i)(1)(A).  FDORA replaces the term “preclinical tests (including tests on animals)” with a newly defined term “nonclinical tests.”  FDORA § 3209(a)(1).  The law defines this term to mean “a test conducted in vitro, in silico, or in chemico, or a nonhuman in vivo test that occurs before or during the clinical trial phase of the investigation of the safety and effectiveness of a drug.”  FDORA § 3209(a)(2).  The definition goes on to list potential options for such tests: cell-based assays, organ chips and microphysiological systems, computer modeling, other nonhuman or human biology-based test methods such as bioprinting, as well as animal tests.

As to biosimilars, FDORA amends the statutory language regarding criteria for the demonstration of biosimilarity for a 351(k) biologic.  Previously, the law stated that the demonstration of biosimilarity could be based on data derived from:

(aa) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components;

(bb) animal studies (including the assessment of toxicity); and

(cc) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity and potency in 1 or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product.

42 U.S.C. § 262(k)(2)(A)(i)(I).

FDORA replaces the language in (bb) regarding animal studies with “an assessment of toxicity (which may rely on, or consist of, a study or studies described in item (aa) or (cc).”  FDORA § 3209(b).

While these changes to the IND and the biosimilarity provisions represent real changes to the words governing FDA’s authority under the FD&C Act, we think it is worth asking just how measurable and immediate an impact they will have on day-to-day decision-making of the FDA and its review staff.   The pre-existing statutory language did not require animal testing. Rather, the provisions did, and still do, leave it up to FDA’s discretion what methods and tests are most appropriate under the circumstances.  In both contexts, FDORA amends the language to more explicitly allow for alternatives to animal testing but does not mandate the acceptance of any of these alternatives.

In our experience, FDA is inherently an empirically driven body of scientists, physicians, and policy-makers. It will likely take time to supplant decades of reliance upon existing animal testing methods used to investigate drug pharmacology and toxicology. Alternative methods will require significant research investment to demonstrate their utility for a particular context of use and inform regulatory decision-making.

However, there are signs that FDA is receptive from a policy perspective to alternative methods.  The 2017 Predictive Toxicology Roadmap laid out some of the FDA’s thinking around the need for new toxicology methods driven in part by a desire to find alternatives to animal testing.  In 2019, FDA formed an agency-wide Alternative Methods Working Group indicating that it viewed the applicable scope of alternative methods to go beyond just toxicology research.  More recently still, FDA requested $5 million in its FY 2023 budget request to support the New Alternatives Method Program to “replace, reduce and refine animal testing (the 3Rs), and improve predictivity of nonclinical testing.”  As FDA notes in its budget request, “FDA cannot develop and implement alternative methods alone, so through this initiative FDA will expand qualification processes, provide clear guidelines to external stakeholders developing alternative methods, and fill information gaps with applied research to advance new policy and guidance development.”

Ultimately, regardless of any changes made by FDORA, it will be up to the science surrounding new alternative methods, and FDA’s acceptance of the evidence base to support them, to demonstrate the suitability of these alternative tests as replacements for animal testing. In our experience, FDA review divisions will engage with sponsors about their plans to implement novel methods in their development programs but have yet to let them replace traditional animal testing in a measurable way. To us, some of the hype regarding the changes FDORA made to the law regarding animal testing may be overselling the law’s impact. Meaningful change in this arena will require the investment of time and resources to achieve the scientific advancement it promises.

FDA has not been shy about its distaste for the Catalyst decision; the Agency has published on its website the litany of problems that arise from it and has sent emails and letters to stakeholders essentially urging them to contact Congress to address the decision.  Indeed, FDA was pushing Congress heavily to legislatively overturn the Catalyst case but ultimately failed to get the provision included in either the User Fee package or FDORA.  So what’s FDA to do when it can’t get the courts or Congress to support its position?  Ignore the decision!  FDA announced in the Federal Register on January 24 that, regardless of the Catalyst decision, the Agency “intends to continue to apply its regulations tying the scope of orphan-drug exclusivity to the uses or indications for which a drug is approved . . .” with the exception of the specific product at issue in the Catalyst case.

In brief, the Eleventh Circuit held in Catalyst that the term “same disease or condition” in the Orphan Drug Exclusivity provisions relates back to the entire disease or condition designated in the Orphan Drug Designation provisions rather than the indication ultimately approved, as FDA had been interpreting the scope of Orphan Drug Exclusivity.  This means that Orphan Drug Exclusivity for an approved designated drug would block the “same drug” for the same disease or condition rather than just the specific indication.  In the case at issue, FDA had approved Catalyst’s Firdapse (amifampridine) with Orphan Drug Exclusivity for the treatment of Lambert-Eaton Myasthenic Syndrome (“LEMS”) but subsequently approved another manufacturer’s amifampridine product for pediatric LEMS during the pendency of the Firdapse exclusivity period.  Catalyst sued, arguing that its Orphan Drug Exclusivity protected the use of amifampridine in the entire LEMS population—adults or pediatrics—under the statute, and the Eleventh Circuit agreed, concluding that the phrase “same disease or condition” in the Orphan Drug Exclusivity statute “unambiguously foreclosed FDA’s interpretation of the provision” as limiting Orphan Drug Exclusivity to the approved indication.  At the Court’s direction, FDA withdrew approval of the amifampridine product for use in pediatric patients but made it quite clear that it did not agree with the Eleventh Circuit’s decision.

The Notice in the Federal Register serves to “address the uncertainty created by the circuit court’s decision in Catalyst.”  For clarity therefore the Agency announced that is has decided to “continue to apply its existing regulations tying orphan-drug exclusivity to the uses or indications for which the orphan drug was approved.”  Even though the Court’s reading of the “unambiguous” statute was quite clear, FDA explained that its decision is appropriate based on the Agency’s reading of the statute—notwithstanding the fact that FDA’s reading of the statute conflicts with the Eleventh Circuit.  So even though the Eleventh Circuit expressly found otherwise, FDA maintains that:

the statutory text does not unambiguously require that orphan-drug exclusivity extend to the entire disease or condition for which a drug received orphan-drug designation if the drug is only approved for some uses within that disease or condition. Further, FDA believes that its statutory interpretation embodied in its regulations best advances the Orphan Drug Act’s purposes, appropriately balancing the need to incentivize the development of drugs for rare diseases and conditions with the need to provide patient access to orphan drugs.

FDA implicitly has told the Eleventh Circuit that the Agency’s interpretation of the Orphan Drug Act trumps the Court’s.

FDA’s announcement in the Federal Register that the Agency will not apply the Eleventh Circuit’s decision beyond amifampridine essentially takes the position that the decision has no precedential value in the view of the Agency.  In other words, FDA is going to technically comply with the Eleventh Circuit decision with respect to amiframpridine but will otherwise pretend that the Eleventh Circuit’s interpretation of the Orphan Drug Exclusivity provisions never happened.  Specifically, FDA said that “the Court ordered FDA to set aside its approval of Jacobus’s drug, and FDA has set aside that approval.”  That’s all the decision called for, and that’s all the Agency intends to do—in FDA’s eyes, it’s done everything the Court asked.

Regardless of the merits of FDA’s position on the Orphan Drug Act provisions, it’s open defiance of the Eleventh Circuit’s interpretation of the Orphan Drug Act is certainly a bold strategy.  But of course it’s not unprecedented.  FDA did the very same thing when the D.C. Circuit held that the plain language of the exclusivity provisions of the Orphan Drug Act requires FDA to recognize Orphan Drug Exclusivity for any drug that FDA has designated and to grant marketing approval without demanding proof of clinical superiority.   There, FDA announced a “Clarification of Policy” that that decision—the Depomed decision—applied only to the drug at issue (Gralise) and that the Agency “intends to continue to apply its existing regulations . . . to require the sponsor of a designated drug that is the ‘same’ as a previously approved drug to demonstrate that its drug is ‘clinically superior’ to that drug upon approval in order for the subsequently approved drug to be eligible for orphan-drug exclusivity.”  In the same way that FDA “doubled-down” on its pre-Depomed approach, it’s doing the same here.

FDA’s Depomed “Clarification of Policy” led to additional lawsuits from Eagle and United Therapeutics challenging FDA’s demand for proof of clinical superiority, effectively requiring the Agency to relitigate the issue until Congress eventually enacted a legislative fix, and we expect the same will happen here.  Obviously, a broader scope of Orphan Drug Exclusivity is a huge boon to an orphan drug sponsor, so it stands to reason that a recipient of Orphan Drug Exclusivity would want to ensure the broadest scope possible and would fight to secure it.  FDA likely anticipates such a lawsuit too, and for that reason, is likely to continue lobbying Congress for a legislative fix.  But until then, we will sit down with some popcorn and watch the orphan drug lawsuits unfold.

In early 1984, a year after President Reagan signed the Orphan Drug Act into law, the FDA was not seeing the anticipated avalanche of requests for orphan drug designation.  At that time, new Federal laws on drugs were far and few between.  FDR signed the 1938 law that required that drugs be safe & JFK signed the 1962 law that required that drugs also prove they have a benefit.  So when patients led by Abbey Meyer and Marjorie Guthrie (Woody Guthrie’s widow) had championed the 1983 law to create incentives for developing drugs for those with rare conditions, the FDA was excited at this once-in-a-generation new law as this was FDA’s 3ed major drug law in nearly half a century.  FDA created a new office directly under the Commissioner and promoted FDA’s drug center director, Dr. Marion Finkel, to lead this new Office of Orphan Products Development.

Now in early 1984, after a year of anticipation, nearly nothing was happening, but for a handful of therapies that had been in development and were the poster children for the “patients’ campaign” that had led to the new law.

The Deputy Commissioner of FDA, Dr. Mark Novitch, went to Phil Paquin, leader of drug policy which then was in the Office of Compliance in the Center for Drugs and Biologics (yes, a single Center at that time) and asked Phil to try to figure out why the new law was not seeing the expected kind of activity.

Phil called a very new regulatory counsel (my title) into his office and asked me to tackle this.  Realizing that this was a huge opportunity and I was green and that Phil’s office had many seasoned & excellent regulatory counsel like Steve Unger (who led the IND Rewrite & later became FDA Ombudsman) and Mike McGrane (who led the NDA Rewrite, revising the entire set of regulations on NDAs that is now Part 314 of Title 21 of the Code of Federal Regulations), I replied that someone with more seniority and experience may be better equipped for this assignment.  Phil however insisted that he wanted me to take this on & by myself.

I read the provisions of the new law and saw two provisions that seemed to be possible stumbling blocks that could be frustrating uptake of the new law: (1) a provision required that to be designated an orphan drug, a sponsor had to prove that it could not recoup its research & development costs during the 7 years of market exclusivity— essentially a government provided monopoly on marketing; and (2) another requirement for being designated was that the drug could not be capable of being patented.  (I suspect that this may have been included because some may have argued that if there was patent protection for an orphan drug, there would be no need for the 7 years of orphan drug exclusivity).   Well, while my reading of the new law revealed these as two possible barriers to industry embracing the new law, yet what to do about these?

First, I was surprised to learn that FDA had economists, and the senior economist, Rus Scarato, was happy to help me craft language to guide sponsors who were unsure how to prove that economically they would be incapable of recouping R&D costs over a 7 year period of monopoly marketing.  (Later I was asked to draft the regulations to implement the new law , which is another story and which was accomplished only with the adroit collaboration with a colleague, Emery “Rico” Sturniolo.  See 21 C.F.R. § 316.21(c) for the language explaining how to verify that R&D costs could not be recovered by US sales.)

Second, FDA did not and still does not have any patent law expertise in-house but our sister agency, NIH, did and does, and so I worked with NIH patent counsel to come up with a sample affidavit that a corporation’s patent counsel could provide to FDA that would affirm that the drug in question could not qualify for a US patent.  Of course, no patent counsel “worth their salt” would ever WANT to make a statement against their interest that they were incapable of coming up with any possible way to show that this drug’s use in treating a rare condition was indeed “new” and “not obvious”.

Armed with this as my view of the two possible reasons the new law had not taken off as FDA had expected, and armed also with my two possible solutions, neither of which seemed to be wholly satisfying to industry (for what company wants to open its “books” to the government on all of its costs & projected revenues and what patent counsel wants to give a statement to the government that it can not figure out any way to argue for a patent on some aspect of a drug’s use for a rare disease), I went to see Dr. Finkel in her office.

I sat down on the opposite side of her large wooden desk, across the table from this soft-spoken person who was regarded by everyone as one of the best leaders and thinkers inside FDA and explained to her that I thought I had figured out why companies were not beating a path to her office and also come up with possible solutions.   Dr Finkel listened and after hearing me out, she picked up her black, rotary dial phone on her desk, called someone, and what I heard next was: “Henry, we think we have some issues with your new law but we also think we have solutions.” And she handed me the phone without explaining who she was talking to.  The person on the other end was Congressman Henry Waxman, the “author” of the Orphan Drug Act.  I explained again the two possible issues or impediments and two possible yet unsatisfactory solutions, that were nevertheless my best attempts at fixes to each problem.

Abbey Meyers, Rep. Henry Waxman, Senator Nancy Kassebaum, and Dr. Finkel then came up with much better solutions than mine!!!  Thanks GOODNESS!  They came up with the 1984 and the 1985 amendments to the Orphan Drug Act which removed the requirement that to be an orphan drug one could not be patentable and which created a simple 200,000 persons diagnosed with the rare condition as the alternative criterion for qualifying to be an orphan drug.  (The economic pathway was not eliminated but left as an alternative that has almost never been used…perhaps fodder for one of many, nearly countless possible follow-up stories to this first one!).

The singular lesson that I draw from my initial baptism into the field, as well as from my 40 years of working to address the suffering of our sisters and brothers with rare conditions, is this: There is an incredible “Power of One!”

All my experience is this field tells me over and over again how much each one of us can do.  Each person is incredibly powerful in this arena.  Dr. Novitch, Dr. Finkel, Mr. Paquin, Mr. Sturniolo, Mr. Scarato, NIH patent counsel….these public health service servants of all Americans.  Abbey Meyers, Marjorie Guthrie, Rep. Henry Waxman, Sen. Nancy Kassenbaum….patient advocates and those in Congress (both members and their staffs) who marched and worked to create this new law and make it work.   Untold numbers of researchers in academia and in industry.  Investors who back this kind of longshot research when many others would say “smart money” should go where the biggest markets are.  Individuals who’s lives were changed by a family member, usually a child, who just happened to be unlucky in the spin of the genetic roulette wheel, and who left everything else and devoted their careers to helping their child and all others similarly affected, heroes to me like Martine Rothblatt of United Therapeutics, John Crowley of Amicus and Matt Wilsey of Grace Science and that list could go on and on and on.

My lessons learned from four decades is this: You too are whoever you are and Whatever your position….Know that you too have incredible abilities to effect real change by doing what you can.  Know that.  Act on that.  IT is REAL!  Onward, onward, ever onward!

A recent analysis of statistics on FDA’s website, prepared for a presentation at a good manufacturing practices (GMP) conference in San Diego next week, shows a dramatic increase in the percentage of FDA drug manufacturing facility inspections that result in an “Official Action Indicated” classification.  This means that if your drug manufacturing facility is inspected, it is nearly twice as likely as before that FDA will follow up with regulatory or enforcement action, which can include Warning Letters, freezes on drug approval applications or on issuing export certifications, requests for a recall, seizures, or requests for consent decrees.

The analysis was prepared for Pharma Conference’s conference on February 8 and 9 in San Diego (“Current Hot GMP Topics”), linked here, where Hyman, Phelps & McNamara, P.C., Director Doug Farquhar will be presenting on three areas: enforcement areas of primary concern, the conduct of internal investigations, and contacting FDA about inspections.  Other speakers at the conference include Alonza Cruse, the Director of the Office of Pharmaceutical Quality Operations within FDA’s Office of Regulatory Affairs; several prominent drug manufacturing consultants with significant FDA experience; and attorney Jennifer Bragg, an attorney formerly at FDA and now a nationally recognized lawyer advising FDA-regulated companies facing government investigations and related enforcement challenges.

Mr. Farquhar will be presenting the results of research on FDA’s inspection database which he and HPM Legal Assistant Aisha Evans conducted.  The analysis shows, predictably, that FDA inspections of drug manufacturing facilities dropped precipitously during the first two years of COVID, but are gradually ramping up again, consistent with FDA’s predictions (see August 2022 blogpost linked here).  The chart below shows the number of inspections per fiscal year (FY) (which runs from October 1 through September 30).  FDA, Inspections Database (last visited Jan. 29, 2023).

*Legal Assistant/Paralegal