Hyman, Phelps & McNamara, P.C. (HP&M) is proud to announce that two associates, Serra Schlanger and Rachael Hunt, will be hosting a program on telemedicine for FDLI’s New to Food and Drug Law Group (NFDL).

Telemedicine: Key Issues to Consider When Advising Clients, will take place on March 7, 2019 from 12pm – 1:30pm at HP&M in Washington, D.C.  Telemedicine, the use of telecommunication technology to remotely provide health care services, is an emerging interest for clients in the FDA sector.  For example, many FDA-regulated companies are now using internet platforms to engage with patients and potential customers.  The use of the internet in this context touches on FDA regulations, state law requirements, and a host of other issues.  This program will introduce subjects to consider when working with clients interested in exploring telemedicine as a new business opportunity or as a component of an existing platform.

For additional information, including a link to register, please visit this website.

The United States Department of Justice (“DOJ”) announced on February 8, 2019, the use of a new weapon in its enforcement arsenal to help manage the opioid crisis.  It involved a coordinated effort including DOJ’s Prescription Interdiction & Litigation (“PIL”) Task Force, which deploys all available criminal, civil, and regulatory tools “to reverse the tide of opioid overdoses in the United States,” stated the press release announcing the civil action, here.

The government filed under seal a civil Complaint in the United States District Court for the Middle District of Tennessee against two affiliated Celina, Tennessee, pharmacies — Oakley Pharmacy, Inc., d/b/a Dale Hollow Pharmacy and Xpress Pharmacy; the pharmacies’ owner, Thomas Weir; and pharmacists John Polston, Michael Griffith, and Larry Larkin.  The Complaint alleges that  defendants were dispensing, and billing Medicare for, prescriptions in violation of the Controlled Substances Act and the False Claims Act.  The Complaint also alleges that defendants’ dispensing of opioids was tied to the deaths of at least two people and the emergency medical treatment of other individuals for drug overdoses.

Just what exactly is so unusual about the government’s action here?

First, the government proceeded against the pharmacies and their owners/employees in secret, so to speak, by filing the civil action under seal, and then seeking an ex parte temporary restraining order and preliminary injunction, which is an extraordinary remedy because the defendant does not receive notice of the action in advance of the court proceeding.  The court unsealed the Complaint after hearing the government’s motion and entering the TRO against defendants.  The government’s memorandum in support of the TRO stated it was necessary to proceed with under seal filings and an ex parte TRO pursuant to 21 U.S.C. § 843(f), given defendants’ three-year DEA regulatory history described in the Complaint and TRO memorandum, a need to immediately halt illegal activities, and an alleged real threat that defendants would continue to violate the Controlled Substances Act and harm the public. Defendants allegedly violated their corresponding responsibility to ensure that prescriptions were issued for a legitimate medical purpose under 21 C.F.R. § 1306.04, but, in the alternative, also violated 21 U.S.C. § 841(a)(1), by knowingly and intentionally distributing and dispensing controlled substances outside the usual course of pharmacy practice, by filling, for example, an unsigned prescription and multiple prescriptions that presented with multiple “red flags,” according to the declaration of the government’s pharmacy expert.

The government also stated that the ex parte proceeding was necessary because it intended to execute search warrants to obtain dispensing records, files and other evidence of illegal conduct from the pharmacies’ premises, and was concerned that, with notice, Defendants could take steps to alter or destroy records.

Second, the government chose to first file in federal court a Complaint and a Motion for a TRO, instead of pursuing DEA’s typical (and expected) administrative remedy in a corresponding responsibility case, which is seeking a DEA administrative Immediate Suspension Order (“ISO”) under 21 U.S.C. § 824(d) and 21 C.F.R. § 1301.36.  The ISO has the same impact as the TRO such that the pharmacy registrant is immediately “suspended” from handling controlled substances, without notice to the registrant, upon service of the ISO.  In addition, an ISO does not require a filing or court intervention – the DEA acting administrator, after consideration of the facts and circumstances, may issue the ISO after determining there exists an imminent threat to the public health or safety.

In this case, however, the government noted at page 19 of its Memorandum in support of its TRO that DEA is “separately considering” an ISO (but we don’t know why it would need to do so at this point).  However, the government stated an ISO would not have the ability to “restrain” the conduct of the individual defendants named in the Complaint because those individuals are not DEA registrants.  The government also noted that the ISO lacks the “finality” of the injunctive relief sought in the underlying lawsuit.  However, we note, as well, that a TRO and Preliminary Injunction are indeed interim remedies; if defendants choose to do so, the injunction matter will be fully heard by the court pursuant to Fed. R. Civ. P. 65.

Third, the government’s Complaint ties – in great detail – the pharmacies’ allegedly illegitimate prescriptions to violations of the False Claims Act, implicating the False Claims Act when prescriptions are filled for “illegitimate medical purposes“ or are not “reasonable and necessary” for the treatment of illness or injury.   Although DEA has used in a similar approach in one other enforcement matter (against long term care pharmacy PharMerica), the government to our knowledge has not alleged violations of the False Claims Act in pharmacy corresponding responsibility matters.  If successful, the government will be entitled to civil monetary penalties and treble damages for falsely billing Medicare for illegally dispensed prescriptions.

The government’s press release concluded with the following warning to pharmacists:

The action supported today by the Drug Enforcement Administration should serve as a warning to those in the pharmacy industry who choose to put profit over customer safety,” said D. Christopher Evans, Special Agent in Charge of DEA’s Louisville Field Division, which covers Tennessee, Kentucky, and West Virginia. “Pharmacists serve on the front lines of America’s opioid epidemic and they share responsibility with physicians to protect those whom they serve from the dangers associated with prescription medications.  We will be vigilant in holding them accountable.

As avowed dog-lovers and FDA law enthusiasts, a recent Complaint filed in the District Court of D.C. caught our attention.  Vanda Pharmaceuticals filed a Complaint on February 6, 2019 alleging that FDA’s insistence that Vanda perform a 9-month dog study with its drug candidate tradipitant before extending human trials beyond 90 days violates the Administrative Procedures Act (“APA”).  Vanda, it seems, may be on a mission to shake up FDA’s long-standing policies with respect to animal testing.

As described in the Complaint, Vanda is developing tradipitant, a neurokinin 1 receptor (NK1R) antagonist, for the treatment of several human diseases including gastroparesis.  In Spring 2018, Vanda sought to extend an 8-week open-label extension Phase II study with tradipitant by adding a 52-week open-label extension period.  However, FDA repeatedly asserted that Vanda was required to conduct a 9-month non-rodent toxicity study with tradipitant before performing any studies in humans lasting longer than 90 days.  After some back and forth and procedural maneuvering, including Vanda’s proposal of a different 52-week tradipitant open-label extension study, FDA eventually imposed a partial clinical hold on Vanda’s two 52-week studies until a 9-month non-rodent toxicity study is performed.

Unable to convince FDA that the 9-month non-rodent toxicity study is unnecessary, Vanda sued FDA for violation of the APA.  Vanda alleges that imposing a clinical hold without a demonstration of unreasonable risk to the safety of subjects and imposing “requirements” without engaging in notice-and-comment rulemaking were arbitrary and capricious in violation of the APA.  Vanda argues that the nonclinical animal studies already performed included multiple 3-month chronic toxicity studies in dogs, and multiple acute and chronic rodent toxicity studies, including 3 and 6-month studies, none of which identified clinically relevant safety signals for use of tradipitant in humans.

Vanda cites FDA’s reliance on the non-binding policy document, Guidance for Industry, M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (Jan. 2010) (referred to as the “ICH Guidance” because the document was created by the International  Conference for Harmonization and subsequently adopted by FDA as a non-binding guidance document), addressing nonclinical safety studies to support the conduct of human clinical trials and marketing authorization for pharmaceuticals, as the source of the additional study requirement.  The Complaint alleges that FDA did not perform an “Unreasonable Risk Determination” relating to tradipitant, as required under 21 U.S.C. §§ 355(i)(3)(B)(i), (ii).  These statutory provisions require FDA to demonstrate that “the drug involved represents an unreasonable risk to the safety of the persons who are the subjects of the clinical investigation” or that a clinical hold should be issued for another reason.  Vanda argues that this provision requires FDA to determine that a large animal study beyond three months was necessary to prevent an unreasonable risk to the safety of the clinical subjects in Vanda’s human trials.  Indeed, Vanda argues that:

• the 9-month canine study was not scientifically justified in light of the extensive nonclinical safety testing that had already been done of tradipitant, as well as other related compounds;
• scientific research and regulatory developments subsequent to the ICH Guidance support the view that such a study in canines is unlikely to identify additional toxicities that would be clinically relevant to humans and materially relevant to FDA’s decision-making; and
• requiring such an additional study, which would result in the death of every canine participant, is inhumane and unethical in the absence of any expectation that it would lead to any clinically relevant findings.

Further, Vanda alleges that FDA’s regulations do not specify that chronic toxicity studies must be conducted in non-rodent species; that such studies must be conducted in particular non-rodent species; or, that such studies must have a specified duration.  Instead, Vanda argues, FDA’s regulations call for appropriate toxicity studies based on the drug and clinical development program at hand under 21 C.F.R. § 312.23(a)(8)(ii) (stating that “[d]epending on the nature of the drug and the phase of the investigation, the description [of toxicological effects of the drug in humans and animals] is to include the results of acute, subacute, and chronic toxicity tests . . . .”).  But the only alternative to the 9-month dog studies that FDA offered would still eventually require Vanda to conduct the 9-month study and would therefore require the sacrifice of even more dogs.

The Complaint touches on a lot of criticisms commonly lobbed at the  agency – blind enforcement of certain requirements, regulating by guidance document, outdated policies.  They are indeed common critiques of the Agency.  But litigating this particular application of FDA policy seems drastic.

Of note, in our experience, FDA generally requires a nine-month toxicity study in large animals prior to late-phase clinical trials or marketing.  We note that while testing in beagles is expensive, it’s likely less expensive than prolonged litigation.  And, given the clinical hold on the study, the clinical development of tradipitant is stalled while Vanda pursues this litigation.

Given that the issues raised by Vanda are essentially questions of scientific judgment and statutory interpretation, a court seems likely to defer to FDA discretion in accordance with Chevron.  See Chevron U.S.A., Inc. v. Natural Resources Defense Council, Inc., 467 U.S. 837 (1984).  And if Vanda does win this lawsuit, the court is likely to remand the issue back to FDA for further consideration and justification.  See Prevor v. FDA, No. 1:11-cv-01187-RMC (U.S. Dist. Ct., D.D.C., decided September 25, 2012).  Vanda would then be left in the same place it is now but after several years of litigation.  And, in the end, Vanda may still need to complete at least one dog study to get approval of tradipitant.  The delay during the pendency of litigation risks a competitor coming to market first, which would mean Vanda losing any NCE exclusivity that may have attached to the active moiety.

While we do not have insight into Vanda’s motivation for this lawsuit, the company appears to be using this issue to launch a springboard for reform of animal testing in the pharmaceutical industry.  Given that litigation seems to be one of the only ways to get FDA’s attention (waiting years for a response to a Citizen Petition isn’t exactly efficient), maybe this will bring some change to FDA requirements.  Indeed, Vanda published an Open Letter to the FDA on February 5, 2019 stating that these longer-term studies resulting in the deaths of young beagles, pigs, monkeys, or other animals are unnecessary, unethical, and inhumane.  Vanda argues that these types of studies should be the exception rather than the rule and reserved for instances with a strong, science-based rationale for conducting them.  Vanda points to a large body of published scientific evidence concluding that 9-month dog studies rarely identify toxicities that were not already identified in 3-month studies or other information that is important to understanding a drug’s impact on humans.   In its letter, Vanda asks for other companies to stand with Vanda in lobbying FDA to abolish its “one-size-fits-all approach to animal research, including nine-month, non-rodent toxicity studies, which results in the unnecessary sacrifice of too many dogs and other animals.”

Vanda does note that it understands the necessity of animal testing but is simply trying to limit the unnecessary testing.  Indeed, this could be an effective animal advocacy strategy.  And the Open Letter seems to reflect genuine concern about animal welfare and animal testing. The likelihood of not doing those dog studies, at least in this specific instance given the discretion afforded to FDA for scientific determinations, may be low, but Vanda appears to be committed to the cause.  The beagles thank you, Vanda.

You might remember our prior post on FDA’s proposed expansion of the Abbreviated 510(k) Program. FDA recently issued a final guidance on this program with a brand-new name: Safety and Performance Based Pathway. Other than the new moniker, the final guidance does little to change the framework set forth in the draft. It does, however, provide some much-needed clarification on a few points. The draft guidance received 14 comments, and it appears the final version did a good job of taking these comments into consideration.

Overview of Framework

By way of background, for purposes of determining substantial equivalence in a premarket notification submission, section 513(i)(1)(A) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) provides that:

[W]ith respect to a device being compared to a predicate device, that the device has the same intended use as the predicate device and that the Secretary by order has found that the device –

(i) has the same technological characteristics as the predicate device, or

(ii) –

(I) has different technological characteristics and the information submitted that the device is substantially equivalent to the predicate device contains information, including appropriate clinical or scientific data if deemed necessary by the Secretary or a person accredited under section 523, that demonstrates that the device is as safe and effective as a legally marketed device, and

(II) does not raise different questions of safety and effectiveness than the predicate device.

FDA has administratively established a few different flavors of 510(k) submission by which to demonstrate substantial equivalence: The Traditional 510(k), the Special 510(k), and the Abbreviated 510(k). The prior Abbreviated 510(k) program allows a sponsor to demonstrate some of the performance characteristics necessary to support a finding of substantial equivalence by showing conformity to FDA-recognized consensus standards. The revised program, dubbed the Safety and Performance Based Pathway, relies on the use of guidance documents, special controls, and FDA-recognized consensus standards to demonstrate all performance characteristics. In some circumstances, no direct comparison testing would be required. A predicate device would still be identified but testing of the proposed device would be conducted against objective performance criteria.

Devices Appropriate for the Safety and Performance Based Pathway

Not all devices are eligible for this Pathway. It is only appropriate when FDA has determined that:

(1) the new device has indications for use and technological characteristics that do not raise different questions of safety and effectiveness than the identified predicate,

(2) the performance criteria align with the performance of one or more legally marketed devices of the same type as the new device, and

(3) the new device meets all the performance criteria.

FDA intends to maintain a list of device types appropriate for the Safety and Performance Based Pathway on its website. Moreover, when FDA issues a guidance pursuant to this program to establish performance criteria for certain device types, the agency will identify the relevant product codes, appropriate intended uses, and appropriate indications for use that will be supported by the outlined performance criteria.

Identification of Performance Criteria

In addition to a list of device types appropriate for this pathway, FDA will publish the guidance documents that identify the performance criteria for each device type, as well as the testing methods recommended, if feasible. Sponsors should not use performance criteria in FDA-recognized consensus standards that have not been identified in FDA guidance as suitable for this program.

When selecting performance criteria and test methodology or establishing new performance criteria and test methodology through guidance, “FDA intends to rely on the experience and expertise of FDA staff, information in literature, and analyses of data available to FDA on existing devices within a device type to determine the performance criteria and associated testing methods that could support a finding of substantial equivalence for a given device type.” The draft guidance did not mention that FDA would rely on potentially confidential data from prior 510(k) submissions. Although FDA is not permitted to disclose these data outside the agency (21 C.F.R. § 807.95), they already make use of them for comparative purposes in 510(k) reviews (e.g., in deciding what testing parameters they will accept).

FDA Review of Data

In response to a comment, FDA provided a table summarizing the amount and type of information necessary to support a finding of substantial equivalence:

The reference to “FDA-recognized standard” refers to FDA-recognized consensus standards indicated in the relevant Safety and Performance Based Pathway guidance for use for a particular device type. Performance criteria in FDA-recognized consensus standards that have not been identified in FDA guidance for use in the Safety and Performance Based Pathway should not be used in this program. However, with respect to test methodologies, although FDA may recommend a test methodology for the performance criteria, a submitter may choose to use an appropriate testing methodology other than what is specified or recommended to demonstrate the performance characteristics.

One big question mark from the draft guidance was how a change in the eligible devices impacted those products already on the market or those products with pending submissions. FDA clarified that, when there is a change, such as when a device type is removed from the list or an updated final guidance is issued, the change would apply prospectively to devices for which a 510(k) has not yet been submitted. For example, if a 510(k) is submitted for a device type before FDA determines that device type is no longer eligible for the program, the device will still be reviewed under this framework. However, FDA notes that the device may be subject to other action, as appropriate, to address the reason for the modification or removal from the eligibility list, for example, if there was a safety concern.

We remain optimistic that this expanded pathway will be useful to industry and allow for greater efficiency and decreased testing burdens on certain device types, though we suspect that most device types will likely not be eligible, i.e., it will be a niche pathway. It remains to be seen how quickly FDA can issue the product-specific guidance, especially given the disruption from the government shutdown earlier this year.

Medical devices provide important diagnostic and treatment benefits to patients. Every day, thousands of patients are the beneficiaries of amazing technology that often did not exist even 10 years ago, and certainly not 50 years ago.

At the same time, these medical devices can pose risks to patients that sometimes lead to injuries even if, on net, the benefit of the device exceeds the risk. Additionally, some devices that seemed at first to provide important benefits may not be as effective as thought or may turn out to be unsafe. Unlike drugs, devices are typically improved iteratively, making them safer and/or more effective over time. That still means patients early on may be more prone to suffer adverse events.

The Food and Drug Administration (FDA) is one of the guard rails in place to ensure that devices reach the market with a reasonable assurance of safety and effectiveness. The agency is also entrusted with monitoring post‑market events and manufacturing to ensure that devices that prove to be excessively risky are either made safer or removed from the market. There is no known way to prevent all adverse events.

These thoughts are prompted by an unfortunate op-ed in the Washington Post with this headline: “The FDA is still letting doctors implant untested devices into our bodies.” The headline is literally false, because FDA requires testing on all implanted devices. All implanted devices are subject to bench and animal testing, and most implanted devices are subject to clinical testing as well.

Still, the authors object to the fact that FDA permits marketing of a certain types of implanted devices without clinical testing; they think this rule should be changed to require all implanted devices to be clinically tested. The authors blame “[t]wo key loopholes” they say must be closed to ensure proper clinical testing. One is the 510(k) clearance pathway and the other is the filing of a “supplement” to obtain permission to market modified versions of devices that already have premarket application (PMA) approval. The authors charge that a combination of corruption, regulatory capture and/or obtuseness has prevented FDA from closing these purported loopholes.

The authors are not correct to describe either the 510(k) pathway or PMA supplement pathway as “loopholes.” A “loophole” is “an ambiguity or omission in the text through which the intent of a statute, contract, or obligation may be evaded.” The 510(k) and PMA supplements pathways, to the contrary, are fundamental elements of device regulation. They are centrally enshrined by Congress in the Federal Food, Drug, and Cosmetic Act (FDCA) (see, for example, sections 513 and 515). FDA could not unilaterally close these purported loopholes even if it wanted to do so. An act of Congress would be necessary. The authors do not acknowledge this fact.

Perhaps even more importantly, these so‑called loopholes do not actually exist. The authors seem to think that FDA lacks statutory authority to require clinical data to support either a 510(k) clearance or a PMA supplement approval. In fact, FDA does have such statutory authority, and there are many instances in which it has required clinical data for 510(k) submissions and for PMA supplement filings.

FDA does not require clinical testing for every device type and testing requirements vary widely by device type. But this variation flows from the statutory scheme directing FDA to regulate the heterogenous universe of devices by placing them in Class I, II, or III by level of risk (Class III being the highest level). Even in the realm of implanted devices, there are variations. Some implanted devices need to be clinically tested to provide reasonable assurance of safety and effectiveness. Others do not. FDA has authority to tailor testing requirements to the risk posed by a device type, including implanted devices.

The op‑ed seems to argue that all implanted devices should be subject to the most rigorous level of clinical testing (including for all modifications). It would be not be intelligent, however, to force all implanted devices into a procrustean bed of clinical testing regardless of circumstance. By imposing unnecessary clinical testing requirements in some cases, the authors’ proposal would make some beneficial devices less accessible to patients without good reason. As a result, patients would be harmed. The authors tout the benefits of their proposals but fail to address the possible costs.

It is true, as the op‑ed complains, that few devices are clinically tested in the manner of drug testing. But that is because devices are not drugs. For almost half a century, Congress has repeatedly directed FDA to regulate devices differently than drugs. The authors seem to blame FDA for following the congressional directives. They also seem to imply that FDA should start requiring that implanted devices undergo the same type of clinical testing as drugs. This approach would have to be authorized by Congress. It would also be a terrible idea, because of the profound differences between devices and drugs that have led to different testing requirements in the first place.

Unfortunately, the authors of the op‑ed seem to devote most of their energy to sweeping ad hominem attacks on the honesty and integrity of FDA officials. But FDA officials cannot simply refuse to follow the law or rewrite it as they please. That seems to be what the authors of the op-ed are demanding, because they aim fire at FDA officials and never acknowledge the role of Congress in establishing the current system. Note also that under the current regulatory framework FDA requires many (if not most) implanted devices to be clinically tested. Why would that be so if FDA officials were in the pocket of industry, as the authors allege?

No one contends that the regulatory system for devices operates perfectly. For instance, even FDA would probably agree that surgical mesh intended for transvaginal pelvic organ prolapse repair should have been placed in Class III in 2002 and subjected to intensive clinical study prior to general marketing. But FDA’s errors can also run the other way. If they unduly delay or block beneficial devices, that harms patients as well. These errors are particularly insidious, because the devices kept from the market are invisible. Patients who die from a missed diagnosis or lack of a cure will never know it if the technology that might have saved them is stymied by the regulatory process. Therefore, it is incumbent upon FDA to strike a proper balance that minimizes the risks of new technology but does not unduly delay the benefits. That is easier said than done! It is especially easy to criticize FDA’s decisions with the benefit of 20/20 hindsight.

All would agree that it is wise to continue to scrutinize both the regulatory framework and FDA’s decision making. Both should be the subject of public discussion and proposals for improvement. But such proposals must be rooted in a good understanding of how the system actually operates. Such proposals also need to present a fair account of the benefits and costs of proposed reforms. And, very importantly, mud‑slinging personal attacks have no place in the public discourse about FDA; it is not how we will make progress.

With a little over a year under FDA’s belt implementing its Comprehensive Regenerative Medicine Policy Framework (which we blogged about here), CBER has updated its current thinking with the issuance of final versions of the two Regenerative Medicine Advanced Therapy (“RMAT”)-related guidance documents:

• Expedited Programs for Regenerative Medicine Therapies for Serious Conditions (“Expedited Programs for RMAT”); and
• Evaluation of Devices Used with Regenerative Medicine Advanced Therapies (“Devices Used with RMAT”).

It is obvious from the nature of many of the changes found in these final guidances that they are based upon learnings by CBER’s Office of Tissues and Advanced Therapies (“OTAT”) as it gains more and more experience with reviewing both a range of RMAT designation requests and more advanced cell and gene therapy development programs. Those of us that work in this space appreciate CBER’s continued attempts to keep the industry updated on its evolving regulatory framework. For example, many of the changes in these 2019 RMAT guidance documents were forecasted by Commissioner Gottlieb and CBER Director Marks in their January 2019 statement on new policies to advance the development of cell and gene therapies, which we blogged about here. These guidances go further than that statement by clarifying the types of therapies which are eligible for the RMAT designation program and the preliminary clinical evidence required to warrant expedited development and review.

There were no substantive changes to the guidance on Devices Used with RMAT (previously discussed here), so we will focus the remainder of this post on updates made in the final Expedited Programs for RMAT guidance (“2019 RMAT guidance”).

Updates to the RMAT Program

Before we describe the changes to the RMAT program, we first note that there were no substantive changes in the final guidance’s discussion of the 4 other expedited programs (i.e. fast track designation, breakthrough therapy designation, accelerated approval, and priority review) which are programs not specific to cell and gene therapies.

Definition of RMAT: Narrowing & Expanding Its Scope

The 2019 RMAT guidance clarifies FDA’s interpretation of regenerative medicine therapies as defined in Section 506(g)(8) of the Federal Food, Drug and Cosmetic Act (“FDC Act”). Section 506(g)(8) defines regenerative advanced therapy as “including cell therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products, except for those regulated solely under section 361 of the Public Health Service Act (“PHS Act”) (42 U.S.C. 264) and [21 C.F.R. Part 1271].” The first update to the interpretation of this provision is with regard to cell therapies. FDA clarifies that it interprets “cell therapies” to include both allogeneic and autologous cell therapies, as well as xenogeneic cell products. 2019 RMAT guidance at 2.

Then, while the draft guidance included FDA’s interpretation that gene therapies meet the definition of a regenerative advanced therapy even though not explicitly listed in the statute (see discussion of this evolution here), the 2019 RMAT guidance clarifies that this interpretation is limited to “human gene therapies” and explicitly excludes microorganisms (e.g., viruses, bacteria, fungi) that are not genetically modified. Id. The 2019 guidance also states that genetically modified cells includes those that lead to a “sustained effect on cells or tissues”, moving away from requiring “durable modification of cells or tissues”. Id.

Clarifying How to Qualify for RMAT Designation

FDA provides additional clarification to sponsors surrounding the preliminary clinical evidence required for an investigational product to be eligible for RMAT designation. FDA considers it essential for preliminary clinical evidence to be generated using the product that the sponsor intends to use for clinical development. Id. at 6. This is directly in line with Commissioner Gottlieb and CBER Director Marks’ January 2019 joint statement on the development and regulation of cell and gene therapies. This statement emphasized that efficient development of cell and gene therapies will focus on perfecting the manufacturing of the final product prior to the initiation of clinical studies. In the 2019 RMAT guidance, FDA acknowledged that manufacturing regenerative medicine therapies is complex and noted that manufacturing changes made to products during the development program will not necessarily preclude or rescind RMAT designation, but rather be considered on a case-by-case basis. Id.

FDA also made a slight modification to the factors CBER will consider when determining whether preliminary clinical evidence is sufficient to support RMAT designation. Rather than consider the “nature and meaningfulness” of the outcomes, the 2019 RMAT guidance clarifies that the “consistency and persuasiveness” of the outcomes will be considered, among other listed criteria that remain unchanged (e.g., the rigor of data collection, the number of patients or subjects, and the number of sites, contributing to the data; severity, rarity, or prevalence of the condition, and bias). Id.

It is also noteworthy to mention that the 2019 RMAT guidance requires sponsors to provide not only a rationale for the investigational new drug meeting RMAT designation, but also a description of the product. This implies that companies may not have been providing sufficient information to allow FDA to make this determination when considering RMAT designation applications. Id. at 7.

CBER’s Evolution in Thinking about Developing Cell and Gene Therapies

Considerations in Clinical Trial Design

Similar to the draft version of the guidance, the 2019 RMAT guidance articulates that CBER will consider clinical trials that incorporate adaptive designs, enrichment strategies, or novel endpoints in support of a BLA for regenerative medicine therapies. The most substantive change to this section of the guidance is the addition of historical controls as an acceptable innovative trial design for regenerative medicine therapies. FDA clarifies that natural history data may provide the basis of a historical control, but “only if the control and treatment populations are adequately matched, in terms of demographics, concurrent treatment, disease state, and other relevant factors.” Id. at 11-12. Adequate matching on key prognostic factors has been a staple of FDA’s consideration of strength of historical controls, so it is not surprising to see CBER endorse this approach.

The guidance also adds that trial designs in which multiple clinical sites participate in a trial investigating a regenerative medicine therapy that is manufactured at each site using a common manufacturing protocol with the intent of sharing the combined trial data to support separate BLAs from each of the individual centers/institutions could be considered the “same drug” for purposes of orphan-drug designation and exclusivity. Id. at 12. This was also forecasted by the Commissioner and CBER Director Marks’ January 2019 statement, as noted above.

Relatedly, FDA clarifies that in these situations where a trial is conducted at a specified number of clinical sites, each site would be required to meet the BLA requirements, including current good manufacturing practice (“cGMP”) requirements. Flagging an important regulatory consideration for sponsors in this scenario, FDA recommends that sponsors address any concerns regarding orphan-drug exclusivity prior to agreeing to pool their data, which would prevent the approval of multiple BLAs. Id.

An Earlier Opportunity for Interactions Between Sponsors and CBER Review Staff

The last section of the 2019 RMAT guidance encourages sponsors of regenerative medicine therapies to engage with CBER OTAT review staff early in the product development process. The final guidance recommends that sponsors obtain early nonbinding, regulatory advice from OTAT through an “INitial Targeted Engagement for Regulatory Advice on CBER producTs” (“INTERACT”) meeting. Id. at 13. This appears to be the formalization of a “Pre-Pre-IND meeting” where sponsors can discuss early pre-clinical, pharmacology/toxicology, CMC, and clinical development issues that need to be addressed prior to moving forward with the submission of a pre-IND meeting request. More information on INTERACT meetings can be found here and here.

*Law Clerk

Yeah, you know me. Given Commissioner Gottlieb’s clear proclivity for blog posts with song titles rather than Orange Book puns, we’ll stick with those for a while. We just hope the Commissioner likes early 1990s rap as much as he likes rock from the 1970s and 1980s.

But now, on to our regularly scheduled blog post. In another one of the many steps FDA has taken in the recent past to address drug pricing and enhance generic competition, FDA published a new guidance on Competitive Generic Therapy (CGT) last week. Once again, today’s guidance is part of the Commissioner’s Drug Competition Action Plan, designed to facilitate competition in the drug industry in an effort to address and control escalating drug prices. FDA has already released guidance documents, MAPPs, lists, and ICH proposals addressing generic competition, demonstrating the Agency’s significant attention, thought, and commitment to expediting generic competition. This guidance is another piece to that, explaining the procedural steps that generic manufacturers must undertake to take advantage of the statutorily-enacted CGT designation and related exclusivity.

CGT was signed into law as part of the Food and Drug Administration Reauthorization Act in August 2017. Section 803 of FDARA added section 506H to the FDC Act, which established an expedited development and approval pathway for generic versions of drugs for which there is inadequate generic competition, defined as a drug for which there is not more than one approved drug in the active section of the Orange Book (this “not more than one” can refer to either the RLD or to an ANDA referencing the RLD). Expedited development may include product development meetings, pre-submission meetings, mid-review cycle meetings, coordinated and cross-disciplinary review, and expedited review. FDA will strive to act on the ANDA prior to the GDUFA goal date, but does not guarantee it, and the guidance suggests that, in addition to CGT designation, eligible applicants may separately qualify for priority review under MAPP 5240.3.

Along with expedited review, CGT comes with a period of 180-day exclusivity for the first approved ANDA applicant with a CGT designation referencing an RLD with no unexpired patents or exclusivities listed in the Orange Book at the time of ANDA submission. As the guidance points out, not all drugs designated CGT will be eligible for CGT exclusivity. Drugs may be designated as CGT because the RLD has inadequate generic competition (not more than one approved drug in the active section of the Orange Book), but not eligible for CGT exclusivity if a patent or exclusivity is listed in the Orange Book at the time of ANDA submission. Further, the CGT-designated application must be approved on the first day on which any application for such CGT is approved to receive the eligibility.

There can be multiple first approved applicants for the same CGT, and CGT exclusivity may still be available even if an ANDA is already approved at the time of the first approved applicant’s approval provided that the first ANDA approved did not have CGT designation. Indeed, the first CGT-designated drug to receive approval with CGT exclusivity faced this exact situation. Further, CGT exclusivity is not available if the first approved applicant is or has been otherwise eligible for 180-day exclusivity under 505(k) of the FDC Act (paragraph IV exclusivity) and the ANDA cannot be a drug for which other ANDA applicants were eligible for but forfeited paragraph IV exclusivity.

Importantly, CGT exclusivity is triggered by the first commercial marketing (and notice to FDA of such marketing) of any first approved applicant. However, FDA is not blocked from approving subsequent ANDAs for the same RLD until this exclusivity is triggered. This means that if there is a delay in the first commercial marketing of a first approved applicant, other applicants can be approved and can start marketing prior to the CGT-exclusivity trigger. We have already seen this happen, and FDA emphasizes this point in this CGT guidance. The guidance also notes that CGT exclusivity may be selectively waived, may be relinquished, or may be forfeited for failure to market within 75 days of approval (starting the day after approval).

FDARA was passed in August 2017, so the CGT program has been in effect since then. But since this guidance is the first direction FDA has really given to generic manufacturers, practitioners have kind of been winging it with requests thus far. Indeed, the Agency has already fielded many requests over the last 1.5 years. Indeed, many requests have been denied because they were submitted after the submission of an ANDA. As FDA emphasizes in the guidance, the law requires a CGT request to be made prior or at the time of the submission of an ANDA. FDA will categorically deny a Request for Designation if it’s submitted after the submission of the original ANDA – even if the ANDA was submitted prior to the availability of CGT designations.

Procedurally, the guidance provides that Requests for Designations submitted prior to the submission of an ANDA should be in writing and may be submitted as either a stand-alone request or as an accompaniment to the pre-submission facility correspondence through the Electronic Submission Gateway. Alternatively, Request for Designation may be made in the cover letter to an ANDA submission in Module 1 of the Common Technical Document. The Request should include the pre-assigned ANDA number and a statement supporting the Request for Designation, including identification of the RLD and the strengths for which CGT designation is sought. Information supporting the applicant’s assertion of inadequate generic competition must also be included.

On February 11, 2019, Dr. Gottlieb issued a statement that appears to build on statements from December 2018.   In December 2018, as part of remarks to the FDLI Enforcement, Litigation, and Compliance Conference, Dr. Gottlieb had alluded to FDA’s plans to step up its efforts regarding dietary supplement safety and deceptive claims.  Dr. Gottlieb expressed concern that the industry had grown and outpaced the Agency’s capacity to manage new risks.  As a first step, he had created a Dietary Supplement Working Group at the FDA, “comprised of representatives from multiple centers and offices across the agency” tasked to take “a hard look at what more the FDA can be doing within our existing authorities, including re-examining our own internal operating structure and procedures – and what new authorities might make sense.”

The February 11 statement provides additional details.  As Dr. Gottlieb mentions, the Dietary Supplement Health Education Act (DSHEA) is almost 25 years old. The industry today is very different from the industry in 1994; among other things, it has grown significantly; “[w]hat was once a $4 billion industry comprised of about 4,000 unique products, is now an industry worth more than $40 billion, with more than 50,000 . . . different products available to consumers.”  As a result, FDA has had to consider how to keep up with this growth and how it can continue to ensure that dietary supplements are safe, maintain product integrity, and to foster an environment of informed decision making by consumers and health care professionals.

Dr. Gottlieb announced five initiatives to increase oversight:

1. Rapid response tool: Dr Gottlieb mentioned that, in an effort to increase communication speed to consumers, the Agency has developed a rapid-response tool to alert the public when a supplement contains an illegal ingredient or poses a health risk. No further details were provided.
2. Update of FDA’s policies regarding New Dietary Ingredient Notifications (NDINs): Under the law, NDINs are required for new dietary ingredients (i.e., dietary ingredients that were first marketed after October 15, 1994) that are not already present in the food supply in a form not chemically altered. The NDINs provide FDA with an opportunity to evaluate safety.  As readers of this blog know, FDA believes that the number of NDINs is too low; the Agency believes that there are many dietary ingredients marketed that are new dietary ingredients (NDIs) that would require an NDIN.  Thus far, FDA has made two attempts to provide clarity about its policy regarding when an ingredient is an NDI and when an NDIN is needed.  Gottlieb’s comments suggest that FDA may make another attempt.  It plans to update its policy to “foster the submission” of NDINs by possibly providing some sort of reward (e.g, exclusivity) and help ensure that the regulatory framework is both sufficiently flexible and adequately protects public safety. FDA plans to schedule a meeting with industry this spring.
3. Creation of a Botanical Safety Consortium, a public-private partnership with the goal of providing appropriate tools to evaluate the safety of botanical ingredients. Among other things, this group “will look at novel ways to use cutting-edge toxicology tools, including alternatives to animal testing, to promote the goals of safety and effectiveness we share with consumers and other stakeholders.”
4. Enforcement actions against unlawful claims and ingredients: Dr. Gottlieb reports that FDA has improved efficiency of its internal processes regarding enforcement actions against illegal ingredients and points to actions against tianeptine, highly concentrated caffeine, and male enhancement products that contained sildenafil and/or tadalafil as examples. He mentions that the Agency will continue its efforts to take actions against unlawful claims and develop new enforcement strategies, and points to the concurrent press release regarding FDA’s action against companies marketing dietary supplements with illegal claims for Alzheimer’s.  The Agency sent 12 warning letters and five advisory letters to marketers of more than 58 products which claims to prevent, treat, or cure Alzheimer’s disease and other serious health conditions such as diabetes and cancer.  Three of these warning letters were jointly issued by FDA and the Federal Trade Commission.
5. Modernization of DSHEA. DSHEA is approaching its 25th anniversary.  While Dr. Gottlieb recognizes the need to preserve DSHEA’s “essential balance,” he believes it might be valuable to consider certain amendments.  He mentions FDA plans to engage in a public dialogue regarding the possible need to modernize DSHEA to establish avenues for dietary supplement exclusivity, providing industry with incentives to develop new products. Dr. Gottlieb also mentions the possibility of creating an FDA registry, for the mandatory listing of dietary supplements and ingredients.  Presumably, such a registry would allow FDA to better track dietary supplements and concentrate enforcement efforts.

We will be monitoring FDA’s actions in 2019.

On February 5, 2019, FDA issued the guidance document The Least Burdensome Provisions: Concept and Principles (Final Guidance).  This version supersedes the prior version in place since October 2002.  FDA published a draft of the guidance (Draft Guidance) in December 2017, which we blogged on here.

As in the Draft Guidance, the Final Guidance defines “least burdensome” to be “the minimum amount of information necessary to adequately address a relevant regulatory question or issue through the most efficient manner at the right time.”  Final Guidance at 4.  The three elements of the definition, the minimum information necessary, the most efficient means, and the right time, continue to be the least burdensome principles discussed in the guidance.  Overall, there are not any many differences in the Final Guidance compared to the Draft Guidance.

The seven guiding principles that FDA intends to apply, and industry is also encouraged to apply, when taking a least burdensome approach are unchanged, although additional details are added to their discussions.  Related to industry’s least burdensome submission of material, FDA adds in the Final Guidance that “[i]ndustry should not submit information unrelated to the regulatory decision to FDA” and that “[i]ndustry should reference applicable FDA guidance documents where FDA recommendations were considered.”  Id. at 8.

It can be a challenge for sponsors to know exactly what will be used in the regulatory decision making as the Agency continues to request new and different information to establish a reasonable assurance of safety and effectiveness or substantial equivalence.  For 510(k)s, sponsors are required to include a signed statement that no material fact has been omitted and thus, may question whether omission of a study they performed might be problematic even if it does not seem necessary for regulatory decision making.

Additional examples of FDA’s use of less burdensome approaches have been added.  Though not discussed as a problem with the least burdensome provisions, in addition to adding examples, FDA also removed an example from the Draft Guidance of their use of registries initially designed for postmarket surveillance to support expanded indications for vaginal mesh devices.  FDA has been criticized for their oversight of these and other implanted devices where reports of safety issues are raised after being placed on the market.

There are several additions to the Final Guidance that should be welcomed by industry.  For example, FDA says, “when discussing alternative approaches, FDA intends to take appropriate consideration of the time and resource implications of [their] additional information requests,” and “[t]he type and amount of minimum information requested by FDA can change over time based on new information that the Agency receives and a better understanding of the technology.”  Id. at 13, 19.  This latter statement is made in the context of FDA’s discussion of “smart regulation,” with examples such as 510(k) exemptions and enforcement discretion provided to support it.  However, it often seems that perhaps more often, the changes over time go in the other direction toward requesting new and different data, studies, labeling, and so forth.

The Final Guidance also expands on the discussion of FDA’s intent to use least burdensome principles when contributing to global harmonization efforts and their down classification of devices.  The last addition of note is a section titled “Just-in-time testing,” which promotes the “right time principle for IDE applications” allowing certain early feasibility studies to be “based on less nonclinical data than would be expected for a traditional feasibility or pivotal study.”  Id. at 22.

While industry may still feel that they are continually being asked for more information, data, and studies to support their devices, the Final Guidance, by way of sharing examples where FDA has used least burdensome approaches, suggests that, in many cases, it could be worse.  As noted in the Final Guidance, readers are encouraged to interact with the Agency early on so as to develop least burdensome approaches, especially in situations where their device may have or be perceived to have different risks.

FDA released its annual Report to Congress on 505(q) Citizen Petitions last week – the Tenth Annual Report to Congress on Delays in Approvals of Applications Related to Citizen Petitions and Petitions for Stay of Agency Action for Fiscal Year 2017.  The Report, which is required by FDC Act § 505(q)(3), gives us the picture and numbers from FDA’s experience during Fiscal Year 2017 (“FY 2017”) with citizen petitions subject to FDC Act § 505(q).  The Report provides updated numbers for FY 2017 and largely repeats both FDA’s concerns about petitioning expressed in previous reports (see our previous posts here, here, here, here, here, here, here, here, and here) and the trends the Agency has been seeing in petitioning. It does not mention recent actions taken by the Agency to try to curb the alleged use of citizen petitions to “game” the system (perhaps, as described below, because the actions occurred in FY 2018).

By way of background, FDC Act § 505(q) was added to the law by the 2007 FDA Amendments Act (“FDAAA”) and is intended to prevent the citizen petition process from being used to delay approval of pending ANDAs and 505(b)(2) applications.  The law was amended by Section 301 of Pub. L. No. 110-316 (2008), and again by Section 1135 of the 2012 FDA Safety and Innovation Act (“FDASIA”).  Among other things, FDASIA changed the original 180-day response deadline to 150 days, and made the law applicable to citizen petitions concerning biosimilar applications submitted to FDA pursuant to PHS Act § 351(k). In June 2011, FDA issued final guidance on FDC Act § 505(q).  That guidance was revised in November 2014 to account for changes made to the law by FDASIA.  In January 2012, FDA issued proposed regulations to amend the Agency’s citizen petition regulations to implement changes made to the law by Section 505(q). FDA issued a final rule in November 2016.

Most recently, in October 2018, FDA issued  a revised draft guidance that describes factors FDA will consider in determining whether a petition is submitted with the primary purpose of delaying the approval of a generic application (see our previous post here).  Although the statute provides that FDA may summarily deny a petition submitted with the primary purpose of delaying ANDA, 505(b)(2) application, or 351(k) biosimilar approval, the Agency has never done so.  FDA’s actions and words continue to build a firmer basis and procedure for someday doing so.

Under FDC Act § 505(q), FDA shall not delay approval of a pending ANDA, 505(b)(2) application, or 351(k) biosimilar application as a result of a citizen petition submitted to the Agency pursuant to 21 C.F.R. § 10.30 (citizen petition) or § 10.35 (petition for stay of action), unless FDA “determines, upon reviewing the petition, that a delay is necessary to protect the public health.” FDA is required to “take final agency action on a petition not later than 150 days after the date on which the petition is submitted.”  FDA may not extend the 150-day period “for any reason,” including consent of the petitioner.

FDC Act § 505(q)(3) requires that each Report to Congress specify: “(A) the number of applications that were approved during the preceding 12-month period; (B) the number of such applications whose effective dates were delayed by petitions . . . during such period; (C) the number of days by which such applications were so delayed; and (D) the number of such petitions that were submitted during such period.”  FDA says in its Tenth Annual Report to Congress that:

During the FY 2017 reporting period, the Agency approved 763 ANDAs, 57 505(b)(2) applications, and 3 biosimilar biological product applications. No approvals for biosimilar biological product applications or ANDAs were delayed because of a 505(q) petition in this reporting period.  The approval of one 505(b)(2) application was delayed because of one 505(q) petition.  During FY 2017, FDA received 25 505(q) petitions.

The delayed 505(b)(2) approval was delayed by 28 days. “FDA was concerned that if it approved the 505(b)(2) application before resolving the issues raised in the petition and later concluded that one or more of the arguments against approval were meritorious, then the presence on the market of a drug product that did not meet the requirements for approval could negatively affect public health,” says FDA in the report (in what is now boilerplate language).  FDA does not identify by name or application number the particular approval delayed.

As to the number of 505(q) citizen petitions submitted in FY 2017, the Report says that the Agency received 25 petitions, which is up from 19 in FY 2016. The outcomes of FDA’s 210 petition responses from FY 2008 through FY 2017 are shown in a table included in the report. Approximately 67% (141 petitions) of the 210 petition decisions have been denials, while another approximately 25% (53 petitions) have been denied in part and granted in part.  Only about 5% (10 petitions) have been granted.  Two petitions were granted in FY 2017, which is the first year in which FDA has granted a 505(q) petition since FY 2013.  We think both of those petition decisions concerned the availability of New Chemical Entity exclusivity (see here and here).  The remaining 6 petitions (about 3%) were voluntarily withdrawn by the petitioner.  (You can view all relevant petitions on the FDA Law Blog Citizen Petition Tracker.)

As to 505(q) petitioning trends and FDA concerns, the Agency continues a trend of paring down comments that appeared in previous reports. That being said, FDA’s bottom line in the FY 2017 Report maintains the tone adopted in the FY 2016 report and concludes with the statement, “Accordingly, as part of the Drug Competition Action Plan, FDA is reviewing what actions can be taken to address these issues.”

FDA Commissioner Dr. Scott Gottlieb announced the Agency’s Drug Competition Action Plan (“DCAP”) in Spring 2017 (here).  The intent of the DCAP is to encourage generic drug development and competition.  Since the creation of the DCAP, FDA has taken several steps to implement that plan, including holding a public meeting in July 2017, issuing REMS guidance in May 2018 (here), and issuing last week a Manual of Policies and Procedures on internal FDA responsibilities and procedures for developing a single, shared system REMS or a separate REMS (here).   Given FDA’s statement that the Agency is reviewing what actions can be taken under the DCAP to address citizen petition concerns, more new citizen petition initiatives may be on the horizon.

The recent government shutdown gave us some time to reflect on 2018, a year that was full of device-related posts.  Inspired by the recent Academy Awards nominations, we are now listing our Top Ten Device Posts of 2018.  Some are blockbusters, and others indie stories, but they all earned a coveted place in the HPM Top Ten.  Accompanied by a brief explanation for why they made the list, they are:

1. Multiple Function Device Products – FDA Clarifies Its Approach (May 8, 2018)

The draft guidance indicates that FDA will not regulate functions of a multi-function product that do not meet the statutory device definition or are devices that are subject to an existing enforcement discretion policy.  Although issued in the context of medical device software, FDA states that it will apply the same principles to traditional devices as well.

2. A Future Regulatory Paradigm with Potential Broader Implications (May 29, 2018) (FDA’s Pre-Cert Program)

FDA’s request for feedback on the Software Precertification Program, in which data is leveraged so that FDA can adopt a risk-based, streamlined approach to Software as a Medical Device review.  This could – someday – replace the need for a premarket submission or allow for a streamlined premarket review for higher risk products.

3. IVD Technical Assistance—2 posts
   • FDA’s IVD TA: It’s Not Just Technical Assistance (Aug. 14, 2018)
   • HP&M Weighs in on FDA’s “Technical Assistance” to Proposed IVD Legislation (Nov. 2, 2018)

FDA was asked to provide Technical Assistance regarding the Diagnostic Accuracy and Innovation Act (DAIA), intended to provide a regulatory framework for Laboratory Developed Tests.  FDA advanced a different framework than that set forth in DAIA, one which essentially revamps the regulation of all In Vitro Diagnostics.  These blog posts consider the implications of the proposed changes for industry.  Many of these suggestions were incorporated in revised draft legislation.  (See our recent post on draft IVD legislation here).

4. FDA Issues Final Rule on Voluntary Malfunction Summary Reporting Program for Device Manufacturers (Sep. 25, 2018)

The Voluntary Malfunction Summary Reporting Program permits manufacturers to report certain device malfunctions for low-risk products in summary form on a quarterly basis, as an alternative to the Medical Device Reporting (MDR) requirements.  This program has several significant limitations, described in detail in the blog post.

5. Final Guidance Issued for Considering Benefit-Risk Factors in 510(k)s with Different Technological Characteristics (Oct. 5, 2018)

FDA sets forth a framework for analyzing the benefit-risk profile of a new device when determining whether it is as safe and effective as the predicate device in the review of substantial equivalence.  This guidance is intended to improve predictability, consistency and transparency in the 510(k)-review process.

6. If at First You Don’t Succeed, Try, Try, Try Again: FDA Issues Plan to Increase Efficiency of 510(k) Third Party Review Program (Oct. 12, 2018)

FDA announced a plan for revamping the 510(k) Third Party Review Program, including the issuance of a draft guidance that says it all: “510(k) Third Party Review Program.”  This blog post reviews the current Third Party Review Program, how this new guidance purports to change it, and our assessment of its likelihood of making a difference.

7. FDA Issues Two New Guidance Documents on Voluntary Consensus Standards, Consolidating and Replacing Earlier Guidance (Oct. 30, 2018)

This post reviews two new guidance documents that consolidate information on voluntary consensus standards used in medical device premarket submissions: (1) a draft guidance titled “Recognition and Withdrawal of Voluntary Consensus Standards”; and (2) a final guidance titled “Appropriate Use of Voluntary Consensus Standards in Premarket Submissions for Medical Devices.”

8. Possible Major Changes to 510(k) Program Ahead (Nov. 26, 2018)

This post reviews the implications of an announcement by FDA Commissioner Dr. Scott Gottlieb and Dr. Jeffrey Shuren, Director of the Center for Devices and Radiological Health, that FDA is planning to “modernize” the 510(k) process through the elimination of old predicates and the creation of an alternative “Safety and Performance Based” 510(k) Pathway.  This new story got a lot of buzz in the broader media.

9. Failure to File Adverse Event Reports Results in Criminal Pleas for Medical Device Company and Quality Manager (Dec. 12, 2018)

This post outlines a recent example where the government targeted a manufacturer for failure to file adverse event reports associated with its duodenoscope product, rendering the product misbranded.  The plea agreement requires the company to distribute to its U.S. customers a notice about the plea agreement, undertake certain compliance measures specific to MDR processes, and pay a fine of $80 million as well as a $5 million forfeiture.

10. Comments on FDA’s Proposed Rule Governing the De Novo Classification Process (Dec. 13, 2018)

On December 4, 2018, FDA issued a proposed rule that would govern the de novo classification process.  This post analyzes the implications of the proposed rule, including an assessment of whether it unduly increases the burden on applicants.  Spoiler alert.  We think it does.

Honorable Mention: Draft Guidance Explains how Uncertainty should be Handled in Device Premarket Submissions (Oct. 2, 2018)

This post analyzes FDA’s draft guidance, “Consideration of Uncertainty in Making Benefit-Risk Determinations in Medical Device Premarket Approvals, De Novo Classifications, and Humanitarian Device Exemptions,” which is intended to describe factors that FDA will consider when assessing uncertainty as part of a benefit-risk assessment in PMA, De Novo, and HDE submissions.

In all, 2018 was a year filled with worthy contenders for a Top Ten ranking.  With the shutdown, 2019 is off to a slow start, but there’s plenty of time to catch up.

Hyman, Phelps & McNamara, P.C. (“HP&M”) is pleased to announce that Michael Shumsky has become its newest Director.  Mike joined HP&M in February 2019 after nearly 15 years at Kirkland & Ellis LLP, where he played a key role in developing that firm’s FDA and pharmaceutical practices.

As a Director at HP&M, Mike will continue to provide strategic advice and counseling to U.S. and global pharmaceutical companies pursuing FDA approval of NDAs, 505(b)(2) products, ANDAs, BLAs and biosimilar applications.  In addition to helping clients develop successful regulatory strategies and perfect high-stakes regulatory submissions, Mike has litigated a number of significant Hatch-Waxman matters arising from the award or denial of 180-day exclusivity, 3-year and 5-year exclusivity, orphan drug exclusivity, 30-month stays, and REMS-related matters.  Courts and commentators alike have praised Mike’s abilities as both a writer and oral advocate, and he repeatedly has been recognized as a “Rising Star” in both the Life Sciences and Appellate Litigation fields.

Mike graduated from Harvard College, where he was elected to Phi Beta Kappa, and Yale Law School, where he was an officer on the Yale Law Journal.  After law school, Mike clerked for the Hon. Diarmuid F. O’Scannlain on the U.S. Court of Appeals for the Ninth Circuit.  He currently serves as a Lecturer in Law at Columbia Law School, where he teaches a popular seminar on the U.S. Supreme Court.

Readers who work with laboratory tests are likely aware that such tests can be subject to regulation by FDA, CMS, and individual states. A few state laws, particularly those in Maryland, New York, New Jersey, and Rhode Island, currently constrain how some laboratory tests are offered in those states.

On February 2, 2019, two bills were introduced to the Maryland General Assembly to address Maryland’s constraints. HB0526 and SB0495 both propose to modify Maryland Health General Code § 17‑215, which prohibits advertising or soliciting for medical laboratories. The Maryland law currently states: “A person may not directly or indirectly advertise for or solicit business in this State for any medical laboratory, regardless of location, from anyone except a physician, hospital, medical laboratory, clinic, clinical installation, or other medical care facility.” Under Maryland law, a “medical laboratory” includes “any facility, entity, or site that offers or performs tests or examinations in connection with the diagnosis and control of human diseases or the assessment of human health, nutritional, or medical conditions or in connection with job-related drug and alcohol testing.” Md Health Gen. Code § 17‑201(c). The cross-filed bills seek to create an exception to the current prohibition for laboratory tests that are ordered by a physician and performed by a medical laboratory certified under 42 U.S.C. § 263a (e.g., a CLIA-certified laboratory). If passed, the change would take effect on October 1, 2019.

It appears that the advertising prohibition has been in effect in Maryland since 1957, but the reasoning behind this particular law may be lost in the history books. Regardless, there have been many, many changes and developments in the field of laboratory testing and the regulations that apply to laboratory testing over the past 60+ years. For example, federal regulation of laboratory testing was introduced in 1967 (see Pub. Law 90-174 § 5(a)) and then amended by the Clinical Laboratory Improvement Amendments of 1988. FDA’s views and regulation of laboratory tests have also changed over the past 60+ years, particularly for laboratory developed tests (LDTs) (see previous posts here, here, here, here, here, and here). Congress is currently considering changes to the regulatory framework for laboratory tests (see our coverage of the VALID Act here).

We work with a number of clients who have been restricted by the current Maryland law and believe that the law is likely limiting the laboratory testing available to Maryland residents. We will continue to monitor these efforts to expand access to laboratory testing in Maryland.

Since FDA announced in late 2016 that it would not finalize its laboratory developed test (LDT) guidances, it has become clear that any change to the LDT regulatory framework (at least during this administration) would need to come through a statutory change.  The first such proposal came in early 2017 with the release of the Diagnostic Accuracy and Innovation Act (DAIA).  FDA provided Technical Assistance (TA) on the DAIA last summer (see our earlier posts here and here).  As noted in our posts, FDA’s TA was essentially a complete rewrite of the DAIA, and the changes were viewed negatively by many in the industry.

It appears Congress had the opposite reaction, however. Last month, Chairman Walden, Ranking Member Pallone, Representative Bucshon, and Representative DeGette released a discussion draft of The Verifying Accurate Leading-edge IVCT Development (VALID) Act of 2018.  The VALID Act incorporates many concepts of FDA’s TA.  Congress is currently soliciting feedback on the draft through February 15, 2019.

While we do not expect that the discussion draft will be finalized in anything like its current form, we thought our readers would be interested in reading a short summary of the draft bill to understand the revised framework as it is radically different from what IVD manufacturers and labs are operating under today.  Our summary can be found here.  We encourage those with a stake in this legislation to contact their legislators, trade organizations, or other groups to provide feedback to this draft.  If finalized, this legislation could profoundly affect the availability and innovation of diagnostic tests.

We would also note that the discussion draft contains explicit requests for feedback.  Some sections relating to critical topics, e.g., breakthrough IVDs, are blank placeholders, or are bracketed, e.g., transfer or sale of approval or the precertification program.

Finally, we would emphasize that in a bill this complicated, careful drafting is essential.  Even seemingly modest tweaks to the established but complex IVD regulatory universe can have large ramifications, and the draft bill is anything but a modest tweak.

In yet another step to address drug pricing, Commissioner Gottlieb announced last week several new initiatives, including an update to the revered Orange Book.  Cue the crazy Muppet arms!  Proclaiming the Orange Book update a “transparency initiative,” FDA expects that this undertaking will “provide greater certainty around timing of market entry and enable more informed decisions.”  This is all part of the Agency’s extensive effort to enhance competition, which has resulted in several new guidance documents pertaining to generic development, efforts to reform the Citizen Petition process, new priority reviews, an ICH proposal, and other efforts to expedite generic approval.  As Commissioner Gottlieb points out, FDA has made great strides in streamlining the generic review process in the last few years, including record numbers of generic drug approvals and tentative approvals in 2017 and 2018.

Over the course of 2019, FDA intends to issue two Orange Book-focused draft guidances.  The first is a draft guidance document explaining the process for therapeutic equivalence evaluation and the assignment of the TE codes listed in the Orange Book.  This is intended to facilitate requests for TE codes, as well as encourage development of more therapeutically equivalent drugs – particularly under the 505(b)(2) pathway, as 505(b)(2) applicants typically must request a TE code by Citizen Petition (unlike ANDAs, where a TE code is routinely assigned upon listing).  As such, FDA also believes that such clarity on TE codes may facilitate development of complex generics through the 505(b)(2) pathway.  The second Orange Book guidance will be a draft guidance with FAQs about reading and using the Orange Book.

FDA also plans to solicit public comment on the use of the Orange Book with an emphasis on potential enhancements.  It also seems like FDA may finally address whether drug-device patents – or now, given the hi-tech era we are in – drug-digital app patents should be listed in the Orange Book.  Industry has been asking for instruction on this issue for about 15 years, and without word from FDA, many manufacturers have decided to list them anyway if the device is integral to the drug as approved, so it will be interesting to see if FDA will change the current practice.  Again, FDA is doing this for the purposes of transparency so that potential manufacturers can now determine if a digital app patent might block marketing of a generic drug before investing resources.

FDA also announced a new guidance document, Marketing Status Notifications Under Section 506I of the Federal Food, Drug, and Cosmetic Act; Content and Format, which provides notification instructions for discontinued drugs, as required under FDARA.  506I of the FDCA requires manufacturers to provide notification to the Agency of the drug withdrawn from sale or the unavailability of a drug and requires the submission of a one-time report on marketing status for actively marketed drugs.  These statutorily-required notifications are intended to help the Agency understand which products are actively marketed and where there is a need for more generic competition.

Of note, the guidance explains that “withdrawn from sale” does not mean that the NDA or ANDA itself has been withdrawn, but that the drug has been discontinued from marketing – even temporarily.  FDA will use these notifications to determine whether to move products not available for sale to the “Discontinued” list.  Applicants withdrawing their product from sale must submit the notification 180 days prior to withdrawal, and newly approved drugs must submit the notification within 180 days of the date of approval of a drug if that drug will not be available for sale within 180 days of the date of approval.  Notifications are expected to include NDC numbers (for previously marketed drugs); the established name of the drug; the proprietary name of the drug, if applicable; the NDA or ANDA number; the strength of the drug; the date in which the drug will no longer be for sale or on which the drug will be available for sale, if known; and the reason for withdrawing or not marketing the drug.  Application holders who fail to submit this notification may also find their drugs moved from the “Active” to the “Discontinued” list.

Needless to say, we here at the FDA Law Blog are excited.