Attorney East Hampton

By Ricardo Carvajal —

FDA recently published a guidance document reminding proponents of GRAS status of their obligations under the FFDCA and its implementing regulations (which we refer to as the “Reminder Guidance,” available here).  FDA also published a draft guidance document setting out best practices for convening a GRAS expert panel (which we refer to as the “GRAS Panel Guidance,” available here).

The Reminder Guidance provides a useful summary of FDA’s interpretation and application of the GRAS exception to the statutory definition of “food additive.”  It is based primarily on FDA’s regulations and guidance, but also includes in an appendix certain comments and responses drawn from the preamble to the GRAS final rule.  The Reminder Guidance “strongly” encourages submission of GRAS notices to the agency.  For those who decide not to notify FDA of their independent GRAS conclusion, it recommends using the GRAS notification procedure in FDA regulations as guidance, organizing supporting information in the format of a GRAS notice, referring to FDA’s FAQ on GRAS (see here), and making the basis for an independent GRAS conclusion publicly available.  The latter recommendation appears not to recognize the significant investment of resources that a GRAS evaluation can demand.  Comments on the Reminder Guidance, which was issued in final form, can be submitted at any time.

The issuance of the draft GRAS Panel Guidance comes as no surprise; as we discussed in a prior blog posting, the stage was set by external critiques of FDA’s administration of the GRAS exception.  The GRAS Panel Guidance includes a lengthy discussion of the potential for bias in scientific panels that draws on policies and guidance deemed relevant by FDA.  It also provides recommendations on how to select experts to ensure appropriate and balanced expertise, procedural considerations in organizing and managing the deliberations of a panel, assessing and managing conflicts of interest and appearance issues, providing information to a panel, and documenting a panel’s deliberations and conclusions.

Those with an interest in the continued use of GRAS panels in the conduct of GRAS evaluations would be well advised to read the draft GRAS Panel Guidance and consider its potential impacts if finalized in its current form.  As noted in the guidance, the use of a GRAS panel is not required.  To the extent that any final guidance significantly increases the burdens associated with convening a GRAS panel, such guidance could have the unintended effect of discouraging the use of GRAS panels as a mechanism for demonstrating that the safety of the use of a substance is generally recognized by qualified experts.  In that regard, an estimate of burdens associated with adhering to the draft guidance is included in the accompanying Federal Register notice (available here).  Comments on the draft guidance are due by May 15, 2018.

By Larry K. Houck —

The Drug Enforcement Administration (“DEA”), in response to the nationwide controlled pharmaceutical diversion and abuse crisis, now conducts more frequent regulatory inspections in greater depth to identify registrants who violate the Controlled Substances Act and implementing regulations. In addition to inspecting and auditing manufacturers, distributors, importers, exporters, and narcotic treatment programs, DEA diversion investigators now inspect pharmacies, hospitals and practitioners.  These were registrants that historically had not been subject to scheduled inspections.  Registrant noncompliance disclosed during a DEA inspection can lead to significant administrative, civil and even criminal consequences.

Hyman, Phelps & McNamara, P.C. attorney Larry K. Houck, a former DEA diversion investigator, authored an article that appears in the latest issue of the Food and Drug Law Institute’s “Update” magazine. The article, titled “DEA Preregistration and Cyclic Inspection: What Applicants and Registrants Must Know in the Prescription Opioid Epidemic Age,” explains what applicants and registrants must expect during DEA inspections in the current regulatory climate.

By Riëtte van Laack —

As readers of this blog may recall (see here), the purpose of the Sunscreen Innovation Act (SIA) was to speed up FDA’s review of time and extent applications (TEAs). TEA process provides a pathway for adding an active ingredient to an existing over-the-counter (OTC) drug monograph.   Under the TEA program, instituted in 2002, FDA will consider accepting an active ingredient for inclusion in the OTC drug monograph even though the product was initially marketed in the United States only after May 1972.  For active ingredients with marketing experience outside the United States, FDA requires proof that the product: (1) was marketed outside the United States as an ingredient in OTC drugs for purchase by consumers; and (2) was “marketed OTC for a minimum of five continuous years in the same country and in sufficient quantity” (although more than a single country may be appropriate depending on the extent of marketing).  Twelve years after institution of the program, FDA had yet to act on any of the pending TEAs; some of which had been pending for almost a decade.

The SIA was intended to speed up the process of review of TEAs, setting specific timelines and deadlines for FDA to act. Although the focus was on sunscreen active ingredients, the SIA also included provisions to speed up FDA’s review of non-sunscreen active ingredients.

The SIA included a provision requiring that GAO issue a report on FDA’s implementation of the Act. At the end of November, about three years after the enactment of the SIA, GAO issued its report.  The report addresses

1. the extent to which FDA has complied with the SIA requirements;
2. the status of FDA’s review of applications for sunscreen active ingredients; and, in an appendix to the report;
3. the steps FDA has taken to review TEAs for non-sunscreen active ingredients.

Sadly there is little good news. FDA did all it was required to do under the SIA in a timely manner.  It completed review of all TEAs for the sunscreen and non-sunscreen active ingredients.  However, none of the active ingredients is any closer to being marketed in the United States, and consumers will not be seeing any innovative sunscreens on the market any time soon.  For all TEAs for sunscreen active ingredients, FDA determined that additional safety data are needed before FDA can determine that (or whether) the ingredients are Generally Recognized as Safe and Effective (GRASE), which is the standard that must be met for the ingredients to be marketed in the United States without FDA’s premarket approval.

GAO reports that, at this time, none of the sponsors of the TEAs for sunscreen active ingredients have plans to provide the additional safety data; they are either still considering whether to conduct the required additional tests or they have determined not to do so. Reasons for their reluctance include return on investment and the requirement for animal tests.  In addition, some sponsors have expressed concern that even if they were able and willing to generate the requested data, they were uncertain that the agency would not require more tests in the future.

For the non-sunscreen TEAs, the news is no better. In 2016, FDA determined that two non-sunscreen TEAs contained insufficient information to be filed for review.  Three non-sunscreen TEAs were withdrawn in 2016, with representatives of the sponsors citing increased regulatory scrutiny of the active ingredient and the additional safety and effectiveness data requested by FDA as reasons for the withdrawal.  As of November 2017, one TEA remains pending because the sponsor did not request a review framework.  This TEA will be reviewed under the time frame established in FDA’s regulation issued in November 2016, i.e., in 2019.

Thus, despite Congress’s best intentions, the SIA will not result in increased availability of sunscreen active ingredients that have been available to consumers in other countries for more than a decade.

By Jeffrey K. Shapiro —

The field of digital health is relatively new and is growing fast. Because many uses of software for health‑related purposes are within the statutory definition of a medical device, the Food and Drug Administration (FDA) is a major player in determining how digital health will be regulated.  Fortunately, FDA some years ago decided it would regulate with a “light touch.”  This approach was ratified and further delineated by Congress in the Cures Act (Section 3060).  We described that provision in detail in a previous post.   We explained why a “light touch” is the right approach for FDA’s regulation of digital health here and in this piece appearing in a recent issue of Digital Legal Health (see also trade press reports of this talk a few years ago).

Last week, a couple more pieces of the puzzle fell in to place. On December 8, FDA issued two new draft guidances indicating how it will implement the Cures Act as it relates to software.

The first draft guidance is entitled, “Clinical and Patient Decision Support Software” (December 8, 2017).  This guidance was greatly anticipated back in the 2013-14 time frame, but it was post­poned after Congress began considering legislation.  It has finally been issued in draft.  The guidance has a very good summary of the key statutory provision excluding certain categories of software from the definition of a medical device in the Food, Drug, and Cosmetic Act (FD&C Act).  It is worth reproducing in full:

Specifically, section 520(o)(1)(E) of the FD&C Act excludes, from the definition of device, software functions that meet all of the following four criteria: (1) not intended to acquire, process, or analyze a medical image or a signal from an vitro diagnostic device or a pattern or signal from a signal acquisition system (section 520(o)(1)(E) of the FD&C Act); (2) intended for the purpose of displaying, analyzing, or printing medical information about a patient or other medical information (such as peer-reviewed clinical studies and clinical practice guidelines) (section 520(o)(1)(E)(i) of the FD&C Act); (3) intended for the purpose of supporting or providing recommendations to a health care professional about prevention, diagnosis, or treatment of a disease or condition (section 520(o)(1)(E)(ii) of the FD&C Act); and (4) intended for the purpose of enabling such health care professional to independently review the basis for such recommendations that such software presents so that it is not the intent that such health care professional rely primarily on any of such recommendations to make a clinical diagnosis or treatment decision regarding an individual patient (section 520(o)(1)(E)(iii) of the FD&C Act).  [Emphasis in the original.]

The guidance then proceeds to provide information about how FDA’s interprets these four prongs.

Perhaps most interesting is FDA’s commentary on the first prong. It is obvious from the statutory provision that FDA will continue to regulate medical images acquisition/processing/analysis and in vitro diagnostic devices.  It has been somewhat mysterious, however, what technologies would qualify as a “signal acquisition system.”  The statute lacks a definition.  FDA now clarifies that a signal acquisition system “receives, as inputs, signals from sensors that are within, attached to (e.g., EEG, ECG), or external to (e.g., CT, MRI) the human body or sample from the human body (e.g., digital pathology). Id. at 6 n.1.  Technologies that “analyze physiological signs and provide diagnostic, prognostic and predictive functionalities are devices.” Id. at 6.

The other major interpretive issue relates to the fourth prong, which specifies that clinical decision support (CDS) software will be regulated by FDA unless it allows health professionals to “independently” review the basis for clinical recommendations and is not intended to be “primarily” relied upon in a diagnosis or treatment decision. There are a number of ways in which these phrases could potentially be interpreted.  FDA specifies its position this prong is met if the software function explains:

1) The purpose or intended use of the software function;

2) The intended user (e.g., ultrasound technicians, vascular surgeons);

3) The inputs used to generate the recommendation (e.g., patient age and gender); and

4) The rationale or support for the recommendation.  [Id. at 8.]

This approach generally makes sense. It does not require any disclosure of the technical programming and algorithmic complexity underneath the software functionality, but rather, focuses on making transparent  the clinical basis for a recommendation.  It would probably be helpful if item 4) inserted the word “clinical” prior to rationale.”  The clinical rationale appears to be what FDA is describing.

FDA also adds that sources supporting a recommendation or underlying rationale must be identified, made easily accessible, understandable by the intended user, and publicly available. Id at 8.  On this last point, FDA gives the examples of clinical practice guidelines and published literature as “publicly available” sources.   Apparently, a recommendation based upon non‑public information, in FDA’s eyes, does not allow independent evaluation.  It is not clear why that problem cannot be cured by full disclosure of the non‑public information to the intended user.  Or perhaps FDA would agree that it does?  FDA needs to expand this discussion in its final guidance.

The Cures Act did not address the status of patient decision support software. That is unfortunate, because a great deal of useful software is being developed in this realm.  Fortunately, FDA has addressed it in this draft guidance (Section V), and has taken the position that, as a matter of enforcement discretion, it will treat patient decision support software the same as clinical decision support software.  Thus, all of the four prongs in the Cures Act must be met, with due allowances made for the difference between a patient and healthcare professional as the intended user.  The idea is that if these four prongs are met, the software is likely to be low risk.  This approach is very smart and will enable the development of many potentially useful software products for patients.

We have hit the highlights of this draft guidance. It is worth reading all of it, especially because FDA provides many examples to illustrate their position.  Industry often complains about the lack of examples in guidance; that should not be the case for this particular draft guidance.

The other draft guidance issued on December 8 does not require extended discussion. It is entitled, “Changes to Existing Medical Software Policies Resulting from Section 3060 of the 21st Century Cures Act.”  It primarily indicates how FDA will update existing software guidance to square it with the requirements of the Cures Act.  The most important examples of earlier guidance that requires updating include the General Wellness: Policies for Low Risk Devices guidance and the Mobile Medical Applications guidance.

Perhaps the biggest news from this guidance relates to electronic patient health records. In Section 520(o)(1)(C)(ii) of the FD&C Act, Congress specified that such records would not be exempt from device regulation unless, among other things, “certified by the Office of the National Coordinator for Health Information Technology (ONC) Health IT Certification Program.”  In this draft guidance, FDA proposes that it will not enforce this requirement. Id. at 10.  On the merits, FDA’s decision probably makes sense, but it is inappropriate for FDA to declare that it will, on a blanket basis, decline to enforce a recently enacted statutory requirement.  The statute set forth three specific prongs to define electronic health records that will be exempt from regulation, and FDA has proposed to broaden the exemption by disregarding one of the prongs.

As a constitutional matter, the President must “”take Care that the Laws be faithfully executed.” Const., Art. II, sec. 3.  This requirement applies to agencies within the Executive Branch, including FDA.  Therefore, FDA must enforce all three prongs relating to electronic health records until Congress revises the statute to say otherwise.  It is true that FDA has broad enforcement discretion, Heckler v. Chaney, 470 U.S. 821 (1985), but that authority does not go so far as to allow FDA to significantly modify a duly enacted congressional command.

This case can be distinguished from FDA’s ordinary exercise of enforcement discretion to narrow the scope of a very broad statute, based upon lack of resources, among other things. For instance, FDA’s adaptation of the exclusion of clinical decision support (CDS) software to patient decision support (PDS) software is much more defensible.  The statute is so broad that it could sweep up a great deal of PDS software, or not, depending upon how it is applied.  FDA undoubtedly lacks the resources to regulate all PDS software within the scope of the statute.  As set forth in the draft guidance discussed above, FDA is exercising enforcement discretion by borrowing from the provisions Congress enacted as to CDS software to define the type of PDS software FDA views as low risk, and which it will therefore not regulate.  That is qualitatively different than expanding the exemption Congress created for electronic health records by knocking out one of the three conditions Congress set forth as a prerequisite for the exemption.

By John A. Gilbert & Larry K. Houck —

“For Americans under the age of 50, drug overdoses are now the leading cause of death.” DOJ, Attorney General Jeff Sessions Delivers Remarks Announcing New Tools to Combat the Opioid Crisis (Nov. 29, 2017) (here).  “With evidence suggesting that nearly 80 percent of individuals addicted to heroin started out on opioid pain relievers, the link is clear that opioid prescriptions are driving this epidemic.”  Rep. Mark Meadows, Opioid Abuse Deterrence, Research and Recovery Act (here).  These statements by government officials, one representing the Trump Administration, the other from Congress, provide a sobering picture of the nationwide opioid abuse epidemic and form the basis for two new actions designed to stem the opioid crisis.  On November 29, 2017, Congressman Mark Meadows (R-NC) introduced H.R. 4482, the Opioid Abuse Deterrence, Research, and Recovery Act of 2017.  On the same day, Attorney General Jeff Sessions announced several Department of Justice (“DOJ”) and Drug Enforcement Administration (“DEA”) efforts also aimed at addressing the crisis.

Opioid Abuse Deterrence, Research, and Recovery Act of 2017

The Opioid Abuse Deterrence, Research and Recovery Act (“the Act”) would amend the Federal Controlled Substances Act (“CSA”) to require DEA-registered and state-licensed practitioners authorized to prescribe schedule II or III controlled substances to submit a “certification” to DEA that they will not prescribe a schedule II or III opioid “for the initial treatment of acute pain” unless the prescribed quantity is for less than seven days or falls within a State-established prescription limit. “Acute pain” is defined as “pain with abrupt onset and caused by an injury or other process that is diagnostically determined to have minimal risk of escalating in intensity.”  “Acute pain” under the Act does not include chronic pain, pain treated as part of cancer care, hospice, end-of-life care, or palliative care.

Under the Act, the certification would not prevent practitioners from prescribing opioids approved by FDA for opioid use disorder treatment; for immediate, post-operative pain relief; or for longer than seven days if prescribing is consistent “with a clear medical standard of care,” provided that the practitioner documents the prescription in the patient’s medical record and consults the State electronic health record system or prescription drug monitoring program.

The legislation would also require the FDA Commissioner to continue working with stakeholders and encouraging the development of abuse-deterrent opioids. In addition, to understand what led to the opioid crisis, the Act requires the Comptroller General to submit a report to Congress within two years on the health care policy changes that may have contributed to the increase in opioid overdoses and deaths.  The report must include:

1. A review of the federal health care-related legislative, administrative, and judicial decisions that affected access to pharmaceutical pain management strategies;
2. An analysis of the financial and non-financial costs and benefits of reversing or revising such decisions;
3. An analysis of the differences between State prescription drug monitoring programs;
4.  An analysis of the impacts of State and Federal prescribing limitations on patient medical outcomes; and
5. An analysis of the costs of using abuse-deterrent opioids compared to non-abuse-deterrent opioids.

Finally, the Act would require the FDA Commissioner to conduct a study on the feasibility of replacing the prescribing limits in the bill “with evidence-based clinical guidelines,” including a limitation “on the first opioid prescription for patients for an acute pain diagnosis” and “the incorporation into routine medical visits of evidence-based screening tools [to monitor] the misuse of opioids and other controlled substances.”

HPM Comments

We have long believed that effectively addressing the opioid epidemic requires focus on the physicians, doctors, dentists, and other practitioners who are the gatekeepers of public access to controlled substances. It is clear that overprescribing or inappropriate prescribing of controlled substances has been a significant cause in creating and sustaining the opioid abuse crisis.

The Act was clearly drafted with the Centers for Disease Control and Prevention’s (“CDC’s”) Guidelines for Prescribing Opioids for Chronic Pain in mind. While the CDC guidelines voluntarily limit opioid prescribing for chronic pain, the Act limits only the first or initial prescription of schedule II or III opioids to treat acute pain to seven days unless the practitioner fulfills requirements to prescribe for a longer period.  In fact, the Act does not reference prescribing for chronic pain.  Both the Act and the CDC guidelines focus on a theme that we believe is a significant contributor to the opioid abuse problem, that is, overprescribing or inappropriate prescribing of controlled substances.  However, the mechanics of having a prescriber provide a “certification” to DEA is problematic.  There are no details on how prescribers would “certify” (e.g., during the application or renewal process).  More importantly, the Act does not address the regulatory effect of certifying or, even more significantly, failure to comply with the certification.  It also fails to address whether practitioners will self-certify or obtain certification for submission from an official or unofficial organization.  It is worth noting that the CSA and DEA regulations related to sales of pseudoephedrine, provide for a certification by retail sellers that they will not sell in amounts greater than allowed under the CSA.  21 U.S.C. § 830(e)(1)(A)(vii); 21 C.F.R. §§ 1314.35-.42, 1314.101-.103.  Regardless, the Act’s requirements will make practitioners more carefully consider issuing a first opioid prescription for longer than seven days.  The inescapable downside is that some overly cautious practitioners may decline to issue necessary prescriptions to legitimate patients for longer than a week if they do not want to adhere to the requirements to do so or from fear that they will appear on DEA’s radar.

We believe that mandatory training and education for practitioners is more critical and an alternative would be to require that all practitioners who intend to be registered with DEA to prescribe Schedule II controlled substances should certify that they have received such training.

DOJ and DEA Initiatives

Attorney General Sessions announced several initiatives including a restructuring of DEA Field Offices to focus on the opioid abuse problem. The Attorney General announced that DOJ was awarding $12 million to law enforcement agencies in states hit hard by illegal prescription opioid, heroin, and methamphetamine activity.  DOJ awarded $7 million through its Anti-Heroin Task Force Program to investigate heroin and illegal opioid distribution in states with high per capita levels of treatment admissions for heroin and other opioids, and $5 million through the Anti-Methamphetamine Program to states that have “demonstrated numerous seizures of precursor chemicals, finished methamphetamine, laboratories, and laboratory dump seizures.” DOJ, Attorney General Sessions and Acting DEA Administrator Patterson Announce New Tools to Address Opioid Crisis (Nov. 29, 2017) (here).

Attorney General Sessions also announced the formation of a new DEA Louisville Field Division. This new office will strengthen DEA investigation and enforcement efforts under a single Special Agent in Charge in Kentucky, Tennessee, and West Virginia.  The geographic area served by the new Louisville Field Division was previously distributed among the Detroit, Atlanta, and Washington, D.C., Field Divisions.  The Attorney General anticipates that consolidating Kentucky, Tennessee, and West Virginia within a single jurisdiction “will produce more effective investigations on heroin, fentanyl, and prescription opioid trafficking, all of which have a significant impact on the region.” Id.

Lastly, the Attorney General directed every U.S. Attorney to designate an Opioid Coordinator for their district by December 15th. The Attorney General’s memo to all U.S. Attorneys instructed that Opioid Coordinators will be responsible for:

• Facilitating intake of cases involving prescription opioids, heroin, and fentanyl;
• Convening a task force of federal, state, local, and tribal law agencies to identify opioid cases for federal prosecution, facilitate interdiction efforts, and tailor their district’s response to the needs of their communities;
• Advising and training Assistant United States Attorneys on prosecuting opioid offenses;
• Maintaining statistics on opioid prosecutions; and
• Developing and evaluating the strategy to combat the opioid epidemic.

HPM Comments  

The creation of a new DEA Field Office focuses on several states particularly hard hit by the opiate abuse problem. Thus, it makes sense that DEA would consolidate resources to narrow the geographic scope to address these issues.  DEA drug investigations are better coordinated and more efficient when conducted within a single Field Division rather than multiple jurisdictions.  It also seems to us that the creation of an Opioid Coordinator should result in a more focused approach by U.S. Attorney offices to the opioid problem.  We note that in August 2017 the Attorney General had announced the formation of the Opioid Fraud and Abuse Detection Unit, which is a pilot program funding 12 prosecutors nationwide to focus on investigating and prosecuting health care fraud related to prescription opioids. Thus, DOJ/DEA is devoting significant resources to the fight against opioid abuse, which will likely result in more criminal, civil and administrative actions.

By James E. Valentine, Josephine M. Torrente & Jeffrey K. Shapiro –

On November 16, 2017, FDA released a comprehensive policy framework for how the Agency intends to apply existing laws and regulations that govern regenerative medicine products, including human cells, tissues, and cellular and tissue-based products (HCT/Ps). The policy framework is set forth in a series of four guidance documents (2 final, 2 draft) that build upon the regulatory framework for these products, which was completed in 2005.  A guidance document cannot alter a regulation, but can clarify how FDA intends to enforce the regulation.

In a self-described balancing act, Commissioner Gottlieb notes that FDA hopes to foster new and innovative treatment options for patients, while creating a clearer regulatory framework that will allow for greater enforcement ability against those that fall outside of the framework (statement available here).  In addition, the policy framework also serves to implement regenerative medicine-related provisions of the 21^st Century Cures Act, including the Regenerative Medicine Advanced Therapy (RMAT) designation program (see previous coverage here).  Recall, under Section 3033 of the 21^st Century Cures Act, which added Section 506(g) to the Federal Food, Drug, and Cosmetic Act (FDC Act), a drug or biological product is eligible for RMAT designation if:

1. It meets the definition of a regenerative advanced therapy: “cell therapy, 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 [PHS Act] and part 1271 of title 21, Code of Federal Regulations”;
2. The drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and
3. Preliminary clinical evidence indicates the drug has the potential to address an unmet medical need.

The effect of designation means that FDA must take actions to expedite development and review of the drug, including early interactions to discuss the potential for accelerated approval. In addition, a designated drug may be eligible for priority review or accelerated approval under current FDA regulatory standards, and if approved under accelerated approval, would be subject to a confirmatory study.

The final guidance documents, which were addressed in a previous accompanying blog post (here), are:

• Regulatory Considerations for Human Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use;
• Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception.

The two new draft guidances, which are the subject of this blog post, are intended to aid in bringing innovative, safe, and effective products to patients as efficiently as possible:

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

Draft Guidance #1: Expedited Programs for Regenerative Medicine Therapies

The “Expedited Programs for RMAT” draft guidance (RMAT draft guidance) describes several established programs, including Fast Track designation, Breakthrough Therapy designation, accelerated approval, and priority review designation, all of which are detailed in the more generally applicable guidance document entitled “Expedited Programs for Serious Conditions – Drugs and Biologics,” (May 2014) (see previous coverage here) as well as the newly established RMAT designation.

This draft guidance does not change the meaning of established terms such as “serious disease or condition,” “unmet medical need,” “surrogate endpoint,” “intermediate clinical endpoint,” and “clinically significant endpoint,” which were defined in the May 2014 Expedited Programs guidance. This new draft guidance does, however, address how CBER will apply the qualifying criteria for these expedited programs to regenerative medicine therapies, largely through examples.

Definition of RMAT

The RMAT draft guidance notes that regenerative medicine therapies are defined in section 506(g)(8) of the FDC Act, 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].” RMAT draft guidance at 2.  In this draft guidance, FDA interprets section 506(g) to apply to gene therapies, including genetically modified cells, if they lead to a durable modification of cells or tissues (this policy was first announced by Commissioner Gottlieb in August 2017 – see previous coverage here).  FDA also interprets section 506(g) to permit RMAT designation of a combination product (biologic-device, biologic-drug, or biologic-device-drug) when the biological product component provides the greatest contribution to the overall intended therapeutic effects of the product (i.e., the primary mode of action is conveyed by the biological product component).

RMAT Benefits & Qualifying Criteria: Borrowing & Building upon Concepts from other Expedited Programs

The RMAT draft guidance clearly sets out the benefits and requirements of the RMAT designation by comparing and contrasting it to other, more-established expedited programs. With regard to benefits of RMAT designation – that FDA must take actions to expedite development and review of the product – the draft guidance interprets these statutory benefits as equatable to the benefits of the Fast Track and Breakthrough Therapy designation programs, which consist of:

• Opportunities for frequent interactions with the review team;
• Intensive guidance on an efficient drug development program;
• Organizational commitment involving senior managers; and,
• Consideration for rolling review of the BLA.

Then, with regard to the qualifying criteria for RMAT designation, the RMAT draft guidance establishes a broader approach to what qualifies as “preliminary clinical evidence” than FDA set out in the May 2014 Expedited Programs guidance. In addition to accepting more traditional clinical trials as preliminary clinical evidence, the RMAT draft guidance explicitly allows for well-designed retrospective studies and clinical case series that provide data systematically by treating physicians.  In addition, the RMAT draft guidance distinguishes what level of evidence is needed from Breakthrough Therapy designation, noting that RMAT does not require evidence that indicates the drug may offer substantial improvement over available therapies, which is a higher evidentiary bar.  This evidentiary flexibility comes with a key qualification.  The RMAT draft guidance requires the evidence to be generated using the actual product that is planned for clinical development, and not a related product.

RMAT-Specific Accelerated Approval

The RMAT draft guidance sets out that programs with RMAT designation are eligible for Accelerated Approval based on either (a) “previously agreed-upon surrogate or intermediate clinical endpoints that are reasonably likely to predict long-term clinical benefit” or (b) “reliance upon data obtained from a meaningful number of sites, including through expansion to additional sites, as appropriate.” RMAT draft guidance at 9.  While (a) is the traditional standard for Accelerated Approval under Subpart E, (b) is new and specific to RMAT-designated products, and the RMAT draft guidance specifies that this will depend on “whether the evidence of effectiveness is likely to be affected by a site-specific or investigator-specific bias, such that any conclusions regarding the product’s effectiveness could not be reliably generalized to other sites.” Id. This type of Accelerated Approval would likely result in requirements for post-approval clinical evidence about the product through expansion to additional sites.”

The other RMAT-specific Accelerated Approval provision that the RMAT draft guidance implements is the ability for such products to satisfy post-approval requirements via:

• The submission of clinical evidence, clinical studies, patient registries, or other sources of real world evidence such as electronic health records;
• The collection of larger confirmatory data sets as agreed upon during product development; or
• Post-approval monitoring of all patients treated with such therapy prior to approval of the therapy.

RMAT draft guidance at 10.

Considerations in Clinical Trial Design

Moving beyond the formal expedited programs, the RMAT draft guidance, in recognition that many regenerative medicines are being developed to address unmet medical needs in patients with serious conditions, including rare diseases, mentions innovative clinical trial designs that can support a BLA. Specifically, the RMAT draft guidance states that CBER will consider clinical trials that incorporate adaptive designs, enrichment strategies, and/or novel endpoints.

While this has already been done in other areas such as oncology drug development, the draft guidance proposes that, given the limited number of affected individuals in rare diseases that can participate in clinical trials, that several different investigational products may be compared to each other and a common control in a single study.

When selecting endpoints for clinical development, the draft guidance encourages sponsors to obtain input from the affected patient communities about endpoints that might be clinically meaningful – a principle supported by FDA’s Patient-Focused Drug Development Initiative (see previous coverage here).  As an example of such a patient-centric endpoint, the draft guidance discusses how improvement in performance of tasks that require visual function might be more appropriate than traditional measures of visual impairment in conditions that lead to advanced visual impairment; this is an apparent call-out of the endpoint Spark Therapeutics developed for its gene therapy program (see previous coverage here).

GMP Manufacturing Compliance Appears to be Waived

The RMAT draft guidance suggests that clinical trial data can be shared buy multiple clinical sites utilizing a common protocol if any individual site intends to seek BLA approval. While noting that the sites would also need to share a common manufacturing protocol, the RMAT draft guidance fails to address or even mention whether it expects to obtain comparability data for products manufactured at different sites (as it would for a commercial BLA), or whether it expects the clinical sites to expend the very substantial resources that would be needed to assure compliance with Good Manufacturing Practices (GMPs).  While FDA is to be applauded for its efforts in being creative, the resulting regulatory paradigm cannot result in disparate treatment of parties seeking BLA approval.

Draft Guidance #2: Devices Used with RMATs

The “Devices Used with RMAT” draft guidance (Device Evaluation draft guidance) was developed to satisfy the requirement set out in Section 3034 of the 21st Century Cures Act that FDA issue guidance clarifying how FDA will evaluate devices used in the recovery, isolation, or delivery of regenerative medicines.  Accordingly, this guidance discusses what FDA will consider when evaluating the devices used with RMATs.

Applying the Medical Device Regulatory Framework

The Device Evaluation draft guidance largely summarizes the existing medical device regulatory framework, asserting that devices used with RMATs are subject to the same processes and standards. For example, according to the draft guidance, like any other device, FDA has no predetermined list of intended uses or specific attributes that would result in a device used with an RMAT to be classified as a Class III device.  Also, FDA intends to apply the same regulatory principles to the development of devices used with RMATs, including the applicability of the “least burdensome” principle and determination of premarket pathway (e.g., 510(k), de novo, PMA, HDE).

Combination Device-RMAT Products

The Device Evaluation draft guidance attempts to simplify and streamline the application of regulatory requirements for combination device and cell or tissue products. The document articulates FDA’s intent that devices to be used with a specific RMAT may, together with the RMAT, be considered to be a combination product and be evaluated under a BLA at CBER.  However, stand‑alone devices that can be used for the recovery or delivery of approved RMATs (e.g., surgical tools, syringes) may be evaluated independently using premarket submission pathways for devices.  And, as such, FDA commits to apply the least burdensome principle to determine the “minimum required information” necessary for marketing authorization of that device.

Finally, in instances where the RMAT and specified delivery devices are separately packaged but labeled for use together, the two products may comprise a combination product. Where the delivery device may be used with multiple similar RMATs, separate marketing applications for each product may be required, however FDA intends to similarly simplify and streamline the regulatory requirements by reducing redundancy in data requirements (e.g., use RMAT IND studies to support approval or clearance of the device).

Use of a Device with One or More Types of Cell-Based RMATs

Because cell-based RMATs are likely to differ with regard to characteristics that can impact the way the RMAT interacts with different device materials (and, therefore, potentially impact its safety and effectiveness), such as cell viability, differentiation potential, activation state, and ability to respond to stimuli after administration, the Device Evaluation draft guidance discusses factors to consider when a device can be used with only one particular type of cell-based RMAT versus more than one type. Factors include (a) physical characteristics of the RMAT (e.g., cell size and sensitivity to shearing forces) and (b) demonstrated performance and compatibility.

Similarly, if during development, a given RMAT is demonstrated to have characteristics and use requirements that allow it to be administered with a class or subset of delivery devices without compromising safety and effectiveness, the RMAT may be approved on its own with appropriate labeling for use with devices. The draft guidance anticipates this will become more common as experience is gained over time with a specific RMAT or class of RMATs in different use settings.

By Jeffrey N. Gibbs —

On February 19, 2015, FDA granted de novo authorization to 23andMe for genetic tests for autosomal recessive traits that are offered directly to consumers (DEN140044).  Nearly three years later, FDA has proposed a pathway that opens this avenue further.  In a statement on November 6 announcing this action, Commissioner Gottlieb declared, “FDA [is] seek[ing] . . . an efficient pathway to bring these tests to consumers, without sacrificing the assurances offered by FDA oversight.”

The Federal Register notice setting forth the special controls for this new class of devices was not unexpected. FDA’s granting of de novo authorization of the 23andMe test meant that special controls would be issued some day.  The surprise, perhaps, was that it took so long, especially since the proposed special controls so closely track the  types of data that 23andMe submitted.

One aspect of the proposal, though, bears special attention. Typically, after de novo authorization other applicants either need to submit 510(k)s for all subsequent devices in that class (e.g., as happened with Philips’ digital pathology assay [DEN160056]) or are exempt (e.g., as happened after Widex was granted de novo status for wireless hearing aids [DEN100025]).  This time, FDA proposed that a company offering a test would need to obtain a 510(k) for its first test, but then subsequent tests within the class would be exempt.  FDA has called this “a one-time FDA reviewed genetic health risk assessment.”  Thus, in deciding whether to invest in seeking an initial 510(k), companies should consider what other tests within the classification can be added later on without a new submission.

There may be some question as to whether a particular test does fall within the regulation. The definition is not as precisely worded as many other classification regulations: “qualitative in vitro molecular diagnostic system used for detecting variants in genomic deoxyribonucleic acid (DNA) isolated from human specimens that will provide information to users about their genetic risk of developing a disease to inform lifestyle choices and/or conversations with a health care professional . . . .”  This “squishy” reference to “lifestyle choices” and “conversations” is not typical in defining a device classification.

The proposal does not mention one of the most controversial regulatory topics in diagnostics (or devices): FDA’s authority to regulate laboratory developed tests (LDTs) (see our previous posts here and here).  Yet lurking in the background in this proposal is FDA’s view that it does have the power to regulate LDTs.  If it didn’t, then a laboratory could offer an LDT genetic test directly to consumers without FDA oversight.  FDA, though, has repeatedly stated that direct-to-consumer LDTs are not entitled to enforcement discretion.  In the past, FDA has been attacked for trying to regulate LDTs by guidance.  Here, FDA is proposing a regulation that establishes regulation of a type of LDT – direct to consumer genetic tests – albeit in an oblique fashion.

On its face, the regulation would be agnostic. It would apply to tests offered at a site regardless of whether it qualified as an LDT.  Nevertheless, the tests most likely to be subject to regulation under this new classification are LDTs, not genetic tests based on commercial assays.

For labs that decide to pursue this route for their LDTs, the proposal can offer some benefits. Tests that are covered by this regulation could be ordered directly by consumers without the need for any medical review.  That can save costs and reduce the administrative burden.  Also, FDA clearance would allow the tests to be sold in those states where direct-to-consumer LDTs are currently problematic.

Comments on the proposal are due January 8, 2018. While the proposal may seem innocuous on its face, potentially affected stakeholders should carefully think through the consequences and implications of this action, as well as whether they have concerns about the scope of the regulation or the proposed special controls.

On October 30, CDRH issued the Final Guidance “De Novo Classification Process (Evaluation of Automatic Class III Designation)” (the “De Novo Guidance”). This is a final version of the 2014 draft by the same name (see our earlier blog post here). On the same day, CDRH also issued the draft guidance “Acceptance Review for De Novo Classification Requests” (the “De Novo RTA Guidance”).   Subsequently, on November 21, FDA held a webinar regarding the guidances. During the webinar, FDA explained the key provisions of both guidances and emphasized that the De Novo RTA Draft Guidance is not yet in effect. FDA will be posting a transcript, audio recording and slides here.

The final De Novo guidance is virtually unchanged from its 2014 draft. One new addition of note – which the Agency also highlighted during last week’s webinar – has to do with what happens if there is more than one de novo submission pending for a new type of device. The final guidance indicates that if there is more than one de novo submission for the same type of device, CDRH will review both simultaneously. When the first submission is granted, the Agency will notify the sponsor of the second submission (the second sponsor). The second sponsor will have the opportunity to withdraw their de novo and then submit a 510(k) establishing substantial equivalence to the first de novo (appropriately referencing information in its original de novo). While the guidance says it does not anticipate such a situation will arise, it will be a difficult situation for the second sponsor because it will lose its significant de novo submission user fee (currently $93,229). Even though the second sponsor will be able to reference the data in the de novo application, marketing authorization will be delayed while a 510(k) submission is prepared and a new review clock is initiated.

The Agency raised a few additional interesting points regarding the De Novo Guidance during the webinar. First, CDRH clarified that unlike 510(k)s which are cleared and PMAs which are approved, de novo requests are “granted.” This may be an important promotional point for companies after their de novo is granted, and a helpful semantic distinction. Second, a webinar participant asked how to determine if a de novo or a PMA is the appropriate regulatory pathway. We expected the Agency to refer the caller to the 513(g) process, a response that we have had several clients receive. Instead, however, CDRH indicated that it is up to the company to determine if its product fits within the definitions of Class I, II, or III, and it will also depend on the company’s business strategy. While it was somewhat surprising to hear CDRH defer to the company’s judgement and preference regarding classification when it directly affects the regulatory pathway, we are certain FDA would provide guidance if requested through the appropriate pathway (e.g., the 513(g) process).

The draft De Novo RTA Guidance is also unremarkable. The draft guidance contains checklists and looks very similar to the 510(k) RTA. Like the 510(k) RTA process, the de novo administrative review will occur in the first 15 days after receipt of a submission. In addition, the draft guidance gives the CDRH reviewer discretion to determine if missing items can be addressed interactively instead of refusing a submission.

Unlike the 510(k) RTA checklist, the De Novo RTA Guidance contains two checklists: a high-level checklist of required items; and a more detailed checklist of recommended items. If the submission contains the items on the second checklist, the guidance recommends including a completed copy of the second checklist. There is some duplication between the two checklists, e.g., both lists include a classification summary. In addition, the second list appears to include information that one would expect to see in a de novo submission. For example, the second list includes labeling and full tests reports. These are items that are typically required in a premarket submission; they are not optional. According to the guidance, a de novo request should only be refused if items on the first checklist are missing. Because of the duplication and the appearance of apparently required items on the option list, we expect that it may be administratively difficult to implement the two-checklist approach.

CDRH is accepting comments on the draft guidance through December 29. Once a final version of the guidance is issued, according to the draft, there will be a 60-day delay on implementation meaning that de novo submissions received in the first 60 days after issuances of the final guidance will not be refused for failure to include all required items. This will be important for companies with de novo submissions in process of being drafted to allow them time to comply. Although the De Novo RTA Guidance is not yet final, sponsors would be wise to begin reviewing and operationalizing the checklists now to ensure that their submissions contain the appropriate content for review.

Sherman, set the Way-Back Machine.

A press release from the U.S. Department of Justice announced that the former Compliance Director of Pharmakon Pharmaceuticals, Inc. has pleaded guilty in Indiana to conspiring to defraud the United States government by lying about failed potency tests of drugs that the pharmacy had compounded. This brings back memories to me about another Pharmakon, in another part of the world.

But, first, the current news. Caprice Bearden was indicted earlier this year by the U.S. Attorney’s Office for the Southern District of Indiana for her conduct while Director of Compliance at a compounding pharmacy located in Noblesville, Indiana, owned by Pharmakon Pharmaceuticals, Inc. She pleaded guilty on November 21 to the most of the charges in the Indictment (Indictment). She admitted to a statement of facts stating that she was aware of serious super-potency of drugs including morphine sulfate and midazolam, although she told FDA investigators she was not aware, prior to reports to FDA about superpotency in later lots (Plea Agreement). According to the Indictment against her and pharmacy owner Paul Elmer, sterile drugs compounded at the pharmacy were distributed to hospitals, including a hospital where the drugs were used in a neonatal intensive care unit, and caused serious distress to at least one patient. Ms. Bearden’s sentencing is not yet scheduled. Mr. Elmer is scheduled to go to trial on April 16, 2018.

So why the obscure reference to a frequent saying by a minor character in the Bullwinkle and Rockie cartoon series (a reference probably lost on any readers under the age of 60)? Because years ago, in Tampa, Florida, our firm represented a drug manufacturing company named Pharmakon. The U.S. Food and Drug Administration (FDA) and the Department of Justice demanded that Pharmakon, and its owner Abelardo Acebo, sign a “Consent Decree” which included, characteristically, a grant of broad shutdown powers to FDA. If they refused to sign, FDA would file a lawsuit. Like very few other companies, Pharmakon refused the Consent Decree, and faced an injunction action brought in federal court. The government failed to win a Preliminary Injunction against Pharmakon, and the presiding judge appointed as a special master the expert who had testified on behalf off Pharmakon at the Preliminary Injunction hearing, to monitor Pharmakon and file regular reports with the Court. He did so. But about three years later, the final hearing on the injunction request was held, the circumstances had changed, and the judge ruled against Pharmakon, forcing it to shut down.

No connection is known to exist between the two Pharmakons, except in the synapses of this blogger.