November 21, 2017, Outsourced Pharma, Insights quoted.
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November 13, 2017, Law 360, Insights quoted.
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DOJ Settlement Highlights Risks of Failure to Comply with Terms of Risk Evaluation and Mitigation Strategies
This week's $58 million settlement between Novo Nordisk and DOJ illustrates that failure to comply with the requirements of a REMS, including requirements to communicate risk information about a drug, can have costly results.
In this case, the drug product's REMS required the company to deliver certain messages about the nature and seriousness of a serious risk. The government alleged that the company minimized that risk in communications with prescribers and failed to comply with the REMS requirement.
Companies should pay close attention to this development in implementing its REMS programs.
Last month, the Food and Drug Administration, the European Commission, and the European Medicines Agency announced that they had signed confidentiality commitments to facilitate sharing non-public information related to establishment inspections. The commitments tie in with the regulators’ broader initiative to recognize each other’s current good manufacturing practice inspections.
Press reports about these commitments have focused on FDA’s new commitment to share trade secret information with its EU counterparts. This development is not insignificant, but FDA’s authority to share the information is subject to notable limitations.
What else is noteworthy about these commitments? FDA’s agreement not to publicly disclose certain categories of information it receives from the EU regulators. This development is of interest because, as of 2012, FDA has had the authority not to publicly release certain non-public information received from foreign governments that it would otherwise have to release under the Freedom of Information Act (FOIA). As a result, FDA is authorized, and arguably has committed, to withhold certain non-public information it receives from its EU counterparts, even if the information forms the basis of an enforcement or regulatory action, such as a warning letter issued for failure to comply with cGMP or a response to a citizen petition. The Agency has yet to announce that it intends to exercise this authority; however, its potential implications should be on stakeholders’ radar as FDA begins to recognize the inspections of EU regulators as part of its Mutual Reliance Initiative.
FDA’s Commitment to Share Trade Secret Information with EU Regulators
FDA has long shared non-public information, including confidential commercial information, with its EU counterparts, pursuant to FDA regulations. FDA regulations do not authorize the sharing of trade secret information; however, as of the passage of the Food and Drug Administration Safety and Innovation Act (FDASIA) in July 2012, FDA has had the authority to share certain trade secret information with foreign governments under limited circumstances, under Section 708(c) of the Federal Food, Drug, and Cosmetic Act. The confidentiality commitments signed last month mark the first time FDA has entered into an agreement to use this new authority to share trade secret information with a foreign regulator.
What information can FDA now share and in what circumstances? As long as FDA has a confidentiality commitment in place that meets statutory requirements, the Agency can share trade secret information:
The first category of trade secret of information is subject to a major limitation: it is constrained to trade secret information that the foreign government already has the authority to obtain. If a foreign government lacks the authority to obtain trade secret information from an establishment, it will be unable to receive that information from FDA.
The second category of trade secret information that FDA can share with a foreign government is limited to circumstances in which FDA believes that a drug has a reasonable probability of SAHCODHA, and then only “as part of an inspection” or to alert foreign governments to the potential need for an investigation.
Section 708(c) of the Act does not contain broad authority for FDA to provide trade secret information to foreign governments; however, this new information sharing pathway does has the potential to be useful. For example, even if a foreign government already has the authority to obtain information by other means, FDA’s ability to share unredacted inspectional observations or conclusions with the foreign government could prevent delays in its access to safety-related information.
If FDA wants to share trade secret information with foreign regulators, it must document that each of the requisite statutory criteria have been met. For example, if FDA shares trade secret information with one of its EU counterparts, it will need to have documented, among other things, its determination that the foreign regulator already has the authority to obtain the information and the basis for that determination. Or, in another example, if FDA wants to share trade secret information with a foreign regulator because it believes that a drug has a reasonable probability of causing SAHCODHA, it will need to document its support for that determination. The administrative records for at least some of these determinations likely will need to be made on a case-by-case basis. The Agency has yet to announce how and whether it intends to develop, maintain, and make available the administrative records supporting these determinations.
Finally, it is important to note that the confidentiality commitments referenced above do not cover sharing the information with individual countries that are members of the EU; FDA still needs to enter into commitments with those countries for the types of trade secret information at issue to be shared.
To enter into such a commitment with another country, the FDA Commissioner him or herself has to certify that the government of that country has the “authority and demonstrated ability to protect trade secret information from disclosure.” FDA has not articulated how it might make that type of certification for member countries. The foreign government also has to commit to protect the information exchanged from public disclosure, unless the sponsor gives written permission to disclose, or the Secretary of HHS makes a specific type of public health emergency declaration.
FDA’s Commitment to Withhold Non-Public Information It Receives from EU Regulators
As noted above, the newly signed confidentiality commitments also include FDA’s agreement not to publicly disclose certain non-public information it receives from EU regulators, without the written authorization of the owner of the information. This aspect of the commitments is significant, especially given FDA’s new authority to withhold from the public certain information received from foreign governments.
Section 708(b) of the Federal FD&C Act, added by FDASIA, provides that FDA does not have to release under the FOIA “any information relating to drugs,” that a foreign government voluntarily gives FDA, on certain conditions:
Section 708(b) also provides that the written agreement between FDA and the foreign regulator must specify the time period within which FDA agrees to withhold the shared information. If no time period is specified, then, after 36 months, FDA has to use the FOIA for determining whether information must be released publicly.
It is not clear whether FDA intends to use its Section 708(b) authority to withhold information received from EU regulators pursuant to the confidentiality commitments signed last month. The commitments do not explicitly call out Section 708(b) and do not include a time period within which FDA must keep the information non-public.
Most of the types of non-public information cited in the commitments as examples of information FDA might receive from the EU regulators include information FDA would generally have the authority to withhold under FOIA; however, the commitments do cite to certain types of information—e.g., national security information, law enforcement information, and internal, pre-decisional information—that FDA arguably would not have the authority to withhold under FOIA if received from a foreign government. FDA would have to invoke Section 708(b) to withhold records it could not otherwise withhold under FOIA. (For you FOIA experts out there, Section 708(b) is an Exemption 3 statute, so FDA would cite to Exemption 3 as a basis for withholding such records.)
What are the implications of FDA’s agreement to withhold non-public information received from its EU counterparts? As noted above, they could be significant, especially as FDA begins to recognize the cGMP inspections of EU regulators as part of its Mutual Reliance Initiative. If FDA is authorized, and has agreed, to withhold certain information it receives from EU regulators, it could obscure Agency transparency in a variety of ways. For example, FDA could withhold information that forms the basis, in whole or in part, of an Agency action. FDA could also choose to withhold certain types of information received from a foreign regulator that FDA would not ordinarily consider withholdable under FOIA—given, for example, FOIA's presumption of disclosure for deliberative process and certain law enforcement agency documents—but that the foreign regulator does. As such, stakeholders should be aware of the contours of this authority and its potential implications.
In November, I will be speaking on a panel at the FDANews Inspections Summit entitled “US/EU Mutual Recognition of Drug GMP Inspections: Practical Consequences for Manufacturers,” which likely will cover these and other issues. Join me and my fellow panelists there!
July 5, 2017, Law 360, Expert Analysis
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On Tuesday, May 23rd, 2-3:30, I will join former FDA colleagues Lynn Mehler, Abby Brandel, and Carla Cartwright for a FDLI webinar on risk evaluation and mitigation strategies (REMS).
The webinar will cover key aspects of FDA practice and guidance, enforcement trends, and considerations for the development of single, shared system (SSS) REMS. We will also address how the CREATES Act legislation, which would create a cause of action to obtain restricted product samples and facilitate shared REMS, has the potential to impact the future of SSS REMS development.
For more information, and to register for the webinar, click here.
In the Final Days of the Obama Administration, FDA Emphasizes the Importance of Premarket Review and the Approval Standard
In the run up to the end of the Obama Administration, FDA issued a series of documents that, at their core, serve to further the Agency's stated interest in maintaining the integrity of the premarket approval standard for medical products. These documents include:
It is not unusual for an outgoing administration to try and solidify its legacy in its last days and weeks, especially where the incoming administration has articulated contrary views on key issues. During the Obama Administration, the evolving legal landscape in the area of the First Amendment called into question aspects of the premarket approval process and standards for assessing the safety and efficacy of medical products. In addition, last year some stakeholders voiced concerns that provisions of the 21st Century Cures Act and rumblings of renewed interest in federal right-to-try legislation (since introduced in the House and Senate) also threatened to compromise the approval standard. And then reports emerged that potential candidates for FDA commissioner in the Trump Administration have suggested eliminating the efficacy standard.
The timing of the issuance of these documents bring to mind the refrain in Hamilton about Alexander writing "day and night like he's running out of time." To be sure, the sensitive nature, complexity, and length of the documents that FDA issued in the last month of the Obama Administration indicate that they were in various stages of development for several weeks or, in some cases, likely months. Nonetheless, in the last days and weeks of the Administration, FDA staff and senior officials may have felt especially compelled to forestall perceived threats to the requirements and standards for premarket evaluation, both by putting forth arguments in support of the approval standard and by providing clarifying guidance to address concerns about parameters for dissemination about unapproved uses.
1. Article on Benefit-Risk Assessments by Commissioner Califf in JAMA
On January 20, outgoing FDA Commissioner Dr. Robert Califf published a viewpoint article in JAMA calling for a harmonized benefit-risk framework for medical product approvals. In it, Califf emphasizes the importance of FDA's independent evaluation of medical products for safety and effectiveness prior to approval of new products and indications. He argues that the role the Agency plays in the review process is "fundamental to assuring the public and clinicians" that products' benefits outweigh their risks when used according to labeling. Califf highlights the value of "well designed clinical trials" to inform rigorous, independent, pre-market benefit-risk assessments and pointedly warns that "a system that lacked this critical check by an independent FDA would unleash harmful products; eschewing premarket evaluation that included both safety and efficacy would be major mistake."
2. FDA Memorandum Added to Public Hearing Docket on Communications Regarding Unapproved Uses
On January 18, FDA announced that it added a memorandum entitled “Memorandum: Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products" to the docket for the public hearing that FDA held on the topic on November 9 and 10, 2016. According to FDA, the Memorandum is intended to provide additional background on the issues FDA is considering as part of its comprehensive review of its regulations and policies, including a discussion of First Amendment considerations. FDA has extended the comment period for the public hearing until April 19, 2017.
The Memorandum is a heavily footnoted 60-page document that lays out support for the premarket review frameworks for medical products from both a legal and public health perspective, much of which the Agency has stated previously in various fora. In it, FDA walks through the "substantial government interests related to health and safety" that are implicated by firm communications regarding unapproved uses of approved or cleared medical products. FDA asserts that it has sought to strike a careful balance in implementing its authorities, supporting medical decision-making for patients in the absence of better options, but without undermining incentives to seek approval/clearance of medical products. This process, argues the Agency, reduces the need to rely on unapproved uses, which carry risks to patients.
In its discussion of First Amendment considerations, FDA argues in support for its authority to rely on speech as evidence of intended use. Importantly, the Agency highlights limitations on the Amarin and Caronia decisions, including asserting that, in the Polansky case, the Second Circuit confirmed that Caronia did not foreclose FDA's ability to prove misbranding where promotional speech provides evidence that a drug is intended for a use that is not included in its FDA-approved labeling.
FDA returns to the importance of premarket review in tackling arguments that its statutory and regulatory authorities constitute unconstitutional content- and speaker-based restrictions on speech under Sorrell. As part of its argument that premarket review restrictions on firms are appropriate, FDA asserts that focusing restrictions on firms that control (and thereby have an economic motivation related to) distribution of products, as opposed to independent healthcare providers and researchers, furthers the substantial government interest in preventing harm to the public health.
FDA also includes a list of possible alternative approaches to regulating speech, while noting its concern that none of them appear adequate to address "the complex mix, and sometimes competing, interests at play." Of note, FDA voices concerns that some of these alternative approaches, including "allowing firms to actively promote an approved use as long as they disclose that a use is unapproved and include other appropriate warnings," "educating health care providers and patients to differentiate false and misleading promotion from truthful and non-misleading information," and permitting "promotion of unapproved uses listed in medical compendia" would undermine FDA's thorough and rigorous scientific premarket review process.
Not to be overlooked in the Memorandum are three appendices totaling about 25 pages that lay out (A) a summary of statutory and regulatory authority by product category; (B) examples where commonly accepted unapproved uses have led to patient harm; and (C) examples of products marketed for unapproved uses that caused harm. Appendix A reiterates FDA's legal authorities, including to require premarket review, in great detail. In Appendices B and C, FDA supports its arguments in for the importance of premarket review by providing almost a dozen examples of instances in which it says unapproved uses resulted in harm.
3. FDA draft guidances on sharing healthcare economic information and communications that are consistent with FDA-approved labeling
FDA issued two draft guidances for comment on January 18th related to medical product communications. These draft guidances provide some clarity around the types of communications that FDA may consider false or misleading or that provide evidence of a new intended use. This type of guidance, although by no means a silver bullet in the heart of future First Amendment litigation, helps FDA address some stakeholder concerns and questions about the parameters of FDA restrictions on communications that go beyond the four corners of the FDA-approved labeling. Importantly, issuance of the draft guidances also offers an opportunity for stakeholder comment.
“Drug and Device Manufacturer Communications With Payors, Formulary Committees, and Similar Entities—Questions and Answers." This long-awaited draft guidance contains FDA's current (draft) thinking on key concepts in Section 502(a) of the Federal Food, Drug, and Cosmetic Act, as amended by both section 114 of the Food and Drug Administration Modernization Act of 1997 and Section 3037 of the 21st Century Cures Act, which provides that health care economic information (HCEI) shall not be considered false or misleading if, among other things, it "relates to an [approved] indication." The guidance includes examples of the types of information that FDA considers (and does not consider) to relate to an approved indication, as well as the type of evidentiary support firms should have for their HCEI, and the information firms should include when disseminating HCEI.
The guidance also moves beyond interpretation of Section 502(a), which applies to approved indications, to address common questions related to dissemination of information about investigational drugs and devices to payors prior to FDA clearance or approval.
“Medical Product Communications That Are Consistent With the FDA-Required Labeling—Questions and Answers": This draft guidance provides information for medical product firms about how FDA evaluates their medical product communications, including their promotional materials, that present information that is not contained in the FDA-required labeling (including the FDA-approved prescribing information) for the product but that may be consistent with the product's FDA-required labeling. It includes a number of examples of information that could be considered consistent (and could not be considered consistent) with the FDA-required labeling for a product. The guidance clarifies that, if a firm's communication about a drug is consistent with its FDA-required labeling, that communication alone does not provide evidence of a new intended use.
The guidance also addresses the level of evidentiary support a firm should have for communications that are consistent with its FDA-approved labeling. Importantly, FDA clarifies in the guidance that it would not consider false or misleading those communications that are supported by evidence that does not satisfy the approval standard based solely on failure of the evidence to satisfy that standard. FDA explains that it would not consider such communications false or misleading for failing to satisfy the approval standard alone, given that the safety and efficacy of the drug for the conditions of use in the FDA-required labeling have already been established during the approval process.
4. Final rule amending FDA's intended use regulations.
On January 9th, FDA issued a final rule amending its intended use regulations (21 CFR 201.128 and 801.4) "to reflect how the Agency currently applies them to drugs and devices." These changes have sparked some controversy because of the disparity between the changes to the codified language in the proposed and final rules and, more significantly, the nature of the changes themselves.
FDA had previously issued a proposed rule in September 2015. The document was a short 10 pages, most of which concerned the Agency's proposal to clarify when products made or derived from tobacco are regulated as drugs, devices, or combination products. Just a few paragraphs of the preamble focused on the Agency’s proposal to amend its regulations regarding intended uses. FDA explained that it was "taking the opportunity" to make corresponding changes to the existing intended use regulations "and to conform them to how the Agency currently applies these regulations to drugs and devices generally." FDA emphasized that the proposed changes to the intended use regulations were clarifying only and would not reflect a change in the Agency's approach regarding evidence of intended use.
To this end, FDA proposed striking the sentence at the end of its intended use regulations which states that, if a manufacturer knows that a drug is to be used for unapproved uses, it is required to provide "adequate labeling" for the drug. As it likely would be impossible to craft such "adequate labeling" in accordance with applicable law without the drug being the subject of an approved application for the uses at issue (See, e.g., Section 502(f)(1) of the FDCA and 21 CFR 201.100), the effect of this sentence has been that knowledge that a product is being used for an unapproved use could form the sole basis for an Agency determination of intended use. FDA also proposed adding the phrase "for example" in one sentence in the intended use regulations to clarify that the circumstances in which a drug is offered and used for an unapproved use (with the knowledge of persons legally responsible for the drug's labeling) is just an "example" of how intended use may be shown.
In support of the proposed changes, FDA cited to a 2010 brief in the Allergan litigation, which states that "[i]n practice, FDA usually does not treat an unapproved use as an intended use solely because the manufacturer knows that the unapproved use is taking place." Of note, in the proposed rule, FDA cited to the brief for a slightly different proposition: not that, "in practice," it "usually does not" use knowledge alone as intended use, but that the Agency categorically "would not regard a firm as intending an unapproved new use" for an approved or cleared product “based solely on the firm’s knowledge that such product was being prescribed or used by doctors for such use." The proposed rule does not explain this shift from using the provision infrequently to viewing it as vestigial in nature.
FDA noted in the proposed rule that the Agency "may look to 'any ... relevant source,' including but not limited to the product's labeling, promotional claims, and advertising" in determining a product's intended use. Citing to U.S. v. Travia, 180 F. Supp.2d 115, 119 (D.D.C. 2001), FDA also asserted that it can consider "objective evidence" of a manufacturer or distributor's intent, which may include "a variety of direct and circumstantial evidence," such as "any circumstances surrounding the distribution of the product or the context in which it is sold." (In the Travia case, the district court held that nitrous oxide (sold in a balloon) met the statutory definition of a "drug"; the court found that the circumstances surrounding its sale--in the parking lot of RFK at a concert--demonstrated the seller's intent that the product was being used to affect the structure or any function of the body.)
On January 9th, FDA published the final rule amending its intended use regulations. Having received over 1900 comments on the proposed rule, the Agency spends a significant portion of the preamble to the final rule addressing comments related to First Amendment issues and tying its consideration of speech as evidence of intended use to the public health benefits of its premarket review requirements.
FDA reiterates the same rationale for changing the intended use regulations as it did in the proposed rule; however, in a surprise twist, the final codified language does not track the changes to the codified outlined in the proposed rule. Instead of deleting the final sentence of the intended use regulations outright as proposed, FDA has replaced that sentence with language emphasizing that FDA considers "the totality of the evidence" in considering the objective intent of a manufacturer. FDA explains that it is “amending” of the last sentence of the regulations “to avoid the potential misinterpretation that a manufacturer’s knowledge of an unapproved use of an approved/ cleared medical product, without more, automatically triggers requirements for that manufacturer to provide additional labeling.”
The agency also appears to walk back its statement that it “would not” base a new intended use determination on a firm’s “knowledge that such product was being prescribed or used by doctors for such use” alone. Instead, the preamble to the final rule says that the Agency “does not, absent extraordinary circumstances, regard a firm as intending an unapproved new use for an approved or cleared medical product based solely on that firm’s knowledge that the product was being prescribed or used by doctors for such use.”
Not surprisingly, the final rule is already the subject of a citizen petition (petition for stay and for reconsideration) from the Medical Information Working Group (MIWG), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the Biotechnology Innovation Organization (BIO). The rule already has a delayed effective date of March 21, 2017, in accordance with the Trump Administration memorandum imposing a regulatory freeze pending review. Given the reaction to the new language in the final rule, and the fact that a new FDA commissioner has not yet been chosen (much less confirmed), it seems likely that the effective date may get pushed back further still.
In late November, FDA issued a revised draft of its guidance on the submission of quality metrics data. The initial draft of the guidance, issued in July 2015, had announced FDA’s intent to require the submission of quality metrics data using, among other things, its relatively new authority to request certain records or information in advance or in lieu of an inspection: Section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FDCA), added by Section 706 of the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA). The Agency’s proposed approach met with some pushback from various stakeholders, who raised both technical issues and concerns that FDA lacks the legal authority to compel the submission of quality metrics data as described in the draft guidance.
More than a year later, FDA has published a substantially revised version of the draft quality metrics guidance. Here are five key takeaways from the revised draft guidance:
1. Submission of quality metrics will be voluntary until FDA undertakes rulemaking
In the revised draft guidance, FDA announces its intent to initiate a “voluntary phase” of the quality metrics reporting program. The Agency reiterates its authority to require the submission of quality metrics data under Section 704(a)(4) of the FDCA, but does not intend to exercise that authority in implementing this voluntary phase of the reporting program. FDA also notes that it does not intend to take enforcement action based on errors in a quality metrics submission made as part of the voluntary phase of the program, provided the submission is made “in good faith.”
FDA anticipates accepting the voluntary submission of data through an electronic portal starting in January 2018. After evaluating the results of the voluntary phase of the quality metrics program in 2018, the Agency intends to engage in the rulemaking process.
2. FDA is focusing on a more limited set of metrics
In the draft guidance published in July 2015, FDA sought the submission of four primary metrics and three optional metrics. In the revised draft guidance, FDA has pared that down to three primary metrics: lot acceptance rate, invalidated out-of-specification rate, and product quality rate. The Agency notes that it intends to use this voluntary phase of the program to learn more about this limited set of quality metrics and associated analytics, and that related metrics may be added as the program evolves.
3. All types of manufacturing establishments can participate
FDA focused on reporting at the product (active pharmaceutical ingredient (API) or finished dosage form (FDF)) level in the initial draft guidance. Product-specific submissions were to include data for each manufacturing establishment. FDA now states that it continues to encourages the submission of product reports segmented by manufacturing site but revised the draft guidance to contemplate submission of either (a) product reports segmented by site or (b) site reports segmented by product. FDA also provides that all types of drug manufacturing establishments (e.g., manufacturers of excipients) can participate in the voluntary phase of the reporting program.
4. FDA intends to publish a tiered list of reporter categories to incentivize the submission of quality metrics data
As an incentive for the submission of quality metrics data during the voluntary phase of the program, FDA intends to publish a list of five “recognition categories” of product and site reporters, ranked by whether the reporter has submitted some or all the requested data. For example, the category “Product Reporter Top Tier” will include product reporters that submit all the requested data for all covered establishments in the supply chain for the product for the full year reporting period. “Product Reporter Mid Tier” includes product reporters that identify all covered establishments in the manufacturing supply chain for the product and submit all requested data for at least one of those establishments for the full year reporting period.
5. FDA continues to have high hopes for the quality metrics program
Despite FDA's decision to downshift to a voluntary reporting program, the revised draft guidance reflects the Agency's continued belief in the value of quality metrics data to inform its risk-based decisionmaking. During the voluntary phase of the program, FDA intends to use quality metrics reporting to inform its surveillance inspection risk-based model and share how that reporting has reduced the frequency of inspections. FDA also expects to use the submissions collected on a voluntary basis to facilitate early resolution of potential quality problems, reduce the likelihood of disruptions in the drug supply, address potential drug shortages, help FDA prepare for and hone the focus of its inspections, and encourage manufacturing improvements across the drug lifecycle.
FDA intends to expand on these goals during its “fully implemented” quality metrics program, after rulemaking is complete. This implementation process is likely to take years, and the probability of it moving forward apace remains to be seen under the new administration. The burdens and benefits experienced by reporters during the voluntary phase of the program likely will affect the scope and timing of any future rulemaking process.