On November 26, 2018, the U.S. Food and Drug Administration (“FDA”) announced the process for clearing most medical devices for marketing is being updated to incorporate changes the FDA laid out in an April draft guidance. For over forty years, most medical devices have entered the United States market through the 510(k) clearance process. The 510(k) process offers an expedited approval process available only for products that are substantially equivalent to products already on the market (known as predicate devices). The FDA is considering no longer allowing sponsors to rely on predicates older than ten years and making public information about cleared devices that relied on predicates more than ten years old. In addition, the FDA intends to finalize guidance establishing an alternative 510(k) pathway with different criteria that reflect current technological principles.

In a statement, FDA Commissioner Scott Gottlieb reasoned that newer products relying upon older predicates might not reflect new performance standards or latest scientific and medical understanding. Commissioner Gottlieb believes this change will promote the continual improvement of medical devices. However, the announced change received quick pushback. Many manufacturers argue that reliance upon older predicates can be necessary when no newer predicates are available, and older predicates can provide data that helps sponsors make new devices safer. In addition, many industry-observers believe the FDA’s plans may contradict and exceed its statutory authority, and therefore require additional support from Congress.

If the current proposal becomes law, the implications will include increased costs for manufacturers forced to innovate because of the inability to rely on older predicates. The agency’s statement indicates that new medical devices that utilize the 510(k) pathway should be better than predicates, rather than the applicable legal standard of substantial equivalence. Thus, manufacturers can anticipate increased agency scrutiny when submitting information in the 510(k) summaries. In addition, manufacturers may need to make alternative plans if developing a new device based on an older predicate.

The Food and Drug Administration (FDA) issued a draft guidance (Draft Guidance) on July 11, 2016 that allows some generic drug manufacturers holding an Abbreviated New Drug Application (ANDA) to update the label of the drug they manufacture with new safety information.  The Draft Guidance provides new clarifications and recommendations to generic drug manufacturers seeking to update a generic label after withdrawal by the name brand manufacturer of the reference listed drug (RLD) (a “Withdrawn RLD”).  The Draft Guidance explains how a generic manufacturer may submit an updated label of a generic drug to the FDA for approval after withdrawal of the RLD.  The FDA must approve the proposed new label before the new generic label may be issued.  The Draft Guidance also reminds applicants that the FDA continues to retain the authority to request the ANDA-holder with a Withdrawn RLD to update the label of the drug under its ANDA for safety reasons.

The issue of generic labeling was put in the spotlight in 2011 with the US Supreme Court’s decision in  PLIVA, Inc. v. Mensing, 131 S. Ct. 2567 (2011), which held that generic drug manufacturers could not be held liable for failure to warn under state tort law because such laws were preempted by FDA regulations.  The specific regulations at issue prohibit generic manufacturers from changing a drug label unless and until the label of the RLD is amended.    Per Justice Thomas:

[t]he FDA denies that [generic drug manufacturers] could have… unilaterally strengthen[ed] their warning labels. The agency interprets… [its regulations] to allow changes to generic drug labels only when a generic drug manufacturer changes its label to match an updated brand-name label or to follow the FDA’s instructions. 

In response to public outcry over the decision in PLIVA, the FDA published a proposed rule entitled, “Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products” (Proposed Rule). This Proposed Rule gives generic manufacturers much broader powers and responsibilities over the labels of the generic drugs they manufacture.  The Proposed Rule was issued in 2013 and has been subject to controversy within the pharmaceutical industry.  This controversy has led to multiple delays in the finalization of the Proposed Rule and the unusual step by appropriations committees in the House of Representatives and the Senate to approve budgets that prohibit spending on the Proposed Rule.  As we reported in a June blog post, publication of the Proposed Rule has now been pushed out to at least the Summer of 2017.

In the interim, FDA’s Draft Guidance focuses on changes to generic drug labeling under a much narrower set of circumstances where the New Drug Application (NDA) of the RLD has been withdrawn by the brand name manufacturer for reasons other than safety or efficacy.

Currently, holders of a NDA or ANDA are each required to collect post-marketing safety data and provide the FDA with reports and safety data they receive for a drug under an NDA or ANDA. Based upon the data and reports submitted to the FDA, the FDA may request or require a change to the label of the corresponding drug (either a NDA or an ANDA with a Withdrawn RLD) in accordance with 21 USC §355(o)(4).  Additionally, NDA holders have available a mechanism by which the NDA holder can update the label of the drug under the NDA on its own or by providing a suggested label to the FDA for review.  This mechanism has typically been unavailable to ANDA holders. (See “Guidance for Industry: Safety Labeling Changes – Implementation of Section 505(o)(4) of the FD&C Act,” footnote 10).  The Draft Guidance clarifies that this second avenue for updating a drug’s label is available for an ANDA holder with a Withdrawn RLD if changes become necessary based upon new safety information it obtains.

Additionally, the Draft Guidance describes the other sources of data available to the holder of an ANDA with a Withdrawn RLD to aid in determining whether a label should be updated. Specifically, the FDA suggests that such an ANDA holder should review the labels of other drugs, both NDAs and ANDAs, containing the same active ingredient as they may have been updated more recently than the label of the RLD at the time it was withdrawn.

The ability to update a label under these circumstances is important for an ANDA holder with a Withdrawn RLD to avoid misbranding allegations. As the Draft Guidance states:

as a Drug is used over time, the scientific community’s understanding of the drug may evolve based on data from various sources…. Therefore, the labeling of ANDAs that rely on the withdrawn RLD might eventually become inaccurate and outdated, resulting in labeling that is false and/or misleading…

While review of new data and undergoing the process of supplementing a drug’s label with new safety information may be burdensome for ANDA holders, it is likely preferable to the risk of facing misbranding allegations.

The avenue for updated labeling in the Draft Guidance also resembles the concept of Expedited Agency Review (EAR) included in the alternative to the Proposed Rule issued jointly by the Generic Pharmaceutical Association (GPhA) and the Pharmaceutical Research and Manufacturers of America (PhRMA). While the Draft Guidance only applies to a very small and specific set of generic labels, the similarities between EAR and the FDA’s process for updating the label of an ANDA with a Withdrawn RLD demonstrates cooperation between the FDA and industry to at least find common ground on the issue of generic labeling. While the recommendations set forth in the Draft Guidance may be a sign the FDA is willing to listen to industry suggestions, the Draft Guidance’s impact is too limited to predict whether the FDA will  continue to search for middle-ground with the remaining generic labeling issues raised in the Proposed Rule.

Per the listing in the Federal Register, any comment on the Draft Guidance must be submitted by September 9th, 2016 in order to be considered in rendering the final guidance.

FDA is the subject of a lot of criticism, some deserved, and some not.  However, I don’t think FDA gets enough praise when it does something right.  Therefore, I thought it was important to follow up on my previous blog and let everyone know that FDA has cleared up some of the ambiguities I mentioned there.

Specifically, on December 9th, FDA issued draft guidance making it clear that federal, and not state, law determines whether a company needs to register with FDA as a wholesale distributor or 3PL as required by the DSCSA.  This clarification likely has the greatest impact on prescription drug manufacturers because the DSCSA added an exemption to the scope of activities considered to be wholesale distribution and triggering wholesale distributor licensure obligations under the DSCSA.  Under the new definition, a manufacturer distributing its own drugs is no longer considered to be engaging in wholesale distribution.

FDA should be lauded not only for providing this clarification, but for the timing of its release.  I am not sure if it was merely a coincidence, but FDA issued this draft guidance the day after the comment period for FDA’s Pre-emption Guidance ended.  And by releasing it before the effective date of the reporting requirements for wholesale distributors, manufacturers have one less thing to worry about as they prepare to implement the track and trace requirements that commence on January 1, 2015.

Notwithstanding all of the good to come out of this guidance, there are still many ambiguities it does not address, such as whether states are permitted to require manufacturers to be licensed as wholesale drug distributors come January 1, 2015.  Hopefully, now that the comment period for the Pre-emption Guidance has closed, FDA will work diligently to issue final guidance and clarify this and the other remaining ambiguities.

For those entities required to report, I encourage you to review the draft guidance and evaluate whether the requirements it imposes align with the DSCSA.  FDA is accepting comments to the Draft Guidance through February 9, 2015.  For those who do not have to report, I encourage you to take advantage of the opportunity to spread a little holiday joy and submit comments thanking FDA for providing this clarification in a timely manner.

FDA's Second Guidance on the Drug Supply Chain Security Act Misses the Mark

Although FDA appropriately identified the need for guidance on the Effect of Section 585 of the FD&C Act on Drug Product Tracing, Wholesale Drug Distributor and Third-Party Logistics Provider Licensing Standards and Requirements; the Draft Guidance issued by FDA this month does not ask the right questions.

In November 2013, Congress enacted the Drug Supply Chain Security Act (“DSCSA”) with the intent of establishing a “Uniform National Policy” for wholesale distributor and third party logistics provider (“3PL”) licensure.  Congress hoped to achieve this goal by adding Section 585 to the Federal Food Drug and Cosmetics Act (FD&C Act) which prohibits states from:

Establish[ing] or continu[ing] any standards, requirements, or regulations with respect to wholesale prescription drug distributor or third-party logistics provider licensure that are inconsistent with, less stringent than, directly related to, or covered by the standards and requirements applicable under section 503(e) (as amended by [the DSCSA]), … or Section 584. 

This preemption provision was a welcomed addition to the FD&C Act because it signaled the end of the patchwork of state laws governing wholesale distribution of prescription drugs.  However, it soon became evident that there was some disagreement about Congress’ intent and that additional guidance on the scope of this preemption provision was needed.

Therefore, when I saw that FDA had published this draft guidance, I was excited, until I started reading it.  Unfortunately, it became immediately apparent that FDA was not addressing the questions stakeholders are struggling with.  From personal experience, the following questions are some of the most important ones left unanswered by this guidance:

  • Does FDA interpret Section 585(b), the wholesale distributor and 3PL preemption provision, to establish a regulatory floor or both a ceiling and a floor with respect to wholesale distributor and 3PL licensure?FDA's Second Guidance on the Drug Supply Chain Security Act Misses the Mark

The draft guidance restates the language applying preemption to state laws that are inconsistent with or covered by the DSCSA.  Yet its conclusion appears to ignore this language and interpret the DSCSA as establishing a floor.

Although I believe that Congress intended the DSCSA to establish both a floor and a ceiling, I recognize that Congress could have done a better job communicating this intent.  Notwithstanding the existence of some ambiguities regarding Congress’ intent, the DSCSA clearly states that Congress intended to create Uniform National Standards governing wholesale distribution and 3PL licensure.

Additionally, at least some weight should be given to the fact that the scope of Section 585(b) evolved as the DSCSA worked its way through Congress.  When initially introduced in the Senate as a standalone bill (S.957), Section 585(b) would only have preempted those state laws that were less stringent than the federal Law, and thus would have only established a regulatory floor.  Therefore, FDA should not just ignore the fact that Section 585(b) was ultimately expanded to prohibit states from enforcing laws that are also inconsistent with, directly related to or covered by the federal law, regardless even if FDA has a higher approval rating than Congress.

Assuming FDA concludes that the DSCSA establishes both a regulatory floor and ceiling, it will be important for the final guidance to describe how stakeholders should evaluate whether a state law is preempted by the DSCSA.

  • Come January 1, 2015, will states be permitted to continue requiring prescription drug manufacturers to be licensed as wholesale distributors with respect to the distribution of the manufacturers’ products?

As of January 1, 2015, the distribution of a prescription drug by its manufacturer is expressly excluded from the definition of wholesale distribution under Section 501(e) of the FD&C Act.  Therefore, it would appear that the answer to this question is “no” because doing so would be inconsistent with the federal law.  However, FDA should consider directly answering this question to resolve any ambiguities created by the draft guidance.

  • Assuming the answer Question 2 is “no,” could states impose any state licensure obligations on manufacturers relating to the distribution of the manufacturers’ prescription drugs?  If so, could such requirements impose the same obligations that are applicable to wholesale distributors? Could such licensure requirements be tied to a manufacturer’s distribution of its own products?

Although it appears that manufacturers cannot be required to be licensed as wholesale distributors, it is less clear whether states would be wholly prohibited from licensing prescription drug manufacturers.  Understanding states may be interested in continuing to require manufacturers to be licensed in their state, it would be helpful if FDA could provide some guidance on what types of licensure programs would be permissible.

  • Between January 1, 2015 and the effective date of the new regulations promulgated pursuant to Sections 583 and 584, which federal standards will states need to compare their laws against? 

The only federal standards that will be in place come January 1, 2015, will be the standards included in Sections 501(e), 583 and 584 of FD&C Act.  As the provisions in 583 and 584 only provide general guidelines for the regulations to be promulgated by FDA, it is unclear which state requirements will be permissible and which will be prohibited.  For example, pursuant to Section 583(b)(6) the regulations promulgated by FDA must require the mandatory physical inspection of any facility used in wholesale distribution and Section 583(c) would allow these inspections to be performed by an approved third-party accreditation or inspection service.  However, until the regulations are promulgated it is unclear as to what the scope of these inspections would be.  More specifically, can states continue to require wholesale distributors be VAWD accredited as a condition of licensure?

Stakeholder Engagement Is Important to Ensure the Benefits of the DSCSA are Realized

The answers to these questions will not only provide stakeholders with the guidance they need, they also will provide insight into whether the DSCSA will be successful in eliminating the inefficiencies caused by the current patchwork of state laws governing prescription drug wholesale distribution.

I likely did not identify all of the areas where stakeholders want FDA to provide additional guidance.  Therefore, it is important for all stakeholders to let FDA know what questions need to be answered in the final guidance by submitting comments before December 8th, 2014.