Since 2017, the FDA has been working on a proposal to create a new type of patient-focused labeling for certain outpatient drug products that would be specifically targeted for patient use. That proposed rule, which would establish Patient Medication Information (PMI) as a type of labeling, has now been published. But while the rule emphasizes a brief, patient-friendly approach, drug and biologics companies may find the proposal difficult to operationalize.
Regulatory background and context
- The FDA uses various controls, including labeling and warnings, to ensure that medical products are used appropriately and safely. Prescription drug labeling is a core component of the regulatory requirements for these products, with the FDA tasked with reviewing the format and content of labeling as part of its regulatory mandate. Prescription drug product labeling is typically intended to provide a synopsis of the information and data that the FDA relied on to approve the product, and guide the prescriber on appropriate use (e.g., information on contraindications, instructions for use and intended use populations, dosing and safety information).
- Within the realm of FDA-required labeling, there are currently a few different types of information a sponsor might develop specifically for patient use: medication guides, instructions for use (IFU), consumer medical information (CMI) and patient package inserts (PPI). However, only in certain circumstances are sponsors required to develop these materials for patient use. For example, medication guides address issues that are specific to particular drugs or drug classes. They might be required as part of a product’s Risk Evaluation and mitigation Strategy (REMS) or if they are deemed necessary to prevent serious adverse events, inform patients on the potential for serious side effects, and/or inform a patient on the importance of medication adherence to ensure a medication’s effectiveness.
- However, a longstanding critique of most FDA labeling is that it is complex and generally difficult for laypersons to understand, interpret or read in its entirety. Because the point of most labeling is to be comprehensive – to contain essentially every single possible outcome of warning – many persons prescribed drugs don’t read the labeling (or at least not in full).
- This critique has not been lost on the FDA, and since 2017 the agency has been looking at a potential new potential approach to labeling called “Patient Medication Information (PMI)”. As the FDA wrote in the Unified Agenda at the time, the types of information that accompany a drug product often are not designed specifically for the use of the patient: “Research has shown that frequently the information received is duplicative, incomplete, conflicting, or difficult to read and understand and such information is not sufficient to meet the needs of patients,” FDA explained. “The current system does not consistently provide patients with useful written information to help them use their prescription drug products safely and effectively.”
- The FDA recently concluded its work on a proposed rule focused on PMI. The regulator sent the rule to the White House’s Office of Information and Regulatory Affairs (OIRA) on October 4, 2022. While OIRA’s review of major rules often take a few months, its review of the PMI proposed rule took an unusually long time – more than seven months. OIRA eventually released the rule for release by the FDA (with changes) on May 10, 2023.
- The FDA has been working on this issue for quite a long time, even pre-dating the developing of the proposed rule. The FDA first proposed a rule on “Prescription Drug Labeling: Medication Guide Requirements” in 1995, which was finalized in 1998. However, over the last decade the FDA and other stakeholders have acknowledged that there are opportunities for improvement. In 2007, the FDA held a public workshop to hear from the public about the Medication Guides system; per the agency, “the public testified that the Medication Guides distribution processes needed improvement” and that it should be “shorter and easier to read.” Later that year, Congress adjusted the FDA’s statutory framework to allow Medication Guides as a potential element of REMS (as noted above). In 2009, the agency held a workshop to discuss the gaps in existing frameworks and present some new options for discussion, including four “prototypes” of potential PMIs. These prototypes, and the intended form and function of a PMI for prescription drugs, were further refined in a series of workshops with the Brookings Institute between 2010 and 2014. Also in 2010, the agency held a two-day public hearing on the subject; following the feedback and lessons from the Brookings Institute and the FDA’s own work, the agency then “narrowed down” the four PMI prototypes to two options, which were further studied by RTI International under a contract with FDA.
- After a lengthy development process, the FDA today published its proposed rule, Medication Guides: Patient Medication Information. The proposed rule would significantly revamp 21 CFR 208 (Medication Guides), as well as create 21 CFR 606.123 (relating to establishments that collect blood and blood components intended for transfusion).
- At its most basic, the new PMI format would apply to all drugs and biological products that are “used, dispensed, or administered on an outpatient basis and for blood and blood components transfused in an outpatient setting.” The PMI itself would be a one-page document that would include a standardized format and content, and would be subject to FDA review and approval.
- The format of the PMI: At just one page (8.5×11 inches) in length, the PMI would need to include only the most essential information. FDA proposes that the PMI include four key headings: The drug name, important safety information, common side effects and directions for use. Brevity is the point, according to FDA, which cited research showing that patients “prefer a simplified one-page format for written patient information and are more likely to read information that is short and concise.” FDA also intends to impose requirements related to the use of capital letters (only for certain headings, the drug name and acronyms), the use of “bold” type, and the font color (only black) and size (no smaller than size-ten font). In addition, the PMI would not be able to use pictograms or icons, and would not be able to be promotional in tone. Each section would have other required sub-headings (e.g., for the “Important Safety Information” section, the subheaders “Warnings,” “Do not take” “Serious side effects” and “Tell your health care provider before taking”).
- The content of the PMI: The regulation describes, in broad terms, what must be included in the PMI. Each section has its own requirements, with information intended to be “concise and cased on and consistent with the prescription drug product’s PI.” For example, the “Warnings” section would require a “summary of the information found in the prescription drug product’s boxed warning, if any, that is most relevant for patients to know for the safe and effective use of the prescription drug product.” The “Do not take” section would include any circumstances (if they exist) “in which the prescription drug product should not be used.” The rule would also required the inclusion of “common listed side effects” that are considered clinically relevant to the patient “in terms of seriousness and frequency.” To denote that the side effects reflect an abbreviated list, the PMI would also include a statement that, “These are not all the possible side effects,” and that patients should contact their health care provider if they experience other effects. Curiously, there is no direction for the patient to seek out the full FDA-approved labeling.
- Information included in the PMI: FDA intends that the PMI would “highlight the most important information that patients need to know to help them use their prescription drug products safely and effectively.” The PMI is not intended to be a substitute for the Prescribing Information (PI), and is also not intended to be adequate directions for use.
- Development of the PMI: The FDA notes that when companies are developing their respective PMIs, they will not be required to conduct consumer testing, as “FDA lacks empirical evidence demonstrating that consumer-tested PMI directly results in benefits to patients over non-consumer-tested PMI.” However, companies may employ this testing at their discretion, and has invited comment on this aspect in its proposal.
- Multiple PMIs: “In certain circumstances, FDA may require more than one PMI for a prescription drug product, associated with a single PI, when one PMI cannot adequately convey the safe and effective use of the drug to patient,” FDA wrote. “This may occur in instances where there are two or more formulations of a prescription drug product described in a PI.”
- Maintenance of the PMI: PMIs would need to be updated “when new information becomes available that would cause PMI to become inaccurate, false, or misleading.” For generic drugs, PMI would also need to be updated when the Reference Listed Drug’s PMI is updated (or FDA’s template – see below).
- Use of the PMI: Beyond just requiring the PMI to exist, the proposed rule would also require authorized dispensers to “provide PMI to patients each time a prescription drug product for which an FDA-approved PMI exists is used, dispensed, or administered on an outpatient basis.” While the “default” method of distribution would be in paper, the rule also permits electronic distribution “upon a patient’s request.”
- Implementation of the rule would take place over a five-year period, intended to give companies ample time to develop and obtain approval for PMIs. Given the number of approved drugs and biologics on the market that are dispensed on an outpatient basis – and their generic and biosimilar equivalents – the additional workload on FDA’s labeling review staff could be considerable. The five-year implementation period would be phased, with some applications affected immediately (new applications for approval of licensure), some affected within a year of approval (already-pending applications, and medications that already have a Medication Guide), and others affected based on when they were approved (2 years for those approved after 2013, 3 years for those approved after 2008, 4 years for those approved after 2003, and 5 years for all other drugs). It’s worth noting that FDA’s definition of approval includes efficacy supplements, and not just the date of first approval.
- PMIs would be warehoused in an “online central repository” managed by the FDA, similar to how the agency manages other drug labeling assets in its FDALabel database. This would allow them to easily be searched by both the public and industry. FDA also notes that it’s considering establishing a second database, “potentially through a public-private partnership, of consumer-tested phrases and terms that would assist in the development of written patient materials, including PMI.”
- Impact on generics: According to the rule, generic drugs would need to have a PMI that is “the same as that of the reference listed drug (RLD) except for certain differences in labeling permitted under law.” Interestingly, FDA envisions that it would “create a PMI template for approved ANDAs” in certain cases, such as if the RLD has been withdrawn and no PMI was approved for the RLD before it was withdrawn. The regulation also establishes a process for the review of PMIs and the submission of equivalent PMIs by sponsors of generics. Based on our read, the design of this process seems intended to avoid having PMI serve as a stumbling block for potential generic competition.
- Impact on blood and blood components: The rule would apply the same PMI requirements to blood products and transfusions as it does to drugs and other biologics. As the FDA explains, “The requirement to create PMI and make it available for distribution to transfusion services applies to all establishments that collect blood and blood components for transfusion. However, only licensed blood establishments would be required to submit PMI to FDA for approval.” The regulation does “specifically invite public comments” on several topics related to blood and blood components, including on the adequacy of information materials currently made available to patients, the feasibility of industry “jointly developing PMI documents,” and the electronic storage of PMI for blood products on FDA’s website.
- Waivers: Companies may request a waiver from the PMI requirements. FDA may grant a request for a waiver if it determines that “any requirements is inapplicable, unnecessary, impracticable or contrary to patients’ best interested for a particular prescription drug product.” However, the FDA says that it anticipates “rarely granting a waiver to the one-page format requirement,” which it considers a “key feature” of the PMI. It may also consider requests for additional time to comply with the PMI requirement.
- Eliminating duplication: The proposed regulations aren’t only intended to be additive. FDA says it plans to withdraw the current regulations requiring Medication Guides for certain prescription drug products that would otherwise be covered by a PMI. This withdrawal would take place “after all prescription drug products that currently have Medication Guides have FDA-approved PMI.”
- Impact on drugs with Patient Package Inserts: An interesting note in the proposed rule notes that after the five-year implementation schedule, it would withdraw current regulations that require Patient Package Inserts once existing PPIs have been converted to PMI. This would notably affect oral contraceptives and estrogen-containing products.
- Dispensing PMI: While the rule requires PMI to be dispensed to patients by outpatient providers, FDA does that it does not anticipate “that PMI would be provided each and every time a prescription drug is used … but rather the first time the prescription is used, dispensed, or administered and each time a prescription is dispensed.” While paper dispensing of the PMI is the default method, the proposed rule is also permissive of electronic distribution methods.”
- Some exemptions: Vaccine manufacturers are likely to benefit from the FDA’s proposed rule. That’s because FDA states that with “few anticipated exceptions, we propose to exclude manufacturers of preventive vaccines that do not have a Medication Guide from the requirement to create and distribute PMI.” Patients would instead obtain access to the same information by way of the CDC’s vaccine information statements (VISs), which effectively accomplish a similar goal.
- Does a standardized one-page format really work for all drugs? One notable omission in the regulation is any sense that the FDA has actually pressure-tested its own proposed approach. In theory, FDA’s proposal sounds great. A short, patient-friendly label that just talks about the highlights of the medication. But a few elements are likely to make its operationalization exceptionally difficult. First, FDA insists that the PMI will be a maximum of one page, and that exceptions to this approach will be rare. Second, FDA insists upon the inclusion of a substantial amount of information. As anyone who has ever tried to pack for a long trip undoubtedly knows, there’s only so much you can pack into a single suitcase before you need a second one. In the same way, we anticipate that some companies are going to seriously struggle to figure out how to include all of the required and suggested information into their PMI. And as FDA notes, in some cases multiple PMIs may be necessary, leading to a lot of extra work for sponsors (and the FDA, for that matter).
- How will companies determine which information is worthy of inclusion or exclusion? We anticipate that this will be, operationally, by far the most complex part of developing PMIs for companies. After all, companies already have FDA-approved labels. But streamlining them down to a single page meeting all of FDA’s requirements is likely to be time-consuming. And while we aren’t lawyers, we also do wonder if these abbreviated labels might invite lawsuits from plaintiffs lawyers contending that patients weren’t warned about a specific risk that they argue could be more important than another risk included in the PMI.
- What about the impact on REMS for products that have medication guides? Looking through the FDA’s database of approved Medication Guides, what’s clear is that there will be one critical problem for companies converting existing Medication Guides to REMS: Deciding what information to keep. Almost universally, existing guides are several pages – generally around 5 pages, according to our quick and unscientific review. The PMI, meanwhile, is supposed to be just one page in length. If FDA does propose to replace existing Medication Guides for the specified drugs and biologics with PMI, we expect that it may receive some pushback from patient safety advocates concerned about a lack of access to critical information. After all, the PMI proposed rule right now effectively treats drugs with complex and critical side effects the same as far safer drugs that just happened to be administered on an outpatient basis.
- What’s an “outpatient” drug? For a rule that is exclusively aimed at drugs that are dispensed on an “outpatient” basis, there’s one glaring omission from the list of defined terms in the proposed rule: Outpatient. Sure, you can mostly understand its meaning by reading other defined terms, but we still think it’s somewhat unusual that FDA uses the term 63 times over 115 pages and somehow doesn’t define it.
- The proposed rule comes as the FDA is looking at making patient-facing labeling friendlier across the board. The FDA has been increasingly focused on making sure that the information provided to individuals (including patients and caregivers) is useful for those populations. The FDA’s Office of Prescription Drug Promotion (OPDP), which researches the ways that different segments of the health care system interpret and think about information about prescription drugs, has recently been increasingly focused on the way that information specifically given to patients or caregivers are considered by those stakeholders. In addition, the agency is working on a proposal that would allow certain digital tools to be considered part of a drug’s labeling, known as Prescription Drug Use Related Software (PDURS), which is due out later this year an intended to help patients better understand their medications by leveraging technology (e.g., mobile apps) as an extension of labeling. On the non-prescription side, in June 2022 the FDA released a long-awaited proposal to allow for more flexibility in over-the-counter drug product labeling (also initially announced in 2017, like the PMI rule), that would help OTC product sponsors provide more dynamic options for providing patient information through an Additional Condition for Nonprescription Use (ACNU). While these research projects and policies cover a range of topics, they all have a key unifying theme: Patients and caregivers need to receive better information about drug products, that is designed with their needs in mind, not simply more information.