Do I need one?

When do I need to start developing a REMS and how long does it take?

Who needs to participate in the REMS process?

How do I decide which risks go into the REMS and which don’t?

What information goes into the Proposed REMS and what goes into the Supporting Document?

How complete does the REMS documentation need to be?

How do I decide which tools are needed?

Do I need to pretest the tools?

What assessment interval should I propose? What performance threshold level is acceptable?

How do I measure pharmacist compliance with Medication Guide distribution?


Do I need one?

About 33% of new molecular entities approved since FDAAA became effective on March 25, 2008 have required a REMS, and 80% of these required a Medication Guide with a REMS assessment. So, REMS are becoming more common than in the past, although they are not yet “the rule.”

The fundamental question to answer before you can determine if your product needs a REMS is whether FDA will consider labeling alone to be sufficient to ensure that benefits outweigh risks. Clues to the answer can come from FDA’s RiskMAP (REMS predecessor) guidance, precedents from what was required for other products, communications with FDA, and other products in the same or similar medication class.

As a general statement, risks such as QT prolongation, hepatotoxicity, blood dyscrasias, and fetal abnormalities have often required such programs. Risks such as drug-drug interactions, psychiatric effects, toxic rashes, certain lab abnormalities, and use in off-label populations have also required REMS on occasion.

For drugs intended to treat more serious conditions (e.g., chemotherapy for cancer) the risks of the underlying condition to some extent raise the tolerance for what is considered to be an acceptable risk or adverse effect of the medication. .

When do I need to start developing a REMS and how long does it take?

We like to think about 2 phases of writing a REMS for a compound in clinical development. The first starts prior to NDA or BLA submission and results in a REMS that is included as part of that submission. The documentation process for this phase may take 6-12 weeks, depending upon resources, the scope of the risk(s), and the degree to which more complex REMS elements are needed.

The second phase starts several months prior to product approval. The process is more complex, because it involves planning for REMS implementation, REMS assessment, and revisions based on Advisory Committee and FDA feedback. We recommend starting this process 4-6 months prior to the PDUFA date.

Of course, for products that are already commercialized, the receipt of a letter from FDA about the need for a REMS requires immediate action.

Who needs to participate in the REMS process?

Maybe the question should be “who doesn’t?” REMS development is perhaps second only to drug development and commercialization as a true multi-disciplinary effort. Expertise is needed from clinical, regulatory, legal, biostatistics, and marketing experts, while the documentation and preparations require drug safety, risk management, document writing, medical education, marketing research, graphics design, project management, and training staff.

The creation of a multi-disciplinary REMS Implementation Team is strongly advised which, together with project management, project coordination, and subject matter expertise, can help assure that nothing falls through the cracks, vendors are being coordinated, and the program is ready at product launch.

How do I decide which risks go into the REMS and which don’t?

Judgment is required but, in general, limiting the REMS to the one or two risks that cannot be addressed by labeling is advised. That being said, the availability of REMS communication tools is another opportunity to convey other important risk information to physicians, pharmacists, and patients. But the emphasis within the tools needs to be strongly focused on the REMS goal(s) and objective(s).

Beyond the question of which risks should be included in the REMS, there are other questions about “who”, “when”, and “what.”

One aspect of “who” has to do with whether a particular patient subpopulation has been identified who should not receive the medication or who should only receive it when the physician, pharmacist, and patient are able to comply with the REMS specifications. A second aspect of “who” is which physician or physicians should be prescribing the medication and whether they require any special training or certification. A third aspect of “who” is whether the pharmacist needs to play a role in controlling distribution of the medication and whether they require any special training or certification. A fourth aspect of “who” is whether the patient has a role in managing the risk, in which case a Medication Guide may be required.

“When” refers to whether or not there is a particular high-risk period or periods in the course of treatment during which the physician and patient need to be particularly vigilant. A risk that occurs only during the first 3 months of therapy may mean that the REMS program is limited to that particular period.

And the “what” has to do with what information needs to be communicated to physicians, pharmacists, and patients, in what sequence, at what frequency, and what other tools beyond communication and education may be needed.

What information goes into the Proposed REMS and what goes into the Supporting Document?

We look at the Proposed REMS as an overview of the REMS program that will be made publically available on the FDA website. In general, companies have chosen to limit the information in the Proposed REMS; for example, listing only the timetable for when assessments will occur, but not describing what will be measured and how.

The details behind the overview are generally described more fully in the REMS Supporting Document, including description of tools and protocols that may or may not be appendices to the Proposed REMS.

How complete does the REMS documentation need to be?

“Very”, especially if you are close to FDA approval. Prior to that point, a best effort towards completeness should be made, recognizing that some tools, protocols, and instruments cannot be finalized until final labeling is agreed. Such labeling-dependent content can be written provisionally, acknowledging that it may be subject to change.

How do I decide which tools are needed?

This is the “art” of risk management. Medication Guides are the most commonly used tool, but they will not be sufficient if physicians and/or pharmacists need to be educated and they will not be necessary if only physicians and/or pharmacists need to be educated.

For physicians, Communication Plan elements such as Dear HCP Letters and Physician Brochures are most commonly utilized, each providing different levels of detail. These may need to be further supplemented by enabling tools, algorithms/charts, case studies, and training programs.

FDA is increasingly looking for companies to commit to using multiple and alternative dissemination vehicles for such tools, including those can be tracked or audited.

Do I need to pretest the tools?

Companies often conduct baseline assessment of physician and patient comprehension of draft tools they have developed, giving them some confidence that they are on the right track and helping inform early improvements. That being said, it does not appear that baseline marketing research of tool comprehension is required.

More important to FDA is whether the tools are effective in imparting knowledge and understanding of the risks among targeted stakeholders. Companies may want to consider doing validation testing and/or early post-launch sampling to gauge whether this is occurring.

What assessment interval should I propose? What performance threshold level is acceptable?

It depends. FDAAA set a minimum assessment interval of 18, 36, and 84 months after REMS approval, but it appears FDA may be raising the bar by expecting more frequent testing in some situations. Initial assessment intervals of as early as 6 months and 12 months have increasingly been expected.

Answering the question about needing a threshold and at what level is complex. There was an expectation about thresholds in the RiskMAP guidance, but the jury is out on this until REMS guidance is published. It is an important decision, as it affects sample size calculations, statistical methods, and the information collected to inform program improvement.

A secondary question is “threshold for what?” If the measurement system is marketing research and the metric is patient understanding of the risk, then typical performance levels of 50-80% have been used as evidence that the program is effective. However, if the measurement system is claims data analysis and the metric is compliance with required lab testing, then the tolerance for non-compliance may be much lower and hence the threshold greater than 90%.

How do I measure pharmacist compliance with Medication Guide distribution?

In the absence of bar coding technologies to track Medication Guide receipt and dissemination by pharmacists, the best surrogate appears to be using downstream patient market research surveys to measure patient understanding of risks and how the patient received the information.

Questions can be posed within patient surveys that go beyond assessing their understanding to also asking which REMS tool or tools they recognize. Additional questions about whether they ever received a Medication Guide from a pharmacist and the percent of time they received a Medication Guide can also be posed.

 

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