Understanding the expectations and challenges
The pharmaceutical and medical device industries are seeing a substantial increase in combination products, and the related regulatory environment has been very dynamic. Recently, I was privileged to moderate a PharmaVOICE webinar on the latest U.S. FDA post-marketing safety reporting (PMSR) ruling and guidance. Expert panelists1 included:
- Nataraj Dhananjaya, Director, Safety Systems & Analytics Drug Safety & Pharmacovigilance for Alkermes
- Hemang Maisuria, Director, Medical Safety & Risk Management; Global Safety Lead for Agios Pharmaceuticals
- Susan Neadle, Senior Director, Global Value Chain Quality Design; Lead Design Council; Head Combination Products CoP for Johnson & Johnson and vice-chair for the FDA Combination Products Coalition Post-Market Safety Reporting Working Group
Defining Combination Products
The U.S. defines a combination product as a drug and device; a biological product and device; a drug and biological product; or a drug, device and biological product (21 CFR §3.2(e)). Each of these constituent parts is governed by a specific set of FDA regulations, and the combined regulations apply to the combination product. The FDA further sub-classifies combination products:
- Single-entity combination products – the drug and device, or the drug and biologic, integrally form one product that cannot be taken apart
- Co-packaged combination product – the drug and device form one package, but they are individual constituents
- Cross-labeled combination products – constituent parts whose labeling reciprocally designates the other constituent part to achieve the combined use
Primary mode of action is an essential concept. A mode of action (MOA) is the functionality or the contribution that a constituent part makes to the product’s function. The primary mode of action (PMOA) is the one that provides the most important functionality and dictates the review panel and reporting requirements.
Understanding Reporting Requirements
The goal of PMSR is to protect public health by ensuring that combination products are safe and effective. FDA 21 CFR §4B applies to the reporting of events – occurring inside or outside the U.S. (OUS) – against U.S. market authorization holder (MAH) combination products. July 31, 2020, was the official date for FDA PMSR compliance.
Addressing the Challenges
One PMSR challenge is same-similar reporting for OUS adverse events against that MAH’s U.S.-registered product having the same or similar constituent parts. Also, there is a five-day information-sharing requirement between constituent part applicants for a cross-labeled combination product when there is a death or serious injury (21 CFR §803.3) or an adverse experience (21 CFR §314.80(a) and §600.80(a)). Information must be shared whether the event is expected or unexpected.
Q: What are the considerations for device- and pharma-led companies?
A: Both drug and medical device businesses must understand the language. For example, serious injury and AE reporting could be interpreted differently for a drug vs. a medical device. Under 21 CFR 803, 806, the event requires reporting if it could possibly result in serious injury or death. On the drug side, AE reporting typically means something negative has already occurred.
Q: What is the reporting requirement regarding malfunctions?
A: Companies can provide separate reports for drug AE and device malfunction, but the FDA wants to avoid duplicate reporting. Companies can submit all reporting through the lead PMOA. For example, if a company has a drug-led combination product, the form for drug reporting will include a field to reflect the device code so that the company can include malfunction information. Reporting is required within 15 days.
Q: What information sharing is required for cross-labeled products?
A: Cross-labeled products, whose constituent parts reciprocally reference each other in their labeling, require each of those parts to achieve the combined-use intended purpose for the combination product. One interpretation is that the definition of reciprocal cross-labeling means the constituent parts make up the cross-labeled product; the parts labeled are the only ones impacted for reporting. Another perspective is that cross-labeling applies to cross-collaboration, where a company has one-way, designated labeling and still expects information sharing, with all AE and malfunction information passed on to collaborative partners.
Q: What process and system changes might be required?
A: Companies must understand the requirements, including the need to report AEs for combined products under malfunction reporting. Communication with and education of the safety team – and all departments involved – are critical. Quality management processes must capture product information plus malfunction reporting, and the data must meet quality requirements. The legal department should understand the regulatory and reporting changes, as these may impact partnership agreements. Finally, ensure that risk management tools and techniques are updated and tested.
Q: Where are more resources for information?
A: The FDA guidance document is comprehensive, including sample scenarios and FAQs. See FDA.gov for PMSR information, including helpful examples.
1Facts and opinions expressed by participants are not necessarily the opinions of their organizations or affiliates.