Kari Miller, Regulatory and Product Management Leader, Pilgrim Quality Solutions
In the first two parts of this series, Combination Products: Past, Present and Future, we reviewed the historical path of combination products and the complex road to regulatory and quality compliance for this product category, leading up to today’s current state. It is important to recall that Combination Products is its own product category, independent of Medical Device, Drug, and Biologics. We discussed that fact that combination products have their own cGMP (21 CFR Part 4), but the cGMPs of the constituent parts (i.e. devices, drugs, and/or biologics) must not be neglected either.
While reviewing the current regulatory and compliance environment for combination products, much clarity has been added with the establishment of The Office of Combination Products (OCP) and the definition of its role. The OCP is responsible for not only the combination product classification and agency assignment, but it coordinates and oversees the regulations regarding combination products. It also resolves disputes between agencies and/or Sponsors.
Early in the product development lifecycle of a combination product, the manufacturer must establish the product’s classification by determining its Primary Mode of Action (PMOA) in accordance with 21 CFR 3.2(m). This determination results in the product’s assignment to the appropriate primary FDA center: Center for Drug Evaluation and Research (CDER), Center for Devices and Radiological Health (CDRH), or Center for Biologics Evaluation and Research (CBER).if the In cases where the PMOA is unclear, Sponsors may request support from the OCP by submitting both a Pre-Request for Designation (Pre-RFD) and a Request for Designation (RFD) early in development to ensure accurate designation.
Finally, in Parts 1 and 2 of this series, we reviewed one of the major influencers of the current regulatory and compliance status of combination products by reviewing the 21st Century Cures Act Section 3038, and its role in speeding the assignment of the primary agency center and primary mode of action.
Combination Product Market
More and more manufacturers of pharmaceuticals or medical devices are developing technologies that straddle the traditional definitions of a drug or medical device, and the financial impact of this segment is shaking up the marketplace.
The global combination products market in 2017 was reported as $30.5 billion USD and it’s predicted to reach an estimated value of $115 billion USD by 2019, with many predicting it will achieve $178 billion USD by 2024.
Geographically, North America dominated the global combination products market and it’s expected to continue that lead in terms of revenue. However, Asia-Pacific is considered the most lucrative growth market for combination products due to the increase in incidences of cardiovascular diseases, diabetes-related disorders, and obesity expected in the region through 2019.
Global Market Growth Drivers
From a universal, worldwide perspective, high incidence rates of chronic pain-causing diseases, along with the rapidly aging world population, are the key drivers for the global combination products market. Other key market growth drivers include:
- Government and NGO initiatives to promote drug delivery implants
- Rising number of interventional cardiologists
- Increase in the demand for minimally invasive surgeries
Innovation in Combination Products
According to global industry analysis combination products are emerging as innovative medical products due to their contribution to advancing medical care, and are thus expected to have major impact in the coming years with the following advantages:
- Reduced occurrence and intensity of adverse side effects
- Improved patient compliance
- Controlled release/administration of drug
- Targeted drug delivery for uniform drug concentration
- Reduced infection rates
These anticipated impacts are highly appealing and are driving the demand for combination products, so it’s inevitable product innovation is occurring at an increasing rate. For example, in the future, the introduction of biodegradable drug delivery will provide further growth opportunities for various drug-device combination products. This technology is most appealing to patients with ongoing medical conditions that require consistent treatment with daily injections or weekly procedures, a more commonplace circumstance with the aging world population. Biodegradable drug delivery technologies improve patient compliance by reducing the tedium and fatigue that comes with daily treatments. With the growing trend in at-home healthcare, treatment compliance and consistency is paramount to the patients’ health and safety.
While everything is looking up within this market segment, one of the major growth constraints for combination products will be the potential for product recalls resulting from adverse side effects in patients. This will be one of the major challenges for the industry to address as the reduction of adverse side effects is often one of the major goals for a combination product. In particular, minimization of adverse side effects will be key to the success of the expanding at-home health care arena.
Future Regulatory and Compliance Initiatives
Over the coming years, the Office of Combination Products (OCP) will be developing IT infrastructure to better support inter-center coordination for pre-market review and enhanced information sharing with access to post-market safety reporting (PSR) data. This advancement is required to meet timeframes required for remediation and problem resolution between Sponsors, OCP and the primary agency centers.
Enforcement activity around 21 CFR Part 4 compliance can be expected to increase in the coming years. With the most recent updates to 21 CFR Part 4 being issued in January of 2017, the primary agency centers (CDRH, CDER, and CBER) have had some time to get their arms around the new cGMP guidelines for combination products, and the OCP is working with the primary agencies to expand their understanding and application of the cGMP for combination products.
Finally we can expect to see the FDA continue to develop and clarify regulations around specific combination products as the Agency uses more teams of investigators to support combination product inspections.
The Life Sciences industry finds itself in an interesting place. Innovation is occurring in combination products, and the category is a major industry growth segment. Staying abreast of the regulatory and quality compliance requirements of combination products will continue to be a challenge as the FDA’s management activities have demonstrated. The best course of action for anyone who is developing, or intends to develop a combination product is to engage with the OCP early — and often — in the development cycle.
Whether your product is going to be marketed in the US (FDA), Australia (TGA), Europe (EMA), the UK (MHRA), or the rest of the world (ROW), it’s critical to understand that the industry’s primary focus is promoting and protecting public health. As such, the proper management of combination products, and engaging and working with the regulators as trusted partners, are essential to achieving the common goal: patient health and worldwide public safety.
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