Since the beginning of the 21st century, we‘ve seen a massive upsurge of innovative combinations between drugs, devices, biologics, and most recently software and AI. Drug-eluting implants, ingestible electronics, smart pacemakers, insulin pumps, patches and all sorts of wearables that monitor, record, analyse and transmit data among multiple parties within increasingly complex infrastructures.
Hybrid medical products are creating paradigm shifts in medicine and healthcare with faster, cheaper, safer and more effective treatment programmes. However, whilst research keeps accelerating and novel tech multiply as you read this text, the FDA is increasingly left struggling to decide how exactly to regulate them.
Medical combination products, as they‘re officially termed, are not a recent phenomenon. Nor are the challenges they pose to traditional regulatory frameworks. Yet, the FDA has not to this date designed and launched a single market approval pathway for this unique category, but has been trying to fit it into its existing structures. As a result, the real issues associated with rapid technology development are not being adequately addressed, and innovations that have the potential to make treatments more affordable, effective and safe end up being slowed down rather than facilitated.
The first medical combination product that got FDA approval was the drug-eluting stent. It was first implanted into a human patient back in 1999, and became commercially available between 2002-2004, marking a historic revolution in interventional cardiology.
In December 2002, the FDA established a new entity to regulate such innovations – the OCP (Office of Combination Products), and rolled out a a definition whereby a combination product is any product which „constitutes a combination of a drug, device or biological product“. The newly established body complements the existing CDER (Center for Drug Evaluation and Research) and CDRH (Center for Devices and Radiological Health) sub-agencies, which are responsible for the regulation of drugs and devices, respectively.
Rather than serving as a single review point for the new product category in a similar way to the CDER and CDRH, however, the OCP has a purely administrative function – to assign a combination product for premarket review and postmarket regulation to either the CDER or CDHR based on a „primary mode of action“, and to resolve any internal disputes between or within the two centres regarding these processes. The primary mode of action is defined as “the single mode of action of a combination product that provides the most important therapeutic action.”
In the case of the drug-eluting stent, the OCP determined that the primary mode of action is that of a device, and assigned it for review to the CDHR. The CDHR classified the stent as Class III, which required an investigational device exemption and PMA. Regardless of its device status, though, due to the fact that the stent was coated with a drug there were significant concerns regarding safety and efficacy, which necessitated regulation from the CDER as well. Dual regulations and internal bureaucracy thus contributed to the considerable delay of the market approval.
Another 4 years passed until second generation drug-eluting stents became publicly available. They did not enjoy a shorter time-to-market, even though they were not fundamentally different to first generation ones in terms of design and function.
Nowadays, there are plenty of predicate drug-eluting stents on the market that could support a Class II downgrade, but the FDA still classifies these devices as Class III. Whilst the agency surely has good reasons for maintaining such stringent regulations, this case study should serve to inform designers and manufacturers about indicative timelines and regulatory hurdles they can expect to face when it comes to bringing combination products to market.
Despite all challenges, within 5 years of FDA‘s first approval, drug-eluting stents became a multi-billion dollar vertical market within medical implants. The industry was boosted even further in 2008, when the FDA issued a dedicated document providing detailed regulatory guidance on coronary drug-eluting stents.
In November 2017, the FDA approved the world‘s first smart pill, a tablet equipped with a sensor microchip that monitors whether bipolar disorder or schizophrenia patients have taken their medication. The sensor is ingested with the tablet and sends information to a wearable patch, which then transmits it to a smart phone app patients can use to track their treatment. If they wish, patients can provide access to the data gathered by the sensor to their doctors, caretakers or family.
As the system‘s primary mode of action was determined to be that of a drug, it was reviewed and granted market approval by the CDER. The sensor technology and patch designers claim that the low manufacturing cost and wide compatibility of the microchip are not only an appealing alternative to conventional drug treatment programmes but can open up a $100 billion industry niche.
Whilst CDER has the authority to regulate similar drug-delivery systems, it can also apply device regulations when necessary. Therefore, even though CDER would generally be the lead centre for the review and approval of smart pills, the process might as well involve CDRH regulations and authorities.
In an attempt to navigate intense scrutiny combined with relative lack of clarity and certainty more easily, smart pill developers thus tend to submit their tech to multiple approval processes simultaneously so that device and drug components can be regulated separately. If the FDA issues a dedicated regulatory guidance on smart pills just like it did with drug-eluting stents, we will surely see this novelty explode into a multi-billion dollar market, too.
End of part 1
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