As one-third of all medical products under development are combination products (meaning a combination of a drug, device or biologic), the US Food and Drug Administration (FDA) is undertaking the tricky task of modernizing the agency’s regulations around these products, which often present unique questions on risks and benefits, two FDA officials wrote in a recent commentary in Nature.
Nina Hunter, FDA’s associate director for science policy, and Rachel Sherman, FDA’s deputy commissioner for medical products and tobacco, point to two primary goals in modernizing the combo product regulations: Advancing an evidence-based approach to developing, evaluating and approving such products, and increasing operational efficiencies within FDA.
"Fortunately, the current regulatory framework has provided sufficient flexibility to accommodate new thinking. However, as we seek to understand how best to regulate combination products, it is crucial that we carefully examine the assumptions built into the FDA regulations, definitions, standards and policies to ensure that we can evolve towards a system that is well suited for its intended purpose," Hunter and Sherman write.
21st Century Cures
The recently enacted 21st Century Cures Act includes provisions related to combo products and the authors note that moving forward, FDA will have to find a way to "provide clear rationales for combination product designations, to ensure timely inter-centre coordination and to work with sponsors to help clarify and establish clear premarket and postmarket expectations."
In some circumstances, the new law authorizes sponsors of combo products to rely on FDA’s prior findings of safety or effectiveness or substantial equivalence, Hunter and Sherman note, adding that "FDA may conduct assessments of existing policies, procedures and information technology systems, and make necessary modifications; establish new tracking systems; and support programme implementation."
The agency also may need to develop new policy documents to implement the section of the new law related to combo product innovation, particularly as FDA’s review of such products "often involves multiple discipline review areas governed by different regulations."
In April 2016, FDA established a "Combination Product Policy Council," and sponsors of such products recently weighed in on what that council should focus its efforts on, including inter-center disagreements and implementation of the Cures Act provisions.
In August 2016, FDA launched a new pilot project on inter-center consults among FDA for combo products, and in January, FDA released final guidance describing and explaining the current good manufacturing practice requirements for combo products, as well as draft guidance on human factors studies for generic combo products.
As Hunter and Sherman note, the complexity and variety of these products "has created substantial challenges to efficient regulation of combination products as science and technology advances, and products evolve, often rapidly.
"From drug-eluting stents and nicotine patches, to polymeric hydrogel matrices that deliver controlled amounts of therapeutic agents, to balloon catheters filled with radioactive liquid suspensions, the universe and complexity of combination therapies is rapidly expanding, as are the technologies that underpin their manufacture," they write.
They also offer the examples of adjusting the microbiome as a novel therapeutic approach for the treatment or prevention of a wide variety of diseases, and the combination of live human or animal cells with device components to replicate the function of a failing organ.
"For example, early preclinical studies suggest a possible role for commensal Bifidobacterium to enhance anti-tumour immunity in vivo. Certain live biotherapeutic products (LBPs) are regulated as biologics. It may be possible to combine the use of a LBP with a cancer drug to achieve a synergistic anti-tumour effect," they write. And though the two therapeutics would normally be regulated under different pathways (as a biologic and as a drug) the two components are administered separately so they may not be a combo product, "depending on such factors as whether they are co-packaged or need to be used together to achieve a therapeutic effect," Hunter and Sherman write.