Combination products with digital interfaces. Antibody-drug conjugates. Complex drugs. Synthetic biologics. They’re all examples of how technology is expanding the ambit of what’s considered a drug beyond the current U.S. binary regulatory system of small molecules and biologics.
Such products could be the cog in efforts to lower U.S. drug prices through increased competition, as they don’t readily fit into either the generic or biosimilar universe. For instance, given that small-molecule drugs have different exclusivities than biologics, which exclusivities should apply to a product combining a small molecule and a biologic? And would a future follow-on of that product be a generic or a biosimilar?
Finding a regulatory answer to spur competition to new drug technologies will become even more troublesome as those technologies continue to evolve and the lines between small molecules and biologics or drugs and devices blur.
So far, rather than address the problem, lawmakers have focused on making the FDA force the square pegs of new drug technologies into one of the existing two round holes – preferably the one that will yield the most competition.
The challenge is in creating regulatory systems for a more diverse body of products, said David Fox, a Hogan Lovells partner and member of the law firm’s global life sciences management team. The “it’s this or that” regulation of drugs is not going to cut it in the future, he told BioWorld, especially as patients come to expect drug products with an interactive interface such as digitally enabled inhalers or smart injection systems.
What’s needed in the drug space is the flexibility that was built into the medical device regulatory system in the 1970s in recognition that the regulatory path had to encompass everything from tongue depressors to MRI equipment, Fox said. At that time, drugs were mostly limited to small molecules, with vaccines and blood products making up the biologics landscape. But today, the field is far more diverse, ranging from aspirin to CAR T-cell therapies.
A former senior lawyer at the FDA, Fox suggested adding one or two new categories to the agency’s regulatory pathways. One would be for nonbiologic, complex drugs. Rather than trying to hammer follow-ons of those drugs into the current generics pathway, which doesn’t call for clinical trials, the FDA should have a separate path for such generics.
Fox also recommended a regulatory pathway for combination products, as it can take years to fit an individual product with its device component into the current generic drug regime. As an example, he pointed to the difficulty in bringing a generic Epipen (epinephrine, Mylan NV) to market.
Feeling the heat
The suggestions are not new ideas, but they are taking on more urgency as Congress pressures the FDA to increase competition to help control prescription drug prices and as the agency, in accordance with the 2010 Biologic Price Competition and Innovation Act (BPCIA), prepares to deem proteins approved as new drug applications (NDAs) as biologic license applications (BLAs) on March 23, 2020.
That deeming will remove insulin and other proteins previously regulated as drugs from the small-molecule universe, making them off-limits for generic competition but open to biosimilar competition. That is, would-be competitors will have to develop biosimilars and also apply for determinations of interchangeability, a potentially more expensive development route that may call for clinical trials and, in the case of interchangeables, what could be extensive switching trials.
The BPCIA deeming provision created an unintended consequence for chemically synthesized follow-ons to insulins by putting them in a regulatory no-man’s land, as it would have prevented them from coming to market as biosimilars or interchangeables because they weren’t biologics. And since they wouldn’t be able to reference a product whose NDA had been deemed a BLA, they also would have been denied the generic pathway, which is limited to follow-ons listing approved NDAs. Thus, the only option would be for the synthesized polypeptides to be developed as new drugs, a much more resource-intensive path.
To correct the problem it had created and encourage competition, Congress expanded the definition of a “biological product” to include chemically synthesized polypeptides. Included in the fiscal 2020 spending bill passed in December 2019, the provision will enable the polypeptides to be approved as biosimilars.
It could be argued that the change is appropriate because the chemically synthesized products have a protein-like activity in the body. But on the other hand, the increased regulatory oversight of biologics versus small molecule drugs generally stems from the complexity inherent in the manufacturing of biologics from live biological systems. If a biologic is able to be manufactured through synthetic processes, the manufacturing concerns associated with traditional biologics manufacturing may no longer be such an issue.
Broadening the definition of a biologic could impact more than insulins and add more complexity to the regulation of complex drugs in the future. For instance, when the FDA was considering the first generics of Teva Pharmaceutical Industries Ltd.’s blockbuster multiple sclerosis drug, Copaxone (glatiramer acetate), the Jerusalem-based company said would-be follow-ons should have to undergo clinical trials following a development path akin to a biosimilar because the drug had a “protein-like structure.”
In responding to Teva’s citizen petition, the FDA acknowledged that Copaxone’s mechanism of action remained unknown to some degree and was incompletely characterized. As for atomic weight, the agency said Copaxone resembled a biologic, tipping the scales at 5 to 9 kilodaltons. (A biologic has a molecular weight of at least 5 kilodaltons.) And like a biologic, Copaxone varied from batch to batch.
Despite all that, the FDA followed the rigid line between small molecules and biologics laid out in the Hatch-Waxman Act and insisted on regulating Copaxone follow-ons as generics because the drug is a copolymer – not a protein. The provision in the spending bill softened that rigid line.
Meanwhile, a few weeks after opening the door for more complex drugs to be regulated as biologics, Democratic and Republican leaders of the House Energy and Commerce Committee wrote to the FDA questioning the regulatory lag in approving complex generics.
In a Jan. 17 letter to FDA Commissioner Stephen Hahn, they asked whether additional actions may be necessary to encourage generic development of the products, some of which are high-cost drugs.