FDA Approval of Biologic Drugs under 505(b)(2) Expected to Increase

By James DeGiulio --

Choosing the appropriate regulatory pathway for biologics drug approval by the U.S. Food and Drug Administration has historically not been a strategic decision to be made by drugmakers.  In most cases, only one pathway is applicable to the particular drug product.  The traditional NDA 505(b)(1) path is for new drugs, the abbreviated new drug application (ANDA) path is for generics, and the 505(b)(2) path covers the middle ground, including reformulations and combinations of existing drugs.  Most new biologic drugs today are approved via a Biological License Application (BLA) rather than an NDA, and are subject to the provisions of the Biologics Price Competition and Innovation Act (BPCIA).  Historically, however, approval of biological products as "drugs" required a NDA filing under 505(b)(1), even if the drug was "generic" and based on a reference biological drug product.  A recent run of FDA approvals for "generic" biologic drugs

under 505(b)(2), including Sandoz' recombinant human growth hormone Omnitrope, is drawing attention from biotech drugmakers and may influence their choice of approval pathway, according to an October 10 article published in BioWorld.

The 505(b)(2) pathway, often referred to as a "paper NDA," is an attractive alternative for companies seeking to enter a drug market, for it allows a drugmaker to incorporate preexisting data, including data from expensive clinical studies, into its NDA by reference.  This results in a substantial savings in approval costs; the average 505(b)(2) approval costs $3-7 million dollars, which is far less than the estimated $1.3 billion to bring a new drug to market under 505(b)(1).  However, the 505(b)(2) pathway also comprises uncertainty, as approval requirements are determined on a case-by-case basis and can sometimes require extensive trials despite the availability of preexisting data.

Despite this uncertainty, producers of "generic" or "follow-on" biologic drugs and prodrug compounds are currently pursuing the 505(b)(2) pathway as a viable strategy for products in their pipeline, according to XenoPort Inc. CEO Ronald Barrett.  XenoPort's prodrug Horizant, used to treat restless leg syndrome, was recently approved by the FDA only after the drugmaker refilled its NDA under 505(b)(2) after receiving a complete response letter from its first 505(b)(1) filing.  However, others are skeptical that pursuing a 505(b)(2) path from the beginning would have saved XenoPort time or money.  Since the reference drug gabapentin was never approved for restless leg  syndrome, it is possible that more extensive clinical trials than is appropriate for a 505(b)(2) NDA would have been required.  Nonetheless, last month XenoPort filed for approval of Horizant under 505(b)(2) in postherpetic neuralgia, conducting just one Phase Ill trial to support its bid for approval, and also has a 505(b)(2) filing planned for a multiple sclerosis drug.

Of course, if it is available, the 505(b)(2) path is not always the best choice for all prodrugs and follow-on biologic drugs, for there are tradeoffs in the time and money saved with the 505(b)(2) pathway.  Most of the drugs approved via the 505(b)(2) pathway are reformulations such as liposomal encapsulations, and are not blockbusters.  In addition, these reformulations often get just three years of exclusivity.

Today, specialty pharma and drug delivery companies are most active in 505(b)(2) filings, but this is expected to change soon.  As biologics continue to account for an increasing number of new therapeutics approved, utilization of the BPCIA biosimilar pathway will increase, and fewer standard ANDA opportunities will become available to generic drugmakers.  In addition to biosimilars, generic companies are moving into follow-on biologic drugs, and will further look to drug delivery and other ways to reformulate existing drugs.  To compete, brand biotech and pharma companies will be forced to follow the generics in ramping their own reformulation and drug delivery efforts, perhaps calling upon 505(b)(2) for approval.

Comments

[Ronald A. Rader]

It should be noted that only a small portion of biopharmaceuticals and absolutely no products regulated as biologics are approvable through 505(b)(2)! Thus, the title and most use of "biologics" in this article are wrong. 505(b)(2) only applies to those relatively few, generally simpler (e.g., insulin, somatropin, calcitonin) biopharmaceuticals regulated as drugs, not biologics, largely due to grandfathering and historical regulation of similar (including animal- and human-derived) products as drugs.

Biologics now have their own biosimilar approval pathway.