505(b)(2) PREPARATION AND SUBMISSION
In the ever-competitive marketplace(s) you compete in, exclusivity is often the only way to secure a singular advantage. 505(b)(2) offers an opportunity for developers to secure up to three, five or — for orphan products — seven years of exclusivity. Moreover, there are intricacies that allow for extended exclusivity (e.g., if the FDA requests pediatric studies on a new drug, the drug may be eligible for six additional months of exclusivity). DSI is experienced in attaining and winning every type of 505(b)(2) exclusivity and tailors development programs for the life of products to maximize commercial opportunity.
"BIOSIMILARS" UNDER THE 505(b)(2) PATHWAY
Prior to the passage of the BPCIA, the 505(b)(2) pathway, could be used to obtain approval of certain follow-on biologics. Like the 351(k) pathway, the 505(b)(2) pathway allows the applicant to rely on the safety and effectiveness data of a previously-approved product. The 505(b)(2) pathway, while largely used to obtain approval of small-molecule drugs, has been used on several occasions to obtain approval of biologics that are similar to the reference product and marketed as biosimilars in Europe.
What are the differences between the 505(b)(2) and 351(k) pathways?
Fundamentally, the 351(k) pathway concerns products that are regulated as biologics under the BPCIA, while the 505(b)(2) pathway concerns products that are regulated as drugs under the Food Drug & Cosmetic Act (FD&C). The pathways involve vastly different regulatory frameworks.
A GUIDE TO THE 505(b)(2) REGULATORY PATHWAY
A company may wish to create a new dosage form that is faster acting, combines two active ingredients in a novel way, or provides a route of administration or mechanism of drug delivery that patients or doctors prefer over previous versions. Also, a company may wish to seek approval for a new indication for an already-approved drug or carry out an Rx-to-OTC switch. Such new products often contain well-understood active ingredients that are present in existing, approved drug products (reference drugs); so, companies must only create a bridge between what is already known about the previously approved reference drug and the novel drug product or indication. The 505(b)(2) NDA pathway makes this possible. In Europe, a regulatory approval route similar to the 505(b)(2) pathway is the hybrid procedure.
How to Achieve Success for 505(b)(2)
One of the greatest mistakes that the Sponsor of a 505(b)(2) can make is to have an unsuccessful Pre-IND meeting. For many companies, obtaining FDA buy-in and successfully activating an IND are critical steps for securing investments. The 505(b)(2) process. Here’s how:
- The 505(b)(2) process begins with the pre-IND meeting with the FDA, then moves to formulation development (and nonclinical studies, if necessary) and then to the IND filing.
- In proposing a 505(b)(2) development strategy in a pre-IND meeting, the objective is to gain FDA input and concurrence with the nonclinical studies, with the chemistry, manufacturing, and controls (CMC) strategy along with the clinical research plans in a way that minimizes the number of new studies required and data necessary.
Timing of CMC work differs
For a 505(b)(2) product, the clinical trial materials for Phase I studies (often demonstrations of clinical bioequivalence) must be representative of the commercial manufacturing process, including packaging. In general, the three stability batches that will be used for shelf-life determinations are also prepared at this time. As a consequence, a good deal of CMC work must be invested prior to initiating even Phase I studies.
- Formulation Development: The CMC strategy is paramount in a 505(b)(2) submission because frequently the formulation, components and/or the active pharmaceutical ingredient (API) has been altered compared with the reference product, and the effect of each of these changes must be evaluated to assess any effects on safety and efficacy. However, comparing the new, proposed formulation with that of the reference drug (via bridging studies), explaining the rationale for the changes, and establishing that the new drug product is safe, pure and potent can usually form the basis for the pharmaceutical development section of a 505(b)(2) NDA.
- Phase I: The specific type of Phase I bridging study for a 505(b)(2) product depends on the nature of the dose form and the reference product. For an immediate-release oral dosage form, for example, the Phase I study is often a fasting, single-dose, crossover bioavailability/bioequivalence (BA/BE) study in healthy human volunteers in which the new drug product is compared with the reference product using pharmacokinetic assessments. In some cases, the requirement for an in vivo bioequivalence study can be waived via a formal request called a biowaiver.
- NDA Submission: The success of NDA preparation and submission depends heavily on up-front planning and awareness of FDA expectations throughout the entire drug development process. A company may wish to create a new dosage form that is faster acting, combines two active ingredients in a novel way, or provides a route of administration or mechanism of drug delivery that patients or doctors prefer over previous versions. Such new products often contain well-understood active ingredients that are present in existing, approved drug products (reference drugs); so, companies must only create a bridge between what is already known about the previously approved reference drug and the novel drug product or indication.
The Biosimilars Pathway
Congress, through the Biologics Price Competition and Innovation Act (BPCI Act) of 2009, created an abbreviated licensure pathway for biological products that are demonstrated to be biosimilar to or interchangeable with an FDA-approved biological product. This pathway was established as a way to provide more treatment options, increase access to lifesaving medications, and potentially lower health care costs through competition.
FDA requires biosimilar and interchangeable biological products meet the Agency’s rigorous approval standards. That means patients and health care professionals will be able to rely upon the safety and effectiveness of the biosimilar or interchangeable product, just as they would the reference product.
The 505(b)(2) pathway offers marketing approval for certain “biosimilars” – at least for now. In addition to a more predictable regulatory pathway, the litigation pathway for 505(b)(2) products is more familiar and predictable as well.