FDA approval options for follow-on biologics
Follow-on biologics, new versions of previously approved biopharmaceutical products intended to mimic the therapeutic effect of the approved product and compete for market share, have been approved by the FDA either as completely new biological products requiring submission of a full Biologics License Application (BLA) or under section 505(b)(2) of the Federal Food Drug and Cosmetic Act.
With the passage of the Biologics Price Competition and Innovation Act (BPCI) in 2010, follow-on biologics manufacturers were presented with a third, abbreviated, pathway for approval. Each alternative has specific requirements and certain advantages and disadvantages compared with the others. Entities considering bringing a follow-on biologic to market must carefully consider the relative pros and cons of each route in determining which is best for a given product.
While the cost of clinical trials and the possibility of data or market exclusivity will often be the primary considerations, manufacturers should also consider factors such as the nature of differences between the follow-on product and the approved product, the likely potential market share the follow-on will capture and the desire for patent certainty at the time of launch.
Biosimilars (including interchangeables)
The BPCI introduced, for the first time ever in the US, an abbreviated approval pathway for follow-on biological products deemed to be ‘biosimilar’ to a previously approved biological product. In order to qualify as a biosimilar, the biosimilar applicant must demonstrate that their product is 1) highly similar to the reference product, i.e. the approved product, notwithstanding minor differences in clinically inactive components, and 2) there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity and potency.
A primary advantage of the new abbreviated pathway for biosimilars is that the biosimilar applicant is able to rely on the safety and/or effectiveness data of the previously approved biologic (the reference product). In theory, this will significantly reduce the amount of clinical data that must be submitted to obtain approval, and therefore reduce the time and expense required to obtain approval of the biosimilar product.
Moreover, biosimilar products that meet the heightened standard of being interchangeable with the reference product are deemed automatically substitutable with the reference product and are entitled to a limited period of post-approval market exclusivity.
Yet another advantage of the biosimilar route is that the BPCI provides for a patent dispute resolution procedure that provides the biosimilar applicant with a statutory mechanism to challenge the reference product sponsor’s patents and obtain some degree of patent certainty prior to actual launch of the biosimilar product.
The biosimilar route, however, also has a number of limitations. First, the BPCI is new and, at the time of going to press, the FDA had not yet issued any regulations to implement the law. Second, in contrast to the abbreviated approval pathway for small molecules established by the Hatch-Waxman Act, the biosimilar pathway will require, at least for the time being, significant clinical trials to be conducted by the applicant.
The regulatory details of the pathway remain to be defined and the anticipated reductions in the amount of clinical data and time needed to obtain approval remain unclear.
Another limitation is that the period of market exclusivity provided by the statute is only available to the first biosimilar product deemed to be interchangeable with a given reference product (as opposed to the first product that is merely biosimilar).
Moreover, the exclusivity only prevents the approval of other interchangeable products during the exclusivity period. It does not prevent the entry into the market of other biosimilar products. Also, only interchangeable products can be substituted for the reference product without the intervention of the healthcare provider who prescribed the product.
Moreover, the BPCI establishes a 12-year period of data exclusivity for the reference product, which bars approval of any biosimilar product for a period of 12 years after the approval date of the reference product. Finally, the biosimilar pathway is not available for follow-on products that differ from the reference product in some aspect of safety, purity or potency.
505(b)(2) Approvals
Section 505(b)(2) is actually a provision of the Federal Food Drug and Cosmetics Act, and is one of three established types of new drug application (NDA). It allows a sponsor of a new drug to rely, at least in part, on the FDA’s safety and effectiveness findings for a previously approved drug. The intent of the statute was to avoid unnecessary duplication of preclinical and certain human studies.
Nevertheless, the applicant must still provide any additional preclinical or clinical data that the FDA deems necessary to ensure that the differences from the reference drug do not compromise the safety or effectiveness of the follow-on product. Although 505(b)(2) is a type of NDA, it has been used in the US to obtain approval of follow-on biologics where limited clinical data is necessary to show that the follow-on is the same as the reference product.
The 505(b)(2) approval route can be used for a wide-variety of products, particularly those that represent a limited change from a previously approved drug. Traditionally, typical changes to the reference product allowed under 505(b)(2) include: changes in formulation, dosage strength or form, combination, or slight modification of the active ingredient.
A major benefit of the 505(b)(2) pathway is the potential avoidance of significant clinical trials. Another advantage is that it is possible for products approved under 505(b)(2) to receive an AB rating and be automatically substitutable for the reference product.
Also, a 505(b)(2) applicant can obtain three years of market exclusivity for their product if one or more of the clinical investigations, other than bioequivalence studies, was essential to approval of the application. Moreover, an applicant can get five years of exclusivity for a new chemical entity and may also be eligible for orphan drug exclusivity or pediatric exclusivity.
The major drawback with the 505(b)(2) application is that it is only available for biologics in limited circumstances. Specifically, the BPCI act contains provisions that phase out 505(b)(2) as an approval pathway for biologics over time. 505(b)(2) can be used to seek approval for a biologic only until March 23, 2020, and only for follow-on biologics of a class for which a product has already been approved under 505(b)(2).
Another drawback is that the nature of the ‘additional information’ needed by the FDA to determine whether the differences between the follow-on product and the reference product are insubstantial need to be determined empirically in each case. This can lead to significant uncertainty in terms of approval time and cost for the 505(b)(2) applicant.
Finally, the filing or approval of a 505(b)(2) application may be delayed due to the patent or data exclusivity protection on the reference product, and 505(b)(2) applicants must include patent certifications in their applications and must also provide notice of certain patent certifications to the NDA and patent holders of the reference product.
Biobetters
A ‘biobetter’ or ‘biosuperior’ is a type of follow-on biologic that is distinct from and improves on the reference biologic, and is capable of having clinical and market advantages over the reference biologic. For example, improvements can be made that reduce immunogenicity or provide greater potency than the original molecule. Biobetters are attractive because the targets have already been validated by other biotherapeutics.
For example, the presence of a validated target therapeutic antibody against CD20, epidermal growth factor receptor (EGFR) or tumor necrosis factor alpha (TNFα) only adds to the motivation to develop improved versions of these established antibodies. Approval of biobetters will require clinical trials, however, and there will likely be large competition with many companies targeting the same therapeutics.
Since clinical trials will be involved, data exclusivity will be available for biobetter applicants. Although it is unclear as to the amount of data that will be needed, it will presumably be more than that needed for a biosimilar submission. This will result in higher costs. Additionally, as opposed to the patent provisions in the Biosimilar Act, there is no statutory procedure to challenge patents prior to launch, thus there is a higher degree of uncertainty with respect to patent litigation.
Conclusion
With the passage of the BPCI last year, parties seeking to obtain approval of a follow-on biologic product now have three possible options to reach this objective.
Each route offers distinct advantages and disadvantages. Follow-on developers must take into consideration factors such as desired time and cost to market, possible data exclusivity for the reference product, the potential for market exclusivity offered by the biosimilar and 505(b) (2) pathways, degrees of differences between the follow-on and reference product, and the desire for patent certainty at time of product launch, in concluding which option is best for them.
Paul A. Calvo is an associate at Sterne, Kessler, Goldstein & Fox PLLC. He can be contacted at: pcalvo@skgf.com
Timothy Shea, Jr is a director at Sterne, Kessler, Goldstein & Fox PLLC. He can be contacted at: tshea@skgf.com
