Opinion: Boehringer Ingelheim May Win Regulatory Language Change Despite Weak Argument

Boehringer Ingelheim (BI) is one of the most prestigious biopharmaceutical companies developing biosimilars in the United States. BI has 1 monoclonal antibody product (adalimumab, Cyltezo) licensed as a biosimilar and several other products under development.

On December 2, 2020, the company filed a citizen's petition asking the FDA to change its interpretation of the term strength in the Public Health Service Act (PHS) to allow biosimilar developers more flexibility in developing formulations and enable active drug delivery in smaller volumes. The FDA has accepted the petition for review and will likely take a few months to respond.

I have reviewed the BI petition and conclude that BI has overlooked some compelling arguments that could have helped persuade the FDA to make this pivotal change. I am presenting my analysis of this petition along with alternative arguments to support the petition.

The focus of the BI petition is to address the technical and legal issues that biosimilar developers face in meeting the definition of a biosimilar product under the Biologics Price Competition and Innovation Act (BPCIA), which is authorized by the PHS Act and states that the “route of administration, the dosage form, and the strength of the biological product are the same as those of the reference product.”

BI's Requests

The BI petition suggests the FDA take the following actions:

• Interpret the term strength as it is used in section 351(k) of the PHS Act to mean the “total drug content” in the drug container (eg, single-dose vial, prefilled syringe) regardless of concentration or total volume.
• Revise agency guidance documents on biosimilar development, interchangeability, and the BPCIA to be consistent with this interpretation.
• Apply this interpretation to pending and approved 351(k) applications, amendments, and supplements, including advice provided during biosimilar biological product development meetings and in review correspondence, such as complete response letters.

The issue of product concentration arises mainly in the formulation of monoclonal antibodies (mAbs) where the dosing is higher. The first generation of mAbs were for intravenous (IV) infusion because the larger injection volume made self-administration impractical. Traditionally, the concentration of mAbs ranges from 4 to 200 mg/mL. High-concentration products can be injected subcutaneously, increasing patient compliance and reducing hospital patient visits. However, a high protein concentration (≥ 50 mg/mL) creates formulation challenges with regard to colloidal properties and physical and chemical protein stability, and resolving these issues can allow the innovators to secure additional formulation patents that extend their market exclusivity. A good example is the new Humira (adalimumab) presentation, which is citrate-free and twice as concentrated as the original product.

Although the definition of the administration route and the dosage form is clear, the strength definition is not. According to section 351(k)(2)(A)(i)(IV) of the PHS Act:

1. In general, a sponsor of a proposed biosimilar product or proposed interchangeable product with an “injection” dosage form (eg, a solution) can demonstrate that its product has the same strength as the reference product by demonstrating that both products have the same total content of drug substance (in mass or units of activity) and the same concentration of drug substance (in mass or units of activity per unit volume). In general, for a proposed biosimilar product or proposed interchangeable product that is a dry solid (eg, a lyophilized powder) from which a constituted or reconstituted solution is prepared, a sponsor can claim that the product has the same strength as the reference product by demonstrating that both products have the same total content of drug substance (in mass or units of activity).
2. Although not a part of demonstrating the same strength, if the proposed biosimilar product or proposed interchangeable product is a dry solid (eg, a lyophilized powder) from which a constituted or reconstituted solution is prepared, the 351(k) application generally should contain information that the concentration of the proposed biosimilar product or proposed interchangeable product, when constituted or reconstituted, is the same as that of the reference product when constituted or reconstituted.

Weaknesses in the Argument

It is noteworthy that these guidelines were moved from final guidance to draft guidance in 2018, a sign that the FDA has not confirmed the definition of strength. BI argued that even though the definition of strength in the revised guidance is moved from final to draft, this has little meaning because the context remains the same. I disagree with this assertion. The FDA will not move a guidance from final to draft without having the intention to accept changes. The FDA is willing to accept arguments relating to the definition of strength.

BI claims that the FDA’s interpretation of strength is unreasonable because it encourages, or at least permits, brand sponsors to use minor concentration changes as an anticompetitive tactic to prevent biosimilar and interchangeable biological products from coming to market, thereby depriving patients of access to more-affordable biological products, contrary to the goals of the BPCIA. I disagree with this conclusion because it is not the FDA's role to consider the “accessibility” issue. The reference product developer must present a sound and rational argument before the FDA will allow the change—it can never be an unjustified proposition. This argument of BI’s reduced the strength of their case for a different interpretation.

BI further misunderstood the issue when they claimed that the FDA should not treat lyophilized products differently when defining the concentration. A lyophilized product is diluted to a similar concentration as the reference product before administration, so it is appropriate if the lyophilized powder quantity's active content is different.

BI’s case is significantly weakened by the following statement in the petition:

Finally, even assuming Boehringer Ingelheim’s other arguments do not compel an interpretation of “strength” to mean only “total drug content,” FDA should still exercise discretion to change its policy because that definition better promotes the goals of the BPCIA, and there are no countervailing regulatory interests that outweigh this important benefit. Accordingly, FDA should reverse this policy and interpret “strength” to mean “total drug content” without regard to concentration.

A regulatory agency does not make decisions based on any consideration other than a scientific justification. Although the purpose of the BPCIA is to introduce more-affordable products, it should not be expected that the FDA reinterpret the legislation based on soft considerations.

Although the FDA may allow a developer to commercialize a generic medicine before the patent expires on the originator product, the FDA will not do this for biosimilar producers, so it is up to the biosimilar developer to create a strategy to go around patents. As a patent law practitioner in this field, I see many opportunities to challenge these patents and, when this is not possible, change a product’s concentration and present it as a scientific argument rather than a strategy to obviate potential infringement of an intellectual property.

I agree with BI that a medicine's strength is the amount of active ingredient (ie, the drug that it contains). It has little to do with the volume of a liquid, so it is appropriate to vary the liquid injectable concentration.

In general, subcutaneous (SC) injections of mAbs are preferred over IV administrations from patient compliance and ease-of-use perspectives. For mAb-based therapies, typically, high doses in the range of hundreds of milligrams to a gram are needed per dose to achieve the desired therapeutic concentration. To administer such a high dose range in a volume less than 1.5 mL by the subcutaneous route, as required by FDA, these mAb formulations may need to be prepared at a concentration greater than 100 mg/mL. However, such highly concentrated mAb preparations can present challenges in the manufacturing process as well as for stability.

The solubility of mAbs can be enhanced by adding nonreducing sugars, such as sucrose, and kosmotropic salts, such as sodium chloride, which changes the conformation and provides preferential hydration. In recent years, many mAbs that were first approved as IV infusion solutions have been reformulated into higher concentration SC versions. Examples of therapeutic proteins that were originally formulated for IV administration and subsequently developed for SC administration include abatacept (Orencia, Bristol Myers Squibb), alemtuzumab (Lemtrada, Sanofi Genzyme), rituximab (MabThera, F. Hoffmann-La Roche), tocilizumab (Actemra, F. Hoffmann-La Roche) and trastuzumab (Herceptin, F. Hoffmann-La Roche). Rituximab (Rituxan) was initially approved for administration in non‐Hodgkin lymphoma at a dose of 375 mg/m² body surface area as 1.5‐ to 6‐hour IV infusions; the new formulation for SC administration is 12 times more concentrated.

Although the switch from IV to SC route does have some patient advantages, the more convincing reason for the originator products to switch the route of administration is to preclude biosimilars if the new formulation has patent protection. A patent search for “higher concentration monoclonal antibody” and “subcutaneous” yields more than 1000 patents.

The approach taken by BI to convince the FDA to allow different concentrations in the formulation is most likely aimed at reducing the injection volume, which is always desirable, either in IV or SC administration. The correct argument for seeking a reinterpretation of “concentration” should be based on the BPCIA description that a biosimilar product may have different inactive ingredients. When a formulation is changed for whatever reason, the optimization of the solution's thermodynamic stability may require a different concentration. So, if a different formulation is allowed, it should also be allowed to have a different concentration, higher or lower. This is a scientific suggestion that should strongly support the request for clarification in the guidance. Support of a formulation with a different concentration can be provided from the demonstration of the comparable stability and bioavailability of the biosimilar candidate with the reference product.

I anticipate that the FDA will decide in favor of the BI petition, despite the weak approach taken by BI.