505(b)(2): Regulatory Pathway for New Drug

There are three FDA drug approval pathways for new drug applications and abbreviated new drug applications (ANDA) which are: 505(b)(1) NDA, 505(j) ANDA, and 505(b)(2) NDA. Out of these, the advantages of 505(b)(2) pathway are significant. The developer can reference safety and efficacy data in the marketing application of the innovator product rather than conducting costly preclinical and clinical studies. In addition, if clinical studies are required to convince FDA of the new product’s safety and efficacy, the clinical program is typically much less comprehensive due to the 505(b)(2) applicant’s ability to reference the innovator’s approved product.

505(b)(1) NDA

The 505(b)(1) is a full NDA application. Studies under the 505(b)(1) pathway are conducted by and for the sponsor and are the primary sources of data used to gain FDA approval for a new drug to be used by patients in the US. Of the three pathways, the 505(b)(1) requires the most time and resources.

505(j) ANDA

The 505(j) ANDA application is used to approve a generic version of a drug that is already on the market when the innovator drug is nearing patent expiration. The main requirements for an ANDA are demonstration of bioequivalence (BE) versus the innovator product and typically a food effect study if the new product is an oral dosage form.

505(b)(2) NDA

The 505(b)(2) incorporates elements of a full NDA (505(b)(1) and an ANDA (505) (j). In that way, the 505(b)(2) is often called a “hybrid application” – a blending of old and new drug information – in the context of seeking FDA approval of a new drug product. The 505(b)(2) is usually reserved for situations in which a modification (often an improvement) is being made to the innovator drug resulting in the creation of a whole new “drug product” with its own exclusivity. Not surprisingly, the European equivalent of the 505(b)(2) application is officially known as the Hybrid application.

A 505(b)(2) NDA contains full safety and effectiveness reports but allows at least some of the information required for NDA approval, such as safety and efficacy information on the active ingredient, to come from studies not conducted by or for the applicant. This can result in a much less expensive and much faster route to approval, compared with a traditional development path [such as 505(b)(1)], while creating new, differentiated products with tremendous commercial value.

Advantage of 505(b)(2)

More than 50% of approved drugs on the market contain poorly water-soluble APIs, which typically are associated with poor bioavailability, suboptimal drug delivery, ineffective drug efficacy, and side effects. This creates a huge opportunity in generating 505(b)(2) products, which address unmet medical needs by applying formulation technologies to overcome those difficulties. A key feature of the 505(b)(2) pathway is the 505(b)(2) sponsor can rely upon clinical data or literature produced by other companies.

The 505(b)(2) pathway allows manufacturers to acquire FDA approval without performing all the work required with a traditional NDA. The 505(b)(2) strategy can be an option to improve existing drug products with a new indication, dosage form, dosing regimen, strength, combination with other products, new route of administration, elimination of food effect, switching from a prescription drugs (Rx) to an over the counter (OTC), non-prescription product that differs from the OTC monograph, and orphan drug indications.

The 505(b)(2) NDA pathway can reduce drug development costs and accelerate the time to market by leveraging existing public data using clinical bridging and regulatory strategies. Whether or not a drug qualifies for the 505(b)(2) pathway depends on the active ingredient, drug formulation, clinical indication and other factors.

In short, 505(b)(2) provides a midway between 505(b)(1) and 505(j) in terms of the volume of new evidence required to be generated and submitted to the FDA. For sponsors and investors, 505(b)(2) pathway presents as a lower risk, time and cost option, and meantime a great market potential especially as many of the “blockbuster drugs” patents and other protected drugs are expiring. Above image is a schematic representation of the three FDA approval pathways.

A 505(b)(2) application can be utilized for a variety of different marketing applications, including:

• Branded Generics
• Drug Efficacy Study Implementation (DESI) Drugs
• Drug-device Combinations
• Orphan Drugs
• Prodrugs

Biological therapeutics, so-called biosimilars, are not suitable for approval under the 505(b)(2) pathway.

Product development with 505(b)(2)

There are a few key points to keep in mind when deciding on an excipient. Firstly, the choice of excipient is one that should be made during the early stages and after the target product profile (TPP) has been defined. The TPP specifies the desired characteristics of a drug, which can include safety or efficacy-related properties. This is crucial because from a technical standpoint, a drug may need improved solubility or to achieve higher drug loading to meet the TPP.

Physicochemical properties are not the only area of importance in drug development however, if the project is to be successful, patient concerns and commercial factors should also be considered when choosing an excipient, namely:

• For patients, key concerns are ease of administration and reduced side effects, so excipients should ideally improve performance in these areas.
• From a commercial standpoint, IP protection is critical.
• Developing a robust patent portfolio is a key part of the commercial strategy for drug products.

The patents on new drug products often reference several formulations utilizing different excipients and formulation techniques to provide protection that is as broad as possible for the innovator. As such, obtaining intellectual property (IP) protection on a 505(b)(2) product can be particularly difficult, and new ingredients and technologies may be required to navigate these IP challenges.

Novel excipients for 505(b)(2) success

Novel excipients, even ones that may not yet have precedence of use in the desired route of administration, can be an excellent choice if they truly enhance the formulation and you can establish a reasonable safety profile.

On the 505(b)(2) pathway, it is especially feasible to use excipients that may have precedence in another route of exposure, as in any case the safety profile from the existing product will need to be bridged to the new use.

Additionally, there has been feedback from the market that the use of novel excipients is desired, so the FDA is taking steps to encourage the use of new technologies. This includes the Novel Excipient Review Pilot Program, which allows excipient manufacturers to obtain FDA review of certain novel excipients prior to their use in drug formulations. For oncology compounds in particular, the risk-to-benefit ratio can allow more flexibility from the FDA in order to get life-changing drugs in the market.

When reformulating drugs on the 505(b)(2) regulatory pathway, the choice of excipient is critical and must balance technical, patient, and commercial needs. Novel excipients from an experienced supplier with the right processes in place can be a key cornerstone of successful 505(b)(2) development.

By both enhancing the formulation in line with the TPP and conferring patent protection, drugs incorporating novel excipients are well positioned to both benefit from a competitive edge in the market and improve patients’ quality of life.

Finally, it is important to consider quality and security of supply in novel excipient selection. There is a difference between incorporating a benchtop academic polymer versus a well-characterized, GMP-manufactured excipient product from a trusted supplier. Choosing the latter can mitigate batch-to-batch variation and ensure there is supporting data to show the polymer is safe for use in commercial products.

Selecting an excipient supplier

Settling on the right novel excipient is important, but the quality and reliability of the supplier should also be assessed before the final choice is made.

In summary, pharma companies should look for an experienced excipient manufacturer with:

• Robust, GMP manufacturing processes in place
• A polymer that can be manufactured without wide batch-to-batch variation.
• The information necessary to assure the FDA that the excipient is safe for use for the intended purpose, along with stability data.

Benefits of 505(B)(2)

505(b)(2) is particularly valuable for pharmaceutical and generics companies looking to alleviate competitive forces in their environments while still wanting to benefit from a development process that eliminates most nonclinical studies as well as extensive safety and efficacy tests.

• Relatively lower risk because of previous drug approval
• Lower cost accelerated development due to fewer studies.
• May qualify for three, five or seven years of market exclusivity.

The advantages offered by the 505(b)(2) pathway are not limited to reduced risk and competitive differentiation. The 505(b)(2) route can also help with lifecycle management, spanning all companies from small to large pharma.?

The 505(b)(2) route allows companies to concentrate on how to make the best formulation – one that will allow differentiation in the marketplace and that can enable incremental improvements such as more patient-friendly dosage forms.?

Selecting appropriate inactive ingredients, or excipients, is crucial when optimizing a new formulation for the 505(b)(2) pathway. For instance, innovators seeking improved solubility of an active pharmaceutical ingredient (API) and Intellectual property (IP) protection can turn to an excipient that offers these advantages. Novel excipients supported by adequate safety data for the intended use can be the key to unlocking the benefits of the 505(b)(2) pathway.?

Conclusion

Introduced by the Hatch-Waxman Amendments of 1984, the purpose of 505(b)(2) pathway is to avoid unnecessary duplication of research for the approval of a clinically significant improvement to a previously approved drug by allowing for the use of data not developed by the NDA applicant.

The 505(b)(2) pathway offers well-balanced advantages to researchers, investors, regulatory agents, and ultimately to the patients. It stimulates new drug investigation as well as promotes the improvement of existing drugs. To take advantage of this application route by (re)formulating with advanced technologies, and to expedite the development and approval course, it is important though, for the sponsors to fully understand not only the scientific scope but also regulatory and intellectual affairs.

The 505(b)(2) regulatory pathway provides an appealing middle ground for drug developers. Innovation is encouraged and rewarded, however, the costs and risks inherent to NCE development are greatly reduced. Though the development process is longer than introducing a generic, a 505(b)(2) product is not a copycat. By design and intent, such drugs are meant to bring meaningful improvements to the market and, ideally, to the patients who rely on the medications to treat a disease or chronic condition. For these reasons, the 505(b)(2) pathway has emerged as a viable and desirable opportunity for pharmaceutical companies of all sizes, providing a fertile ground for innovators and marketers alike.