What is a 505(b)(2)?

The 505(b)(2) New Drug Application (NDA) is a streamlined NDA process in which the applicant relies upon one or more investigations conducted by someone other than the applicant and for which the applicant has not obtained right of reference. In other words, the 505(b)(2) pathway enables investigators and/or manufacturers to apply for approval without having to repeat all the drug development work done for an innovator drug. 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. 505(b)(2) submissions can be advantageous because they can often lead to a faster route to approval when compared to traditional development pathways such as 505(b)(1) NDA, while creating new, differentiated products with commercial value. 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

Overview of 505 Regulatory Pathways

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.

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.

Notable 505(b)(2) Approvals

Several companies have successfully utilized 505(b)(2) applications in order to receive approval for drugs that are currently on the market. Some examples include but are not limited to:

• Bendeka™ (bendamustine hydrochloride) – Eagle Pharma
• Zuplenz® (ondansetron) – Strativa
• Avycaz® (ceftazidime-avibactam) – Allergan
• Omnitrope® (somatropin rDNA origin) – Sandoz
• Narcan® Intranasal (naloxone hydrochloride) – Adapt Pharma
• Xuriden™ (uridine triacetate) – Wellstat
• Yosprala™ (aspirin-omeprazole) – Innovida Pharmaceutique

Identifying Potential 505(b)(2) Drug Candidates

When considering the feasibility of pursuing the 505(b)(2) pathway, it is essential to identify if your drug product has documented market differentiation, low risk of development, and high profit potential. The types of products listed below are ideal 505(b)(2) candidates:

• Drugs with changes in dosage form, strength, formulation, dosing regimen, or route of administration
• Drugs with new active ingredients (in some cases)
• Drugs with new indications
• New combination products
• Prodrugs of an existing drug

Of note, biological therapeutics (also known as biosimilars) are not suitable for approval under the 505(b)(2) pathway.

Benefits of the 505(b)(2) Pathway

The 505(b)(2) strategy can be valuable to pharmaceutical companies for a variety of reasons. This pathway can alleviate some of the cost and time associated with the traditional full NDA. In addition, utilization of the 505(b)(2) pathway can eliminate the need for most nonclinical studies and extensive safety and efficacy tests. Other benefits may include:

• Potential of lower risk due to previous drug approval
• Faster development and lower cost due to fewer studies needed
• Potential to qualify for 3-7 years of market exclusivity

505(b)(2) Program Development Strategies

505(b)(2) development can be challenging but offers tremendous opportunity for sponsors. When planning to create a 505(b)(2) development program, you must determine how the new drug product is different and similar to the innovator drug, especially in relation to its pharmacokinetic (PK) characteristics. From there, you can leverage all information relevant to the new drug product by creating a “PK bridge” linking the in vivo performance of the new drug product to that of the innovator drug product. Understanding how to best link the two products is an essential step in maximizing the full streamlining capability of the 505(b)(2) approach. Having a robust PK development plan in your 505(b)(2) strategy allows for rapid advancement of the regulatory approval process at minimal cost. For example, when considering oral products, PK studies that address bioequivalence, bioavailability, multiple-dose PK, and food effect can often meet the minimum PK requirements.

Navigating the 505(b)(2) Submission Process

There are four main components to be aware of when navigating the 505(b)(2) submission process which are: candidate identification, candidate assessment, product planning and the pre-IND meeting.

Candidate Identification

Identifying drug products that are suitable for the 505(b)(2) process is an essential first step in minimizing the risk of failure and taking advantage of this more streamlined route to approval. Often this can be done with a few nonclinical studies. Early in the Phase 1 program, it is important to keep in mind that the PK profile of the new product does not have to mimic that of the innovator product exactly. The PK profile should be “as favorable” as that of the innovator product, taking into consideration the intended use of the new product. That way a 505(b)(2) candidate should present a low development risk and an increased potential payoff by differentiating itself from the rest of the market.

Candidate Assessment

In order to reduce the risk of costly errors, candidate assessment prior to development is vital and can establish the value proposition of a product concept for investors. A proper candidate for a 505(b)(2) application should have scientific, medical, regulatory, and commercial viability.

• Scientific Viability: Evaluating scientific aspects of the candidate, including stability and preparation of the product, scalability of manufacturing, and availability and affordability of active and inactive ingredients.
• Medical Viability: Establishing a clear niche for the product, such as a unique solution to an unmet need. In addition, the risk/benefit and appeal to the proposed patient population should be considered.
• Regulatory Viability: Determining the availability of clinical trial data or other data that may be used to gain approval. Distinguishing information that could be presented on labeling for future promotional activity should also be considered.
• Commercial Viability: Determining the availability of a viable market for the product and assessing the potential for future competition or substitution, as well as what is needed to ensure reimbursement and optimal pricing.

Product Planning

During the product planning stage, a potential developer should assess ways to incorporate existing data into their development strategy. In addition, the options for market exclusivity should be considered. Some products may qualify for distinctions such as orphan drug exclusivity (seven years), new chemical entity (NCE) exclusivity (five years), “other” exclusivity (three years, if certain criteria are met), and pediatric exclusivity (six months added to existing exclusivity/patents). While NCE exclusivity is often thought of only for 505(b)(1) drugs, it is also possible to gain NCE exclusivity via the 505(b)(2) pathway.

505(b)(2) Pre-IND Meeting

The pre-investigational drug application involves a pre-IND meeting with the FDA before the eventual IND filing. The pre-IND process for the 505(b)(2) vs. 505(b)(1) pathways differs greatly. Major distinctions include:

• Order of steps: Unlike the 505(b)(1) process, 505(b)(2) is initiated with the pre-IND meeting, moving into formulation development and additional studies (if deemed necessary), and concluding with the IND filing.
• Goals and strategy of the pre-IND meeting: The objective of a 505(b)(2) pre-IND meeting is to gain input from the FDA and concurrence with the studies, clinical research plans, and chemistry, manufacturing, and controls (CMC) strategy in order to minimize the number of new studies required for approval. Obtaining this input from the FDA can be vital to securing investments for many companies.
• Number and type of required studies: The ability to use public data or previous FDA findings through the 505(b)(2) pathway may allow for programs to conduct bridging studies, preventing the need for some clinical or nonclinical studies traditionally required for a 505(b)(1).
• Timing of CMC work: The clinical trial materials for Phase 1 studies should be representative of the commercial manufacturing process (including packaging) for a 505(b)(2) product. Generally, the three stability batches to be used for determination of shelf-life are to be prepared at this time as well. As a result, a great deal of CMC work must be completed prior to the initiation of studies, even for Phase 1.
• Timing of studies: Due to the reliance on pre-existing data, clinical studies can be started simultaneously and developed in parallel. With the reliance of pre-existing data, a Phase 3 study can be initiated before completing all the Phase 1 studies and without having to conduct a Phase 2 study, which saves time and money.

Conclusions & 505(b)(2) Experience

Allucent’s senior scientific staff has extensive experience supporting 505(b)(2) development programs from both a strategic and operational perspective. Our approach is to match regulatory knowledge with scientific, clinical, nonclinical, and overall drug development expertise to find the right path for your 505(b)(2) program. Allucent has been involved with dozens of 505(b)(2) programs. In one instance, Allucent provided end-to-end 505(b)(2) submission support to a client seeking 505(b)(2) approval. Allucent has also managed FDA meetings and acted as our client’s regulatory affairs point of contact. In addition, we have addressed reference-listed drug (RLD) availability issues by devising alternative strategies as well as supporting the overall program. Contact us to learn how we can provide support for 505(b)(2) development and approval needs.