The 505(b)(2) new drug application (NDA) is one of three U.S. Food and Drug Administration (FDA) drug approval pathways and represents an appealing regulatory strategy for many clients. The pathway was created by the Hatch-Waxman Amendments of 1984, with 505(b)(2) referring to a section of the Federal Food, Drug, and Cosmetic Act. The provisions of 505(b)(2) were created, in part, to help avoid unnecessary duplication of studies already performed on a previously approved (“reference” or “listed”) drug; the section gives the FDA express permission to rely on data not developed by the NDA applicant.
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.
Regulatory Pathways At a Glance
Appropriate for drug products that are the same as approved products
Hybrid between an ANDA [505(j)] and full NDA [505(b)(1)]
Full application - Data predominantly obtained from studies conducted by the sponser
For example, 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 based on Article 10 of Directive 2001/83/EC — Read more about the hybrid procedure >
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 low 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
Navigating the 505(b)(2) Approval Pathway
While the 505(b)(2) pathway offers a unique opportunity for rapid approval, success hinges on identifying products that have documented market differentiation, low development risk and high profit potential.
Ideal 505(b)(2) candidates include:
- Drugs with new indications
- Drugs with changes in dosage form, strength, formulation, dosing regimen or route of administration
- New combination products
- Prodrugs of an existing drug
- In some cases, drugs with new active ingredients
Potential types of 505(b)(2)s include:
- Branded generics
- DESI drugs
- Orphan drugs
- Drug-device combinations
Biological therapeutics, so-called biosimilars, are not suitable for approval under the 505(b)(2) pathway.
Predevelopment assessment of candidates is essential to establish the value proposition of a product concept for investors and to reduce the risk of costly errors. To build evidence that will substantiate a product’s potential value, the following questions must be considered:
Does the science make sense? For instance, is the formulation stable and readily prepared? Is manufacturing scalable? Are active and inactive ingredients available and affordable?
Does the product have a clear niche in the medical specialty? Is it effective for solving a unique problem or solving a problem in a unique way? Does it present an acceptable risk/benefit? Is there evidence the product would be appealing to the proposed patient population?
What clinical trials or other data will be required to gain approval? Can development be expedited? Would exclusive marketing rights (“exclusivity”) be available? What distinguishing information can be presented on the labeling for eventual promotional activity?
Is there a viable market for the product? What is the potential for future competition or substitution? What is needed to ensure reimbursement? What is the optimal pricing?
In 2014, 50 percent of all NDAs approved have been 505(b)(2) drugs, with 41 new 505(b)(2) drugs approved compared to the same number of new molecular entities. This percentage is expected to rise to more than 80 percent over the next few years.
Blog: The 505(b)(2) Approval Pathway Provides Opportunities for Generics Companies Seeking New Revenue Streams
“Traditional” new drug development and approval — generally required for a new chemical entity drug that has not been approved before or that doesn’t have a significant marketing history in the U.S. or elsewhere — takes place under the provisions of section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act. When it comes to 505(b)(1), the passage from “promising molecule” to “approved drug” is long, difficult, risky and expensive. Typically, achieving drug approval under the 505(b)(1) pathway — which requires the completion of new studies to establish the safety and efficacy of the drug in a specified disease or condition — can cost the sponsor up to 15 years and a billion dollars. Because a 505(b)(2) product can rely in part on the FDA’s previous findings on the safety and efficacy of an active ingredient as well as data available in the public domain, at this product planning stage, a potential developer of a 505(b)(2) should seek ways to weave such existing data into the product’s development strategy to reduce its size, scope, timeline and, therefore, cost.
In addition to representing a faster, less expensive path to market, products approved under the 505(b)(2) pathway can also sometimes qualify for several types of market exclusivity such as orphan drug exclusivity (seven years), new chemical entity exclusivity (five years), "other" exclusivity (three years for a "change" if certain criteria are met), and pediatric exclusivity (six months added to existing patents/exclusivity).
The accelerated path to approval and prospect of exclusivity make 505(b)(2) a cost-effective and commercially attractive route when the conditions are right.
The 505(b)(1) pre-IND development process is fairly straightforward: 1) conduct required nonclinical (animal) pharmacology, pharmacokinetics and toxicology studies; carry out early preformulation studies and select a lead formulation to advance; develop appropriate analytical methods; gather stability data on the active ingredient and the dosage form; and develop a proposed clinical protocol; 2) complete a pre-IND consultation with the FDA in which the sponsor presents findings from its nonclinical studies and manufacturing and analytical data, as well as a proposed clinical trial, in order to gain FDA agreement to move to human testing; and 3) file the investigational new drug (IND) application.
Compared to 505(b)(1), the 505(b)(2) process differs greatly. Here’s how:
- First, the order of the steps above is different: 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.
- Second, the goals of the pre-IND meeting for a 505(b)(2) product are also different than for a 505(b)(1). 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 and with clinical research plans in a way that minimizes the number of new studies required. For many companies, obtaining FDA buy-in and successfully activating an IND are critical steps for securing investments.
- Third, the number and type of studies required are different. Since the 505(b)(2) pathway allows the use of public data or the FDA’s previous findings in lieu of novel trial data, some development programs may conduct bridging studies that preclude the need for nonclinical or clinical studies, or both.
- Finally, the timing of studies is different. Because 505(b)(2) development plans rely largely on pre-existing data, nonclinical and clinical studies can often be started simultaneously and developed in parallel, significantly shortening the overall time to market.
Together, these differences represent a formidable multifaceted challenge. When mishandled, the early steps of 505(b)(2) development can end in product-development failure. On the other hand, when managed skillfully, these first steps can result in important victories for the sponsor, including reduced costs, a clear path to approval and immediate interest from investors — early expert guidance is vital.
White Paper: Obtaining FDA buy-in and successfully activating an IND are critical steps for securing investments.
The chemistry, manufacturing and controls (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.
- 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.
- Since public data may be used in lieu of novel trial data, numerous nonclinical studies and safety and efficacy tests may not be necessary to achieve 505(b)(2) approval.
- Because 505(b)(2) candidates often have known safety profiles and previous demonstrations of efficacy, risk is diminished, which fosters investment appeal.
- 505(b)(2) often allows nonclinical and clinical studies to be completed in parallel, abridging the process even further.
In certain instances, the 505(b)(2) pathway enables the Phase I process to be reduced to a single study. This study, known as a Phase I bridging study, is used to compare the human pharmacokinetic profile of the proposed drug product with that of the reference product (a clinical bioequivalence study). Done properly, a bridging study allows a company to reference the established safety information for the original drug.
- 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. Repeat-dose studies as well as those conducted in the fed state are sometimes required as well.
- In some cases, the requirement for an in vivo bioequivalence study can be waived via a formal request called a biowaiver.
Phase II studies, which are required in 505(b)(1) NDAs, are designed to confirm the pharmacokinetic profile of the product, ensure safety in patients and determine the minimum effective dose and the maximum effective/tolerated dose. In contrast, certain 505(b)(2) development programs require no Phase II or Phase III studies (e.g., dosage form changes may rely on Phase I pharmacokinetic studies alone).
- In some 505(b)(2) NDAs, Phase II and Phase III studies can be combined.
For a standard 505(b)(1) NDA, Phase III generally consists of two large, well-controlled studies (often referred to as pivotal studies) that include hundreds or even thousands of patients and are designed to produce statistically and clinically meaningful evidence of the product’s safety and efficacy. Once again, because a 505(b)(2) submission can rely in part on existing data, Phase III studies are often not necessary.
- If a Phase III study is required for a 505(b)(2), such as when approval is sought for a prodrug of a previously approved active ingredient, only one study is often necessary versus the two generally required for 505(b)(1).
- Fewer patients may be needed for 505(b)(2) product clinical trials due to the existing large exposure information available in the public literature or in the FDA’s databases.
Sources of existing data to support 505(b)(2) submission:
- Data previously accepted by the FDA as part of a marketing application
- Data available in the public domain (including data for indications not previously approved by the FDA)
- Foreign clinical trial data
White Paper: Foreign Trial Data
The success of NDA preparation and submission depends heavily on up-front planning and awareness of FDA expectations throughout the entire development process. To enhance the quality, organization and completeness of an NDA submission, it’s vital that the application derives from detailed knowledge of FDA filing requirements, the use of established and well-accepted methodologies and the design of accurately focused clinical studies.
- Before submission, audits of bioequivalence studies and bioanalytical analyses can reinforce the accuracy of data submissions to the FDA and help further expedite drug approval and market launch.
- While a 505(b)(1) may require more than a decade to reach NDA submission, the 505(b)(2) pathway requires a fraction of that time — a 505(b)(2) can be developed and reach FDA approval in as little as 30 months.
505(B)(1) VS. 505(B)(2) Drug Development Timeline
||< 1-2 Years
To maximize the return on a 505(b)(2) investment, having a plan in place to increase new drug marketability is key. The basis of this plan should have already been set when the feasibility of the product was assessed, and questions such as What is needed to ensure reimbursement? and What is the optimal pricing? should be investigated and answered in this phase to determine how to best drive physician preference, consumer requests and sales.
- Unlike drugs approved under the 505(j) approval route for generics, where exclusivity can only be obtained for 180 days, a 505(b)(2) may qualify for three, five or seven years of market exclusivity.
Is 505(b)(2) For You?
If you’re looking to reposition an existing product or expand your portfolio with a differentiated product, the 505(b)(2) approval pathway is your best way forward, and Camargo is your ideal partner. In fact, we offer Ready 4 Action, a proprietary feasibility assessment to evaluate the scientific, medical, regulatory and commercial aspects of your product development opportunities. Ready 4 Action will help you make correct go/no-go decisions and set the cornerstone of your product development plan.
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