The 505(b)(2) NDA is an FDA drug approval pathway, established by the Hatch-Waxman Amendments of 1984, which allows companies to leverage existing data from previously approved drugs. This reduces the need for duplicating studies, offering a faster and less expensive route to market compared to the traditional 505(b)(1) pathway.
505(b)(2) candidates include drugs with new dosage forms, combinations, or indications, relying on well-known active ingredients. It is especially useful for companies seeking to avoid competitive pressures while reducing costs and time by minimizing nonclinical studies.
The 505(b)(2) pathway allows companies to develop new products based on existing, approved drugs by creating a bridge between the known data of a reference drug and a new product or indication. Companies might pursue faster-acting formulations, novel combinations of active ingredients, or improved delivery mechanisms. It also enables approvals for new uses or over-the-counter (Rx-to-OTC) switches of already-approved drugs. This route leverages well-understood ingredients, reducing the need for redundant studies. A similar regulatory process exists in Europe under Article 10 of Directive 2001/83/EC.
How to Start?
Candidate Identification: Ideal 505(b)(2) candidates include:
- New combination products
- Drugs with changes in dosage form
- Drugs with changes in strength
- Drugs with changes in formulation
- Drugs with changes in dosing regimen
- Drugs with changes in route of administration
- Drugs with new indications
- Prodrugs of an existing drug
- In some cases, drugs with new active ingredients
Feasibility: Candidate Assessment Predevelopment assessment is critical to reduce risks and demonstrate a product's value to investors. Key areas to evaluate include:
- Scientific Viability: Is the formulation stable, scalable, and cost-effective?
- Medical Viability: Does the product address a unique medical need, offer an acceptable risk/benefit, and appeal to its target population?
- Regulatory Viability: What clinical data are needed for approval? Can the process be expedited? Will the product qualify for exclusivity?
- Commercial Viability: Is there a market for the product? What is the competition, reimbursement potential, and ideal pricing?
The 505(b)(1) pre-IND (Investigational New Drug) process is straightforward, involving nonclinical studies, formulation development, FDA consultation, and IND filing. The 505(b)(2) pathway, however, differs significantly:
Steps involved
Pre-IND meeting :It begins with an FDA pre-IND meeting. The primary goal of a pre-IND meeting for a 505(b)(2) product development strategy is to obtain input from the FDA on a sponsor's planned studies and strategies. The pre-IND meeting can help with:
- Reducing the risk of a clinical hold: The meeting can help identify potential clinical hold issues.
- Securing investments: Getting input from the FDA can be important for securing investments.
- Streamlining the approval process: The meeting can help streamline the approval process and reduce costs.
Some tips for pre-IND meetings include:
- Understand what the FDA is expecting.
- Know when to move on from a discussion.
- Be mindful of how much time to spend on each issue.
- Submitting iPSP/PREA: Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration must include an assessment of the product's safety and effectiveness for the claimed indication(s) in pediatric patients, unless this requirement is waived, deferred, or inapplicable. Sponsor need to jusity the proposed waiver or deferral to FDA and it needs to be agreed upon.
- Conducting studies planned in pre-IND approval for PK bridging
- Submission to US-FDA
- Review process and approval
505(b)(2) Advantages:
Unlike 505(b)(1), the 505(b)(2) pathway can utilize existing public data and FDA findings on the active ingredient's safety and efficacy, reducing the size, scope, and timeline of development. This reliance on prior data cuts costs and speeds up approval.
Market Exclusivity for 505(b)(2): Products may qualify for various exclusivity periods:
- Orphan drug exclusivity: 7 years
- New chemical entity exclusivity: 5 years
- Other” exclusivity: 3 years for certain changes
- Pediatric exclusivity: 6 months added to existing patents/exclusivity
Example:
The approval processes for Lipitor (atorvastatin) and Atorvaliq (a new Liquid formulation of atorvastatin) differ in complexity and regulatory pathways:
Lipitor (Atorvastatin):
- Approved under the 505(b)(1) pathway as a new chemical entity.
- Required extensive clinical trials to establish safety and efficacy from scratch.
- It took longer and cost more due to the need for comprehensive studies, which spanned over 10 years and cost up to $1 billion.
Atorvaliq (Atorvastatin liquid Oral Suspension):
- Approved under the 505(b)(2) pathway.
- Relied on existing safety and efficacy data from Lipitor's approval.
- Required only bioequivalence studies.This was discussed with the FDA during the p-IND meeting and finalised, resulting in a faster, more cost-effective approval process.
In short, Lipitor's approval involved a full set of clinical trials, while Atorvaliq benefited from the 505(b)(2) pathway, allowing it to use Lipitor's established data, significantly reducing time and cost.
505(b)(2) offers a faster, less expensive route to market with the added benefit of potential exclusivity. It represents a more cost-effective and commercially appealing alternative to traditional 505(b)(1) drug development.
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