Among the regulatory pathways for small molecule drugs in the United States, the 505(b)(2) option occupies a middle ground. Intended for modifications of an existing treatment, it requires much more evidence than a generic but allows the sponsor to use data from a previous application. Companies can thus avoid unnecessarily repeating studies and shorten their development time.
At a recent clinical seminar in Shanghai, attendees learned about the intricacies of 505(b)(2), the corresponding hybrid medicinal product pathway in the European Union and the differences from applications for biosimilars or generics. Developers in the Asia Pacific region are eager to better understand this topic because the Chinese pharmaceutical industry is developing rapidly with support from the government. “They view 505(b)(2) as a potentially faster way to market,” said Eric Lang, MD, Vice President and Global Head of Clinical Drug Development Leaders, Early Phase Development Solutions. To succeed, however, sponsors will need to consult with experts who can help them develop a regulatory strategy and consider market access issues as well.
Meeting Safety and Effectiveness Standards
The 505(b)(2) pathway is intended for drugs that modify an existing approved product. Examples include:
- A new dosage, formulation or administration route (such as switching from topical to oral delivery)
- Expanding to a new population with a different indication
- A combination product containing active ingredients that have been previously approved
- A change from prescription to over-the-counter indication
- A change to an active ingredient (e.g., a different salt, ester complex or chelate)
The sponsor can rely partly on data that was previously submitted in an earlier application, either by the same sponsor or another company. In the latter case, the new sponsor can reference the data if the patent has expired or the original company has issued a letter of approval. This approach may allow the applicant to perform fewer animal studies or provide data from a single new efficacy trial instead of replicate evidence.
However, the standards for 505(b)(2) approval are the same as they would be for a new drug application under the 505(b)(1) pathway. “You need to show exactly what you need to show for a 505(b)(1), which is safety and effectiveness,” Lang said.
The European equivalent of 505(b)(2) is the hybrid medicinal product pathway. This category is used for cases that do not meet the strict definition of “generic medicinal product” because changes have been made to the active ingredient, indications, strength, formulation or administration route. The standards are fairly similar to those for 505(b)(2), although European authorities do not always require replicate evidence.
A Closing Window for Biologics
There are significant differences between 505(b)(2) and 351(k), which is for biosimilars. In a 351(k) application, the sponsor must demonstrate that the drug is highly similar to the reference product. In a 505(b)(2) application, “you’re changing something fairly substantial,” Lang said.
In the past, some developers were able to use the 505(b)(2) pathway for very simple biologics such as insulin. However, this option for biologics approval will be available only until 2020; after that, the applications must go through 351(k). Lang advises companies to discuss their cases with regulatory authorities to decide the most appropriate course of action.
505(b)(2) also differs from the 505(j) pathway for generic small molecules in the amount of evidence required. In a generic application, the sponsor only needs to show that the products are equivalent or nearly equivalent. A small trial is generally sufficient for approval. The requirements for 505(b)(2) are considerably more stringent, but if the drug is approved, the treatment can be a branded product as long as the sponsor maintains exclusivity.
To create a successful 505(b)(2) application, Lang suggests that the sponsor work with a team of experienced drug developers who are familiar with the regulations. In its discussions with the FDA, the company must strike a delicate balance. “You need to make a proposal that is sensible—but not overly aggressive—so it is more likely to be approved,” Lang said.
Companies also should keep market access issues in mind. Clearing regulatory hurdles is important, but so is ensuring that the product is sufficiently differentiated from others on the market. “Getting approval doesn’t mean that anybody wants to buy the product,” he said. Sponsors need to focus on the right comparators in order to demonstrate that the new treatment is unique.
Bill Hanlon, PhD, Vice President and Head of Global Regulatory Affairs, notes that large pharmaceutical companies often use 505(b)(2) to add indications and expand labels. “They’re constantly innovating with their own drugs,” he said. If Asia Pacific developers take advantage of this pathway as well, they can benefit from an abbreviated route to market.
With a strong presence in the Asia Pacific region, we can help developers navigate complex regulations and increase their chances of approval. Our experts also provide guidance on market access, clinical trial design, biomarker testing and other key aspects of global drug development.