An Increasing Number of Companies Are Using a Once-Obscure FDA Drug Approval Pathway

Regulatory NewsRegulatory News | 08 April 2015 |  By 

Companies are increasingly using a lesser-known regulatory pathway to get new doses, formulations or combinations of drugs approved by the US Food and Drug Administration (FDA), a review by Thompson Reuters has found.


In the US, pharmaceutical products are in general approved in one of three ways:

  • A drug never before approved by FDA for a specific condition is approved using a New Drug Application (NDA) through the 505(b)(1) pathway
  • A generic drug referencing an already-approved NDA is approved using an Abbreviated New Drug Application (ANDA) through the 505(j) pathway
  • An over-the-counter (OTC) drug is approved by referencing an existing monograph

These three pathways collectively account for most of the products on the market. There are, however, several other pathways by which a drug can obtain approval.

One of the most popular of those alternative pathways is the 505(b)(2) pathway, which is designed to allow the approval of a drug which isn't new, but differs in several meaningful aspects. As described in FDA's 1999 guidance document, Applications Covered by Section 505(b)(2), a 505(b)(2) application:

"[I]s one for which one or more of the investigations relied upon by the applicant for approval 'were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted.'"

In plain terms, the 505(b)(2) sponsor is relying upon clinical data or literature produced by other companies or entities.

But why would a company want to rely on that data? The most common reason is that the 505(b)(2) sponsor has made "changes to previously approved drugs," including its recommended dose, its formulation, its route of administration, its strength, or the drugs with which it is combined.

The 505(b)(2) pathway was created with the intent "to encourage innovation without creating duplicate work and reflects the same principle as the 505(j) application: it is wasteful and unnecessary to carry out studies to demonstrate what is already known about a drug," FDA explained in its guidance.

For example, if a company were to reformulate a drug such that it could be taken just once per day instead of three times per day, it could use the 505(b)(2) pathway to minimize the amount of original data it would need to submit in support of its new drug. Regulators could instead rely upon existing data showing that the reference drug is safe and effective, and focus on determining whether the changes made to the new drug alter its safety or efficacy.

For more on the 505(b)(2) pathway, check out this White Paper from Camargo

An Increasingly Popular Pathway

The 505(b)(2) pathway may be little-known, but it's no longer little-used. A new report out this week from Thompson Reuters finds that FDA now reviews more 505(b)(2) applications each year than it does 505(b)(1) applications (i.e. New Drug Applications).

505(b)(2) - Number of Applications Filed

In 2014, for example, FDA reviewed 56 of the 505(b)(2) applications—the highest number since at least 2002, and possibly ever.

The surge in 505(b)(2) approvals has been led by several factors, Thompson Reuters found. Twenty-five of the 56 505(b)(2)s approved in 2014 were new formulations of existing drugs, while 16 of the 56 were new doses of existing drugs. In four cases, manufacturers sought approval for a previously unapproved drug based on existing studies not entirely conducted by the sponsor.

505(b)(2) - Types of Applications

Thompson Reuters also found that despite the decreased evidence required to approve a 505(b)(2) application, approval times are not necessarily faster than drugs approved through the 505(b)(1) pathway.

Median Approval Time (Days)
Non-Expedited Review54950346 Days
Expedited Review35437824 Days

505(b)(2) reviews were, on average, slower by 46 days for standard-review drugs and 24 days for expedited-review drugs.

"This means that it’s more attractive for a sponsor to provide the full data to support the approval of its product by launching an [New Molecular Entity], while benefiting from an expedited review process, rather than launching a 505(b)(2) application without being granted any expedited review process," Thompson Reuters explained.

That analysis does not, however, take into account the cost of conducting clinical studies or the time saved by not conducting the studies. The Reuters analysis notes that these costs "must be considered seriously, especially since FDA approval is not a guaranteed end result." The 505(b)(2) pathway may be slightly slower, but it also mitigates many of the drug development risks faced by companies, the report adds.


Thompson Reuters Study


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Tags: 505(b)(2)

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