FDA's 505(b)(2): Overview
The 505(b)(2) drug approval pathway is a New Drug Application (NDA) pathway that is considered a hybrid between the 505(b)(1) pathway used for brand-new drugs, which requires full clinical studies and is generally a lengthy and costly process; and the Abbreviated New Drug Application (ANDA) process, used for generic drugs. 505(b)(2) is used for drugs that utilize the same active ingredients used in previously-approved drugs, but in novel ways, such as new indications or dosages. Because of this, 505(b)(2) applicants may include research completed by other entities in their applications, unlike 505(b)(1) applicants. However, the drug may not be an exact replica of an already-approved drug; if that is the case, the applicant must utilize the ANDA pathway. Below is an overview of the 505(b)(2) pathway, including its origin and purpose as it relates to the other two approval pathways, the process by which drug developers apply via the 505(b)(2) pathway, and the types of drugs that would, and would not, qualify for approval within this pathway.
The FDA's 505(b)(2) NDA pathway: overview
The US Food and Drug Administration (FDA) offers three regulatory pathways by which drugs can be approved. The first is the 505(b)(1) pathway, often colloquially referred to simply as the New Drug Application (NDA) pathway, is reserved for brand-new drugs utilizing novel active ingredients in novel ways, and, as such, has steep requirements regarding clinical trials and evidence attesting the drug's safety and efficacy. On the other end of the spectrum is the 505(j) pathway, almost universally referred to (even by the FDA itself) as the Abbreviated New Drug Application (ANDA). This pathway is reserved for generic forms of already-approved drugs, and simply requires that the applicant demonstrate that the original drug, or "reference listed drug," is the same as the proposed generic form.
The 505(b)(2) functions essentially as a middle path for drugs that are not entirely new, but are not generic forms of existing drugs, either. Created in 1984 by legislation termed the Hatch-Waxman Amendments, this pathway "is intended to streamline the development and U.S. Food and Drug Administration (FDA) approval of pharmaceutical products that incorporate already-approved pharmacological agents." It allows applicants to provide studies conducted by other entities for other drugs with the same active ingredients, unlike 505(b)(1) applicants, who must provide research conducted specifically for the drug in question. This allows for several benefits, including a decreased risk, given that the active ingredients have already been approved; decreased costs, given that fewer studies need to be conducted; and a potential three, five, or seven year exclusivity period in which the drug will face no competition.
The 505(b)(2) application process
As Camargo Pharmaceutical Services, specialists in the 505(b)(2) approval pathway, explain, the 505(b)(2) application process begins long before an application is actually completed and submitted. Potential applicants must navigate the following steps:
- First, potential applicants must ensure that the drug for which they are seeking to apply are viable, in scientific, medical, regulatory, and commercial terms. In other words, scientific evidence must suggest that the drug is feasible; the medical landscape must demonstrate a need for the drug, or a niche in which the drug would be helpful; the drug must meet the qualifications for the 505(b)(2) pathway, not one of the FDA's other two approval pathways; and there must be a market for the product.
- Next, potential applicants must complete the pre-Investigational New Drug (pre-IND) process and obtain Investigational New Drug (IND) status so the necessary studies can be conducted. Note that while 505(b)(2) applications may include preexisting research, they also need to include new research to demonstrate that the novel aspects of the drug are safe; this is why IND status is necessary.
- Third, potential applicants must complete formulation development, creating the drug for which they are seeking approval via the 505(b)(2) pathway. Care must be taken in this step to note the ways in which the previously-approved active ingredient or drug is altered to form the new drug, because this information is vital to the eventual approval of the new drug.
- Fourth, non-clinical research is conducted. As explained above, the 505(b)(2) pathway allows applicants to utilize previously existing research to demonstrate the active ingredients' safety and efficacy; this is the stage at which this research is gathered.
- Fifth, any necessary clinical trials are conducted to demonstrate the safety and efficacy of the new drug, and to demonstrate that the active ingredients used in the new drug are the same as previously-approved ingredients. The latter trials are called "bridging trials," and are necessary to construct a "bridge" between the new drug and drugs that have already been approved.
After each of these steps has been completed, applicants can consolidate the necessary information gathered in these steps to create the 505(b)(2) application itself, and finally submit it to the FDA for review.
505(b)(2): drugs that would, and would not, qualify
As discussed above, the 505(b)(2) pathway is for drugs that utilize previously-approved active ingredients in novel ways. The following are drugs that would qualify for this pathway:
- A drug with a previously-approved active ingredient in a new dosage form.
- A drug that combines two or more previously-approved active ingredients in a new way.
- A drug with a previously-approved active ingredient utilizing a novel "route of administration or mechanism of drug delivery."
- A new indication for a previously-approved drug.
- A drug that has already been approved, but is only available via prescription (Rx) and its developer is seeking to make it available over-the-counter (OTC).
Below are types of drugs that would not qualify for the 505(b)(2) pathway:
- A drug that is a replica, or "pharmaceutical equivalents," of an already-approved drug; these are considered generic drugs and must be approved via the ANDA pathway. (Note: if a pharmaceutical equivalent is approved after a 505(b)(2) application is submitted, that application may still be approved.)
- A drug for which a "bridge" cannot be constructed, using some combination of available scientific literature and new studies, to demonstrate that the drug's active ingredients are the same as ones that have been previously approved.
- A drug that utilizes entirely new active ingredients; these drugs must be approved via the 505(b)(1) pathway.
The FDA's 505(b)(2) drug approval pathway is a "hybrid" pathway between the extensive 505(b)(1) pathway for brand-new drugs and the relatively minimal ANDA pathway for generic drugs. It allows developers of drugs that utilize previously-approved active ingredients in novel ways to avoid the costly requirements of the 505(b)(1) pathway while still retaining eligibility for a substantial period (three, five, or seven years) of market exclusivity (as opposed to the six-month eligibility of ANDA pathway drugs). Potential applicants must demonstrate the drug's viability, complete the IND registration process, formulate the drug itself, and conduct both clinical and non-clinical research prior to submitting a 505(b)(2) application. Some drugs that would qualify for this pathway include drugs utilizing previously-approved active ingredients with new indications, delivery methods, or combinations; pharmaceutical equivalents or entirely new drugs would not qualify.