FDA's 505(B)(2)

Part
01
of two
Part
01

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.

Conclusion

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.
Part
02
of two
Part
02

FDA's 505(b)(2): Approved Products

The U.S. Food and Drug Administration (FDA) has three drug approval pathways and 505(b)(2) new drug application (NDA) is one of these pathways. The pathway's name, 505(b)(2), refers to the corresponding section of the Federal Food, Drug, and Cosmetic Act. The 505(b)(2) pathway ensures that studies previously performed on approved, listed, or referenced drugs are not duplicated.

The total number of 505(b)(2) approvals increased from 43 in 2014 to 63 in 2017. According to the "Drugs@FDA: FDA Approved Drug Products" database, the number of 505(b)(2) approved drugs having a "Type 5 Submission Classification" in 2018 was 42.

RESEARCH STRATEGY

The number of 505(b)(2) approvals from 2014 to 2017 were obtained from Camargo Pharmaceutical Services. Camargo Pharmaceutical Services is a drug development services provider specializing in the 505(b)(2) approval pathway as well as similar European processes. Camargo’s uses its proprietary 505(b)(2) database along with FDA’s public databases such as drugs@FDA and the Orange Book to keeps track of 505(b)(2) approved drugs. Camargo updates the number of drugs approved via the 505(b)(2) pathway to incorporate any drugs with tentative approval in the past years. Camargo has compiled and updated the number of 505(b)(2) approvals for the years 2003 to 2017.
The number of 505(b)(2) approvals for each year between 2014 and 2018 are as follows:

505(B)(2) APPROVALS IN 2014

A total of 43 drugs were granted 505(b)(2) approvals in 2014.

505(B)(2) APPROVALS IN 2015

A total of 45 drugs were granted 505(b)(2) approvals in 2015.

505(B)(2) APPROVALS IN 2016

A total of 45 drugs were granted 505(b)(2) approvals in 2016.

505(B)(2) APPROVALS IN 2017

In 2017, the number of drugs that received the 505(b)(2) approvals increased to 63.
Although not required as per the research criteria, we have compiled a list of names of the 505(b)(2) approved drugs (with Type 5 Submission Classification only) and the details of their manufacturers, approval date, active ingredients, submission classification, and submission status in "2017 Type 5" tab of the attached spreadsheet. Using the list of 505(b)(2) approved drugs and their details, we identified the companies with the most number of drugs approved.

From the 63 approved drugs, Exela Pharma SCS LLC had three drugs registered, while Baxter Healthcare Corporation, Fresenius Kabi USA, NOVO, Sanofi-aventis US, and Xellia Pharms APS had two drugs approved via the 505(b)(2) pathway in 2017.

505(B)(2) APPROVALS IN 2018

The total number of 505(b)(2) approvals in 2018 was extracted from the FDA's database, "Drugs@FDA: FDA Approved Drug Products," which publishes a list of original as well as supplemental approvals from the NDAs, ANDAs, and BLAs on a monthly basis. The list includes information on both original and tentative approvals and is updated as of March 23, 2019. We used this list to find the number of monthly 505(b)(2) approvals having a Type 5 Submission Classification and added them to get the number for 2018.

A total of 42 drugs were granted approval through 505(b)(2) pathway (Type 5 — New Formulation or New Manufacturer) in 2018. We have compiled a list of names of the 505(b)(2) approved drugs and the details of their manufacturers, approval date, active ingredients, submission classification, and submission status in "2018 Type 5" tab of the attached spreadsheet.

Among the 42 drugs, Sun Pharma Global obtained 505(b)(2) approvals for three drugs, while Aurobindo Pharma Ltd, Eyepoint Pharms, Hospira Inc., and Mylan Labs Ltd obtained approvals for two drugs each.

Sources
Sources

From Part 01
Quotes
  • "A 505(b)(2) application is an NDA submitted under section 505(b)(1) and approved under section 505(c) of the FD&C Act that contains full reports of investigations of safety and effectiveness, where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use."
  • "An ANDA is an application for a duplicate6 64 of a previously approved drug product that was submitted and approved under section 505(j) of the FD&C Act. An ANDA relies on FDA’s finding that the previously approved drug product, i.e., the reference listed drug (RLD)7 67 , is safe and effective. An ANDA generally must contain information to show that the proposed generic product (1) is the same as the RLD with respect to the active ingredient(s), conditions of use, route of administration, dosage form, strength, and labeling (with certain permissible differences) and (2) is bioequivalent to the RLD."
  • "A 505(b)(2) applicant may rely on FDA’s finding of safety and/or effectiveness for a listed drug only to the extent that the proposed product in the 505(b)(2) application shares characteristics (e.g., active ingredient, dosage form, route of administration,strength, indication, conditions of use) in common with the listed drug. The applicant, though, is expected to establish a bridge (e.g., by using comparative bioavailability data) between the proposed drug product and each listed drug that the applicant seeks to rely upon to demonstrate that reliance on the listed drug is scientifically justified."
  • "To the extent that the listed drug and the drug proposed in the 505(b)(2) application differ (e.g., a product with a different dosage form or a product that is intentionally more bioavailable than the listed drug), the 505(b)(2) application must include sufficient data to support those differences."
  • "If FDA has approved one or more pharmaceutically equivalent products18 137 in one or more NDAs before the date of the submission of the original 505(b)(2) application, the 505(b)(2) applicant must identify one such pharmaceutically equivalent product as a listed drug (or an additional listed drug) relied upon but need not provide a scientific bridge to that product unless it is scientifically necessary to support approval."
Quotes
  • "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."
  • "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."
Quotes
  • "People who are interested in drug development may be aware that New Drug Applications (NDA) and Abbreviated New Drug Applications (ANDA) are 2 of the FDA’s regulatory pathways for how prescription drugs can be approved and ultimately reach the market. In basic terms, NDAs are for new drugs that have not yet been approved and ANDAs are for generic products. However, there is an additional pathway that’s a hybrid between the 2 known as 505(b)(2)."
  • "NDA, also called 505 (b)(1), is the format that manufacturers use to bring a formal proposal to the FDA that a new drug should be approved and made available for use by patients in the United States. The NDA includes a great deal of information about the drug being evaluated including the ingredients, how it’s made, pre-clinical (animal model) study results, clinical trial results in humans, what the drug does in the body, and how it will be packaged."
  • "ANDA is used to gain approval for a generic version of a drug that is already on the market. Earning approval through this pathway involves the manufacturer providing evidence to the FDA that the generic product is comparable to the currently approved product through analytical chemistry and bioequivalence evaluations. The approved indication, dose route, and strength for the generic will be the same as the original (or reference) product."
  • "The 505 (b)(2) pathway provides manufacturers who have certain types of drugs with an opportunity to acquire FDA approval without performing all the work that’s required with an NDA. These drugs are not strictly generics, but are often not entirely novel new molecular entities either. 505 (b)(2) can be an option for drugs with a new aspect related to indication, dosage form or regimen, strength, combination with other products, or other unique traits."
  • "A key feature of the 505 (b)(2) pathway is that it allows a manufacturer to submit their product for FDA review by including data and/or study results originally collected by another manufacturer or researcher. The manufacturer of the 505 (b)(2) eligible product needs to build a connection between their version of the product, or the active ingredients in it, and the reference product. For example, this could include data and results of bioanalytical testing, pre-clinical studies, or even clinical trial results."
  • "If successful in their effort to include supporting evidence from other researchers in their submission, the manufacturer of the 505 (b) (2) candidate won’t have to re-run these studies themselves. While the 505 (b) (2) path allows for using the research of others as a component of their FDA submission, the manufacturer of the 505 (b) (2) product may still need to complete some of their own research in other areas to help fulfill all the various requirements of the FDA to earn approval."
Quotes
  • "The 505(b)(1) regulatory pathway is the traditional New Drug Application (NDA). This pathway is used to obtain the approval of a new drug whose active ingredients have not previously been approved. As you can imagine, this type of submission requires extensive research including both clinical and nonclinical studies to prove the product’s safety and efficacy for the indication being sought."
  • "The 505(b)(2) regulatory pathway is another type of NDA submission that can be used to obtain the approval of a new drug. This type of submission differs from the 505(b)(1) NDA in that the product in question contains similar active ingredients to a previously approved drug. As such, the data included in the submission can rely, at least partially, on the Agency’s findings of safety and effectiveness related to another product."
Quotes
  • "Section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act is intended to streamline the development and U.S. Food and Drug Administration (FDA) approval of pharmaceutical products that incorporate already-approved pharmacological agents. This provision was meant to encourage innovation and reduce the amount of duplicative research required for the approval of a clinically significant improvement to a well-characterized chemical entity."
  • "The 505(b)(2) regulatory pathway provides for FDA approval of a drug based in part on data that was not developed by the sponsor of the application, including published literature references and data previously reviewed by the FDA for the approval of a separate application. The scope of data from a prior application that can be referenced by a new sponsor is determined with FDA input and can include part of the required preclinical or clinical studies for approval."
Quotes
  • "Camargo Pharmaceutical Services is the most experienced global strategist providing comprehensive drug development services specialized for the 505(b)(2) approval pathway and analogous European processes. By assessing the scientific, medical, regulatory and commercial viability of product development opportunities, Camargo systematically builds and executes complete development plans that align with business strategies and that ensure FDA buy-in every step of the way."