The § 505(b)(2) New Drug Application Safety Paradox

By: Edward Allera
Chairman of The 505(b)(2) Platform 
The New Drug Landscape
FDA approves approximately 120 new drug applications (“NDAs”) annually.  Of these, applications submitted under § 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (“FFDCA”) constitute the majority of NDAs filed (70%) and approved (60%) each year.  Although the sample size is not extensive, these data are important to both FDA and the individual companies that file or contemplate filing a § 505(b)(2) NDA.  These figures illustrate the fact that sponsors are increasingly developing drug products that are not new chemical entities (“NCEs”) but, rather, rely upon certain data and information that is already known about drugs that FDA previously approved.  These data also highlight the fact that FDA is increasingly  asking for “new” data that will be required to approve a § 505(b)(2) NDA.
In the case of § 505(b)(1) NDAs, the primary reason that these applications fail—both today and historically—is due to the sponsor’s failure to establish the correct dosage.  This is a well-known phenomenon that can cut an otherwise promising § 505(b)(1) development program short as the sponsor works to restart and recruit more patients to its clinical trial program.  The associated costs concurrently increase as does the lost opportunity cost.  Likewise, our research suggests that § 505(b)(2) NDAs face an analogous problem that accounts for many of the failures of these particular applications that arise even before an NDA is filed—namely, the Safety Paradox.
The Safety Paradox
In the case of § 505(b)(1) NDAs, FDA approves a particular drug containing a particular active moiety for a particular indication.  The NDA safety package for an NCE is centered on these and other characteristics.  All too often, however, a § 505(b)(2) sponsor concludes that FDA’s historical safety assessment of the NCE (i.e., the reference drug) will satisfy the safety requirements for the § 505(b)(2) NDA.
Sponsors are often enamored with the potential new use of the drug, often after studying the drug for a number of years.  The entity becomes like their child; they see only the positive side.
What § 505(b)(2) sponsors frequently fail to realize is that drug safety is not static.  The reference drug’s post-approval adverse event profile and pharmacovigilance data may reveal safety signals that require addressing in the § 505(b)(2) NDA.  Furthermore, the product or indication changes that a § 505(b)(2) sponsor introduces in its own drug development package means that the § 505(b)(2) NDA will need to include new safety data reflective of these changes despite the fact that the drug has already been shown to be safe by adequate tests by all methods reasonably applicable to show if the drug is safe.- hence the Safety Paradox.  
The Safety Paradox slows the road to § 505(b)(2) NDA approval, leading to unexpected delays.  Often these delays can be anticipated, and therefore minimized or eliminated, with careful planning during the § 505(b)(2) NDA drug development process.
Why the Safety Paradox?
The approval of a § 505(b)(1) NDA for an NCE does not provide a § 505(b)(2) sponsor with carte blanche to rely upon the reference drug’s safety package without it developing new safety data that reflects the change(s) introduced into the product or its use.  For example, a change in patient population, dosage form, dosage strength, route of administration, length of use, or indication which is the essence of a § 505(b)(2), creates different questions and may require §505(b)(2) sponsors to develop new safety data related to the change.
Moreover, § 505(b)(2) sponsors must be cognizant of what safety events may have arisen since FDA approved the reference drug:  Has the drug become a huge commercial success leading to vastly greater patient exposure than anticipated leading for greater patient exposure? Have new safety signals emerged in a given patient user subpopulation?  Has the concomitant use of certain medications led to a spike in adverse event reporting?  What labeling changes has the § 505(b)(1) sponsor introduced since approval that may offer insight into post-approval safety challenges?  As more data on drug usage becomes available after controlled clinical trials are completed and the product is marketed to a broader patient population, the safety profile of any drug will more than likely change.  Further, issues may arise with other drugs in the same therapeutic class.  FDA expects that a § 505(b)(2) sponsor will consider these changes during its own drug development program.
These considerations are particularly relevant if a sponsor anticipates filing a §505(b)(2) NDA for an active moiety that has been approved abroad but not in the U.S.  In this case, the sponsor may rely on studies conducted by others as well as published literature.  However, FDA is often reluctant to accept this type of real world data for drugs marketed outside of the U.S., even when there is a long history of use.  This also creates a potential hurdle to approval that may well result in the need to conduct additional safety studies.  Often applications for U.S. were filed, and a safety issue arose that precluded or discouraged additional clinical work for U.S approval.  Thus is one facing a biased FDA reviewing division? Knowing whether and how much additional safety data will be required can only be addressed by engaging with FDA during the drug development process.
A § 505(b)(1) sponsor faces an approval path that is relatively straightforward, albeit lengthy and expensive.  The amount of preclinical data and the timing of such studies as they relate to the start of clinical trials can vary, but the basic required elements of the safety package and the questions to ask FDA are well-understood.  FDA has issued numerous safety guidance documents for potential sponsors that take into account safety studies for the method of administration, drug-drug interactions, drug-food interactions, fetal exposure, or potential carcinogenicity.
In the case of § 505(b)(2) NDAs, the drug approval path is shorter when the sponsor critically evaluates the type of safety data that is needed well in advance of NDA submission.  Advance preparation, including a thorough safety analysis of the reference drug, is as critical to §505(b)(2) NDA success as is a freedom to operate opinion relative to an active moiety’s patent protection.
           
Conclusions
Filing a § 505(b)(2) NDA is becoming an increasingly attractive option for introducing a drug to the market because of the ability to obtain regulatory exclusivity and to list patents in FDA’s Orange Book.  The Safety Paradox, however, remains an important issue for many § 505(b)(2) sponsors to consider.  To tackle the Safety Paradox, a sponsor must be willing to ask both itself and FDA difficult questions early in development.  Doing so will eliminate or reduce unexpected questions about the drug’s safety profile late in development, and will allow sponsors to proceed in the most timely and cost-efficient manner possible.
As a member of The 505(b)(2) Platform™ we can help you identify the need for a Safety Review and who can help you develop a multi-part analysis for your § 505(b)(2) NDA asset. A proper Safety Review helps minimize the risk of missing existing critical safety information about the reference drug, and develops the necessary additional safety data to support the proposed change to the reference drug. To become a member by registering at www.505b2.org/membership.