​For decades, several basic concepts have driven drug development.  New drug sponsors first developed and received FDA approval for new chemical entities as immediate release tablets dosed two to three times per day.  These first-in-class drugs were seldom the best, and competitors continued to improve the molecules through basic concepts of organic medicinal chemistry, including beta-blockers, H2 receptor blockers, ACE inhibitors, calcium channel blockers, and statins.  Other companies added clinical benefits to improve patient compliance by extending release times to decrease the number of doses required per day, or by developing new topical patch technologies for easy administration of extended release products having lower toxicity.  Congress recognized the value of these improved clinical benefits when, in 1984, it enacted the Hatch-Waxman Amendments which provided sponsors with three-year exclusivity for such changes made to a new chemical entity that had been approved in a § 505(b)(1) NDA.  This three-year exclusivity applied whether the changes were approved in the form of a § 505(b)(2) NDA or a supplement to the original § 505(b)(1) NDA.
 
Although FDA has never specifically defined “conditions of use,” technologies providing improved clinical benefit have served as the foundation for the conditions of use that have been granted market exclusivity.  Learning about disease mechanisms of action has been the focus of research for decades and, more recently, genetic profiling has become increasingly vital for treating certain patients, such as oncology patients.  This information has, in turn, led to new approaches to treat chronic, severe, and life-threatening diseases.  Patient-specific therapies and dosing has led to improved clinical benefit by improving the technologies, tests, and delivery systems associated with patient care.  The competition among drug sponsors and drug developers has become increasingly fierce.
 
In July 2019, the U.S. District Court for the District of Columbia remanded a case to FDA for clarity on the definition of “conditions of use” with respect to the grant of three-year exclusivity.  The issues in this case (Braeburn Inc. v. FDA) go to the heart of § 505(b)(2) NDA development.  Both FDA and the court struggled to develop a standard for “conditions of use” that was not arbitrary and capricious.  The Center for Drug Evaluation and Research’s Exclusivity Committee argued that it has used an “innovation” standard for determining exclusivity eligibility, after struggling with a number of approaches that focused on product labeling.
 
As part of a continuing trend of skepticism over FDA’s scientific and legal decisions, the court was unwilling to grant extensive deference to the Agency’s decision.  Instead, the court has demanded that FDA establish boundaries for what constitutes a drug product’s “innovation.”  Significantly, FDA has concluded now that, at least in this case, the patient population has no bearing on “innovation.”
 
FDA’s decisions in light of this case are going to be critical to § 505(b)(2) NDAs and their sponsors.  These issues merit further industry discussion, and continued engagement with FDA.  What are your thoughts on the scope of exclusivity for § 505(b)(2) NDAs?  Please send us your comments to meetings@505b2.org or to our Linked In page.
The 505(b)(2) Platform™ is the only non-profit industry organization championing the cause of § 505(b)(2) products and their sponsors.  We are leading the way, actively working with the FDA to develop more appropriate guidelines and other issues.  Become a member of The 505(b)(2) Platform and help ensure the continued value of your development program and currently marketed products.

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.