A 505(b)(2) application is a new drug application that requires full safety and effectiveness reports, but allows some of the information required for approval to come from studies not conducted by the applicant. This approach can lead to faster approval, and at less expense, compared to that required for traditional 505(b)(1) new drug applications (NDAs). Unfortunately, sponsors seeking to develop products using this pathway have little FDA guidance. The only 505(b)(2)-specific guidance was issued in draft form in 1999, leaving sponsors to rely on 505(b)(1) guidance, which many times is inadequate or overkill for modifications to already marketed drugs. To fill this gap, the FDA encourages sponsors to meet with the agency very early in the development of the product.
 
To determine the development requirements for 505(b)(2) products, the best time to discuss approval requirements is at a pre-investigational new drug (PIND) meeting. A well-conducted PIND meeting can result in a strategic plan that defines the steps needed to bring a product to development while a failed meeting can result in time and money wasted due to clinical holds, duplicated or unnecessary studies, or even a rejected NDA.
 
The goal of the 505(b)(2) PIND meeting
The purpose of the PIND meeting is to review with the FDA the data from the public literature and the additional studies (the gap), if required, that are needed for NDA approval. The idea is to convincingly demonstrate to the FDA which public data can be used to support your application and gain its agreement that your development program is adequate for the product you are trying to develop. Inclusion of public data to fulfill some of the NDA requirements allows the sponsor to propose alternate study designs that can, in many cases, be much smaller than typical studies used for 505(b)(1) applications. A successful PIND can save time and money by outlining a pathway that requires less expensive studies and that also can strengthen the possibility for the future success of the program at the application phase.
 
How to prepare for a PIND meeting
I recently moderated a roundtable discussion on this topic at a meeting of the American Association of Pharmaceutical Scientists (AAPS). The panel included two experts from the FDA who work in the area of 505(b)(2) applications. We had an enlightening discussion of how to prepare questions and a submission package for a PIND meeting, how to conduct the meeting and how to respond to FDA feedback. All the participants agreed that preparation is the most important part of the process. The PIND meeting is only 50 minutes, and no additional information can be added during the meeting; so, everything must be in place before it starts.
 
The first step is to put together a meeting request with the questions you want the FDA to consider. This must include all of the relevant questions necessary to define the entire development program. Failure to ask all the questions at the PIND stage may mean that the FDA will not have what it needs to connect the dots between the public literature and the clinical studies during the IND process or at the time of the application for approval.
 
It is also important that the FDA review discipline being addressed by the question is clearly stated in the meeting request. The FDA panelists at AAPS said they are frequently frustrated by requests that are not clear about the review discipline needed. When this occurs, sponsors either fail to get their questions answered or create a situation in which the FDA is left scrambling at the last minute to have the correct FDA reviewer at the meeting to address the question.
 
Next is the meeting submission package. This contains all the supporting information that justifies the position the sponsor is taking on the public literature being proposed for the development program. In turn, this information is used to justify the design of the trials that are being proposed by the sponsor. The presentation of the public data you will rely upon as part of your application is key. The FDA cannot consider the validity of your supporting literature if it is only provided as a list of relevant references. FDA reviewers want to see that you have evaluated the strength of the data, and they need for you to clearly demonstrate your data’s validity as a bridge to your studies. For this, you need to lay out the data, both favorable and unfavorable, in tables and figures that show how the data relate to your development program or, in the case of unfavorable data, why that information doesn’t apply to your product.

Finally, many sponsors don’t take advantage of the preliminary written feedback provided by the FDA prior to the meeting and don’t get their replies back to the product manager before the PIND meeting. According to the FDA panelists, this type of misstep is completely avoidable and diminishes a sponsor’s chances of having a successful PIND meeting.
 
Once the meeting has started, it must be run efficiently to get through all the relevant questions in the allotted time. The sponsor must conduct the discussion to be sure to get FDA agreement on the studies to be developed, including study design and endpoints, as well as on the public information that can be used as part of the application. For instance, if the new 505(b)(2) product involves a new dosage or new combination of an already approved drug, it is important to discuss what data are needed to create a bridge between the approved listed drug and the proposed product. In addition, it is important to come to an agreement on an acceptable indication for testing, particularly if the listed drug was approved for a number of indications.
 
Unlike a 505(b)(1) application in which the PIND meeting is used to define animal studies and the scope of Phase I studies, the 505(b)(2) PIND meeting is used to define the entire development program. Careful planning and hard work at this stage can reduce the likelihood of devastating surprises later and increase your chances of success for a 505(b)(2) NDA.


Ken Phelps applied more than three decades of industry experience to found Camargo Pharmaceutical Services in 2003. As an expert in drug development and the industry authority on 505(b)(2) drug development, Ken leads a team that has guided more than 200 FDA approvals and has the largest percentage of 505(b)(2) submissions of any team submitting to the FDA. He hosts a yearly seminar in Israel geared toward the opportunities 505(b)(2) presents for global companies and routinely presents on the financial challenges caused by the generic cliff.