New Drug Application on the Shoulder of Giants -505 (B)(2) Pathway

A dwarf stands on the shoulders of a giant and can see farther than the giant, an old proverb that emphasizes the importance of making use of the inventions of previous generations. This is better understood by drug manufacturers, who are increasingly relying on existing drug discoveries to obtain permission to improve existing reference drugs, such as new indications, new dosage forms, new formulations and new combinations.

The 505 (B)(2) licensing pathway, established under the 1984 Hatch-Waxman Amendment, allows the sponsor to rely in part on published literature and research not conducted by the sponsor to support the safety and effectiveness of the program. The purpose of introducing this approach is to avoid unnecessary duplication of research and to minimize the time and money wasted in obtaining FDA approval.

Section 505 of the U.S. Food, Drug, and Cosmetic Act distinguishes between applications that contain complete safety and efficacy studies (505 (B)(1)) and applications that contain complete safety and efficacy studies but require permission to obtain at least some of the information from studies conducted by or for the applicant and the applicant has not been granted the right to refer to these studies (505 (B)(2)).

The 505 (B)(2) pathway is becoming increasingly attractive to manufacturers and can be described as an intermediate pathway between a new 505 (B)(1) application and an abbreviated new drug application (ANDA). This approach can shorten the development time and cost, and obtain 3 to 5 years of market exclusive rights, unlike generic drugs with only 180 days of exclusive rights. This path also applies to orphan drugs or children's drugs.

Since 2002, applications approved through 505 (B)(2) have steadily increased, while applications approved through 505 (B)(1) have declined.

ideal candidate direction

The 505 (B)(2) application is applicable to a variety of products, and it is applicable to 5 categories of drugs: one is a new indication; the second is a new combination containing previously approved active ingredients; the third is a new formulation or a new manufacturer; the fourth It is a change in dosage form, specification, route of administration or dosage regimen; five is a change in active ingredient (such as a different salt), or a higher amount of active ingredient.

In contrast, new molecular entities (NME) may benefit from the 505 (B)(1) mechanism. For FDA approval applications in 2014, NME almost all uses 505 (B)(1), while dosage form changes, new combinations, formulation or manufacturer changes, and drugs listed without approved NDA are more commonly 505 (B)(2).

The other side of the coin.

However, the 505 (B)(2) mechanism has its inherent challenges, and this approach may not necessarily ensure a faster application process. In 2014, for applications that did not grant any accelerated review (such as priority review, accelerated approval, breakthrough naming, fast-track approval), the approval time of 505 (B)(2) was shorter than that of 505 (B)(1); However, for accelerated applications, the median approval time of 505 (B)(1) is shorter. This means that 505 (B)(1) will be more attractive if the sponsor can enter the accelerated review process by initiating NME.

In terms of time savings, one reason why the expedited examination approach is more advantageous than the 505 (B)(2) approach is that due to the patent or exclusive rights protection of the reference drug, the filing of the 505 (B)(2) application may be delayed because the applicant filing the 505 (B)(2) application must provide proof of the patent. In general, 505 (B)(1) applies for a patented active ingredient and its formulation, while 505 (B)(2) applies for a patented new formulation, combination or use, but the active ingredient is not patented.

In addition, to ensure the effectiveness and safety of 505 (B)(2) applications, FDA may require additional research, which may result in unintended costs and delays.

Pros and Cons

A complete new application requires extensive preclinical and clinical research support. The sponsor must carefully consider the cost of all these trials, and there is no guarantee that final approval will be possible. In this sense, the risk of seeking 505 (B)(2) is lower because the validity and safety information of the application already exists. An increasing number of sponsors are considering 505 the (B)(2) pathway because they cannot afford to submit a complete application, as evidenced by the increasing number of 505 (B)(2) applications approved by the FDA.

This method of saving time and money is regarded as the "third way", which can enable applicants to avoid competition in the generic drug market and avoid the long-term pre-clinical and clinical trials required by the 505 (B)(1) application. 3 to 5 years of market exclusive rights is undoubtedly an attractive incentive.

However, the challenges and uncertainties inherent in 505 (B)(2) mechanism should not be underestimated. Submitting 505 (B)(2) applications may not save time. Judging from the data analysis of approved applications in recent years, the time saved by this path is almost negligible.

Sponsorors must carefully weigh the pros and cons of each mechanism. In selecting pathway 505 (B)(2), consideration should be given to the extent of research that FDA may require and the additional data that may be needed to support the proposed change. In addition, the issue of intellectual property rights is a potential problem and will delay the approval of the application.

Therefore, while the 505 (B)(2) approval pathway is becoming more and more attractive, it is still necessary for the sponsor to proactively engage with FDA to estimate the amount of new data that needs to be added to the submission to minimize the uncertainty of this mechanism and ensure a smooth approval process.

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