Analysis of Review Times for Recent 505(B)(2) Applications
The Approval Fourth dimension for 505(b)(2) and 505(b)(1) NME Products Is Similar
A recent article by the Tufts Center for the Study of Drug Evolution (summarized here) reported that approval times for New Molecular Entities (NMEs) canonical via the 505(b)(two) pathway are almost 5 months longer than that of NMEs approved by other pathways, 505(b)(i), or 'traditional' NDAs. Unfortunately, this misleading conclusion was based on a small number of approvals that included i outlier that required 5 review cycles and 94 months to blessing. Removing this outlier would have led to the appropriate conclusion that the approval time for 505(b)(2) NME products is in fact similar to those of 505(b)(1) NMEs.
That review times are similar for products canonical via 505(b)(1) and 505(b)(2) pathways is well known, as both pathways are subject to the same rigorous review processes and PDUFA commitments. The real time and cost saving for 505(b)(two) products comes from reduced development programs due to smaller and/or fewer studies rather than abbreviated review times.
Here, we use Premier Consulting's proprietary 505(b)(2) database to look into the most common reasons for delayed approval times and we report that Chemistry, Manufacturing, and Controls (CMC) deficiencies elevation the list. Time and time again, we see that a thorough understanding of the 505(b)(2) pathway could have prevented costly delays in approval times.
505(b)(2) Products Approved in I Review Cycle
Of the applications approved via the 505(b)(2) regulatory pathway from 2009 – 2015, 64.5% were approved with merely 1 review cycle. In some of these cases, preventable review delays occurred due to Turn down-To-File determinations, and the need to submit major amendments.
Common Reasons for Additional Review Cycles
Of the remaining applications in which more than one review cycle was undertaken, a staggering 73.2% involved CMC deficiencies. In 33.0% of applications, CMC deficiencies were the but factor in triggering a second or subsequent review cycle/southward. It is a common misconception that CMC requirements are reduced for 505(b)(ii) products compared with 505(b)(1). Stay tuned for our follow up weblog for greater detail on CMC requirements.
Other common reasons for boosted review cycles were issues with 505(b)(2) strategy (37.ane%), and with demonstrating bioequivalence/conducting comparative bioavailability studies/scientific 'bridging' to other products (21.6%). These cardinal concepts in 505(b)(two) development programs are unique from 505(b)(ane) programs and crave experience to go right the first time.
Other reasons for delays within the Sponsor's control included formal dispute resolutions (4.one%), reject-to-file determinations (three.0%), and information integrity bug (Application Integrity Policy, 2.1%). Delays that were largely out of the Sponsor's control included changing standards (regulatory and/or clinical) including the need for advisory committee recommendations (9.3%), tentative approvals awaiting patent expiration (3.one%), or citizen petitions filed by Sponsors with competing products (1.0%). However, such delays rarely resulted in a new review bike. Annotation that these numbers add up to more than 100% as some products were delayed for multiple reasons.
Outliers
Within the data, several outlier 505(b)(2) applications had much longer approval times. For instance, a production that was approvable from a clinical efficacy and rubber perspective in the beginning review cycle was found to take major CMC deficiencies that dragged the program out for 4 additional review cycles with a resulting approval fourth dimension of nearly 8 years! Farther, this product failed to obtain orphan exclusivity upon approval, as another product had beaten it to the punch by the approval date. Such costly mistakes could have been avoided with CMC oversight from individuals experienced in 505(b)(2) programs.
Within the period analyzed in the commodity (2009 – 2015), the longest 'review time' was just under 12 years. For most of the first half-dozen years of the 12-twelvemonth review fourth dimension for this single product, the review was suspended, equally the awarding was placed under Awarding Integrity Policy for issues relating to data integrity.
In both of these examples and for many other products, demonstrating the clinical rubber and efficacy of the proposed products was non a factor in the delayed approval time.
Effect of Priority Review on Approval
The Tufts assay found that priority review had no beneficial effect on approving fourth dimension for 505(b)(two) products. Unfortunately this is truthful for Sponsors that do not get their 505(b)(two) strategy right early on in the development plan. However, nine of 33 (27.2%) products that were granted priority review were approved within 6 months via the 505(b)(2) pathway. In each of the remaining cases, the approval filibuster was due to deficiencies in the application. We cannot emphasize enough the importance of submitting a complete application based on audio strategy and with all required studies and appropriate pharmaceutical quality (CMC) information, especially if a Sponsor is hoping to enjoy the benefits of priority review.
Misconceptions on 505(b)(2) Approvals
As mentioned above, we note that with a thorough understanding of how the 505(b)(ii) regulatory pathway works, shorter review/blessing times are not expected for 505(b)(2) programs. The existent reward of the 505(b)(2) regulatory pathway is in the reduced scope of the evolution program. This translates into savings in time and cost for the Sponsor. Only the review standards for 505(b)(2) programs are as rigorous as those of a 505(b)(ane) NDA.
Secondly, the Tufts assay compares products approved by the 505(b)(ii) regulatory pathway with that of NMEs. All the same, it is important to empathize what a 505(b)(2) is and isn't in such a comparison, as a 505(b)(2) product tin also be an NME. Further, some not-NME products are approved via the 505(b)(1) rather than the 505(b)(ii) pathway. This helps to explain why the authors believe that "505(b)(2) review time goals mandated in PDUFA V for 505(b)(ii) applications are 2 months shorter than for NMEs." In fact, the PDUFA 5 goals distinguish between review times for NMEs (within 10 months of the threescore-solar day filing review) and non-NMEs (inside 10 months of receipt) nether standard review (or within 6 months of the sixty-twenty-four hour period filing review vs. 6 months of receipt for NMEs and not-NMEs under priority review). And then although many non-NMEs are 505(b)(two)southward, it is an overstatement to suggest that 505(b)(2)s per se should exist discipline to shorter review times.
The same lack of understanding of the 505(b)(2) approval pathway causes the authors to state that "505(b)(two) applications rely heavily on data for previously approved drugs." The authors cite this as a reason to look shorter blessing times for 505(b)(2) products. However, some approvals via the 505(b)(two) pathway do not rely on previously approved drugs. Some rely solely on reports in the literature. This explains why any departure in filing/review times is applicative to NMEs vs non-NMEs rather than 505(b)(2) vs NMEs.
The Tufts analysis noted that the hateful review time for the 11 NMEs submitted via the 505(b)(two) regulatory pathway was 55% longer than that of not-505(b)(ii) NME approvals. The distribution of review times for the eleven 505(b)(2) NMEs ranges from three to 94 months, with a hateful of 20.3 months (median 13.0 months; Tabular array 1). The product with the longest review/blessing time took more than five years longer than the side by side longest review time (26 months, Product 11). As discussed above, this product was approvable in the commencement review bicycle with the exception of CMC deficiencies that took four more than review cycles to resolve. When this outlier is excluded, the mean review time for 505(b)(ii) NMEs drops to 12.9 months, like to that of non-505(b)(2) NMEs (thirteen.8 months).
It is likewise worth mentioning that the article divers approving time equally the time from submission of the NDA to approval of the product. However, this includes Sponsor response time to FDA deportment, and time for which review was suspended. For many of the applications with the longest approval times, Sponsor response times were significant.
Farther, the authors did non specify if the elapsing between tentative approval and last approval was included in their calculation of approval fourth dimension. It is worth noting that nigh formal review is complete at the fourth dimension of tentative approval and that the remaining time is attributable to patent expiration issues with the listed drug rather than delays in FDA review or Sponsor responses. Tentative approval affects the final approving time of some 505(b)(two) and generic (505(j)) products, only not 505(b)(1) products.
Summary
There are many reasons why products canonical via the 505(b)(2) pathway experience more than 1 review cycle and lengthy delays between cycles. Near of these reasons relate to CMC, development strategy, and pharmacokinetic studies. Almost all of these delays were preventable with proper oversight of the evolution program by individuals with expertise in 505(b)(2) approvals. As nosotros recently blogged, information technology is critical to get 505(b)(2) strategy right the showtime time, particularly at the Pre-IND meeting, to salvage on time and costs. Premier Consulting's 505(b)(two) experts have broad experience in CMC, strategy, gap analyses, and pharmacokinetic studies resulting in reduced approval fourth dimension for Sponsors.
To talk to us virtually strategy for your 505(b)(2) product or how to minimize review cycles, read more here or contact us.
Authors:
Angela Drew, PhD
Production Ideation Consultant
Kristi Norris, PhD
Senior Scientific and Regulatory Manager
Wen-Yee Choi, PhD
Scientific and Regulatory Managing director
Source: https://premierconsulting.com/resources/blog/505b2-approval-times-the-real-scoop/
0 Response to "Analysis of Review Times for Recent 505(B)(2) Applications"
Post a Comment