There is still an ‘innovation imperative’ whereby priority-rated new drugs in the US are likely to get more attention and faster approvals from the Food and Drug Administration.

But evidence suggests priority review status is increasingly hard to obtain, while the percentage of priority New Drug Applications (NDAs) gaining first-cycle approval has dropped sharply, notes a new white paper from Parexel Consulting.

The white paper, The Innovation Imperative in the Safety First Era, is Parexel Consulting’s second annual review of the FDA approval process. In particular, it assesses how new provisions in the Food and Drug Administration Amendments Act of 2007, including Risk Evaluation and Mitigation Strategies (REMS) and other safety-first requirements, as well as issues such as the FDA’s workload and staffing challenges, are playing out in the approvals arena.

In an inaugural executive briefing published in September 2008, Parexel Consulting highlighted:

- A decline in the pending NDA workload to at a 25-year low
- An upturn in first-cycle NDA approvals, in some cases to record levels
- A “sudden and stunning” downturn in the proportion of NDA resubmissions obtaining FDA approval in subsequent review cycles

“Much has changed in the intervening 12 months,” the new white paper comments. One marked improvement has been a surge in the number of NDAs pending at the FDA. At the beginning of 2009 the agency had 147 pending NDAs under review, considerably more than the 86 pending a year earlier and the largest volume since 1995. There was a 22% increase in original NDA submissions during 2008.

All the same, that is not necessarily a fillip for innovation. There were 26 approval applications for new molecular entities (NMEs) in 2008, down from 30 in the previous year. Nonetheless, the 2007 figure was a considerable improvement on the 21 NMEs filed for US approval in 2006. And last year’s tally of 26 was in line with the average number of NME submissions during the 2000s, Parexel Consulting points out.

Another indication that innovation is alive and well in pharmaceuticals is a Pharmaprojects analysis from May 2009, which showed that 60% of drugs in Phase I or II trials and nearly 40% of drugs in Phase III trials involve novel or ‘unproven’ targets.

First-cycle approvals

As far as first-cycle FDA approvals are concerned, the Center for Drug Evaluation and Research (CDER) cleared 44% of fiscal year 2008 NDAs in the initial review cycle (to 1 April 2009), roughly the same as in FY2007 (45%). The year before that saw the FDA set a user fee-era record by granting first-cycle approvals to 51% of original NDAs submitted in the FY2006 cohort.

As Parexel Consulting observes, the implications of a first-cycle review for time-pressed pharmaceutical companies are “enormous”. With NMEs cleared in 2008, the overall approval time for applications that made it through in a single review cycle was on average 22.2 months shorter than for NMEs requiring multiple cycles.

One marked development in FY2008 was that the first-cycle approval rate for priority NDAs had reached only 50% as of 1 April 2009. This was on the back of a four-year rise in the first-cycle approval rate for priority NDAs, hitting a peak of 70% for the FY2007 cohort.

The tally for the last fiscal year was the first time in three years that the approval rate dipped below 60% and the lowest rate since the FY2001-FY2003 period, when the drug review process was shaken by a series of high-profile product withdrawals, Parexel Consulting notes.

Emerging FDA data also show the agency is significantly less likely to grant priority review status than it once was. After according the status to 30% of original NDAs filed in FY2005 (a many-year high), the FDA designated only around 20% of applications in FY2006-FY2008 for priority review. During the first five months of FY2009, only 8% of original NDAs filed for review had gained priority status.

More encouraging was the approval trend for NDA resubmissions following the slump observed in last year’s executive briefing. By mid-2009, the new white paper says, “the review fates for NDA resubmissions had roughly normalised with those typical in previous years”.

Missed targets

One other source of concern is the growing number of missed NDA review targets and what that means for application outcomes. For workload and staffing reasons, CDER officials agreed last year for the first time under the user-fee programme to let the centre’s review divisions miss their PDUFA application review goals in some circumstances.

As of 1 April 2009, the white paper notes, the CDER had missed its review targets for 17% of FY2008 New Drug Applications/Biologics License Applications (BLAs), up from 12% for the FY2007 cohort. The overdue figure for FY2008 priority NDAs/BLAs was 36% compared with just 10% for the FY2007 cohort.

CDER officials have presented data showing that, as of 31 October 2008, 60% of original NDAs with overdue reviews had received first-cycle approvals. But among the four overdue FY2008 priority NDAs/BLAs on which the CDER has taken first-cycle action, Parexel Consulting points out, only one has been approved.

Despite these negative trends, there remains “strong and powerful” evidence that the innovation imperative will continue to be a key factor in regulatory and reimbursement reviews, Parexel Consulting believes. The disparity in approval times between new drugs that obtain a first-cycle approval from the FDA and those that do not “suggests that the quality of the NDA submission should supersede other considerations”, the white paper says.