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RPM Report – Regressing to the Mean: FDA Innovative Drug Approvals Drop Back to “Normal” Levels

RPM Report – Regressing to the Mean: FDA Innovative Drug Approvals Drop Back to “Normal” Levels

Last year’s 39 NME approvals is not the “new normal,” Office of New Drugs Director John Jenkins declares. FDA approved just 27 NMEs in 2013. The return to normal also included a quiet December.

For better or for worse, the number of new molecular entity approvals is the most widely cited statistic for gauging whether it was a “good” year or a “bad’ year for the drug industry at FDA.

Thus, the headlines weren’t too surprising when January began: FDA approved “just” 27 NMEs in 2013, a pretty steep drop off from the near-record tally of 39 in 2012. That may not be fair, but, if you are going to get great headlines when approvals spike, there are also bound to be negative headlines when they fall by a third from the prior year.

Thankfully, there is no reason to believe that FDA is suddenly operating at just 70% of 2012 efficiency, or that industry has become 30% less innovative in only a year. The fact is that approval trends fluctuate all the time, and the only meaningful analysis has to look at longer term trends.

As Office of New Drugs Director John Jenkins put it during last month’s FDA/CMS Summit for Biopharma Executives, 27 NME approvals makes 2013 a pretty normal year. By his calculations, FDA has averaged 26 NME approvals per year over the last decade, and 28 per year in the past five years.

The RPM Report tracks a different metric: Innovative Commercial Therapeutics (ICTs), intended to identify truly novel molecules developed for commercial use as therapeutics. In other words, no imaging agents, active metabolites/prodrugs, or “biosimilars.”

The idea is not to diminish the medical or commercial importance of line extensions or other less innovative molecules. Rather, the goal is to flag new products whose active ingredient was not previously known to be safe and effective in humans for any medical use—the highest bar for regulatory success.

Using the ICT metric, the picture is essentially the same as the one Jenkins paints for NMEs overall. Four of the 27 NME approvals do not qualify as ICTs: one pro-drug (Sunovion Pharmaceuticals Inc.’s eslicarbazepine) and three imaging agents. (See box.)

That leaves 23 ICT approvals – exactly in line with the average over the last five years and just a bit higher than the average over the past 10 years (22 ICTs). (See Exhibit 1.)

Back to “Normal”

In fact, Jenkins seemed to be doing his best to pre-empt the narrative that 2013 will be a “down year” for approvals. Rather than focus on how far short FDA will fall from last year’s tally of 39 NMEs, Jenkins hopes that people will recognize the final number as more in line with recent trends – where approvals track with filings, and do seem to be trending modestly higher over time.

Jenkins’ 2013 presentation (delivered December 11) had one very important difference from the 2012 version: this year, Jenkins did not promise a surge in year-end new molecular entity approvals to match the incredibly busy closing days of 2012. Indeed, Jenkins’ comments last year stood out at the time, since the recent pattern has been for the new drug approval flow to be very light in the closing month of the year.

Not surprisingly, Jenkins’ prediction proved correct: FDA approved eight NMEs in the final three weeks of the year to end at an eye-popping 39. (“FDA’s Very Big Year: Drug Approvals Approach Record Levels” — The RPM Report,January 2013)

And, indeed, there was no similar rush in 2013. FDA had approved 26 NMEs at the time Jenkins spoke, and approved just one more in the last three weeks of the year, for a final tally of 27.

[Editor’s note: A replay of FDA Office of New Drugs Director John Jenkins’ annual state-of-the-drug-approval-process presentation during the FDA/CMS Summit for Biopharma Executives is available at]

Thirty-nine approvals, Jenkins stressed, is “not the new normal.” Instead, he argued, with 26 NME approvals as of December 11, FDA is in fact having a “normal” year. He cited a 10-year average of 26 NME approvals per year, and an average of 28 in the most recent five years.

Jenkins stressed the idea that this is nothing more than a “regression to the mean” – and not an indication of a sudden shift in attitude at the agency.

He did highlight some structural factors that may be affecting the numbers as well, including a “phase shift” caused by the launch of the new “Program” for NME reviews, which in effect adds two months to the review timelines for applications filed after October 1 – creating a de facto two month “gap” in the flow of approvals that fell in the midst of 2013. (“FDA “Program” Reviews Are Positive So Far, But Are They Sustainable?” — The RPM Report, January 2014)

There may be another impact of the “Program” as well: hampering the ability of FDA to deliver ahead-of-schedule approvals. That has been almost commonplace in oncology, but Office of Hematology & Oncology Products Director Richard Pazdur sounds like he is finding the new timelines around communication for NME reviews to be a potential source of delay rather than acceleration. (“Cancer Therapies: The Breakthrough Era” — The RPM Report, January 2014)


ICT Approvals Since 1996

Click image to enlarge

Source: The RPM Report

Jenkins also noted that there are fewer resubmissions coming due in 2013 as well – a direct result of FDA’s amazing 2012 performance, where the agency essentially cleared the cupboard of resubmissions while also hitting a record high on first-cycle approvals.

That is all fairly reassuring, and places the emphasis squarely where it has been over the past decade: on the number of applications coming in to FDA, rather than on the number going out.

According to Jenkins, FDA has received 32 NME submissions so far in 2013 – suggesting that the agency will end the year below last year’s 41 NME filings, and more in line with the recent average of about 35 per year. (See Exhibit 2.)


NME Filings and Approvals

Click image to enlarge

Source: Presentation by FDA’s John Jenkins, FDA/CMS Summit for Biopharma Executives, Dec. 11, 2013

The first-cycle approval rate remains relatively high compared to historic trends. However, Jenkins’ data do show a dip on one key measure: the first action approval rate for NMEs in 2013 is at 60% – down from the 80% mark the past two years.

That is not too surprising. The remarkable number is the 80% first action approval rate for the last two years, since that is essentially the same as FDA’s historic overall rate of approval for NME filings after as many cycles as it takes. In other words, over the last two decades, four out of five NME filings will eventually be approved even if they aren’t cleared the first time around—or (for you glass-half-empty-types) one out of five simply never will be approved.

The amazing thing is that FDA was able to make that approval decision for virtually every NME filing on the first cycle in the past two years. That does seem to have changed a bit in 2013, but it was probably unrealistic to expect FDA to continue that level of performance indefinitely.

Of course, that means there will likely be more resubmissions in 2014 for FDA to review and approve – and less reason for FDA to worry about how the data will be interpreted.

A Quiet December, and a Troublesome Long Term Trend

There was another return to normal in 2013: the lack of a last-minute surge in December. Glaxo Wellcome PLC/Theravance Inc.’s Anoro Ellipta was the only NME cleared after Jenkins’ December update, and joined Gilead Sciences Inc.’s Sovaldi as one of just two NMEs approved in December. That compares to eight December approvals a year ago, including five in the last 10 days of the year.

Before the user fee era, December used to be the busiest time for new molecular entity approvals, with a third or more of the annual total coming in the last month of the year. More recently, however, December has been a quiet month, with approval deadlines tied much more to filing cycles rather than year-end desk-cleaning.

In fact, several of the 2012 year-end approvals were well ahead of review deadlines – and thus would normally have “counted” as 2013 approvals, further smoothing out the apparent “drop” this year.

Of course, there is also a less reassuring way to look at the “return to normal” in approvals for 2013: it makes clear just how much of an outlier the 39 NME tally in 2012 really was – and how little evidence there is to support the optimism that industry R&D is recovering.

With 24 ICT approvals, the output from industry R&D is clearly better than the crater experienced during the last decade. ICT tallies were in the teens six times between 2002 and 2010, with a low of 14 ICTs in 2007. Compared to those levels, 24 looks like a pretty healthy number.

But approvals still lag behind the routine figures posted in the 1990s.

ICTs averaged 31 per year from 1996-2002, and with the exception of 2002 (19), there were more than 24 every single year.

Put another way, the “new normal” for approvals is still about 10 novel therapies a year lower than the “old normal,” and that innovation deficit will continue to challenge the industry for years to come.…;