Total NDA/BLA, New Use Approvals Recovered As NMEs Slowed – CDER Report

The declining trend in approval of new molecular entities has not been replicated in reviews of follow-on compounds, new formulations, and new uses, CDER's 2005 Report to the Nation suggests.

After a record-setting 2004, approvals of all NDAs/BLAs and applications for new or expanded uses slipped only slightly, sustaining a strong overall recovery from difficult years in the early 2000s.

These trends may suggest that CDER's efforts to improve the drug review process are having some payoff, despite persistent concerns about the sometimes small cadre of NMEs that are the most closely-watched barometer of FDA's drug review process.

CDER's broad efforts to overhaul its organization and systems are a main theme of the annual Report to the Nation, released Aug. 18 ( ¹ (Also see "Reorganization Is Unifying Theme of CDER FY2005 Report" - Pink Sheet, 15 Sep, 2006.) ).

Improvements, Not Novelty

FDA had been signaling concern over the slowing productivity of the late-stage R&D pipeline even before 2005 produced only 18 NME approvals - the third lowest annual total of the past 25 years. Approvals of new chemical entities declined 47% between 1996-1998 and 2002-2004, Tufts Center for Drug Development Director Kenneth Kaitin, PhD, reported at a Nov. 14, 2005, public hearing on PDUFA.

The transfer of therapeutic biologics to CDER in 2004 has only slightly boosted total approvals of novel agents by the center. Only two novel biologics were approved by CDER in 2005 (² Pharmaceutical Approvals Monthly January 2006, p. 3).

The growing number of late-stage novel product failures - considered a significant factor in declining approvals - may be contributing to a shift by industry to the potentially less risky field of products that improve on existing molecules.

In the cohort of pending NDAs and BLAs with user fees in the remainder of 2006, follow-on type products hold their own with truly novel agents.

Candidates include new variants and derivatives of marketed drugs like J&J's paliperidone, an active metabolite of Risperdal , Sepracor's arformoterol, a single isomer of Foradil , Forest/Replidyne's Orapem (faropenem medoxomil), a faropenem prodrug, Cephalon's Nuvigil (armodafinil), a single isomer of Provigil , and Shire/New River's amphetamine derivative lisdexamfetamine dimesylate ( ³ see related chart ).

Over half of CDER actions on priority NDAs and BLAs, which include NMEs as well as new applications with different chemical classifications, were approvals, the CDER Report shows ( ⁴ see 'Priority NDAs & BLAs' chart ).

The percent of priority NDAs and BLAs actions that are approvals has recovered from its nadir of 37% in 2001, peaking at 69% in 2004 and moderating to 61% in 2005.

Priority NDA/BLA filings have similarly recovered from 2001, when a remarkable low of seven were filed, to 31 in 2004 and 29 in 2005.

Approvals necessarily lag behind filings, and CDER recorded 10-year lows in priority NDA/BLA approvals between 2001 and 2003 with 10, 11, and 14 approvals, respectively, the CDER report shows.

There are, however, signs of recovery in the clearance of priority NDAs/BLAs. Approvals jumped to 29 in 2004, and the decline to 22 in 2005 still places the total within the historical range prior to 2001.

Standard review NDAs and BLAs have followed a different pattern. Filings, for example, have been relatively consistent. From 2000 to 2005, standard filings ranged from 75 to 89; 2001, a dreadful year on most metrics, saw a strong 88 standard NDAs filed ( ⁵ see 'Standard NDAs & BLAs' chart ).

While CDER took a 10-year low number of actions on standard NDAs/BLAs in 2005 (107), the percent of those actions that were approvals (54%) was historically high, marking only the third time in a decade that the approval percentage exceeded 50%.

The year 2004 is an outlier for recent standard NDA/BLA approvals, with 90, as 2005 saw a steep drop back to the total of 58 standard NDA approvals recorded in 2003, and still strong performances in 2002 (67) and 2000 (78). While the 2005 and 2003 approval totals are the same, the pool of applications was not - therapeutic biologics were transferred to CDER in 2004.

Supplemental Approvals Follow Different Pattern

While 2005 was a sharp drop in NDA/BLA approvals compared with 2004, more standard review applications for new or expanded uses were cleared in 2005 (105) than were approved in 2004 (99). Approvals for new or expanded uses have still not returned to the 10-year high of 133 in 2002 ( ⁶ see 'Approvals of New and Expanded Uses' chart ).

After five years of steady climbing to a 10-year high of 237 in 2002, FDA actions on standard review new or expanded uses dropped back, to 178 in 2003, a low 161 in 2004, and 171 in 2005.

The percent of actions in the form of approvals was low at 42% and 56% when the number of actions was historically high, but has been steady at a solid 61%-62% for the past three years.

Priority new use approvals appear to have stayed closer to the startling 48 approvals in 2004, instead of dropping back to historical norms. In 2005, 36 priority new uses were cleared; between 1995 and 2003, totals ranged from single digits to 2003's high of 21.

The pattern of the number of actions on priority new uses tracks the standard review pattern, with a big peak in 2004 with 64 actions moderating to 52 in 2005, still above the range of five to 36 earlier in the decade.

Skyrocketing Generic Applications

FDA's ANDA review staff is adjusting to the pressure of ever-heavier workloads after 2005 produced the fourth consecutive year of record high generic drug applications receipts.

FDA received 777 generic drug applications in 2005, the CDER report notes - a substantial increase from 635 in 2004, 479 in 2003, and 392 in 2002. Before the four-year growth spurt, ANDA receipts had hovered in the high 200s to mid-300s.

"The dramatic increase in receipts of generic drug applications makes it imperative that we process generic drug applications more efficiently," the CDER report states. To that end, FDA has been augmenting its staff while encouraging electronic submissions and is working with the generic drug industry association to improve application quality.