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U.S. Department of Health and Human Services

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Findings: Product and Disease Characteristics: Independent Evaluation of FDA's First Cycle Review Performance – Final Report

Table of Contents


The first-cycle approval rate for the Overall Study Cohort was 50%.  Of the 92 multi-cycle applications, 37 were approved in a subsequent review cycle.  At the time of study completion on January 19, 2008, 38 of the multi-cycle applications had received an Approvable letter (Exhibit 7).

Exhibit 7. Cohort Product Status and Approval Rates

Chart of Cohort Product Status and Approval Rates

The first-cycle approval rate for individual years throughout the FY2002 - FY2007 cohort ranged from 45% to 53%, with the overall Retrospective Analysis Cohort having a first-cycle approval rate (49%) similar to the Prospective Analysis Cohort (52%).

The FY2002 - FY2007 cohort was comprised of 74% NDAs and 26% BLAs (Exhibit 8).  The NDAs had a 43% first-cycle approval rate, while the BLAs rate was higher for both CDER (86%) and CBER (66%).  Of the FY2002 - FY2007 cohort applications, products with Priority designation (45%) had a higher approval rate (68%) than products with Standard designation (36%).

  Exhibit 8. First Cycle Approval Rate for Overall Study Cohort by Year

  Fiscal Year
  2002 2003 2004 2005 2006 2007 Overall
Total Product Applications 29 35 36 38 32 15 185
Approval Rate 45% 51% 50% 50% 53% 53% 50%
  Application Type
NDAs 21 29 28 29 21 8 136
Approval Rate 52% 45% 36% 41% 43% 38% 43%
BLAs 8 6 8 9 11 7 49
Approval Rate 25% 83% 100% 78% 73% 71% 71%
  Review Designation
Standard 20 19 18 17 19 9 102
Approval Rate 35% 42% 39% 24% 37% 44% 36%
Priority 9 16 18 21 13 6 83
Approval Rate 67% 63% 61% 71% 77% 67% 67%
  Application Type and Review Designation
Standard 13 17 13 14 15 6 78
Approval Rate 38% 35% 15% 14% 33% 33% 28%
Priority 8 12 15 15 6 2 58
Approval Rate 75% 58% 53% 67% 67% 50% 62%
Standard 7 2 5 3 4 3 24
Approval Rate 29% 100% 100% 67% 50% 67% 63%
Priority 1 4 3 6 7 4 25
Approval Rate 0% 75% 100% 83% 86% 75% 80%

The higher first-cycle approval rate for Priority-designated drugs, suggesting greater effort to resolve outstanding issues during that cycle, is consistent with FDA’s commitment to provide access to therapies for unmet medical needs.  Given the pronounced effect of review designation (e.g., Priority vs. Standard), Booz Allen reviewed the impact of the review designation on all analyses presented.  When the review designation resulted in a significant finding for the analyses, the data were presented.

Condition Severity and Mechanism of Action

Life-threatening conditions are those conditions that affect a patient’s survival or if left untreated would increase in severity.  Mechanism of action describes how an active substance affects the body and its systems. These product characteristics were deemed as significant since products treating life-threatening conditions may have a different risk/benefit assessment than those products for non-life threatening conditions.  However, these characteristics did not demonstrate notable effects on the rate of first-cycle approval.

In Exhibit 9, products with a novel mechanism of action and indication for a life-threatening condition had a slightly higher rate of first-cycle approval (62%) compared to products that met none of these criteria.  Product applications for life threatening indications had a first-cycle approval rate of 53% and novel mechanism of action applications had a first-cycle approval rate of 59%.  Non-novel products for non-life threatening conditions had a first-cycle approval rate of 39%.  Booz Allen speculates the severity of the medical conditions addressed, the different levels of acceptable risk, and the urgency for new products might explain these findings.

Exhibit 9. Approval Rate vs. Novelty and Indication

Chart of Approval Rate vs. Novelty and Indication

Review Designation and Fee Waivers

FDA has developed several programs to expedite review and facilitate product development (Exhibit 10). Fast Track and Priority review programs are used to facilitate the sponsor-FDA interactions and expedite the review processes for products that address serious diseases with significant unmet medical needs. For products that qualify for Fast Track, which is granted during the Investigational New Drug (IND) phase, the FDA may engage in more pre-submission meetings and communications with the sponsors, as well as consider reviewing portions of the application submitted prior to complete submission of the NDA/BLA. Many Fast Track-designated products also qualify for Priority review, which is granted after the NDA/BLA is submitted, and sets the target date to complete application review at six months (standard reviews have a ten-month target date for completion). Orphan product status, as well as other fee waiver opportunities (e.g. small business waiver), provide financial incentives to sponsors but do not impact the review process independently of a Priority review designation.

  Exhibit 10. Special Development and Review Programs

  Fast Track Priority Review Orphan Status Fee Waivers
Program Benefits
  • Frequent pre-submission meetings and correspondence with FDA to discuss development plan
  • Rolling review (i.e., submit sections of application to FDA) which is dependent upon availability of FDA resources
  • Faster application review goal (6 months vs. 10 months for Standard review)
  • User fee waived
  • Seven year marketing exclusivity
  • Tax credit for up to 50% of clinical testing expenses
  • User fee waived
Eligibility Requirements
  • Treat serious condition
  • Unmet need
  • Unmet need, or
  • Significant improvement over current treatments
  • Treat rare disease or condition
  • Small business submitting first application, or
  • Public health/ innovation issues [9]

These expedited development and review programs seemed effective in driving single-cycle approvals, as 67% of applications with Priority reviews received first-cycle approval, compared to only 36% for non-Priority applications (Exhibit 11). Similarly, higher first-cycle approval rates were observed for Fast Track and Orphan product applications. Qualification for a fee waiver, however, did not impact first-cycle outcomes, with similar approval rates for applications with or without the fee waiver (48% vs. 51%, respectively).  Notably, many Orphan product applications also received Fast Track and/or Priority review designation. Out of the 51 products with Fast Track designation, 32 of the products were submitted by large companies, and 27 (84%) of these products were approved in a single review cycle. Of the Priority review applications, 29 also had Orphan designation, with 21 (72%) of these applications achieving first-cycle approval. Of the 54 remaining Priority review applications, 35 (65%) achieved first-cycle approval. A lack of sponsor’s regulatory experience may be a compounding factor in the first-cycle approval rates for the applications that qualified for a fee waiver since most of these products were developed by small companies with no previously approved products (see Sponsor Characteristics).

Exhibit 11. First-Cycle Approval Rate by Application Type

Chart of First-Cycle Approval Rate by Application Type

Other Product/Disease Characteristics

Several additional product and disease characteristics were analyzed in the study, but did not have an impact on first-cycle approval rates.  There was no significant difference in approval rates for products addressing chronic or acute conditions.  Similarly, differences in product origin (in-house or in-licensed) did not have any effect on the approval rate in the first cycle.  Finally, products with data from international clinical sites or that had prior foreign regulatory approval had similar first-cycle approval rates as those products that did not.

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