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c 2~, 1.11 +_44 yh,9 9z_ • • MONTHLY BULLETIN FDA Issues First Warning Letter Cit GMP Problems Under New CPG Intermedics, Inc. was cited for 13 "serious deviations" from good manufacturing prac- tice (GMP) regulations at its pacemaker manufacturing facility, and is responsible for correcting these and any other violations, ac- cording to a July 27 Warning Letter issued by the Center for Devices and Radiological Health (CDRH). o=) This is the first Warn- ing Letter to implement a GMP enforcement strategy established by a new compliance program guidance (CPG) for GMPs. (M The new CPG, released in June, directs CDRH investigators to do limited, focused in- spections for specific, system-wide deficien- cies, such as those related to complaints and medical device reports (MDRs); to changes made in design or manufacturing processes; and to records of productions lots that failed in- process or finished device testing (see "New GMP Compliance Program Alters Inspection Scope, Strategy," July 1994, p.1). Because the Intermedics letter is the first of what likely will be a series of Warning Letters issued under the new program, medical device manufacturers would be wise to note which de- viations from GMPs are most likely to raise an investigator's eyebrow. Alleged Violations Although the Intermedics' pacemaker manufacturing facility in Angleton, Texas, was inspected before the fi- nal CPG was released to field staff - March 7 through Apri126 - investi- " This is the first Warning Letter to implement a GMP enforcement strategy established by a new compliance program guidance ... " gators had draft copies of the document and al- ready were applying some of its principles, according to an FDA official. The inspection that led to the Warning Letter identified the following 13 alleged violations: • Failure of the quality assurance (QA) program to identify, recommend, or pro- vide solutions for QA problems, and verify the implementation of such solu- tions (21 CFR §820.20(a)(3), see App. II); (See GMP Waming Letter, p. 2) ODE Strives to Meet PMA Review Goals Although the Federal Food, Drug and Cos- metic Act stipulates that all premarket approval (PMA) applications be reviewed within 180 days of their receipt at the Office of Device Evaluation (ODE), in fiscal year 1993 (Oct. 1, 1992 through Sept. 30, 1993), average ODE ~ review time rose from 146 days in fiscal year 1992 to 328 days in fiscal year 1993 - a jump ~ of almost 125 percent (see "ODE's Report Card for FY '93 Indicates Greater Productiv- . ity, Decreased Timeliness," p. 4). To help remedy this problem, a recent ODE internal "Blue Book" memorandum, "Premarket Approval Application (PMA) Closure," directs ODE staff to commit to meeting internal goals that would "ensure that critical milestones are reached and that final regulatory action is taken in a timely and efficient manner." Knowing exactly what steps ODE is taking, and when, can help manufacturers monitor ODE's timeliness and better chart a PMA's path through the ODE review process. Time Frames ODE's memorandum, issued July 8 by ODE Director Susan Alpert, walks the ODE (See PMA Review Goals, p. 3) INSIDE A S&E Summary Key to PMA Process ..... 3 A ODE's Report Card for FY '93 Indicates Greater Productivity, Decreased Timeliness ............. 4 A Restricted Device Rule Previewed ....... 6 A, CDRH Organizational Chart .................... 7 A Legislative Round-up ............... 8 After reading, please file in Bulletins Tab of Guide. DOCUMENT RETRIEVAL SERVICE Source documents available, see order form. ~ Guide to Medical Device Regulation October 1994 Monthly Bulletin • Page 1

t 4 • • End-of-Year Active PMAs ODE's Report Card for FY '93 Indicates Greater Productivity, Decreased Timeliness An analysis of the Office of Device Evaluation's (ODE's) annual report for fiscal year 1993 (FY'93) reveals that ODE has made some headway in increasing the number of approved and cleared applications and submis- sions during that time period (Oct. 1, 1992 through Sept. 30, 1993). (W However, the amount of time each premarket approval (PMA) application or premarket notification (510(k)) submission spent in the ODE review pipeline also increased significantly. Processing time for investigational device exemptions (IDEs) decreased slightly (see Tab 500). PMAs During FY '93, ODE received only 40 original PMA applications (see Tab 700), a decrease from FY '92 that continued a five- year trend of decreasing original PMA re- ceipts, according to the 1993 annual report (the last comprehensive report was issued for FY '91). The total number of PMA actions dropped only slightly, from 332 to 323 . Of the 323 PMA actions, 53 were classified as filing decisions, 68 as approval decisions, and 202 as review activity determinations. Number of PMAs on Upward Trend In a significant upward trend, 24 PMAs re- ceived final approval, which is twice the num- ber of PMAs that received fmal approval in FY ' 92. Another 23 PMAs were found to be approvable, up 27 per- cent from FY'92. The number of PMAs found not approvable also went up by 40 percent. There were no PMA denials issued in FY '93. Review Time Up On the downside, average ODE review time for original PMAs increased from 146 days in FY '92 to 328 days in FY '93, a 125 percent increase. And while the total number of PMAs under review and the end of FY'93 dropped slightly from 164 to 150, the num- ber of PMAs that were active and overdue increased from 36 in FY ' 92 to 45 at the end of FY '93. PMA Supplements PMA supplements submitted to ODE dur- ing FY '93 dropped significantly from 606 to 395. Those supplements receiving final ap- proval numbered 354. ODE average review time for PMA supplements increased from 113 days in FY '92 to 168 in FY '93. The total number of PMA supplements under re- view at the end of FY '93 was 465 (down from FY'92's 485), but the number of active and overdue supplements increased from 98 to 173 (76 percent). 510(k)s Because of an overwhelming 510(k) back- log, ODE committed to reviewing more 510(k)s in FY '93, and it met that goal, but not by much (see Tab 800). In FY '93, ODE received 6,288 original 510(k)s, down slightly from the 6,509 510(k)s received in FY '92. In addition, 3,940 510(k) supple- ments were submitted. During FY '93, ODE rendered 5,073 final decisions on original 510(k)s - an increase of slightly more than 4 percent. Review Times Soar However, this slight increase in the number of final 510(k) decisions rendered does not off- set the dramatic rise in the average review time (See ODE Report Card, p. 5) ^ T~ -..-. D~~{.Rchinn /:rnrrn /ni^

i v • 2r- nd nt. )3. :w 46 25 >er 93 m- ue nd ck- ore but DE wn 1 in )le- DE nal han p. 5) ODE Report Card (continued from p. 4) for 510(k) submissions. The re- port explains that there are two average review times typically re- ported for 510(k)s, as follows: (1) Average Review Time. The average review time based on total time is calculated, in part, by totaling all the times each 510(k) is reviewed by ODE, plus all of the times the 510(k) is on hold while it is un- der revision by the manufacturer (this average is useful to the y Y 0 T ~ w 0 d ~ E ~ z 6000 5000 4000 3000 2000 1000 manufacturers that wish to estimate how long it may take to get a final deci- sion from ODE); and (2) FDA Review Time. The FDA average review time is based only on the total of all times each 510(k) is reviewed by the FDA. Both of these review time statistics increased in FY'93. Total average review time rose from 126 days in FY '92 to 195 days in FY '93 (54 percent); FDA review time increased from 102 days to 162 days (58 percent). "A great deal of rise in the average review times was due to ... programmatic changes, [additional regulatory responsibilities related to the Safe Medical Devices Act of 1990] SMDA, oversight activities, etc., and the impact of the 'reference list' program and the 'Class 1115 10(k)/GMP' inspection program, which became effective during FY '92 and FY '93, respectively," the report contends. However, ODE seems somewhat optimistic about rectifying the situation in the future. 510(k) Prognosis "During the past year, a number of manage- ment initiatives have been undertaken to reduce backlogs and stem the tide of rising review times. These initiatives include the triage pro- cedures, refuse-to-accept policies, and expe- dited review," according to the report. However, industry has complained through- out 1994 that ODE's initiatives are "too little too late," and statistics seem to support that po- sition. At the end of FY '93, 5,157 510(k)s were pending (an increase of 30 percent), and the number of active and overdue 510(k)s at the end of this period was 1,894, up 472 per- cent from 331 in FY '92. FY r_V 0 86 87 FY 88 FY 89 FY 90 Pending 510(k)s All Active Only FY ' \~'Active and over 90 days 91 FY 92 FY 93 IDEs ODE received 241 original IDEs in FY '93, up slightly from the 229 received in FY '92. IDE decisions mirrored that increase: 249 original IDE decisions were made in FY '93, up from 215 in FY ' 92. "This [outcome] is expected," the report states, "The output closely parallels the input because of the short turnaround times [30 days] involved with IDE reviews." The average IDE review time decreased from 30 to 28 days during the period of com- parison, "the lowest it has been since FY ' 88," according to the report, which also notes that 97 percent of original IDE decisions were completed within 30 days. The number of IDEs under review at the end of FY '93 dropped to 14, down from 21 at the end of FY ' 92. IDE Approval Rates Drop ODE cautions industry about one IDE sta- tistic - the percentage of decisions that re- sulted in IDE approval has dropped for the third consecutive year, from 32 percent in FY '92 to 24 percent in FY '93. "It is important that the device industry and ODE do all that they can to keep this rate of approval as high as possible because of the sav- ings in cost and time for the FDA and indus- try alike when IDEs are approved upon their first submission," ODE stresses in its report. 0 Inc Guide to Medical Device Regulation October 1994 Monthly Bulletin • Page 5