August 3, 2004

Letter Calling for Criminal Investigation of AstraZeneca

Lester Crawford, DVM, Acting Commissioner
Food and Drug Administration
5600 Fishers Lane
Rockville, MD  20854

Dear Dr. Crawford,

This letter requests an immediate criminal investigation of AstraZeneca for illegally delaying the submission to the FDA of 23 reports of serious adverse reactions in the U.S. to its cholesterol-lowering drug rosuvastatin (Crestor) for as long as 97 days beyond the allowable 15-day legal limit for reporting such reactions. Included in this large number of violations were 19 U.S. cases of the often life-threatening destruction of muscle tissue known as rhabdomyolysis and 4 U.S. cases of primary kidney failure or insufficiency in patients not having rhabdomyolysis. Twenty of these 23 patients had to be hospitalized. These intentional reporting delays by AstraZeneca, while temporarily succeeding in making their drug appear safer than it actually is, have unquestionably impaired FDA’s ability to promptly assess the safety of this uniquely dangerous drug.

FDA regulations (21 CFR§314.80) state, under the topic of Postmarketing 15-day Alert reports, “The applicant shall report each adverse drug experience that is both serious and unexpected, whether foreign or domestic, as soon as possible but in no case later than 15 calendar days of initial receipt of the information by the applicant.” As shown below (see Appendix), violations of these reporting requirements are punishable by criminal penalties.

“Serious adverse drug experience” is defined in the regulation as including ”Death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity” or, even in the absence of hospitalization, reactions that “may require medical or surgical intervention to prevent one of the outcomes listed in this definition.”  

“Unexpected adverse drug experience” is defined as “an adverse drug experience that has not been previously observed (i.e., included in the labeling).” The only mention in the Crestor labeling of details of rhabdomyolysis with that drug states: “Rare cases of rhabdomyolysis were seen with higher than recommended doses (80 mg) of rosuvastatin in clinical trials.”[1] Since the label does not include a statement about the observation/occurrence of rhabdomyolysis at any dose lower than 80 mg with Crestor, such adverse reactions would be “unexpected.”[2] Yet in all of the cases of rhabdomyolysis that AstraZeneca illegally delayed reporting to the FDA and in which doses were known (18 of the 19 cases), people were using either 10 mg (14 cases), 20 mg (3 cases), or 40 mg (1 case) all less than the 80 mg stated in the label. The label also has no warning concerning acute kidney failure in patients not suffering from rhabdomyolysis.

AstraZeneca belatedly reported these 23 cases (19 of rhabdomyolysis, 4 renal failure) in a report of “periodic” adverse drug experiences even though these adverse reactions were both serious and unexpected.  However, the regulation states that   periodic (quarterly) reports are to be used only for reporting events “not reported” as 15-day alert reports because they do not require 15-day reports and that periodic reports shall be reported “at quarterly intervals, for 3 years from the date of approval of the application, and then at annual intervals.”

From the time of initial marketing of Crestor in the U.S. in mid-September 2003 until July 2nd 2004 (with the exception of the batch of periodic reports sent in on March 5th), the FDA received only eight U.S. 15-day alert reports involving rhabdomyolysis from AstraZeneca, reported as required by FDA regulations. Some of these 15-day reports were sent to the FDA before the March 5th batch and others between March 5th and July 2nd.

On March 5th and on July 2nd, however, the FDA received, in batches marked “periodic reports” a total of 19 new cases of rhabdomyolysis (6 on March 5th and 13 on July 2nd; see Table). Thus, of the 27 U.S. cases of rhabdomyolysis reported to the FDA by AstraZeneca (an additional 10 U.S. cases were reported directly to the FDA by doctors, etc.), eight were reported as 15-day alert reports, as required by FDA law and regulations, but 19 (70%) were illegally delayed for as long as 97 days and for an average of 65 days late, by filing them as periodic instead of 15-day alert reports. Almost one-half (48%, 13 of 27) of all of AstraZeneca’s U.S. reports to the FDA of rhabdomyolysis during the 9 ½ months since marketing began, were sent in on one day, July 2nd, as periodic reports. (In contrast, all foreign reports of rhabdomyolysis were sent in marked as 15-day expedited reports.) Thus, the estimated frequency of such U.S. Crestor reports was much lower until July 2nd since 47% of the cases that had occurred as long as three months earlier had not been reported until that date.   Because of this unacceptable average two-month delay (beyond the legally-mandated 15-day limit) in reporting these 19 cases of rhabdomyolysis, for months the FDA did not have an accurate count of reported cases on which to base a reasonable ongoing assessment of the rate of spontaneous reports per million prescriptions filled for Crestor and to thereby enable comparison between the rate of such adverse drug experiences for Crestor with the rate for other currently marketed statins.  

I urge you immediately to begin an investigation because such apparently criminal behavior by a major drug company, unchecked by FDA enforcement actions, severely impairs the FDA’s ability to promptly and accurately evaluate the safety of marketed drugs. As stated in the Food Drug and Cosmetic Act (FDC Act), excerpted in the appendix, such evaluations are “necessary in order to enable the Secretary to determine … whether there is or may be ground for invoking Subsection (e) [withdrawal of approval].”  

We continue to urge the prompt removal of this uniquely dangerous drug from the market and your investigation of AstraZeneca is quite likely to uncover further reasons to do so. I look forward to a prompt response to this urgent request.

Sincerely,

Sidney M. Wolfe, M.D.
Director
Public Citizen’s Health Research Group

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Table.  Illegal Delays in Reporting 23 Serious Crestor Adverse Reactions to the FDA

Rhabdo or ARF*	Manufacturer number	Date Received by AstraZeneca	Reporting Delay in days **	Date received by FDA
Rhabdo	2004UW04989	5/25/04	23	7/02/04
Rhabdo	4UW05293	3/30/04	79	7/02/04
Rhabdo	4UW07198	4/08/04	70	7/02/04
Rhabdo	4UW05406	4/08/04	70	7/02/04
Rhabdo	4UW05626	3/19/04	90	7/02/04
Rhabdo	4UW05908	4/13/04	65	7/02/04
Rhabdo	4UW08021	4/19/04	59	7/02/04
Rhabdo	4UW08170	4/22/04	56	7/02/04
Rhabdo	4UW08169	4/22/04	56	7/02/04
Rhabdo	4UW06303	3/30/04	78	7/02/04
Rhabdo	4UW08337	4/19/04	59	7/02/04
Rhabdo	4UW04759	3/12/04	97	7/02/04
Rhabdo	4UW03453	3/12/04	97	7/02/04
ARF	4UW05273	4/13/04	65	7/02/04
ARF	4UW07696	4/13/04	65	7/02/04
ARF	4UW08233	4/22/04	56	7/02/04
ARF	4UW08231	4/22/04	56	7/02/04
Rhabdo	4UW00423	1/06/04	44	3/05/04
Rhabdo	3UW15298	11/18/03	93	3/05/04
Rhabdo	3UW15938	12/02/03	79	3/05/04
Rhabdo	4UW00524	1/06/04	44	3/05/04
Rhabdo	3UW16275	12/08/03	73	3/05/04
Rhabdo	4UW00729	1/29/04	21	3/05/04

*  Rhabdo = rhabdomyolysis (serious/life-threatening muscle destruction); ARF = acute renal failure or renal insufficiency
** The number of days delayed beyond the 15 days allowed for such reports

Appendix
 

Federal Law, Regulations and Criminal Penalties Governing Reporting Adverse Reactions of Marketed Drugs

Statutory Requirement for Reporting Adverse Drug Reactions
Section 505 (j) (1) of the Federal Food, Drug and Cosmetic Act (FDC Act) states that the company “shall establish and maintain such records, and make such reports to the Secretary, of data relating to clinical experience… with respect to such drug, as the Secretary may by general regulation. Or by order with respect to such application, prescribe on the basis of a finding that such records and reports are necessary in order to enable the Secretary to determine…whether there is or may be ground for invoking Subsection (e) [withdrawal of approval] in this section.”   21 U.S.C.§355(k)

Regulations Specifying Details for Reporting
As discussed in more detail above, the regulation issued by the FDA under the FDC Act (21 C.F.R Section 314.80) states, under Postmarketing 15-day Alert reports, that “The applicant shall report each adverse drug experience that is both serious and unexpected, whether foreign or domestic, as soon as possible but in no case later than 15 calendar days of initial receipt of the information by the applicant.”

Prohibited Acts
Section 301 (e) of the FDC Act lists, under “prohibited acts” the “failure to establish or maintain any record, or make any report , required under section …505 (k).”   21 U.S.C. §33 (e).

Penalties for Violations
Section 301 (e) of the FDC Act says “[a]ny person who violates a provision of Section 301 [see above] shall be imprisoned for not more than one year or fined not more than $1000 or both .” 21 U.S.C. § 333 (a). Section 303 (b)  increases the penalty to not more than 3 years in jail or not more than $10,000 or both if the violation is committed “with the intent to defraud or mislead.” 21 U.S.C. § 333 (a). 
 

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