Released by FDA:  10/24/03.  Posted by FDA:  11/3/03

Nicholas J. Troise
Director, Regulatory Affairs
AstraZeneca Pharmaceuticals, LP
1800 Concord Pike
P.O. Box 8355
Wilmington, DE 19803-8355

RE:     NDA #50-706
           Merrem I.V. (meropenem for injection)
           MACMIS ID #12005

Dear Mr. Troise:

This letter concerns AstraZeneca Pharmaceuticals LP's (AstraZeneca) dissemination of a promotional sales aid (206578) entitled "TRACKING ANTIMICROBIAL RESISTANCE," and a promotional banner (209017) with the claim "Attacking the Tide of Resistance," for Merrem I.V. (meropenem for injection).  The Division of Drug Marketing, Advertising, and Communications (DDMAC) finds these promotional materials in violation of the Federal Food, Drug, and Cosmetic Act and its applicable regulations because they make unsubstantiated claims about the efficacy of Merrem I.V. in the treatment of resistant pathogens.

Background

On June 21, 1996, Merrem I.V., a carbapenem antibiotic, was approved as single agent therapy for the treatment of intra-abdominal infections¹ and bacterial meningitis² when caused by susceptible strains of the designated microorganisms.  The drug has not been approved to treat conditions caused by resistant pathogens.

Promotion for Unapproved Use/ Reliance on In Vitro Data

Promotional materials are false and misleading if they suggest that a drug is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience. See 21 U.S.C. §§ 321(n) and 352(a).  The promotional materials identified above promote Merrem I.V. for unapproved uses based on in vitro data. Cf. 21 C.F.R. § 202.1(e)(6)(vii).  Specifically, we object to the following:

Sales Aid

In your sales aid you present a chart featuring the prominent header WIC and Susceptibility Data for ESBL-producing K pneumoniae."  Additionally, the accompanying chart presents a comparison of the in vitro MIC concentrations of numerous antibiotics versus ESBL-producing (Extended Spectrum B-Lactamase) K. pneumoniae to suggest that Merrem I.V. is the only antibiotic that demonstrates the lowest MICs while maintaining susceptibility for ESBL-producing K. pneumoniae as the inoculum concentration is increased (i.e., 105 CFU/mL increased to 107 CFU/mL). This presentation suggests that Merrem I.V. is effective for the treatment of ESBL-producing K. pneumoniae.  FDA is not aware of substantial evidence or substantial clinical experience that Merrem I.V. is efficacious versus ESBL-producing pathogens. The data you cite to support this claim are derived from a study³ of 18 in vitro bacterial isolates which, although clinical isolates, were not obtained from patients treated with Merrem.  These data are inadequate to support any conclusions about the efficacy of Merrem I.V. compared to other antibiotics for the treatment of ESBL-producing K. pneumoniae.

Similarly, you present claims such as the headline "A broad spectrum of activity makes it an excellent choice for: Newly Resistant Pathogens, ESBLs...," and such other claims as "In the United States, MERREM I.V. consistently shows high activity against all ESBL-producing strains."  These claims throughout your sales aid presented in conjunction with frequent references to antimicrobial resistance and discussions of in vitro sensitivity patterns suggest that Merrem I.V. is effective against ESBL producing organisms and other "resistant pathogens" in patients.  FDA is not aware of substantial evidence or substantial clinical experience to support these claims.

The Pfaller study⁴ cited in your sales aid fails to provide substantial evidence to support claims that Merrem I.V. is effective versus ESBL-producing bacterial strains and resistant pathogens because the data are not from adequate and well-controlled clinical trials.  The data are taken from the MYSTIC (Meropenem Yearly Susceptibility Test Information Collection), a global resistance surveillance program that compares the activity of meropenem over time with other agents in medical centers that are actively prescribing meropenem.  However, the data are based on in vitro activity rather than evidence from clinical studies.  In vitro data are not an adequate basis on which to accurately predict the clinical effectiveness of an antimicrobial agent. Cf. 21 C.F.R. 202.1(e)(6)(vii).  Such data are properly used in conjunction with clinical data to guide therapy and do not serve as a definitive indicator of clinical effectiveness.  The disclaimer, "in vitro activity does not necessarily correlate with in vivo effectiveness," in small print on two of the eight pages does not correct the overwhelmingly misleading suggestion that the in vitro data are from adequate and well-controlled clinical trials and form an adequate basis on which to determine clinical effectiveness.

Additionally, you present claims such as "The National Nosocomial Infection Surveillance System (NNISS) 1999 data report a 32% increase in the incidence of imipenem-resistant P aeruginosa among nosocomially infected patients in ICUs---this could prove problematic for clinicians in the future."  This is directly followed by the claim "Data from 1999 and 2000 MYSTIC Program show that susceptibility of P aeruginosa isolates actually increased between 1999 and 2000 for MERREM I.V. (78% to 84%)."  The presentation of these claims implies that Merrem demonstrates superior activity against resistant pathogens because of a more favorable resistance pattern than imipenem. FDA is not aware of substantial evidence or substantial clinical experience to support these claims.  As stated above, in vitro data are not an adequate basis on which to accurately predict the clinical effectiveness of an antimicrobial agent. Furthermore, your claims illustrating the resistance patterns of Merrem and imipenem are not consistent with your cited reference (the Pfaller study).  You selectively present statements from the Pfaller study while failing to mention that data from the 1999 and 2000 MYSTIC Program also showed that P. aeruginosa had increased susceptibility to imipenem as well as to Merrem.

Promotional Banner

Your promotional banner presents the claim "Attacking the Tide of Resistance."  This claim suggests that Merrem I.V. is effective for the treatment of drug-resistant pathogens.  As stated above, FDA is not aware of substantial evidence or substantial clinical experience to support this claim of clinical efficacy against resistant pathogens.

Conclusions and Requested Actions

The materials identified above promote Merrem I.V. for unapproved uses, including the treatment of resistant pathogens, based on in vitro data. To suggest that Merrem I.V. is effective for the treatment of drug-resistant pathogens may promote inappropriate prescribing of Merrem I.V. for these pathogens.  Accordingly, your claims cause Merrem I.V. to be misbranded within the meaning of 21 U.S.C. § 352(a).

The development of resistance to antibiotics is an increasing public health concern and as more and more pathogens become resistant to antibiotics, infections caused by resistant pathogens become more difficult to treat.  Inappropriate prescribing and over prescribing of antibiotics are factors that contribute to the development of resistant pathogens, which pose a significant public health concern.

1. You should immediately discontinue use of the sales aid and promotional banner and any other promotional materials for Merrem I.V. that contain the same or similar claims or representations as explained above.
    
2. Please submit a written response to this letter within 10 business days.  Your response should explain how you intend to comply with the above and include a list of all promotional materials with the same or similar claims or representations, with the date on which these materials were discontinued.

You should direct your response to Barbara S. Chong, Pharm.D., BCPS by facsimile at (301) 5946771, or by mail to the Food and Drug Administration, Division of Drug Marketing, Advertising, and Communications, BFD-42 Room 8B-45, 5600 Fishers Lane, Rockville MD 20857.  DDMAC reminds you that only written communications are considered official.

In all future correspondence regarding this particular matter, please refer to MACMIS ID #12005 in addition to the NDA number.

Sincerely,

Shannon R. Benedetto, Pharm.D., MBA
Regulatory Review Officer
Division of Drug Marketing,
       Advertising, and Communications

______________________________________________________

¹ Complicated appendicitis and peritonitis caused by viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, and Peptostreptococcus species.

²  Bacterial meningitis (pediatric patients > 3 months only) caused by Streptococcus pneumoniae, Haemophilus influenzae (R-lactamase and non-Rlactamase-producing strains), and Neisseria meningitidis.

³  Thomson KS, Moland ES. Cefepime, piperacillin-tazobactam, and the inoculum effect in tests with extended-spectrum R-lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2001;45:3548-3554.

⁴  Pfaller MA, Jones RN, Biedenbach DJ, MYSTIC Program Study Group (USA). Antimicrobial resistance trends in medical centers using carbapenems: Report of 1999 and 2000 results from the MYSTIC Program (USA). Diagn Microbiol Infect Dis. 2001;41:177-182.