Food & Drug August 31, 2009 SUMMARY OF DDMAC AND APLB ENFORCEMENT CORRESPONDENCE JULY 2009 In July 2009, FDA s Division of Drug Marketing, Advertising, and Communications (DDMAC) posted two warning letters on its website, and the Advertising and Promotional Labeling Branch (APLB) in FDA s Center for Biologics Evaluation and Research (CBER) posted three untitled letters. The letters addressed the issues below. This summary describes only DDMAC s and APLB s allegations. It does not reflect the recipient s response or analysis by Covington & Burling. Omission/Minimization of Risk A bag drop, branded panels, and an abridged sales aid for Cinryze (C1 Inhibitor (Human)) failed to provide any information regarding the potential risk of thrombotic events associated with the use of Cinryze. According to the Warnings and Precautions section of the package insert (PI), Thrombotic events have been reported in association with C1 Inhibitor products when used off-label at high doses. The statement, In rare cases there is a possibility of allergic reactions in the Important Safety Information section of these materials was also misleading because it minimized the statement in the PI that [s]evere hypersensitivity may occur. Similarly, the safety claim presented in the bag drop that Cinryze [i]s a well tolerated treatment for routine prophylaxis against HAE [hereditary angioedema] attacks was misleading because there are serious risks associated with Cinryze that are inconsistent with the claim well tolerated. According to the PI, Cinryze prophylaxis may result in hypersensitivity reactions or thrombotic events or may contain infectious agents because the drug is made from human plasma. (APLB (untitled), Lev Pharmaceuticals, Inc., June 9, 2009) 1 A holiday promotion postcard for Rowasa (mesalamine) Rectal Suspension Enema made various efficacy claims but entirely omitted risk information for the drug, including the warnings, precautions, and common adverse events associated with the drug. The statement, For Full Prescribing Information visit www.rowasakit.com, written in small type at the bottom of the postcard, did not mitigate the misleading omission of risk information. (DDMAC (warning), Alaven Pharmaceutical LLC, July 13, 2009) An interview with Magic Johnson regarding his experience with HIV and Kaletra (lopinavir/ritonavir) treatment, which was included in a consumerdirected patient testimonial DVD for Kaletra, failed to convey any of the serious risks associated with the drug. Specifically, the first 11½ minutes of the DVD contained an engaging and lively interview with Johnson, including a 1 The Cinryze letter is dated June 9, 2009, but was not posted to the APLB website until July 30, 2009.
discussion of the benefits he experienced from Kaletra. In contrast, the presentation of serious risks associated with Kaletra was relegated to the end of DVD after the interview and was displayed as a running telescript. The only statement of risk information included during the interview was a brief acknowledgement by Magic Johnson that he experiences fatigue[] sometimes ; that portion of the DVD also contained disclosures in SUPERs (text superimposed on images) that Kaletra is not a cure for HIV infection, that [t]he most commonly reported side effects of moderate severity that are thought to be drug related are: abdominal pain, abnormal bowel movements, diarrhea, feeling weak/tired, headache, and nausea, and that children taking KALETRA may sometimes get a skin rash. The interview portion of the promotional DVD omitted any discussion of serious risks, such as contraindications, warnings, and precautions associated with Kaletra. (DDMAC (warning), Abbott Laboratories, July 14, 2009) An exhibit panel for Gamunex (Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified) stated that patients in a large clinical study demonstrated ZERO ZERO reports of aseptic meningitis, ZERO ZERO reports of renal failure, and ZERO ZERO reports of stroke and MI. This overall presentation of ZERO ZERO reports minimized the serious risks associated with Gamunex and was inconsistent with package insert (PI) for Gamunex. In particular, this presentation minimized the boxed warning for Gamunex regarding the drug s potential to cause renal failure and the warnings regarding aseptic meningitis and thrombotic events. Furthermore, as stated in the package insert for Gamunex, because clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. In fact, there have been postmarketing reports for aseptic meningitis and thrombotic events, which are listed in the Warnings and Precautions section of the PI. A footnote regarding these adverse events was insufficient to mitigate the overall misleading impression created by claims of zero reports for these serious adverse reactions. (APLB (untitled), Talecris Biotherapeutics, Inc., July 6, 2009) Overstatement of Efficacy A Slim Jim sales aid for Cytogam (Cytomegalovirus Immune Globulin Intravenous [CMV- IGIV], Human) contained the following claims, among others: Demonstrated survival benefit, and Heart recipients: Significantly greater 3-year survival and 3-year freedom from rejection. These claims were misleading because they implied greater (or longer) survival benefit for patients than is suggested by the package insert (PI) or by substantial evidence or substantial clinical experience. Specifically, there is a lack of substantial evidence or substantial clinical experience for survival claims beyond one year in liver transplant patients given Cytogam, a cytomegalovirus immune globulin (CMVIG), and beyond three months in heart, heart-lung, and lung transplant patients receiving CMVIG plus ganciclovir compared with those patients receiving ganciclovir alone. Moreover, there are no data demonstrating survival benefits for kidney or pancreas transplant patients given Cytogam. One study included in the PI showed a trend toward long-term survival, but the data for survival were not statistically significant beyond one year. Another study found increased survival for a three-month period in heart, heart-lung, and lung transplant patients receiving CMVIG plus ganciclovir compared to patients receiving ganciclovir alone, but the study had limitations in that it was a preliminary cohort study using historical (actuarial) controls and multiple unadjusted endpoints. (APLB (untitled), CSL Behring LLC, July 1, 2009) 2
A holiday promotion postcard for Rowasa (mesalamine) Rectal Suspension Enema stated the following: Unwanted UC [ulcerative colitis] flares can make a surprise visit during the holidays. A change in diet and erratic stress levels may make flare symptoms worse. Make sure your patients are armed and ready with flare relief. Give them the gift of ROWASA Kit now. With a sample and a prescription of ROWASA Kit on hand, your patients are flare ready. They can enjoy the holidays (and so can you!) (emphasis in original). These claims overstated the efficacy of Rowasa by implying that treatment with Rowasa will allow patients and their healthcare providers to enjoy the holidays by successfully treating all the various symptoms of flares from ulcerative colitis despite changes in stress and diet. The fact that Rowasa has been shown to reduce patients disease activity index (DAI) over several weeks does not support the implication that Rowasa will keep all symptoms under control during time periods like the holidays when flares are particularly likely to occur. (DDMAC (warning), Alaven Pharmaceutical LLC, July 13, 2009) In a consumer-directed patient testimonial DVD for Kaletra (lopinavir/ritonavir), Magic Johnson discussed how he was diagnosed with HIV, his experience living with HIV, and his treatment with Kaletra. His statements included the following: [T]he most important thing is that I do manage my disease, and it enables me to then do all the other things. You know, I make sure I take my meds, I make sure that I try to get some form of exercise. It enables me to also be a businessman once I manage my HIV, and I started taking Kaletra over five years ago and it s really been a great part of my regimen. This testimonial suggests that Kaletra has been shown to allow all or most antiretroviraltreatment-experienced individuals to successfully manage their disease and continue to do well (i.e., live a normal life while maintaining undetectable HIV-1 RNA levels) for five or more years. FDA is not aware of substantial evidence or substantial clinical experience to support effectiveness of Kaletra in treatment-experienced adults for five or more years. The personal experience of patients such as Magic Johnson does not constitute such evidence. Although the package insert (PI) includes data through 360 weeks of treatment with Kaletra for patients without prior antiretroviral therapy, these data are not applicable to the patient population represented by the claims in the promotional DVD (antiretroviraltreatment-experienced individuals). According to the Clinical Studies section of the PI, analyses of plasma HIV-1 RNA levels in antiretroviral-treatment-experienced subjects were conducted over a much shorter time period. In addition, the FDA-approved patient labeling (PPI) explicitly states that [t]he long-term effects of KALETRA are not known at this time. People taking KALETRA may still get opportunistic infections or other conditions that happen with HIV-1 infection. These claims of treatment benefit require substantial evidence or substantial clinical experience as demonstrated through adequate and wellcontrolled trials using well-developed instruments that reliably and validly measure the specific concepts at issue. (DDMAC (untitled), Abbott Laboratories, July 14, 2009) Broadening of Indication A Slim Jim sales aid for Cytogam (Cytomegalovirus Immune Globulin Intravenous [CMV- IGIV], Human) contained the following claims, among others: Heart-lung recipients: Fewer deaths from obliterative bronchiolitis, Cytogam offers extra protection and proven safety to high-risk kidney transplant recipients, and Treatment-resistant CMV [cytomegalovirus] presents an extra challenge. These claims broadened the indication for Cytogam by suggesting that: (1) Cytogam has an effect on outcomes that do not have a clear association with CMV infection (e.g., obliterative bronchiolitis) and that (2) Cytogam 3
is efficacious for treatment-resistant (ganciclovir-resistant) CMV disease. Moreover, Cytogam s indication is limited to the prophylaxis of CMV disease associated with transplantation of kidney, lung, liver, pancreas, and heart. In addition, the indication states that in transplantation of lung, liver, pancreas, and heart from CMV seropositive donors into seronegative recipients, prophylactic CMV-IGIV should be considered in combination with ganciclovir. (APLB (untitled), CSL Behring LLC, July 1, 2009) A holiday promotion postcard for Rowasa (mesalamine) Rectal Suspension Enema suggested that Rowasa is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience. Specifically, the postcard states: Unwanted UC flares can make a surprise visit during the holidays.... Make sure your patients are armed and ready with flare relief. These claims misleadingly suggested that Rowasa is approved to treat any patient with ulcerative colitis, but Rowasa is indicated, among other conditions, for the treatment of active mild to moderate distal ulcerative colitis. The postcard failed to present this material limitation, thereby broadening the indication of Rowasa. (DDMAC (warning), Alaven Pharmaceutical LLC, July 13, 2009) Misleading Safety Claims A Slim Jim sales aid for Cytogam (Cytomegalovirus Immune Globulin Intravenous, Human) contained the following claim: Cytogam... Providing an additional layer of protection without the toxicity Transplant patients who received a combination of Cytogam and antiviral medication such as ganciclovir or valganciclovir... This claim was misleading because it suggested that there is no additional toxicity or other risk associated with the use of Cytogam plus an antiviral versus antiviral monotherapy (e.g., ganciclovir or valganciclovir) when used as directed. Furthermore, as set forth in the package insert (PI), the addition of Cytogam may expose the patient to toxicities and other risks associated with intravenous immune globulin therapy. (APLB (untitled), CSL Behring LLC, July 1, 2009) An exhibit panel for Gamunex (Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified) contained a number of misleading safety claims under the subheading, Proven tolerability across all indications. For example, one claim stated: 96% of Gamunex infusions in CIDP [chronic inflammatory demyelinating polyneuropathy] patients and >99% in PI [primary humoral immunodeficiency] patients were free of drugrelated headache. The claim misleadingly implied that only four percent of CIDP patients and less than one percent of PI patients receiving Gamunex suffered from headache. According to the package insert, 32 and 25 percent of patients receiving Gamunex for CIDP and PI, respectively, reported headache. The exhibit panel also stated: In CIDP, the incidence of serious adverse events per infusion was 0.8% with Gamunex vs 1.9% with placebo. This claim was misleading because it was based on one small study that was not designed to examine safety. By emphasizing the small incidence rate of serious adverse events per infusion, the claim minimized the fact that serious adverse reactions are associated with Gamunex, including the case of pulmonary embolism reported in a CIDP clinical study subject described in the package insert. (APLB (untitled), Talecris Biotherapeutics, Inc., July 6, 2009) Misleading Comparative Claim A bag drop for Cinryze (C1 Inhibitor (Human)) presented the claim that Cinryze [p]rovides effective routine prophylaxis without anabolic-steroid-like adverse reactions. In fact, no comparative studies between Cinryze and anabolic steroids are described in the package insert (PI). According to the Clinical Studies section of the PI, [t]he safety and 4
efficacy of Cinryze prophylaxis therapy to reduce the incidence, severity, and duration of HAE [hereditary angioedema] attacks was demonstrated in a single randomized, double blind, placebo controlled multi-center cross-over study of 24 patients. (APLB (untitled), Lev Pharmaceuticals, Inc., June 9, 2009) Omission of Material Facts Branded panels and an abridged sales aid for Cinryze (C1 Inhibitor (Human)) contained graphic illustrations of the efficacy data for Cinryze that were misleading because they failed to present relevant contextual information. Specifically, the materials did not state that efficacy was based on only 22 patients in each treatment group and that there was a broad spectrum of self-reported outcomes in the percent reduction in attack frequency. According to the package insert (PI), the percent reduction in attack frequency during the 12-week period while patients received Cinryze ranged from -85% (i.e., an increase in the number of attacks) to 100% (i.e., a reduction in number of attacks). By failing to include the number of patients studied and the wide variation of individual response in attack frequency or lack of response, the overall presentation of study results misleadingly implied that Cinryze is more effective than has been demonstrated by substantial evidence or substantial clinical experience. (APLB (untitled), Lev Pharmaceuticals, Inc., June 9, 2009) Failure to Provide Adequate Directions for Use A holiday promotion postcard for Rowasa (mesalamine) Rectal Suspension Enema was apparently not disseminated with the full FDA-approved product labeling (PI) for Rowasa, in violation of 21 C.F.R. 201.100(d). (DDMAC (warning), Alaven Pharmaceutical LLC, July 13, 2009) Use of Outdated Product Labeling A consumer-directed patient testimonial DVD for Kaletra (lopinavir/ritonavir) was disseminated with an outdated version of the approved product labeling (PI), in violation of 21 C.F.R. 201.100(d). (DDMAC (warning), Abbott Laboratories, July 14, 2009) If you have any questions concerning the material discussed in this client alert, please contact the following members of our food & drug practice group: Richard Kingham 202.662.5268 rkingham@cov.com Peter Safir 202.662.5162 psafir@cov.com Michael Labson 202.662.5220 mlabson@cov.com Erika Lietzan 202.662.5165 elietzan@cov.com Stefanie Doebler 202.662.5271 sdoebler@cov.com This information is not intended as legal advice, which may often turn on specific facts. Readers should seek specific legal advice before acting with regard to the subjects mentioned herein. Covington & Burling LLP is one of the world s preeminent law firms known for handling sensitive and important client matters. This promotional communication is intended to bring relevant developments to our clients and other interested colleagues. Please send an email to unsubscribe@cov.com if you do not wish to receive future emails or electronic alerts. Covington & Burling LLP is located at 1201 Pennsylvania Avenue, NW, Washington, DC 20004-2401. 2009 Covington & Burling LLP. All rights reserved. 5