Released by FDA: 7/18/00.  Posted by FDA:  8/17/00

Patricia Dewalt, Ph.D. 
Director, Regulatory Affairs 
DuPont Pharmaceuticals Company 
Chestnut Run Plaza, Maple Run 
974 Centre Road 
Wilmington, DE 19805

RE:   NDA 20-972 
        Sustiva (efavirenz) capsules 
        MACMIS ID #8971

Dear Dr. Dewalt:

This letter is to inform the Regulatory Affairs Department of DuPont Pharmaceuticals Company (DuPont) that disseminated advertisements for Sustiva are in violation of the Federal Food, Drug and Cosmetic Act (the Act) and its applicable regulations.  As part of our monitoring and surveillance program, the Division of Drug Marketing, Advertising and Communications (DDMAC) reviewed the following advertisements submitted on Form FDA 2253:

1. the professional advertisement titled “Sustiva achieves a major milestone... So life goes on” 
2. the consumer advertisement titled “Powerful therapy that fits the way you live... So life goes on” 
3. the professional advertisement titled “Extending the limits of power and tolerability. . . So life goes on”

These advertisements violate the Act for the reasons cited below.

Misleading claims 
The claim “... So Life Goes On” is misleading because it broadens the indication for Sustiva by implying that it improves survival in patients with HIV infection.  The approved product labeling (Pl) for Sustiva includes data on HIV viral suppression for up to 112 weeks.  However, Sustiva’s impact on improving survival in patients with HIV has not been demonstrated by substantial evidence.

Your claim that Sustiva is “Establishing a New Standard of Care” is misleading because it overstates the role of Sustiva in HIV therapy.   To support this claim, you reference the Department of Health and Human Services (DHHS) guidelines.  The claim implies that Sustiva alone is a standard of care and misrepresents the current DHHS guidelines. Sustiva monotherapy is not recommended as a standard of care.  Sustiva is listed as one of several drugs that may be included in “strongly preferred” combination drug regimens for therapy-naïve patients with established HIV infection.  The referenced DHHS guidelines list preferred combination regimens but do not identify individual drugs as standards of care.

The claim “In one study, Sustiva kept it [HIV virus] at those levels for more than two years” is misleading because it implies that Sustiva may be used as monotherapy.  The claim attributes the lowering of HIV virus to undetectable levels to Sustiva alone.  The Pl states that Sustiva must be taken in combination with other antiretroviral therapies and that resistance rapidly emerges with monotherapy.  Presentation of a previous statement describing “combination therapies containing Sustiva” does not sufficiently correct the misleading implication.

DuPont presents a claim that Sustiva’s “Pharmacologic properties may minimize resistance.”  To support this claim, DuPont presents the statements “40-55 hour half-life with trough levels 26-fold> IC₉₀ for wild type isolates” and “Penetrates the CSF and lymph nodes.”  This presentation is misleading because the clinical significance of penetration into the lymph nodes or cerebral spinal fluid (CSF) is not known and has not been shown to impact resistance.  Furthermore, the impact of a long drug half-life on resistance is not known.  Finally, this presentation is inconsistent with the Pl which states that “resistant virus emerges rapidly when efavirenz is administered as monotherapy” and “HIV-1 isolates with reduced susceptibility to efavirenz (>380-fold increase in IC₉₀) compared to baseline can emerge in vitro.”

Claims regarding the effectiveness of Sustiva in patients with high baseline viral loads are misleading because they overstate the known efficacy of Sustiva.  You claim that regimens including Sustiva achieve “sustained viral load suppression to < 50 copies/mL in patients with high baseline viral loads.”  However, the clinical study cited (Study 006) was not designed to assess the impact of Sustiva in combination with other antiretroviral therapy in patients with high baseline viral loads (defined in Study 006 as> 1-00,000 copies/mL).  Subset analysis of Study 006 is inadequate to support such a claim.

Statements that Sustiva “fits the way you live” or offers “convenient” dosing are misleading.  The Sustiva P1 recommends bedtime dosing during the first two to four weeks “to improve the tolerability of nervous system side effects” and that Sustiva should not be taken with high fat meals.  Failing to provide this context with your “convenience” claims misleadingly implies that Sustiva can be taken without restrictions.

Unsubstantiated Superiority Claims 
Claims that imply that combination therapies containing Sustiva are superior to all protease inhibitor-containing regimens are misleading because Sustiva’s superiority in combination regimens has not been established by substantial evidence.   For example, DuPont claims that Sustiva is “superior to protease-inhibitor containing regimens for naïve or NRTI-experienced patients.”  However, of the approved protease inhibitors, Sustiva has been compared to only two of six in head-to-head trials.

The claim that Sustiva has “...fewer gastrointestinal (GI) side effects, such as nausea, vomiting and diarrhea, than Viracept” is misleading because it is an unsubstantiated superiority claim.  The ACTG 364 trial was not designed to assess the incidence of adverse drug reactions.  Furthermore, the data from the ACTG 364 trial demonstrated that a similar incidence of Gl adverse effects occurred in the compared treatment arms. While diarrhea did occur more frequently in the Viracept arm (9% versus 3%), the incidence of nausea and vomiting were the same per the Sustiva Pl.

Fair Balance 
All three advertisements lack fair balance because the risk information presented is inadequate.  Contraindications to Sustiva therapy are not included and common adverse reactions (e.g., rash) are omitted.  For example, the “Milestone” advertisement presents numerous efficacy claims, but minimal risk information.  Neither contraindications nor common adverse effects are presented.  In addition, the risk of central nervous system (CNS) effects is minimized by stating that “In a small number of patients, serious psychiatric adverse experiences have been reported” because 53% of patients taking Sustiva report a range of CNS effects.

Requested Action 
DuPont should immediately discontinue these print advertisements and all other promotional materials for Sustiva that contain the same or similar claims or presentations.  We request that DuPont respond, in writing, with its intent to comply with the above. DDMAC should receive DuPont’s written response no later than August 1, 2000.  This response should list similarly violative materials with a description of the method for discontinuation and the discontinuation date.

If you have any questions, please contact the undersigned by facsimile at (301) 594- 6771, or by written communication at the Division of Drug Marketing, Advertising and Communications, HFD-42, Rm 17B-20, 5600 Fishers Lane, Rockville, MD 20857.   In all future correspondence regarding this matter, please refer to MACMIS ID #8971 and the NDA number.  DDMAC reminds DuPont that only written communications are considered official.

Sincerely,

Rebecca Redman, Pharm.D. 
Regulatory Review Officer 
Division of Drug Marketing, 
   Advertising and Communications