TRANSMITTED BY FACSIMILE
March 25, 2010
Nadine D. Cohen Senior Vice President, Regulatory Affairs Biogen Idec, Inc. 14 Cambridge Center Cambridge, MA 02142
RE: BLA #125104
TYSABRI® (natalizumab) injection for intravenous use MACMIS # 18025
Dear Ms. Cohen:
As part of its monitoring and surveillance program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S. Food and Drug Administration (FDA) has become aware of a promotional webcast conducted by Biogen Idec, Inc. (Bigoen) for TYSABRI® (natalizumab) injection for intravenous use (Tysabri). The webcast was conducted twice on each of the following dates for a total of eight webcasts: October 28, October 30, November 2 and November 4, 2009. The webcast is false or misleading because it minimizes important risks associated with the use of Tysabri and omits the drug’s approved indication. The webcast thus misbrands the drug in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & (n); 321(n). See 21 CFR 202.1(e)(3)(ii); (e)(5)(i) & (iii); (e)(6)(i). Furthermore, the webcast was not submitted to FDA thirty days prior to the intended time of initial dissemination or initial publication, as required by 21 CFR 601.45. Moreover, Biogen failed to submit the webcast to FDA under cover of Form FDA-2253 at the time of initial publication, as required by 21 CFR 601.12(f)(4). Cf. 21 CFR 314.81(b)(3)(i).
Background
According to its FDA-approved product labeling (PI), Tysabri’s indication is as follows (in pertinent part):
TYSABRI is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. The safety and efficacy of TYSABRI beyond two years are unknown.
Because TYSABRI increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability, TYSABRI is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate multiple sclerosis therapy.
Safety and efficacy in patients with chronic progressive multiple sclerosis have
not been studied.
Tysabri is associated with numerous risks. The PI contains the following boxed warning for PML (in pertinent part) (bolded emphasis in original; underlined emphasis added):
TYSABRI increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability. Cases of PML have been reported in patients taking TYSABRI who were recently or concomitantly treated with immunomodulators or immunosuppressants, as well as in patients receiving TYSABRI as monotherapy. . . .
- Because of the risk of PML, TYSABRI is available only through a special restricted distribution program called the TOUCH™ Prescribing Program. . . .
- Healthcare professionals should monitor patients on TYSABRI for any new sign or symptom that may be suggestive of PML. TYSABRI dosing should be withheld immediately at the first sign or symptom suggestive of PML. . . .
The PI also contains Warnings and Precautions for PML as follows (in pertinent part, emphasis added):
The absolute risk for PML in patients treated with TYSABRI cannot be precisely estimated, and factors that might increase an individual patient’s risk for PML have not been identified. There are no known interventions that can reliably prevent PML or adequately treat PML if it occurs. It is not known whether early detection of PML and discontinuation of TYSABRI will mitigate the disease. There is limited experience beyond two years of treatment. The relationship between the risk of PML and the duration of treatment is unknown, but most cases of PML were in patients who received more than one year of treatment . . . .
The incidence of PML appears to be lower in patients receiving TYSABRI as monotherapy; however, the number of cases is too few and the number of patients treated too small to reliably conclude that the true risk of PML is lower in patients treated with TYSABRI alone than in patients who are receiving other drugs that decrease immune function or who are otherwise immunocompromised .
The progression of deficits usually leads to death or severe disability over
weeks or months .
There are no known interventions that can adequately treat PML if it occurs.
There is no evidence that plasma exchange has any benefit in the treatment of opportunistic infections such as PML. Because of the increased risk of PML in patients, Tysabri was withdrawn from the market in February 2005. In July 2006, Tysabri was reintroduced to the market with a boxed warning for PML and the TOUCH restricted distribution program.
Tysabri is contraindicated in patients who have or have had PML, and who have had a hypersensitivity reaction to Tysabri. Tysabri also has Warnings and Precautions pertaining to a restricted distribution program for Tysabri (TOUCH™ Prescribing Program), hypersensitivity/antibody formation, immunosuppression/infections, hepatotoxicity, laboratory test abnormalities, and immunizations. The most frequently reported serious adverse reactions in the Tysabri monotherapy trial relative to placebo were infections (3.2% vs 2.6%, including urinary tract infection (0.8% vs 0.3%) and pneumonia (0.6% vs 0%)), acute hypersensitivity reactions (1.1% vs 0.3%, including anaphylaxis/anaphylactoid reaction (0.8% vs 0%)), depression (1.0% vs 1.0%, including suicidal ideation or attempt (0.6% vs 0.3%)), and cholelithiasis (1.0% vs 0.3%). The most common adverse events reported at an incidence of >10% and relative to placebo were headache (38% vs 33%), fatigue (27% vs 21%), infusion reactions (24% vs 18%), urinary tract infections (21% vs 17%), arthralgia (19% vs 14%), depression (19% vs 16%), lower respiratory tract infection (17% vs 16%), pain in extremity (16% vs 14%), rash (12% vs 9%), gastroenteritis (11% vs 9%), abdominal discomfort (11% vs 10%), vaginitis (10% vs 6%), and diarrhea NOS (10% vs 9%).
Minimization of Important Risk Information
The webcast focuses on the risk of PML that is associated with Tysabri. We are particularly concerned with this webcast because it presents numerous statements that seriously minimize the risk of PML. For example, the webcast presents the following claims (emphasis added):
- “Heightened clinical vigilance led to prompt natalizumab discontinuation upon first signs or symptoms suggestive of PML
- The majority of patients who developed PML in the post-marketing setting received plasma exchange . . . to accelerate removal of natalizumab
- Majority of natalizumab-treated patients who developed PML have survived and exhibit varying levels of disability”
This presentation misleadingly implies that Tysabri patients who developed PML and received treatment (e.g., plasma exchange) experienced lessened effects of PML and that patient outcomes will necessarily be improved if Tysabri treatment is stopped at the first sign of PML; this has not been established. According to the Warnings and Precautions section of the PI, “. . . [t]here are no known interventions that can reliably prevent PML or adequately treat PML if it occurs. It is not known whether early detection of PML and discontinuation of TYSABRI will mitigate the disease. . . . There is no evidence that plasma exchange has any benefit in the treatment of opportunistic infections such as PML” (emphasis added). It is misleading to suggest that early detection of PML and prompt discontinuation of Tysabri will lessen any effects of PML.
This presentation also misleadingly implies that a significant portion of Tysabri-treated patients who develop PML survive and may only experience non-severe disabilities; this has not been established. Tysabri’s boxed warning (and Warnings and Precautions section) clearly states that PML is “. . . an opportunistic viral infection of the brain that usually leads to death or severe disability” (bolded emphasis in original; underlined emphasis added). In addition, as of the date of the first webcast, four of the first fourteen cases of PML reported since the reintroduction of Tysabri into the market in April 2006 had resulted in death, at least an additional three patients appeared moribund, and there was insufficient data on the remaining PML cases to make an assessment of outcome to support the implication conveyed by the last claim above (i.e., that Tysabri patients who develop PML are likely to survive and may only experience minor disabilities). This presentation fails to provide any further information on the actual functional status of patients affected by PML (e.g., by a Rankin scale). Overall, this presentation misleadingly minimizes the severity of the risk of PML associated with Tysabri.
In addition, the webcast presents the following claims pertaining to the incidence of the risk of PML:
- “The incidence of PML increases with treatment duration − No cases in MS during the first year of treatment − Incidence in patients treated for < 2 years appears to be <1 per 1000 − Incidence in patients treated for 2-3 years appears to be about 1 per 1000 − Not enough evidence patients treated for > 3 years to be confident of incidence”
- “The incidence of PML in the post-marketing setting is within the 1 in 1000 incidence implied in the label”
These claims misleadingly suggest that the risk of PML can be predicted based on an established treatment time range, when this is not the case. Specifically, the claims above suggest that PML risk can be definitively categorized into timeframes (i.e., 0-1 year, < 2 years, 2-3 years, and > 3 years); however, there is no evidence to support such a categorization of risk assessment. The risk of PML increases steadily over time. It is misleading to suggest that the PML risk associated with Tysabri use can be determined based an arbitrary cutoff of treatment duration.
Omission of Indication
Although the webcast discusses the use of Tysabri in “MS patients,” it fails to communicate any information about Tysabri’s approved indication for multiple sclerosis.
Failure to Submit
FDA regulations require the sponsors of biological products approved through the accelerated approval process, such as Tysabri, to submit promotional materials including promotional labeling and advertisements at least thirty days prior to the intended time of initial dissemination of the labeling or initial publication of the advertisement. A copy of the webcast was not submitted to FDA 30 days prior to the intended time of initial dissemination or publication, as required by 21 CFR 601.45.
FDA regulations also require sponsors to submit specimens of mailing pieces and any other labeling or advertising devised for promotion of biological products at the time of initial dissemination of the labeling and at the time of initial publication of the advertisement for a biological product. Each submission is required to be accompanied by a completed transmittal Form FDA-2253 (Transmittal of Advertisements and Promotional Labeling for Drugs for Human Use) and is required to include a copy of the product’s current professional labeling. A copy of the webcast was not submitted to FDA under cover of Form FDA-2253 as required by 21 CFR 601.12(f)(4). Cf. 21 CFR 314.81(b)(3)(i). We acknowledge an October 28, 2009, email to the Division of Neurology Products (DNP) which states your intent to hold “several webcasts regarding Tysabri and PML,” along with a copy of the invitation, which was sent to all prescribers enrolled in the TOUCH program, to attend this webcast. However, this does not satisfy the requirements described above.
Conclusion and Requested Action
For the reasons discussed above, the webcast misbrands Tysabri in violation of the Act, 21
U.S.C. 352(a) & (n); 321(n). See 21 CFR 202.1(e)(3)(ii); (e)(5)(i) & (iii); (e)(6)(i). Furthermore, the webcast was not submitted to FDA thirty days prior to the intended time of initial dissemination or initial publication, as required by 21 CFR 601.45. Moreover, Biogen failed to submit the webcast to FDA under cover of Form FDA-2253 at the time of initial publication, as required by 21 CFR 601.12(f)(4). Cf. 21 CFR 314.81(b)(3)(i).
DDMAC requests that Biogen immediately cease the dissemination of violative promotional materials for Tysabri such as those described above. Please submit a written response to this letter on or before April 9, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Tysabri that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials. Please direct your response to the undersigned at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD, facsimile at
(301) 847-8444. In all future correspondence regarding this matter, please refer to MACMIS #18025 in addition to the BLA number. We remind you that only written communications are considered official.
The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Tysabri comply with each applicable requirement of the Act and FDA implementing regulations.
Sincerely,
/S/
Amy Toscano, Pharm.D., CPA
Regulatory Review Officer
Division of Drug Marketing,
Advertising, and Communications
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