Inspections, Compliance, Enforcement, and Criminal Investigations
Actelion Pharmaceuticals U.S., Inc. 9/14/10
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|San Francisco District |
1431 Harbor Bay Parkway
Alameda, CA 94502-7070
September 14, 2010
Jean-Paul Clozel, M.D.
Chief Executive Officer
Actelion Pharmaceuticals US, Inc.
5000 Shoreline Court, Suite 200
South San Francisco, CA 94080
Dear Dr. Clozel:
The Food and Drug Administration (FDA or “Agency”) inspected Actelion Pharmaceuticals’ (Actelion’s) facility located at the above address from June 24 through July 20, 2009. The inspection focused on Actelion’s compliance with Postmarketing Adverse Drug Experience (PADE) reporting requirements relating to the following drug products: Tracleer® (bosentan), NDA 21-290; Ventavis® (iloprost), NDA 21-799; and Zavesca® (miglustat), NDA 21-348. Both Tracleer® and Ventavis® are indicated for the treatment of forms of pulmonary arterial hypertension. Zavesca is indicated for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option. FDA’s inspection found that your firm failed to comply with the postmarketing reporting requirements imposed under 21 U.S.C. § 355(k) [Section 505(k) of the Federal Food, Drug, and Cosmetic Act (the Act)] and its corresponding regulations in Title 21 of the Code of Federal Regulations (21 C.F.R.) Section 314.80. Such failure to comply with Section 505(k) of the Act and its corresponding regulations is a prohibited act under Section 301(e) of the Act [21 U.S.C. § 331(e)]. Therefore, FDA concludes that Actelion has engaged in prohibited acts in violation of Section 301(e) of the Act.
The Agency is in receipt of your responses dated August 28, 2009, and September 11, 2009. It has been determined that the corrective actions you proposed are inadequate.
Actelion’s deviations from FDA’s reporting requirements observed during the inspection include, but are not limited to, the following: Failure to develop adequate written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences to FDA under 21 C.F.R § 314.80, and failure to report adverse drug experience information to FDA under 21 C.F.R. § 314.80, each of which is discussed, in turn, below. These deviations resulted in Actelion’s failure to report approximately 3,500 patient deaths reported to Actelion in connection with Tracleer® and Ventavis®, without an adequate basis for not reporting them.
In prelude to our discussion of these deviations, we acknowledge that Tracleer® and Ventavis® are indicated for the treatment of a serious condition that often results in patient death. In issuing this letter we are not concluding or implying that the patient deaths that were not properly reported to FDA in connection with these drugs would ultimately be determined to have been caused by their use, or that further information might not have provided an adequate basis under the regulations for not reporting them. However, Actelion’s written procedures and reporting practices resulted in Actelion’s failure to report them to FDA in the absence of information necessary to support a conclusion that they were not subject to reporting under the requirements of FDA regulation. Actelion is responsible for ensuring that it has a system in place to keep FDA appropriately apprised of adverse events so that FDA can appropriately evaluate the safety of drugs in the postmarket environment.
1. Failure to develop adequate written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences to FDA [21 C.F.R § 314.80].
FDA regulations require written procedures for reporting of postmarketing adverse drug experiences to the Agency. See 21 C.F.R. § 314.80(b). Actelion’s written procedures regarding adverse events reported through its patient-support programs for Tracleer® and Ventavis®, however, establish a process that is in violation of 21 C.F.R. § 314.80(e)(1) as they do not require the reporting of deaths to FDA within 15 calendar days of Actelion’s receipt of information about their occurrence when there is a reasonable possibility that the drug caused the death. Specifically, when Actelion has no information at all about the relationship between a death and its drug product, Actelion presumes that there is no relationship between the two and does not report the death to FDA on an expedited basis. That is not an acceptable basis for such a conclusion.
Specifically, Section 314.80(c) requires applicants to report serious and unexpected adverse events associated with their drug products no later than 15 calendar days of their initial receipt of the information. In the case of adverse events received in connection with postmarketing studies, Section 314.80(e)(1) limits the application of Section 314.80(c), but continues to require the submission of an expedited (15-day) report when an adverse event is serious and unexpected and there is a reasonable possibility that the drug caused the adverse event. Accordingly, serious and unexpected reports received in connection with company-sponsored patient-support programs need to be reported to FDA within 15 calendar days whenever there is a “reasonable possibility that the drug or biological product caused the adverse experience.”
In keeping with 21 C.F.R. § 314.80(e)(1), where initial adverse event information is received through its patient-support programs for Tracleer® and Ventavis®, Actelion is required to report deaths and other serious and unexpected adverse events associated with each drug to FDA no later than 15 calendar days of initial receipt of the information by Actelion if there is a reasonable possibility that the drug caused the adverse event. Reports of death always are considered serious and, for both Tracleer® and Ventavis®, would also be considered unexpected as death is not identified as an adverse event in the product labeling.
In contravention of Section 314.80(e)(1), Actelion’s written procedures used to classify Actelion’s standard operating procedure (SOP) for Tracleer®, set forth in part in GUI-506-SAF-US, do not require reporting of death reports to FDA within 15 calendar days, where there is a reasonable possibility that the drug caused the adverse experience. GUI-506-SAF-US provides that Tracleer® death reports should be classified as “[b4]” and “[b4]” if upon follow-up either no information is obtained at all or the death is confirmed but no other information about the death is obtained. GUI-506-SAF-US further states, “[b4].” The lost to follow-up narrative, set forth in GUI-504-SAF-US, provides:
These reporting procedures are in violation of the Act because they allow Actelion to presume that there is no relationship between a death and Tracleer® even when Actelion has no information at all about the possible relationship. There is, however, a “reasonable possibility” that Tracleer® contributed to a death if there is no information to suggest otherwise. In addition, the procedures do not require Actelion to make a meaningful effort to obtain information about the relationship between a death and Tracleer® at all, much less within a timeframe that would enable Actelion to meet its 15 calendar day expedited reporting obligations were a reasonable possibility that the drug caused a death to be found.
Actelion’s standard operating procedure for Ventavis®, set forth in part in GUI-943-SAF-US, also fails to require reporting of death reports to FDA within 15 calendar days where there is a reasonable possibility that the drug caused the adverse experience. For instance, GUI-943-SAF-US ignores the “reasonable possibility” determination required by Section 314.80(e)(1), providing that events reported in connection with postmarketing surveillance will only be expedited to FDA when they are determined to be “[b4].” GUI-943-SAF-US also defines deaths that are reported to Actelion by a specialty pharmacy and rendered “[b4]” as medically unconfirmed and not related to Ventavis®. As with Tracleer®, these adverse event reporting procedures are inconsistent with the reporting requirements of Section 314.80(e)(1). Contrary to Actelion’s GUI-943-SAF-US Guideline, serious and unlabeled events received in connection with Ventavis® must be reported if there is a “reasonable possibility” that the adverse event is related to the use of Ventavis®, not only where relatedness has been affirmatively established. Where there is a lack of information about a death report associated with Ventavis®, due to the non-responsiveness of a patient’s care provider or otherwise, and there is therefore no information to suggest that the particular death was caused by something other than Ventavis®, there is a reasonable possibility that Ventavis® caused the death.
Actelion’s written response to FDA’s inspectional observations dated August 28, 2009, confirms that Actelion is continuing its policies of not reporting Tracleer® and Ventavis® death reports to FDA on an expedited basis in circumstances where they are not medically confirmed by a healthcare provider, and we find unpersuasive the assertions offered by Actelion as to why its classification of the Tracleer® deaths as unrelated is justified. Actelion makes four assertions in this regard: (1) That the slow rise in the ratio of the number of cases of death reports to the number of exposed patients is as expected; (2) that Actelion submits death reports as line listings in PSURs; (3) that there has been a lack of responsiveness by healthcare providers to Actelion’s requests for information about deaths and that of those healthcare providers who did provide information, only 3% indicated that they believed the deaths were associated with the drug; and (4) that disease progression in patients treated with Tracleer® leads to death.
In general, Actelion’s reliance on its past experiences with adverse event reporting for Tracleer as the basis for its current adverse event reporting procedures and associated assumptions is undermined by the fact that Tracleer’s® indication was expanded in August 2009 to include the treatment of less ill patients -- those with pulmonary arterial hypertension (WHO GROUP I) with WHO Class II through IV symptoms, rather than those with WHO Class IV symptoms alone. Regardless of Actelion’s prior analyses of its Tracleer adverse event reports, there is no basis to assume that future reporting trends will be the same, when the drug is used in these new populations. Also, the fact that patient deaths are accounted for in line listings does not exonerate Actelion for failing to report them in accordance with FDA’s expedited reporting requirements. Third, the fact that healthcare providers have not been responsive to Actelion’s requests for follow-up information suggests that Actelion may need to take further action in accordance with its REMS in order to access the information needed. Pursuant to the REMS for Tracleer®, Actelion agrees to “monitor prescribers’ certification requirements and prescription data and may de-enroll noncompliant prescribers until the requirements are met.”Moreover, we do not agree that a determination of a relationship between Tracleer® use and death by 3% percent of healthcare providers who did respond to Actelion is insignificant or suggestive that those healthcare providers who did not respond to Actelion did not also believe there was such a relationship in the individual cases about which they were being asked.
In accordance with 21 C.F.R. § 314.80, Actelion’s written procedures must be revised to ensure that all death reports associated with Tracleer® and Ventavis® are sufficiently investigated for Actelion to determine whether there is a reasonable possibility that the drug caused the adverse event. The written procedures for these products must also be revised to ensure that all death reports related to Tracleer® and Ventavis® are reported to FDA on an expedited basis where, based either on information received or a lack of information to suggest otherwise, there is a “reasonable possibility” that the drug caused the death.
2. Failure to report adverse drug experience information to FDA [21 C.F.R. § 314.80].
Consistent with Actelion’s violative written procedures discussed above, at the time of the investigation, over 3,500 reports of death of TracleerÒ and VentavisÒ patients had not been sent to the Agency as individual case reports. At least 3,427 of registered TracleerÒ patient deaths and 118 of VentavisÒ patient deaths have not been determined by the patient’s prescriber or healthcare provider (or by other specific information about the death) to be non-attributable to the drugs, thus creating a reasonable possibility that the drugs caused the deaths.
As explained above, death reports associated with Tracleer® and Ventavis® (and obtained through the company’s patient-support programs for those drugs) must be reported in keeping with the requirements of 21 C.F.R. § 314.80(e)(1).
Our review of Actelion’s responses dated August 28, 2009, and September 11, 2009, find your corrective actions to be inadequate. Actelion continues to triage solicited reports of medically unconfirmed death cases as “non-related” for Tracleer® and Ventavis® and report them in annual periodic safety update reports (PSURs) instead of in 15 days on Form FDA 3500A.
Neither the above list of deviations nor the Form FDA 483 “Inspectional Observations” presented to you at the completion of the inspection are intended to be an all-inclusive list of deficiencies at your firm. It is your responsibility to ensure adherence to each requirement of the Act and applicable regulations. FDA requires drug manufacturers to establish written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences to FDA. FDA expects these procedures to assure that all adverse drug experiences are recorded, evaluated, and submitted to the FDA within established timeframes as required by 21 C.F.R. § 314.80.
You should take prompt action to correct these deviations. Failure to promptly correct these deviations may result in regulatory action by FDA without further notice. These actions include, but are not limited to, injunction and prosecution. Furthermore, federal agencies are advised of the issuance of all warning letters about drugs and devices so that they may take this information into account when considering the award of contracts.
We understand that death is a frequent result of the conditions treated by Tracleer® and Ventavis®. For this reason, we believe it is in your interest and FDA’s interest to have procedures that could yield information indicating that the underlying condition was the cause of death. You may also choose to seek a waiver of reporting responsibilities under 21 C.F.R. § 314.90. To facilitate your efforts to address the issues raised in this letter, we request a meeting with you and other senior management at Actelion to discuss them and your proposed response. In particular, we would like to discuss the development of procedures that would involve reasonable diligence in investigating the facts related to these events and that better address when to report these events to FDA. We encourage frequent interactions between your technical staff and FDA in an effort to help Actelion move forward with such corrective action as rapidly as possible.
We request that you notify this office in writing of the specific steps you have taken to correct the noted deviations and to prevent recurrence within 15 business days of your receipt of this letter. Your response should address the comments listed above and include examples of documentation showing that corrections have been achieved. If corrective action cannot be completed within 15 business days, please state the reason for the delay and the time within which corrections will be completed.
Your reply should be directed to the Food and Drug Administration, 1431 Harbor Bay Parkway, Alameda, CA 94502, Attention: Carl Lee, Compliance Officer. If you have questions regarding any issue in this letter, please contact Mr. Lee at (510) 337-6737.
You can find the Act and its associated regulations on the internet through links on the FDA web page at www.fda.gov.
Barbara J. Cassens
Shalom Jacobovitz, President
Actelion Pharmaceuticals U.S, Inc.
5000 Shoreline Ct., Suite 200
South San Francisco, CA 94080
 FDA defines “adverse drug experience” as “any adverse event associated with the use of a drug in humans, whether or not considered drug related . . . .” (21 CFR § 314.80(a)) (emphasis added). A report or information submitted by an applicant to FDA (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the applicant or FDA that the report or information constitutes an admission that the drug caused or contributed to an adverse event. (21 C.F.R. § 314.80(k)).
 In Guidance, entitled Postmarketing Adverse Experience Reporting for Human Drug and Licensed Biological Products: Clarification of What to Report, FDA has explained that Section 314.80(e)
encompasses reports received in connection with company-sponsored patient-support programs and some other similarly solicited adverse event reports. See Guidance for Industry -- Postmarketing Adverse Experience Reporting for Human Drug and Licensed Biological Products: Clarification of What to Report, August 1997, pages 3-4, Section III.
 See id.
 This reporting standard does not apply to reports of adverse events reported in connection with Tracleer® and Ventavis® outside of the patient-support programs for these drug products; adverse events that occur during a postmarket study must be separated and clearly marked as distinct from adverse events reported spontaneously to the company. See 21 C.F.R. 314.80(e)(2). In addition, this standard also does not apply to reports of pregnancy exposures and of liver injury, which are specifically addressed in Tracleer’s® REMS. Nothing in this Warning Letter is to be construed as a modification of the current REMS requirements.
 GUI-506-SAF-US is entitled “Guideline to Processing Adverse Events Classified as Post-marketing Surveillance,” Version No: 02, effective August 15, 2006.
 GUI-506-SAF-US is entitled “Guideline to Processing Adverse Events Classified as Post-marketing Surveillance,” Version No: 02, effective August 15, 2006, page 13 of 15, [b4] Chart.
 None of the applicable postmarket surveillance SOP provisions for Tracleer® provide timeframes within which follow-up must take place.
 GUI-943-SAF-US is entitled “Ventavis® (iloprost) Inhalation Solution Post-Marketing Adverse Event Processing,” Version No: 01, dated January 8, 2009, effective Date: January 22, 2009.
 GUI-943-SAF-US is entitled “Ventavis® (iloprost) Inhalation Solution Post-Marketing Adverse Event Processing,” Version No: 01, dated January 8, 2009, effective Date: January 22, 2009, page 5 of 24 (emphasis added).
 See Response to FDA Inspectional Observation dated August 28, 2009 (Actelion’s Response), at 11 providing in pertinent part:
[W]e are updating our procedures and [b4]
 See Response to FDA Inspectional Observation dated August 28, 2009 (Actelion’s Response), at 7.
 Actelion’s REMS Modification, Dated January 31, 2010 at 3 (emphasis added).