Making Use of the Food and Drug Administration Briefing Documents to
Reconsider the Safety Profile of the Antipsychotic Sertindole
Larry D. Sasich, PharmD, MPH, FASHP Burlington, Ontario, Canada
Elia Abi-Jaoude, MD
Department of Psychiatry, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
NOTE: Below is a manuscript that had been under review by the British Journal of Psychiatry (BJP) for three years and was rejected in August 2016. The reason given by the BJP editors was that the manuscript “does not lend itself to current article formats”. The manuscript is being released primarily for two reasons. First, the importance of accessing freely available FDA documents to obtain a more complete characterization of a drug’s safety and efficacy. Second, to alert patients and prescribers in other countries about the potential risks of sertindole.
For correspondence and contact: Larry Sasich <[email protected]>
In April 2009 an FDA advisory panel voted 13-0 that sertindole was effective in the treatment of schizophrenia but 12-1 that it had not been shown to be acceptably safe. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ PsychopharmacologicDrugsAdvisoryCommittee/UCM198218.pdf
NOTA, Spanish: Este manuscrito ha estado en revisión durante tres años en el British Journal of Psychiatry, y fue finalmente rechazado en agosto de 2016, por una razón meramente formal, la de no cumplir con el formato requerido. SE RUEGA la difusión del texto por dos razones: 1/ Para destacar la importancia del acceso a los documentos públicos de la FDA respecto a la seguridad y eficacia de los medicamentos y 2/ para alertar a pacientes y médicos prescritores de los riesgos potenciales de utilizar sertindol. Para contacto y correspondencia: Larry Sasich <[email protected]>
Sertindole. The EMA report and referrals documents in
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/ Sertindole_36/WC500011855.pdf
ACLARACIÓN, Spanish: Sertindol (marca comercial, Serdolect, en España y otros países, y Zerdol en Alemania) es un medicamento para la esquizofrenia que nunca fue aprobado en Estados Unidos. En Europa fue comercializado en 1996 y suspendido en 1998, por incremento de la mortalidad entre los pacientes. Fue re-autorizado y comercializado en 2002, tras un estudio [Sertindole Cohort Prospective (SCoP)] con 10.000 pacientes en que se dio la misma mortalidad total que con risperidona. Sin embargo, el análisis de los datos de la FDA demostró que con el sertindol es cinco veces más frecuente la muerte súbita por parada cardíaca, y de ahí su rechazo a la comercialización en Estados Unidos. Este incremento del riesgo es excesivo, como concluyen los autores del articulo que se difunde. NOTA: en la ficha técnica europea (de la EMA, European Medicines Agency) de sertindol no se dan los datos que consta en la documentación de la FDA, y se dice:
no han podido confirmar si el sertindol es más arritmogénico que otros antipsicóticos. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Sertindole/
human_referral_000111.jsp
Publication and reporting bias is now widely recognized as an epidemic adversely affecting the clinical trial literature.[1-7] A number of efforts have attempted to address this problem. Recently, Doshi and colleagues have proposed the Restoring Invisible And Abandoned Trials (RIAT) initiative to address reporting biases that undermine the usefulness of the published research on pharmaceuticals. The scientific record would be corrected by publishing unpublished clinical trials or formally correcting or republishing misreported trials.[8] As a highly thorough approach to correct the publication record, the RIAT model involves reanalyzing data and scrutinizing a trial’s clinical study report and other study documents obtained through litigation. Such documents are available for only a minority of clinical trials.
Another source of independent information from clinical trials both published and unpublished are US Food and Drug Administration (FDA) drug approval packages and briefing documents that include rigorous analyses of drugs approved or discussed by the agency. [9-12] FDA scientists review and analyze data submitted by manufacturers when they apply for approval of their drugs. These documents are freely available on the FDA website in compliance with the Freedom of Information Act. Authors have used the FDA documents to highlight discrepancies between published studies and FDA analyses.[2,13] Nevertheless, these valuable sources of independent information remain largely underutilized by the clinical community.
Here we compare the published literature on the safety of the antipsychotic sertindole as reported in the Sertindole Cohort Prospective Study (SCoP; [14]) with an unpublished FDA analysis of data from the SCoP trial. The sources of the unpublished analysis are publically available FDA briefing documents that were prepared prior to an open agency advisory committee meeting reviewing the safety and efficacy of sertindole.[15]
SERTINDOLE REGULATORY HISTORY
Sertindole was approved in the United Kingdom (UK) in May 1996 and later in other European countries through the Mutual Recognition Procedure. A potential safety signal concerning death rates during sertindole treatment was detected in the UK Medicines Control Agency’s Adverse Drug Reaction On-Line Information Tracking database. Due to sertindole’s known effect on the QT interval, there was concern that this possible signal was a reflection of an increased risk of serious and fatal arrhythmias. On November 2, 1998, the Netherlands initiated the marketing suspension of sertindole in the European Union (EU). On June 6, 1999, the European Committee for Medicinal Products for Human Use (CHMP) decided to suspend the marketing authorization in the EU until further data from further studies could be presented.[16]
Based on the results of these studies, the CHMP, on October 18, 2001, recommended lifting the marketing suspension for sertindole. A condition for the re-introduction of sertindole in the EU was that the sponsor commit to accounting for all patients treated with sertindole for at least the first year after the re-introduction of the drug to the market by enrolling them in studies. The sponsor agreed to conduct the Sertindole Cohort Prospective Study (SCoP), a large, randomized, parallel group, active-controlled study comparing the safety of sertindole and risperidone under normal conditions of use and a post-marketing surveillance study.[16]
PUBLISHED SCoP TRIAL [14]
cardiac events including arrhythmias. There were 64 deaths in the sertindole group compared to 61 in those receiving risperidone. The all-cause mortality ratio (sertindole vs. risperidone) was 1.12 (90% CI 0.83, 1.50), a non-statistically significant difference between the two groups. Regarding the second primary endpoint, the Independent Safety Committee classified 16 cases as cardiac events, including arrhythmia, requiring hospitalization, 10 in the sertindole group and six in the risperidone group (HR 1.73 (95% CI 0.63, 4.77)). Of these, four were considered arrhythmia-related (3 sertindole, 1 risperidone); because of the very limited number of arrhythmic events, no formal statistical analysis was performed. The SCoP authors concluded: “In view of the lack of difference in overall mortality, it remains appropriate to consider sertindole as treatment for patients with schizophrenia without cardiovascular disease who are intolerant of at least one other antipsychotic drug.”[14]
FDA BRIEFING DOCUMENTS
In contrast to the SCoP investigators, the FDA reviewers were of the opinion that endpoints other than all-cause mortality were of greater clinical importance. All-cause mortality is known to be significantly higher in schizophrenic patients than in the general population, any cardiac mortality signal could get lost if looking only at all-cause mortality. Because of the QT prolongation seen with sertindole use, it was suggested that the most clinically relevant endpoint would be sudden cardiac death with any sudden unexplained deaths being conservatively classified as cardiac. The reason for this is that significant QT prolongation is associated with Torsades de Pointes, which is itself often never detected but usually leads to sudden death.[17]
The table below is adapted from the medical officers’ review and shows that 13 sertindole cases were classified as sudden cardiac deaths and 3 in those receiving risperidone. The hazard ratio showed an approximate 5-fold increase in the risk of sudden cardiac death with upper limit of the 95% confidence interval approaching 18.
Estimated Hazard Ratio for Sudden Cardiac Death for Sertindole versus Risperidone During the WRT (Whole Randomized Treatment) +30 Days Period
Number of Sudden Cardiac Deaths
Sertindole Risperidone Hazard Ratio 95% CI
13 3 5.102 1.453 – 17.913
The FDA’s sudden cardiac death analysis adds substantially to what was published in the SCoP trial concerning the safety of sertindole.
The FDA analysis of SCoP, made public in April 2009, estimated the hazard ratio for sudden cardiac death with sertindole versus risperidone as 5.102 (95% CI 1.453 – 17.913).[17] The FDA advisory committee voted 12 to 1 that sertindole was not acceptably safe for the treatment of schizophrenia.[18] And sertindole was not approved for use in the US. According to sertindole’s manufacturer the drug was approved in 46 countries, in Europe, Asia and Latin America as of January 2009.[19]
The sudden cardiac death endpoint was not presented in the published SCoP article. We searched whether the FDA’s SCoP analyses have been published by conducting a literature search in Medline, EMBASE and PsycINFO using the following terms:
(sertindole) AND ((sudden cardiac death) OR (sudden death))
present a relatively favorable profile for sertindole.[21-24] An editorial accompanying the published SCoP article describes the study as “a very important trial that largely supports the EU regulatory decision to approve sertindole for use in schizophrenia.” [21]
DISCUSSION
Reporting biases including unpublished or misreported clinical trial results have weakened the literature placing in question the validity of the evidence used to produce review articles; meta-analyses; pharmacoeconomic studies; and clinical practice guidelines that form the bases for clinical and drug policy decisions.[1-7] As a consequence, there is a pressing need for independent sources of evidence.
FDA briefing documents are a category of regulatory documents that may contain unpublished clinical trials and safety and efficacy analyses or both. These documents are prepared for review at open public advisory committee meetings. The Federal Advisory Committee Act requires that any materials made available to an advisory committee also must be made available to the public. The public availability of these materials is subject to the Freedom of Information Act (FOIA), and FOIA exempts certain types of information from public disclosure.[26]
This article reports a previously unpublished analysis showing a substantially increased risk of the risk of sudden cardiac death with the use of the atypical antipsychotic sertindole compared to risperidone. The source of this analysis was publically available FDA briefing documents prepared for the April 2009 meeting of the Psychopharmacologic Drugs Advisory Committee. Advisory committees may be convened to provide the agency with recommendations from outside expert panels. Not all drugs are subject to advisory committee review.
The FDA analysis of the SCoP study data indicates a hazard ratio for sudden cardiac death with sertindole versus risperidone as 5.102 (95% CI 1.453 – 17.913). Based on our review of the literature, the clinical community is not adequately aware of this risk. Moreover, this risk is likely an underestimate considering dropouts due to increased QTc, and exclusion of patients at risk for sudden cardiac death from the SCoP study. Furthermore, the finding is all the more concerning considering that the increased risk is relative to risperidone; a drug that itself confers a risk of sudden cardiac death. [27]
The briefing documents were prepared from data submitted by the drug’s manufacturer in support sertindole’s approval in the US. These documents are detailed, for sertindole the length of the review was 407 pages, and the Statistical Review and Evaluation alone covered 52 pages.[28] The amount of information contained in these documents is extensive and detailed and provides a valuable insight into the safety and efficacy of this drug for those involved in making drug therapy and policy decisions. This amount of detailed information is more than can be communicated in a medical journal report.
The FDA’s SCoP analysis was made public in April 2009 and the journal publication appeared 18 months later in November 2010. Sertindole’s manufacturer funded the published SCoP trial but it is not known if the SCoP authors where aware of the FDA sudden cardiac death analysis at the time their manuscript was being prepared. Nevertheless, briefing documents have been posted on the FDA’s Web site since 2000 and are indexed in Iowa Drug Information Service (IDIS) from the University of Iowa College of Pharmacy (http://itsnt14.its.uiowa.edu). These documents are in the public domain and can be freely used with proper attribution.
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