Dr. Seyfullah DAĞISTANLI SİNYAL ÜRETİMİ FARMAKOVİJİLANS EĞİTİM PROGRAMI (I-II) 16 -17 Ocak 2006 Etap Altınel Otel - Ankara Dr. Seyfullah DAĞISTANLI Welcome. I am Joyce de Langen. I am a pharmacist and I work here at the Netherlands Pharmacovigilance Centre Lareb for three years now. The first year I worked as an assessor at the department of Coding and assessment and since two years I work as a scientist at the research and analysis department.

ADR İŞLENMESİ Veri Girişi Kodlama/değ erlendirme Bildirim ICH E2B Veri Girişi Kodlama/değ erlendirme Bildirim Bilimsel değerlen dirme Analiz Geri bildirim ICH E2B MEB EMEA WHO MAH Yayın This slide shows you in overview the different steps of the way the Netherlands Pharmacovigilance Centre processes her reported ADRs. After receiving the reports of possible ADRs the data are entered in the Lareb2002 database by our department of data entry, all in conformity with the ICH E2b guidelines. The reports are distributed among the assessors who will code and assesses the reported ADRs, as we have demonstrated you yesterday at the workshop assessing reports. After the reports have been coded and assessed the reporter is notified about our findings. The reporter receives a fully computerized feedback-letter with the results of the assessment of the reported ADR. Besides reporting to the individual reporter Lareb exchange their ADRs with other organisations, such as Medicines Evaluation Board, the database of Uppsala Monitoring Centre and the Marketing Autorisation holders. Again all, ICH E2b compatible. In addition, every week three of the assessors discuss the reports they assessed in a weekly scientific meeting with the scientific staff. I believe you will join the scientific meeting this afternoon.The key question of this meeting is whether or not further investigation about a reported ADR is needed. Sometimes this means that more information from the reporter about a reported association is needed. But it might also be possible that the scientific staff decides for a more detailed analysis of the reported association, because they believe a reported association might be a possible new signal. When, after this more detailed analysis, a reported association is indeed considered a potential signal, Lareb informs both the regulatory authorities as the health care professionals by publishing the signal in both national and international signals. As I told you, the proces of signal generating is actually a continue process which involves more or less all the different steps of the process.

Sinyal aramada temel yaklaşım Bilgi Dökümantasyonun kalitesi Olgu-olgu analiz (Case by case analysis) İstatistiksel sinyal arama After this rather short overview of the way Lareb processes her ADRs I want to talk about some considerations on signal detection. First the information included in the initial report. How do we cope with the

Bilginin süzülmesi Öznel ve nesnel nesnel Başlangıç raporu Anahtar sözcükler First the information included in the initial report. How do we cope with the information from the initial report? An initial report generally contains a lot of crude information that has to be transformed into a few key words that match the content of the reports. In addition the original report reflects the subjective opinion of the reporter, which is not always the same as the objective opinion of the assessor.

Case by case analysis (Olgu-olgu analiz) pat A pat B pat C pat D pat E ADR Vd Drug V1 age V2 gender V3 source V4 comed1 V5 comed2 V6 comed3 V7 latency V8 seriousness V9 indication V10 med history V11 fam history V12 clin picture V13 etc V14 V15 .. Vn This slide shows you the different characteristics of five patients. You can see that not all the cases are equally documented. The documentation-grade of a report contributes highly to the value of a possible futural signal.

Rapor karakteristikleri Hasta karakteristiği Yaş Cinsiyet Zamansal ilişki Latent periyot Sataşma/yeniden sataşma (de- or rechallenge) Eşlik eden ilaç Tıbbi öykü Çıktı (out-put)

Statistical signal detection pat A pat B pat C pat D pat E ADR Vd Drug V1 age V2 gender V3 source V4 comed1 V5 comed2 V6 comed3 V7 latency V8 seriousness V9 indication V10 med history V11 fam history V12 clin picture V13 etc V14 V15 .. Vn pat F patG pat H pat I pat J Vd V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 .. Vn Next to the case by case analysis it is also possible to generate possible signals by a statistical approach. Instead of studying the individual case report statistical methods can be used to analyse characteristics set of reports in order to detect new possible signals. Among these different characteristics possible interrelationships might exist that may lead to the detection of new signals.

İstatistiksel sinyal arama Database’de sinyal arama için güçlü enstrüman gerekir Gizli ilişki İlaç ilaç etkileşlmesi Sendromlar Risk faktörleri Yorum gerektirir! That means: Is a certain reported association statistically more present in a data set of reports than might have been expected on basis of coincidence?

Statistical signal detection Orantılı raporlama Odd ratio lokal Bayesian Propagation Neurol Network analysis → Uppsala Monitoring Centre (WHO) ► Orantısızlığı ara! In the past decades, various statistical measures have been developed for the application of computer-assisted quantitative signal detection. Examples of such measures are… Although the idea and methodology behind this measures differ, they all search the data set op reports for disproportionality.

Statistical signal detection Reporting Odds Ratio ADR Other ADRs Drug a b Other drugs c d

Acetylcysteine ve diarrhea Örnek Acetylcysteine ve diarrhea Acetylcysteine a mucolyticum that acts by splitting disulfide bonds in mucoproteins to lower mucus viscosity. Not described in the SPC More than 10 reports

Analiz Temel Sorular Literatür ilişkiyi destekliyor mu? Orantısız İlişki lokal database veya WHO database’inde mevcut mu? Advers etki ilacın farmakolojik özellikleri ile açıklanabiliyor mu?

Acetylcysteine ve diarrhea literatür KÜB YOK Meyler’s Side Effect of Drugs ADR reported by 9% of the patients: diarrhea etc. Micromedex Dutch Reference Books Pubmed Birkaç makale

Acetylcysteine ve diarrhea Lareb database Lareb-database’de toplam 52066 rapor 125 rapor acetylcysteine ile ilgili Diarrhea 2287 raporda belirtilmiş 13 raporda Diarrhea+ acetylcysteïne bildirilmiş

Acetylcysteine and diarrhea statistical signal detection ADR Other ADRs Drug 13 112 Other drugs 2274 49667 = 2.5 = 1.4 – 4.5

Acetylcysteine ve diarrhea WHO-database Toplam 3176114 rapor Bu raporların 2710’u acetylcysteine ile ilgili Database’de diyare ile ilgili 84631 rapor mevcut Acetylcysteine + diarrhea 155 kez raporlanmış ► Reporting Odds Ratio = 2.2 (95%CI= 1.9 – 2.6)

Acetylcysteine ve Diarrhea Doğru sinyal! Although the farmacological mechanism is still unknown the association acetylcysteine and diarrhea is actually a true signal.

TEŞEKKÜRLER

Crystal reports interaction database

Crystal reports Prescription data

Prescription Data

Sonuç About 5,000 reports every year About 400 detailed analyses yearly Yearly almost 50 true signals Almost 30 publications every year