Sperimentazione clinica e farmacovigilanza. Achille P. Caputi Presidente Società Italiana di Farmacologia

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1 Sperimentazione clinica e farmacovigilanza Achille P. Caputi Presidente Società Italiana di Farmacologia

2 Sperimentazione clinica Trial clinici randomizzati (RCTs) Sono accettati come gli studi metodologicamente più corretti per la valutazione dell efficacia di nuovi interventi terapeutici. Nell ambito delle linee-guida rappresentano la prova più rilevante, necessaria a produrre una raccomandazione terapeutica da implementare nella pratica clinica.

3 RCTs: obiettivi L obiettivo principale è quello di dimostrare l efficacia del farmaco. La valutazione della safety è secondaria senza una ipotesi da sperimentare

4 Efficacia e sicurezza: cosa misurare Efficacia: provare qualcosa di positivo (il farmaco ha effetti benefici sulla malattia in questione) si raccolgono e valutano particolari parametri relativi a quella particolare malattia. Sicurezza: provare qualcosa di negativo (il farmaco non ha effetti indesiderati inaccettabili) tutti i dati possono essere rilevanti, indipendentemente dalla malattia da trattare e dalla efficacia del prodotto per quella indicazione

5 Safety and RCTs

6 Some post-marketing withdrawals for ADRs Mibefradil Alosetron Circulation 1998; 98: 31 Lancet 2001; 357: 1544 Troglitazone JAMA 2000; 283: 2228 Cisapride JAMA 2000; 283: 2228 Cerivastatin BMJ 2001; 323: 359 RCTs (some with thousands patients) had failed to detect ADRs; safety profile of some drugs was reported = that of placebo

7 Safety e sperimentazione clinica cosa bisogna sapere RCT non disegnati per valutare la safety Selezione dei pazienti Grandezza del campione inadeguata Co-prescrizioni assenti o stabilite dal protocollo Co-morbifità assenti o stabilite dal protocollo Durata della somminsitrazione stabilita a priori Assenza del placebo EA insorti non sempre imputati al farmaco Practololo Vigabatrina Incompletezza dei dati di safety in RCT L incidenza di disturbi muscolari osservati durante i trial clinici con statine non è stata significativamente diversa da quella osservata con il placebo. (Gotto AM. Safety and statin therapy. Arch Intern Med 2003; 163: )

8 Safety : on-treatment analysis or by intention-to-treat analysis. If toxicity occurs when patients are actively taking the drug, the on-treatment approach may be more powerful than intention-to-treat analyses for detecting important associations with adverse events (ADEs). ADE, however, may persist after drug discontinuation and under these conditions, the on-treatment analysis will systematically underestimate risk, as apparently occurred in the sponsor s analyses. ADEs due to the active therapy may differentially cause dropouts in the active therapy group, resulting in biased results for any end point that may be associated with these ADEs. The preferred method of analysis for RCT is the intention-to-treat analysis with complete follow-up of all randomized patients through the end of the trial. Even if the trial protocol specifies an on-treatment analysis for safety, all safety data should be collected and analyzed by the intention- to-treat method as well. A Psaty BM & Kronmal RA JAMA 2008;299:

9 Sperimentazione clinica pre-marketing Minimizzare i dati di safety Rofecoxib Lumiracoxib (quanto conviene?)

10 Vioxx Gastrointestinal Outcomes Research (VIGOR) Bombardier C et al, NEJM 2000; 343: CV safety results: Rofecoxib vs Naproxen Myocardial infarctions: 0.4 vs 0.1 (RR 2.0) myocardial infarctions were less common in the naproxen group than in the rofecoxib group (RR 0.2; 95% CI, 0.1 to 0.7). Why this difference in the number of AMI? Naproxen inhibits the production of thromboxane by 95 percent and inhibits platelet aggregation by 88 percent, and this effect is maintained throughout the dosing interval; therefore, the effects of regular use of naproxen may be similar to those of aspirin.

11 Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET) cardiovascular outcomes: randomized controlled trial. Farkout ME et al. Lancet, 2004; 364: Discussion An increase in transaminase, of more than three times the upper limit of normal, happened in 2 6% of patients on lumiracoxib, which was more than both non-steroidal antiinflammatory drugs (0 6%), but it was reversible on drug discontinuation. Because TARGET used a supratherapeutic dose of lumiracoxib (two or four times the chronic osteoarthritis dose), our findings could represent an overestimate of the incidence of such laboratory (and any other) abnormalities, both in absolute terms and when compared with therapeutic doses of ibuprofen and naproxen.

12 Introduzione in terapia di un nuovo farmaco cosa bisogna sapere The rapidly widespread and often prolonged use of drugs could mean that even a small increase in the risk of a serious adverse event could be very significant in population health terms

13 What does the story of drug safety teach about RCT We have accepted that RCTs are the gold standard for establishing the balance of long-term drug safety and efficacy. However, even when involving thousands of patients, they have important limitations: - are very costly.. - may preclude the use of placebo, because of ethical considerations.. - the comparisons with other active drugs may be difficult to interpret. Nelson MR et al. MJA 2005: 182:262-3.

14 What does the story of drug safety teach us (1) Events with the TDZ, which follow on the heels of similar, unsuspected concerns about COX-2 inhibitors, anti-arrhythmic therapy, and hormone replacement therapy, has again highlighted the need for a more systematic approach to longterm safety monitoring of long-term drug therapy.

15 What does the story of drug safety teach us (2) A solution to long-term drug safety monitoring might include observational epidemiology. Methods must be developed for early identification of users of new drugs and their subsequent disease history determined by data-linkage to various mortality and morbidity databases (such as hospital admissions, cancer and death registries).

16 I trials clinici pre-marketing NON garantiscono che il farmaco, una volta introdotto in commercio, abbia un beneficio superiore al rischio Proposta

17 What does the story teach about drug s safety? The final test of the safety of a drug is in fact its release for general use. It has been said 43 years ago!!! Witts LJ. Adverse reactions to drugs. BMJ 1965; 5470: Proposta: velocizzare l AIC almeno da parte delle Autorità Italiane se non possibile da parte dell EMEA?

18 Sperimentazione clinica postmarketing e farmacovigilanza

19 REAZIONE AVVERSA DA FARMACI DEFINIZIONE DELL OMS (Tech Rep Serv WHO, n. 498, 1972) Una risposta ad un farmaco che procuri danno, che sia non intenzionale, e che si verifichi alle dosi normalmente utilizzate nell uomo per profilassi, diagnosi o terapia. OBIETTIVO (PRINCIPALE) DELLA FARMACOVIGILANZA L identificazione di eventi avversi correlati all uso di farmaci che siano ignoti o nuovi in termini della loro manifestazione clinica, severità o frequenza Ciò implica la ricerca di segnali preliminari di tali eventi. L OMS definisce un segnale come un informazione segnalata su una possibile relazione causale tra un evento avverso ed un farmaco. Hauben M. Zhou X. Quantitative Methods in Pharmacovigilance. Focus on Signal Detection. Drug Safety 2003; 26:

20 Il segnale Individual case safety reports (ICSR) in children in commonly used drug groups signal detection Brunlöf G, et al. BMC Clin Pharmacol. 2008; 8:1

21 National Electronic Injury Surveillance System Cooperative Adverse Drug Event Surveillance Project (NEISS-AIP) A partire dal ospedali degli USA ADR che inducono accesso ai Dipartimenti di Emergenza ed eventuale successivo ricovero Budnitz DS et al. JAMA 2006;296: Budnitz DS et al. Ann Inter Med 2007; 147: Cohen AL. et al. J Pediatr 2008; 152:

22 Budnitz DS et al. National Surveillance of Emergency Department Visits for Outpatient Adverse Drug Events JAMA, 296: ; 2006 warfarin, insulina, e digossina, con basso indice terapeutico ed alto rischio di tossicità sono causa di circa 1/3 delle ADE nei pazienti > 65 anni: dato importante per la prevenzione

23 National estimates of the numbers, population rates, and severity (measured by hospitalization) of individuals with ADEs treated in ED Active surveillance ( ) through the National Electronic Injury Surveillance System Cooperative Adverse Drug Event Surveillance project (63 EDs) ED visit per ADEs = 21,298 annual estimate: 701,547 individuals ( ) 2.4 ( ) individuals per 1000 population, >65y: annual estimate, 4.9 vs 2.0 per 1000; RR= 2.4 ( ) ADEs induced hospitalization = 3,487 individuals annual estimate: 117,318 [16.7% (13.1%-20.3%)]. >65y: annual estimate, 1.6 vs 0.23 per 1000; RR= 6.8 ( ). Budnitz DS et al. JAMA 2006;296:

24 Number of Cases and Annual estimate of Drugs Most Commonly Implicated in AEs treated in ED (Budnitz DS et al. JAMA. 2006;296: ) On 18 drugs most commonly causing ADEs only 5 do not belong to NSAIDs or antibiotics. All of them are on the market for more than 20 years

25 The preventability of ADRs There is a total break in responsibility between regulators and industry, which provide information on medicines and make them available, and those who prescribe medicines. In several studies, about half of serious adverse reactions have been said to be avoidable. This suggest a serious defect. Edwards I R, The future of Pharmacovigilance: a personal view. Eur J Clin Pharmacol 2008 doi: /s

26 Which drugs cause preventable admissions to hospital? A systematic review (R. L. Howard et al. BJCP 2006) (entire study population: 43,380) What proportion of hospital admissions are drug related and preventable? 3.73 ( ) What are the most common underling causes of preventable drugrelated admissions? Percentage (%) of problem Prescribing 30.6 Monitoring 22,2 Patient adherence 33.3 Drugs involved 4 groups account for >50% (antiplatelets, diuretics, NSAIDs, anticoagulants)

27 Serious ADEs reported to FDA from 1998 through 2005 Moore TJ et al, Arch Intern Med. 2007;167: Serious ADE increased 2.6-fold from to , and fatal ADE increased 2.7-fold from 5519 to Serious ADE increased 4 times faster than the total number of outpatient prescriptions 3. In a subset of drugs with 500 or more cases reported in any year, drugs related to safety withdrawals accounted for 26% of events in that group in 1999, declining to less than 1% in For 13 new biotechnology products, serious ADE grew fold, from 580 reported in 1998 to 9181 in The increase was influenced by relatively few drugs: 298 of the 1489 drugs identified (20%) accounted for of the events (87%).

28 Serious ADEs reported to FDA from 1998 through 2005 Moore TJ et al, Arch Intern Med. 2007;167: Conclusions: These data show a marked increase in reported deaths and serious injuries associated with drug therapy over the study period. The results highlight the importance of this public health problem and illustrate the need for improved systems to manage the risks of prescription drugs.

29 Prescribing Modern drugs are pharmacologically complex. The population is ageing. The use of polypharmacy is increasing. Prescribing is becoming increasingly difficult and the inherent risks of adverse reactions and interactions have increased. A prescription for better prescribing. Aronson JK, Henderson G, Webb DJ, Rawlins MD BMJ 2006; 333:459-60

30 Grazie per l invito e per l attenzione Achille P. Caputi Presidente Società Italiana di Farmacologia