statistical analysis by apurva.pdf
- 2. Overview • Introduction • Safety concern • Sources of safety information & evaluation • Safety monitoring • IND safety monitoring requirements • Causality assessment • Postmarketing safety and reporting • Improving risk assessment & safety • Bayesian Method • Conclusion
- 3. Introduction •All medicinal products carry risks in addition to their possible benefits . •For developing a new medicine, a decision can only be made if both benefits & risks are addressed. • Risk associated with the drug is minimized when medicines of good quality, safety & efficacy are used rationally by an informed health professional & by patients. • Pharmacovigilance helps in reducing the risk of harm by ensuring use of good quality medicines appropriately.
- 4. •Need of international efforts to address drug safety were realized & initiated in 1961, following the Thalidomide disaster. • Guidelines were developed to monitor drugs, foods & environmental contaminants for adverse reactions & toxicity • In beginning, guidelines were restricted to local needs. Globalization - recognized need of a system, accepted internationally, to ensure safety of medicinal products.
- 5. •New drugs: marketed on basis of comparatively limited information, as clinical trials are designed to answer specific questions . •In US, ~ 500 to 2000 patients receive a new drug during clinical trials, & only a few hundred of them are treated > 3-6 months • In clinical trials, critical efficacy endpoints are identified in advance & sample sizes are estimated for assessment of effectiveness . • Common AEs are generally identified & well characterized in prospective trials
- 6. •Infrequent or delayed AE Characteristic depending on their severity and importance to risk benefits and require special techniques •Isolated report- definitive in associating a drug with an AE, if drug administration and event are temporally related, de- challenging or re-challenging. •In contrast with few exceptions phase 2 3 trial are not designed to test specified hypothesis about safety nor to measure identifying AE with any specified hypotheses about safety nor to measure or identify AEs with any pre-specified level of sensitivity. • Exceptions occur when a particular concern related to drug or drug class has arisen & when there is a specific safety advantage being studied.
- 7. •Safety evaluation during clinical drug development is not expected to characterize all the AEs, for example, those occurring in < 1 in 1000 patients •Risks that may be missed include • rare events • events occurring after long-term use • events occurring in special populations • events occurring in association with specific diseases & • events occurring in association with concomitant therapy Introduction
- 8. Safety concerns •Available data depend on the stage of development • Safety information on approved products is reflected in product labelling (Package Insert) •Up-to-date safety information on the products under investigation is found in Investigator’s Brochure (IB) – In vitro testing, Nonclinical pharmacology/toxicology studies – Clinical safety & pharmacokinetic data, if available – For products under investigation, IB is equivalent to Package Insert
- 10. •Pharmacology of drug or pharmacologically related drugs can be useful in identification & exploration of major safety concerns • E.g., clearance pathway of a drug can be indicative of certain potential drug-drug interactions or certain effects of ↓ renal or hepatic function • Similarly, pharmacologic class, & prior experience, could lead to focus on particular laboratory or clinical abnormalities • E.g., muscle or liver abnormalities: HMGCoA reductase inhibitors, •sexual dysfunction: SSRIs & •GI, renal & cardiovascular effects: NSAIDs
- 11. Systematic reviews & meta-analyses of clinical trials •have recently raised concerns about ↑ in risk of •serious adverse outcomes (ischemia & arrhythmia): varenicline Mortality: tiotropium inhaler, Similarly, ↑ risks of MI: rosiglitazone & CHF & fractures: thiazolidinediones (rosiglitazone & pioglitazone) in clinical trials have resulted in regulatory warnings Safety Concerns.
- 12. Sources of safety information & Safety evaluation •Various sources of information are – • Spontaneous ADR reporting schemes, Clinical & epidemiological studies, Worldwide published medical literature, Pharmaceutical companies, Worldwide regulatory authorities, Morbidity & mortality databases, Nonclinical data (in vitro, animals), Post marketing experience & Safety profile of other drugs in the same class
- 13. Nonclinical information •Chemical structure/Drug class – Class toxicities •In-vitro toxicity evaluation – Genotoxicity – Cardiac repolarization • Pharmacology-Toxicology studies in animals – Organ specific toxicities – Carcinogenicity – Teratogenicity Sources of safety information & Safety evaluation.
- 14. Sources of safety information & Safety evaluation •Information from all of these sources is carefully screened & may • identify unexpected SEs; • indicate that certain SEs occur more commonly than previously believed, or that some patients are more susceptible to some effects than others •Such findings can lead to changes in marketing authorisation of medicine – restrictions in use, changes in specified dose of the medicine & introduction of specific warnings of SEs in product information
- 15. •As new information related to a marketed drug becomes available, regulatory agencies - review the data & evaluates any potential drug safety concern • If potential drug safety concern arises, relevant scientific experts within the agency - prompt review & analysis • Period of uncertainty - agency evaluates new safety information to determine whether there is an important drug safety issue related to a specific drug or drug class & whether regulatory action is appropriate Sources of safety information & Safety evaluation.
- 16. •During this period, agency - actively engaged in gathering additional safety information • Sponsors - evaluate new safety information & provide the results of their analyses to agency during this time • As additional data relevant to an emerging drug safety issue become available (e.g., data from an ongoing study or data from available clinical databases) - considered in analysis & decision-making process Sources of safety information & Safety evaluation
- 17. •Upon evaluation of additional data, further regulatory action - revision to product labelling or - Risk Minimization Action Plan (RiskMAP), as appropriate • As agency evaluates a drug safety issue to determine whether regulatory action is warranted - communicate further information to public at appropriate points Sources of safety information & Safety evaluation
- 18. •Knowing if the subject is fit for the trial Aas safety of the subject is of utmost importance, it is necessary to determine whether the subject is fit for the trial or not • For this, investigation brochure (IB) findings are applied to protocol & a prospective subject • Fitness of subject is decided based on Inclusion / Exclusion criteria & by examining the potential for drug accumulation / toxicities , Inclusion / Exclusion criteria – medical history, lab values & concomitant medications used , Examining the potential for drug accumulation / toxicities involves PK parameters, single versus multiple doses & linearity of exposure with dose escalation
- 19. Phase 1 / Pharmacokinetic Trials •Absorption, metabolism, Cmax, AUC, T1/2 – in healthy subjects – in patients • Drug safety profile in dose escalation trials – Healthy volunteers – Safety signals supporting nonclinical findings – New safety signals in humans only.
- 20. •By spontaneously reported symptoms or symptoms reported as a result of a probe or both Spontaneously reported symptoms have advantage of detecting more severe episodes, truly unexpected AEs & identifying what’s important to the patient But, may lack standardization (e.g. within & across trials) Symptoms reported as a result of a probe (using Checklist & Questionnaire) allows standardization within & across trials But, may miss unexpected AEs Ascertainment of Adverse Events .
- 21. Other Safety Assessments/Monitoring •Vital signs • Laboratory evaluations – CBC – LFTs – CPK – KFTs – Pancreatic enzymes • Special safety assessments – Visual, Hearing – Neurological exam – ECG
- 22. Adverse Event / Experience •Any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug related – sign, symptom, or disease – abnormal lab, imaging, ECG, etc – worsening of the above – constellation of the above
- 23. AE Severity Grading Scales •Provide general guidance on parameters for monitoring safety in clinical trials • They are specific to: – Study population – Phase of product development (1-4) – Product evaluated (small molecule, therapeutic biologic, device, vaccine) • Examples: – NCI (National Cancer Institute) – DAIDS (Division of AIDS)
- 24. Serious Adverse Event •An AE or suspected AR is considered “serious” if, it results in the opinion of the Investigator or Sponsor in any of the following outcomes: • death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect, or requires intervention to prevent permanent impairment or damage
- 25. Unexpected Adverse Event •Not listed in the Investigator’s Brochure (IB) or if IB not available or required Not listed at the specificity or severity observed . • Mentioned in IB as anticipated due to pharmacokinetic properties of the drug or occurred with other drugs in this class, but not with the study drug. •Not consistent with the risk information described in the general investigational plan or elsewhere in current application, as amended.
- 26. Investigational New Drug (IND) Safety Reporting Requirements •Unexpected fatal or life-threatening suspected AEs - important safety information & thus, must be reported more rapidly to FDA • Any unexpected fatal or life-threatening suspected AR – reported in no later than 7 calendar days after the sponsor’s initial receipt of the information • If the safety report submitted within 7 calendar days is complete, additional submission within 15 days from day zero is not required
- 27. •Sponsor must also report any findings from •clinical, epidemiological, or pooled analysis of multiple studies or any findings from animal or in vitro testing: significant risk in humans exposed to drug (e.g., mutagenicity, teratogenicity, carcinogenicity) Follow-up IND Safety Report – If sponsor obtains any relevant additional information – submitted no later than 15 calendar days after the sponsor receives the information
- 28. IND annual safety report •required of all IND holders & should include – • most frequent & most serious AEs by body system, list of subjects who died, including cause & list of subjects who dropped out in association with an AE Investigational New Drug (IND) Safety Reporting Requirements
- 29. Expedited Safety Reporting to FDA by Sponsor •Adverse Events that meet all three criteria are reported to FDA (SUSAR): – Serious (S) – Unexpected (U) – Suspected Adverse Reactions (SAR) • Fatal or life-threatening SUSAR should be reported to FDA no later than 7 days • Others SUSAR should be reported to FDA no later than 15 days Drug safety evaluation in clinical trial
- 30. •Statistical analysis can lead to structured & harmonized assessment of causality by decreasing disagreement between assessors, classifying relationship likelihood, marking individual case reports & improvement of scientific evaluation • It can be particularly useful for evaluation of common AEs • Causality assessment can be performed simply by categorizing evidence by the quality of its sources & evaluating evidence of a causal relationship using standard guidelines Causality assessment
- 31. Causality assessment •Various sources for causality assessment can be clinical trials, cohort or case-control studies, time-series studies & case-series • Individual assessment unlikely to help determine attribution for common AEs, i.e. headache, nausea, MI in elderly Such AEs require aggregate analyses using a population approach (risk or rate with study drug vs. control) – Placebo or active control – Other doses in multiple dose studies .
- 32. •Use of standard guidelines for evaluating the evidence of a causal relationship may include temporal relationship, strength of association, dose-response relationship, consideration of alternate explanations, cessation of exposure, specificity of the association & consistency with other knowledge Causality assessment.
- 33. FDA system of managing risks •FDA approves a product: benefits of using a product outweigh the risks for the intended population & use • Major goal of premarketing review: ensure that products are truthfully & adequately labelled for the population & use • Labelling is given considerable emphasis: chief tool the Agency uses to communicate risk & benefit to the healthcare community & patients • Once medical products are in the market - ensuring safety is principally the responsibility of healthcare providers & patients, who make risk decisions on an individual basis
- 34. Postmarketing Safety •Postmarketing surveillance (PMS): practice of monitoring the safety of a pharmaceutical drug or medical device after it has been released in the market • Since drugs are approved on the basis of clinical trials, which involve •relatively small numbers of people who normally do not have other medical conditions which may exist in the general population • Thus, PMS can further refine, or confirm or deny, the safety of a drug after it is used in the general population, who have a wide variety of medical conditions
- 35. Postmarketing Reports •For ensuring drug safety on long term & on a wider population, regulatory authorities ask the marketing authorization holders (MAH) for Reporting of AEs & Periodic submission of safety reports , For serious & unexpected AEs, FDA recommends reports to be submitted within 15 calendar days either foreign or domestic , Follow up to 15-day alert reports should be submitted within 15 calendar days.
- 36. New safety data related to combination therapy •If PSUR is for fixed combination product – summarise important safety information arising from individual component •Information specific to combination can be incorporated into separate section(s) of PSUR for one or all of the individual components of the combination
- 38. Reference 1. Global biostatistcal science Amgen by Amy xia and oi Jiang 2. Wikipedia.com