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ETHICS Ουρανία Δαφνή Καθηγήτρια, Διευθύντρια Εργαστήριο Βιοστατιστικής Πανεπιστήμιο Αθηνών Διευθύντρια Frontier Science Foundation-Hellas (FSF-H) ΜΠΣ Βιοστατιστικής.

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Παρουσίαση με θέμα: "ETHICS Ουρανία Δαφνή Καθηγήτρια, Διευθύντρια Εργαστήριο Βιοστατιστικής Πανεπιστήμιο Αθηνών Διευθύντρια Frontier Science Foundation-Hellas (FSF-H) ΜΠΣ Βιοστατιστικής."— Μεταγράφημα παρουσίασης:

1 ETHICS Ουρανία Δαφνή Καθηγήτρια, Διευθύντρια Εργαστήριο Βιοστατιστικής Πανεπιστήμιο Αθηνών Διευθύντρια Frontier Science Foundation-Hellas (FSF-H) ΜΠΣ Βιοστατιστικής Μάθημα: Κλινικές Δοκιμές Αθήνα, Εαρινό Εξάμηνο 2015

2 Ethical Considerations Important for all researchers (not just physicians treating the patients) to consider ethics Growing public concern Tension between roles of physician as caregiver and investigator  Heightened by industry sponsorship? The Role of Human Subjects Committees (Institutional Review Boards; also called Ethics Committes) Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

3 Outline Overview of ethical issues Historical perspective Modern perspective Procedural aspects of ethical oversight Example: ACTG076 and Lallemant trials. Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

4 Overview Clinical trials are ethical in settings where there is uncertainty about the best treatment  No ethical proscriptions on clinical trials research  Ethical obligation to take steps to reduce ignorance about best treatments There is a distinction between the ethics of clinical trials research in general and the ethics of a particular study  We consider clinical trials research as an ethical endeavor when done right; important, however, to consider ethics of individual trials Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

5 Clinical Research and Clinical Practice Practice  Implies uncertainty  Done primarily for the good of the patient Research  Performed for the collective good or to acquire knowledge. Guided in part by the desire to benefit future patients Distinction depends in part on setting Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

6 Double Standards The Practitioner is free to choose and advocate treatments The Investigator incurs additional, structured ethical obligations Patient and public concerns  The physician as academic investigator  Medicine as “big” business Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

7 Some Ethical Concerns/Aspects of Trials Randomization: concept of “clinical equipoise”  a physician should participate only if he/she has no clear belief of the superiority of one treatment Active versus placebo controls  when is a placebo ethical? Informed Consent:  to ensure patients understand they are part of a research project, that their treatment may be determined by chance, the risks/benefits of each treatment, that they can discontinue at any time without penalty Need to monitoring evolving results  in case one treatment is shown to be superior, inferior, or otherwise not in the patient’s best interests before planned completion of trial Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

8 Historical Perspective The Nuremberg Code  Voluntary consent of patients  No reasonable alternative to the experiment  Anticipated results have a biological basis  Avoidance of unnecessary suffering  No expectation for death or disability  Risk consonant with importance  Subjects protected against risk of death or injury  Research conducted by qualified scientists  Subjects can withdraw at will  The investigator has an obligation to terminate the trial if injury seems likely Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

9 Other Sources of Guidance The Hippocratic Oath  “I will prescribe regimen for the good of my patients... and never do harm”  The Oath contains no prescription on clinical trials or research The Helsinki Declaration  In any medical study, every patient -- including those of a control group, if any -- should be assured of the best proven diagnostic and therapeutic method. International ethical guidelines for research involving human subjects Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

10 Modern Perspective The 1974 NRA requires Institutional Review Boards (IRBs) in the US The 1978 Belmont Report  Respect for Persons (right to autonomy)  Beneficence and non maleficence minimization of risk to research subjects and maximization of benefits to them and others  Justice therapeutic investigations should not involve persons from groups unlikely to benefit from applications of the research Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

11 Proposals To Revise the Declarations Brennan, NEJM, 8/12/99 Current regulations are based on a utilitarian principle  Research is ethical if risks to the participants are outweighed by the general good to be attained The researcher must be committed to the welfare of the research subject The rights of the subject must be respected Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

12 Tensions and Contradictions Utilitarian calculations are not necessarily aligned with a commitment to individual subjects Right to informed consent does not work equally well in all cultures Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

13 Forces Adding to Tensions Growth of for-profit research with emphasis on market principles (profit) Internationalization of research  incentives to seek “low-cost production” Internationalization highlights cultural differences in ethical standards  These trends strengthen utilitarianism Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

14 Proposed Revisions Allow a waiver of informed consent if the IRB judges the risks slight or the practices standard Subjects “will not be denied access to the best proven... therapy that would otherwise be available” Expanded use of placebos  when scientifically and ethically justified  when the outcome is not death or disability Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

15 Some Areas of Current Concern Informed Consent: to what extent should participants in research be told about random assignment of treatment, the possible risks and benefits of each treatment, and the criteria used for monitoring evolving results? Use of placebo in regions where a known standard treatment is not used Confidentiality: To what extent can patient’s data be used in other research activities (other than the study they agreed to participate in) without their consent? Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

16 Implications of Ethical Principles  Good study design  Investigator competence  Balance of harm and benefit  Privacy  Institutional review  Informed consent  Data monitoring (of interim results of a trial) Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

17 Other Issues Oversight of Financial Interests: disclosure of an investigator of any financial ties with companies or competitors that produce the drugs used in the trial. See Schwartz et al, NEJM, 358:1862, Dangers of participation in research sponsored by for- profit entities: will the best interests of the participants be the first priority? Importance of trust of and reliance on the IRB and Data Monitoring Committee Appropriate authorship recognition of contributions: ‘guest authors’ and ‘ghost authors’: see Ross et al (p ) and DeAngelis and Fontanarosa (p ) in JAMA, volume 299, 2008 Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

18 Example: PACTG 076 (N Engl J Med 1994;331: ) One of the major public health problems of the AIDS epidemic is transmission of HIV from mothers to their infants during pregnancy. PACTG 076 designed to test whether Zidovudine (denoted ZDV or AZT) treatment of mother and infant could reduce the risk of transmission of HIV. Randomized mother/infant pairs to ZDV versus placebo (infants only given ZDV briefly after birth). Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

19 A Superiority Trial PACTG 076 was a superiority trial. It was designed to show that the probability of HIV transmission in the ZDV Group (p T ) would be less than that in the placebo control group (p C ) Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

20 A Noninferiority Trial In some cases, we are interested in demonstrating the ‘noninferiority’ of a new treatment to another treatment (  near 0) Example: Lallemant et al. conducted an RCT in Thailand to test the noninferiority of 3 abbreviated ZDV regimens to the 076 regimen (NEJM 2000;343: ) Goal was to see if we can do as well with ‘less’ ZDV Can never prove H 0 (  =0) with certainty; at best we can hope to show  is close to 0. Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

21 Lallemant Trial Arm 1: Standard ZDV for mother and baby Arm 2: Short course ZDV for mother Arm 3: Short course ZDV for baby Arm 4: Short course ZDV for mother and baby Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

22 The Lallemant Trial Because the standard treatment in this study was a regimen of established efficacy, it tested for noninferiority of the shortened ZDV regimens, choosing a threshold for equivalence that would balance public health concerns with clinical benefits. It was assumed that an absolute difference of  0 =6% in the rate of transmission of HIV infection would be the limit for noninferiority Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

23 The Lallemant Trial With this criterion for noninferiority, it was calculated that 1,398 mother-infant pairs would be required to provide more than 90 percent statistical power with a 5% type I error and an 11 percent overall transmission rate. (Type I error here: P[say ‘noninferior’ when new treatment is inferior]) Noninferiority would be established if the upper limit of the one-sided 95% CI for the arithmetic difference in the percentage rates of HIV transmission was less than 6%. Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

24 The Study Protocol Ουρανία Δαφνή Καθηγήτρια, Διευθύντρια Εργαστήριο Βιοστατιστικής Πανεπιστήμιο Αθηνών Διευθύντρια Frontier Science Foundation-Hellas (FSF-H) ΜΠΣ Βιοστατιστικής Μάθημα: Κλινικές Δοκιμές Αθήνα, Εαρινό Εξάμηνο 2015

25 The Study Protocol A Clinical Trial is an experiment testing medical treatments on human subjects We learned that the goals of study design are to control systematic error (bias) and minimize random variation Methods for the design of experiments are well developed but have been narrowly applied in clinical research Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

26 Though students of clinical trials are often most interested in methods of data analysis, good design is more fundamental to the ultimate success of a trial. Problems of poorly designed trials can’t be corrected by clever analysis  Systematic error introduced by deficiencies in design can’t be quantified  Additional variability can’t be removed The Study Protocol Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

27 Internal and External Validity We sometimes use the term “selection bias” to refer to selection of study subjects who do not represent an intended population. Selection bias affects the generalizability (external validity) of randomized trial, but not the internal validity of the study  treatment comparisons still valid for the population represented in the trial Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

28 Goals of Study Design Satisfy Ethical Constraints Use Scarce Resources Efficiently Isolate Treatment Effect from Confounders Reduce Bias Minimize and quantify random error Simplify and validate the analysis Increase external validity Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

29 Study Protocol Preparation of a study protocol is an essential part of the planning process. Though there is no absolute standard for the organization of a protocol, all protocols have common elements. Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

30 Elements of the Study Protocol Background and Rationale Schema (Graphical or Descriptive)  shows the basic design Study Objectives and Endpoint Overview of Study Design Eligibility Criteria  defines the patient population being studied Enrollment Procedures  logistics of how patients are enrolled Treatment Regimen  describes the treatments used Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

31 Elements of the Study Protocol (part 2) Evaluation of Study Endpoints Statistical Considerations  Design Issues  Primary Outcome Measures  Treatment General Allocation Procedures  Data Analysis Plan  Sample Size and Power  Monitoring and Interim Analysis Plans Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

32 Elements of the Study Protocol (part 3) Data Collection and Management Human Subjects Considerations  Informed consent Publication Policies Appendices (case report forms, etc) Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

33 Schema The Schema describes patient flow  Emphasis on screening procedures, stratification criteria, and treatment regimens. May include the schedule of evaluations and treatments Describes the architecture of the study visually. Will be very simple for the randomized parallel groups design Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

34 ACTG Version 5.0 SCHEMA 03/20/92 Title: A Randomized, Double Blind, Comparative Study Of Dideoxycytidine (ddC) Alone Or ddC/ZDV Combination Versus Zidovudine (ZDV) Alone In Patients With HIV Infection Who Have Received Prior ZDV Therapy. Design: Multicenter, randomized, double-blind, phase III study. Population: 750 patients with prior ZDV therapy for > 24 weeks who are either asymptomatic with a CD4 count < 200 cells/mm or symptomatic with a CD4 count < 300 cells/mm. Stratification: Patients will be stratified by HIV disease status (asymptomatic or symptomatic), length of time receiving ZDV (> 1 year of ZDV and < 1 year of ZDV), and systemic or local PCP prophylaxis. Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

35 750 Patients | Randomized | (214 patients) (214 patients) (322 patients) _______________________________ |_______________________________ | | | ZDV two 100 mg capsules ddC two mg tablets ddC two mg and two ddC placebo tablets and two ZDV placebo tablets and ZDV two every 8 hours capsules every 8 hours 100 mg capsules every 8 hours Follow-up: Patients will be followed for up to two years after the last patient is enrolled unless the study is terminated earlier due to interim study results; mean follow-up is expected to be 28 months with a range of months. Patients who have reached a clinical AIDS-defining endpoint (after verification by the study chair) will be offered open-label combination ddC and ZDV. Endpoints: The development of an AIDS-defining opportunistic infection, AIDS-defining malignancy, AIDS-defining wasting syndrome, AIDS-dementia complex, or death. Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

36 Study Objectives and Endpoints Statement of study hypotheses and the endpoints for testing those hypotheses Description of methods of evaluation and for determining study endpoints and toxicities Should link directly and explicitly to study hypotheses Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

37 Eligibility Criteria This section provides a detailed, specific, and quantitative description of inclusion and exclusion criteria. Critical to ensuring uniformity of study population and generalizability Exclusions must be based on characteristics of patients determined before randomization Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

38 Reasons for Eligibility Criteria Defining the target population  Identifying patients who will benefit  Excluding patients who could add variability or complicate interpretation  Identifying (for exclusion) patients that might be harmed by the study treatments because of some condition they have  Other requirements for participation (e.g., language requirements) Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

39 Treatment Regimens A complete description of all therapeutic regimens including  Dosage  Masking procedures  Protocols for dose modification  Criteria for discontinuation Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

40 Evaluation of Study Endpoints A complete and detailed description of the methods used to measure each study endpoint The Protocol is often accompanied by a Manual of Operations that provides an even more detailed and operational description of measurement procedures Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

41 Statistical Considerations Sample Size Considerations Interim Analysis Procedures Study Endpoints and Method for Testing Primary and Secondary Hypotheses, including handling of missing values or incomplete observations Description of other analyses that might be undertaken Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

42 Human Subjects Considerations The ACTG 076 protocol contains a section presenting a risk-benefit analysis and the steps to be taken to protect the mother and infant This reflects the heightened sensitivity about patient well- being produced in part by AIDS activism Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

43 Summary: Protocol Protocol is a key document. It should carefully lay out the study, its rationale, its procedures, and the planned analysis. Poorly designed/flawed studies usually have a poorly developed protocol. Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

44 Subgroup Analyses Ουρανία Δαφνή Καθηγήτρια, Διευθύντρια Εργαστήριο Βιοστατιστικής Πανεπιστήμιο Αθηνών Διευθύντρια Frontier Science Foundation-Hellas (FSF-H) ΜΠΣ Βιοστατιστικής Μάθημα: Κλινικές Δοκιμές Αθήνα, Εαρινό Εξάμηνο 2015

45 Multiple Analyses of Treatment Efficacy Typically, multiple statistical tests are conducted during a trial to compare the treatment groups  Primary endpoint: at interim analyses and final analysis  Secondary endpoints  “Subgroup analyses” Chances of finding a “significant” difference by chance alone can become large as the number of endpoints examined  Common to adjust criteria for “significance” during interim analyses by using a spending function (e.g., O’Brien-Fleming) to control for this source of multiple testing  Since usually only 1-2 primary endpoints, not a big concern here  Secondary endpoint results must be interpreted in light of the number of tests done (e.g., if many, pay attention to chances of false positive)  Subgroup analyses: another concern Need to account for the multiple testing, either formally or in the interpretation of the data Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

46 Subgroup Analyses When assessing the treatment effects separately within the levels of some baseline factor (“covariate”), question is usually “Is there evidence that the relative treatment difference varies among the levels of the covariate?”  Is the treatment effect in males different from that in females?  This is asking whether there is heterogeneity in the treatment effect across patient subtypes  ‘Heterogeneity in effect’ is relative to how we measure the effect: RR, risk difference, OR  Effect heterogeneity represents a treatment-by-covariate interaction in a statistical model; commonly called ‘effect modification’ by epidemiologists. The appropriate way to assess heterogeneity of the treatment effect is to test for a treatment-covariate interaction. Sometimes there is a good clinical or biological basis for expecting an interaction. Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

47 Example: Assessing Treatment Effect Heterogeneity Treatments: A and B Covariate: gender Effect: measured by relative risk (RR):  RR m =treatment relative risk among males  RR f =treatment relative risk among females Null Hypothesis: H 0 : RR m = RR f  Note: Under H 0, risks for men and women can differ. H 0 states only that the relative difference between treatments A and B is the same in men as it is in women. For example suppose true risks are: MenWomen treatment A.8.4 treatment B.4.2 A:B relative risk 2 2 Here H 0 holds because RR m = 2 and RR f =2. If RR m not equal to RR f, H 0 doesn’t hold and we have a “treatment by gender interaction” Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

48 Testing for Treatment Effect Heterogeneity Another approach: within each gender, do a statistical test comparing treatments; e.g. males: A vs B: p=.0005 (favoring A) females: A vs B: p=.63 “A is better than B in males, but not in females” Is this a correct interpretation? Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

49 Separate Analyses within Subgroups can be misleading! Males Females cure no cure cure no cure A B Est’d RR=2 Est’d RR=2 p=.0005 p=.63  Same p-values as on previous page  Yet estimated RR =2 within each gender  It’s only the smaller sample size that leads to the ‘nonsignificant’ result in females  A test of H 0 : RR m =RR f would be nonsignificant since same relative risks. Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

50 Statin Treatment of Patients with Normal LDL Levels After MI (NEJM:1996, 335:1001-9) Among patients with LDL cholesterol levels in the normal range, does treatment with statin drugs after initial MI reduce risk of additional cardiac events? Does the magnitude of the benefit depend on the baseline level of LDL cholesterol? Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

51 Overall Results Patients treated with pravastatin had a 24 percent lower incidence of the primary end point, fatal coronary heart disease or confirmed myocardial infarction, than patients in the placebo group (95 percent confidence interval, 9 to 36 percent; P = 0.003) Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

52 Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

53 Interaction Between Treatment and Baseline LDL Cholesterol The reduction in the rate of coronary events with pravastatin was influenced by the pretreatment level of LDL cholesterol.  The patients with base-line LDL cholesterol levels above 150 mg per deciliter (3.9 mmol per liter; n = 953) had a 35 percent reduction in major coronary events, as compared with  a 26 percent reduction in those with baseline levels of 125 to 150 mg per deciliter (3.2 to 3.9 mmol per liter; n = 2355)  and a 3 percent increase in those with base-line levels below 125 mg per deciliter (n = 851) (P = 0.03 for the interaction between base-line LDL cholesterol level and risk reduction) Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

54 Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

55 Caution ! In present example, interaction is biologically plausible and was postulated in advance of doing the trial Sometimes, however, interactions are only ‘discovered’ posthoc after testing for an interaction of treatment with many baseline factors Posthoc examination of subgroups will commonly reveal certain ones in which the treatment seems to work better or worse than overall. This is inevitable even if there are no real differences in treatment effect within subgroups due to multiple examinations of the data (inflated Type I error). Recommendation: be very cautious in such posthoc analyses and don’t make too much of them. Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

56 Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

57 Ετερογένεια και Αλληλεπίδραση Heterogeneity and Interaction Ετερογένεια της επίδρασης της θεραπείας: διαφοροποιείται ανάλογα με το επίπεδο του δείκτη Ποσοτική ετερογένεια (Quantitative heterogeneity): μία εκ των θεραπειών είναι πάντα καλύτερη, αλλά σε διαφορετικό βαθμό Ποιοτική ετερογένεια (Qualitative heterogeneit)y: η μία θεραπεία είναι καλύτερη σε ένα επίπεδο του δείκτη αλλά χειρότερη σε ένα άλλο Reference for Topic Material : Prof. Richard Gelber Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

58 Estimating the Magnitude of the Treatment Effect += Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

59 Estimating the Magnitude of the Treatment Effect += Ποιοτική ετερογένεια Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

60 Estimating the Magnitude of the Treatment Effect += Ποσοτική ετερογένεια Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

61 Ετερογένεια και Αλληλεπίδραση Heterogeneity and Interaction Ετερογένεια ή διαφοροποίηση επίδρασης (effect modification): μέγεθος της διαφοράς της επίδρασης της θεραπείας μεταβάλλεται στις διαφορετικές υπο-ομάδες Η αξιολόγηση της ετερογένειας απαιτεί έλεγχο αλληλεπίδρασης (test of interaction) Ξεχωριστοί έλεγχοι εντός κάθε υπο-ομάδας δεν μπορεί να καθορίσει ετερογένεια Έλεγχοι αλληλεπίδρασης είναι συχνά χωρίς ικανοποιητική στατιστική ισχύ; Ψευδώς αρνητικά αποτελέσματα (false negative) Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

62 l Δεν είναι εύκολο να επικυρωθεί ένας προβλεπτικός δείκτης l Χρειάζεται να ελεγχθεί η αλληλεπίδραση της θεραπείας και του δείκτη σε μία μεγάλη τυχαιοποιημένη κλινική μελέτη l Το απαιτούμενο μέγεθος δείγματος είναι πολύ μεγαλύτερο (τυπικά τουλάχιστον 4 φορές μεγαλύτερο απ ’ ό,τι για τον έλεγχο των βασικών επιδράσεων) Στατιστική Επικύρωση Προβλεπτικού Δείκτη Κλινικές Δοκιμές Αθήνα, Απρίλης 2015

63 Subgroup Analysis Medical research relies on clinical trials to assess therapeutic benefits. Because of the effort and cost involved in these studies, investigators frequently use analyses of subgroups of study participants to extract as much information as possible. Such analyses, which assess the heterogeneity of treatment effects in subgroups of patients, may provide useful information for the care of patients and for future research. However, subgroup analyses also introduce analytic challenges and can lead to overstated and misleading results. This report outlines the challenges associated with conducting and reporting subgroup analyses, and it sets forth guidelines for their use in the Journal. Κλινικές Δοκιμές Αθήνα, Απρίλης 2015


Κατέβασμα ppt "ETHICS Ουρανία Δαφνή Καθηγήτρια, Διευθύντρια Εργαστήριο Βιοστατιστικής Πανεπιστήμιο Αθηνών Διευθύντρια Frontier Science Foundation-Hellas (FSF-H) ΜΠΣ Βιοστατιστικής."

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