Clinical trials Kata Bölcskei University of Pécs Department of Pharmacology and Pharmacotherapy Clinical trials definition (ICH-GCP): Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. 1
Ethical Principles for Medical Research Involving Human Subjects World Medical Association Declaration Of Helsinki - the investigators must protect the life, health, dignity, integrity, right to selfdetermination, privacy, and confidentiality of personal information of research subjects - the well-being of the individual research subject must take precedence over all other interests - participation of subjects must be voluntary after they were adequately informed about the aims, the procedures and potential benefits and risks of the study - subjects have the right to refuse to participate in the study or to withdraw consent to participate at any time without reprisal - research must conform to generally accepted scientific principles and can be conducted only by individuals with the appropriate scientific training and qualifications - research must immediately stop a study when the risks are found to outweigh the potential benefits - The research protocol must be submitted for consideration, comment, guidance and approval to a research ethics committee before the study begins [ ] independent of the researcher, the sponsor and any other undue influence - research on vulnerable population (e.g. minors, disabled): can only be performed if it is intended to promote the health of the population represented by the potential subject - informed consent must be asked from the legally authorized representative Legal regulation of clinical trials 35/2005. (VIII. 26.) Ministry of Health Regulation: on clinical trials of investigational new medical products for human use and the application of Good Clinical Practice (GCP) standards 235/2009. (X. 20.) Government Regulation: on the authorization process of medical research on humans, of clinical trials of new medicinal products or new medical devices 2
Requirements of clinical trial application - evidence of non-clinical efficacy and safety of the investigational drug (+ clinical efficacy and safety it is not the first clinical trial with the drug!) - evidence of appropriate chemical and pharmaceutical quality of the product - preparation of trial protocol, patient information and informed consent forms with regard to ethical and scientific standards - selection of trial site and principal investigator preparation of required documents application Process of authorization INDEPENDENT ETHICAL COMMITTEE (in HU: Medical Research Council Ethics Committee for Clinical Pharmacology) protocol patient information sheets informed consent forms investigators CVs trial site risk/benefit evaluation positive or negative opinion if + NATIONAL MEDICINES AGENCY (National Competent Authority, in HU: National Institute of Pharmacy) protocol non-clinical (and clinical safety anc efficacy data) pharmaceutical qualitiy of the investigational drug risk/benefit evaluation if + clinical trial authorization 3
Randomized controlled trial (RCT) - the most reliable study type of evidence-based medicine - an interventional trial: investigators apply a drug or other intervention to assess its safety and efficacy - controlled: the effects of the investigational drug is compared to a control group receiving placebo treatment or standard therapy (active control/comparator) - randomized: trial subjects are randomly allocated in one of the treatment groups - statistical methods are used to compare the outcome between the two groups Types of RCT trial designs based on treatment masking/blinding: open,open-label: both investigators and subjects know single-blind: only investigators know double-blind: neither of them know based on the type of control groups: placebo control active control - double-dummy: special case, when the investigational drug and the comparator drug have different appearance, subjects receive 1 investigational + 1 placebo OR 1 placebo + 1 comparator 4
Types of RCT trial designs three-armed comparison: investigational drug, placebo control, active control factorial design: if a combination of treatments (or other factors) is investigated, treatment groups are formed for all the possible combinations (e.g. 2 factors 4 groups) Types of RCT trial designs based on the purpose of comparison: - has to be determined in the protocol prior to the trial - different statistical analysis is used superiority trial: better than placebo or active control non-inferiority trial: not worse than active control equivalence: equal to active control bioequivalence study: comparison of the plasma concentration-time curves of a generic compound with the original 5
Types of RCT trial designs based on the sequence of the study: parallel design: subjects only receive one treatment, either investigational or control cross-over design: subjects receive both treatments one after the other, in different order (after a wash-out period) based on the site(s) of investigation: monocentric multicentric multinational Ethical problems of RCTs physicians are ethically obliged to do no harm, to apply the best proven treatment a randomized trial can violate this ethical principle because they do not know if the investigational treatment has a beneficial effect at all, nor if it is better than the best current treatment Two possible solutions to the ethical dilemma: uncertainty principle : the physician does not know which treatment is better, all patients have an equal chance of benefit or risk equiactivity principle : the physician considers both treatments equal 6
Ethical problems of RCTs Is it ethical to compare to placebo? Declaration of Helsinki 6th Revision (2008) The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists; or where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option. Ethical problems of RCTs Is it ethical to compare to placebo? the use of placebo must be justified in the protocol: - patients must not suffer irreversible damage from participating in the study: placebo must not be used in severe, life-threatening diseases or lengthy trials - if placebo-treated patients condition significantly deteriorates, they must be withdrawn from the trial and given standard treatment another possibility: add-on treatment: investigational drug or placebo is combined with standard-of-care treatment 7
Phase 0 Studies: Exploratory human pharmacology new approach, optional study microdosing OR single subtherapeutic doses extending up to therapeutic range the only purpose is to study human pharmacology of the drug, NOT SUITABLE for assessing safety or efficacy can be authorized with less available preclinical toxicity data methods: pharmacokinetic parameters: high-sensitivity analytical methods pharmacodynamic actions: PET study: receptor binding in target tissue(s) Phase I clinical trials: human pharmacology studies purpose: investigation of TOLERABILITY, PHARMACOKINETICS and (if possible) PHARMACODYNAMICS subjects: healthy volunteers, generally male, 18-40 years EXCEPT if the drug can potentially cause lasting health damage e.g. anti-tumor agents phase I/II study on patients definition of healthy : does not suffer from illness which could influence pharmacokinetics, pharmaco-dynamics or toxicity of the investigational drug 8
Phase I clinical trials: human pharmacology studies gender: women can be included but only if appropriate contraceptive methods are used! number of subjects: generally 20-80 trial site: specialized Phase I trial units with ICU and laboratory support principal investigator: a specialist in Clinical Pharmacology Phase I trial designs randomized, placebo-controlled, SINGLE-blind: in case of emergency it is important that investigators know which subject was given the drug I/a study: acute tolerability: single, escalating dosing I/b study: repeated dose for 1 or 2 weeks - determine maximum tolerated dose (MTD) - pharmacokinetic parameters (C max, t max, T 1/2, AUC) under various conditions (fasting, food interaction, time of the day etc.) 9
Phase I trial designs selection of STARTING DOSE: various recommendations are available to calculate a maximum safe starting dose from preclinical animal toxicity data e.g. animal NOAEL (no observed adverse effect level) converted to human dose/divided by a safety factor (min. 10, but can be a lot higher depending on the severity of potential toxicity, novelty of the therapeutic class etc.) selection of DOSE ESCALATION: arithmetic: 1n, 2n, 3n, logarithmic: 1n, 2n, 4n, Fibonacci: 1n, 2n, 3n, 5n, 8n,modified Fibonacci: 1n, 2n, 3n, 5n, 7n, 9n, 12n Phase I study protocol considerations - start only on few subjects at a time, in case severe intolerance occurs - dose limiting toxicity: laboratory abnormalities or any sign or symptom of vital organ dysfunction (pulse/rr/ecg changes, nausea, vomiting, dizziness, headache etc. ) - include wash-out periods between dose escalations - timing of blood tests: more frequently around the expected C max, continue until 80% of AUC is included 10
Phase II clinical trials: therapeutic exploratory studies purpose: exploration of THERAPEUTIC EFFECT on patients ( pharmacodynamic action!), Proof of Concept provide basis for larger, confirmatory studies (dose selection, endpoint selection) monitor SAFETY in patients subjects: volunteer patients, 18-65 years inclusion/exclusion criteria are generally strict in order to have a homogeneous group of patients trial site: hospital ward having the necessary equipment to perform procedures of the trial principal investigator: a specialist in the area of the intended indication AND in Clinical Pharmacology OR certified GCP training Clinical trial endpoints clinical endpoints are the measures of therapeutic response: clinically meaningful= directly measure the progression of the disease: how the patient FEELS, FUNCTIONS or SURVIVES - must be defined in the protocol prior to the study HIERARCHY of endpoints ( hardness, reliability) survival > definitive event (e.g. myocardial infarction) > laboratory values > CT, MRI scans > measurement of vital parameters > complex scoring of symptoms > VAS (visual analog scale) > QoL (Quality of Life) questionnaire 11
Clinical trial endpoints PRIMARY: the main question of the study e.g. does the treatment improve survival, improve patient s symptoms etc. usually only ONE primary endpoint SECONDARY: can be VARIOUS: additional variables measuring the main objective adverse effect profile additional information on the disease s impact, the patient s well-being e.g. physical activitiy, days of inabililty/hospitalization Clinical trial endpoints BIOMARKER: any measurable parameter which occurs in correlation with a pathological process and has diagnostic or prognostic value SURROGATE endpoints: a biomarker that does not directly measure the therapeutic response but it is in correlation with it - validated surrogate endpoints can be used as PRIMARY endpoints to get approval e.g. blood pressure myocardial infarction, stroke blood glucose complications of diabetes bone density osteoporotic bone fracture 12
Clinical trial endpoints - examples CANCER overall survival, progression-free survival CARDIOVASCULAR DISEASE number of cardiovascular events (myocardial infarction, stroke) RESPIRATORY COPD respiratory function (FEV 1 ), severity of dyspnea DEPRESSION Hamilton depression rating scale PAIN visual analog scale Phase II clinical trials: therapeutic exploratory studies II/a study: pilot study on a small number of patients, can be an openlabel study without control group exploration of dose-response relationship by flexible dosing might need to rely on a surrogate endpoint II/b study: randomized, double-blind, placebo- or active control or add-on trial verify therapeutic response, preferably with the same endpoints intended to use in Phase III dose-response relationship selection optimal dosing for Phase III trials of 13
Phase II is important go/no go decision point: Phase III is lengthy and very expensive! - if the drug was proven safe but not effective enough in the studied disease, another phase II trial can be started in a new indication Phase III clinical trials: therapeutic confirmatory studies purpose: confirmation of THERAPEUTIC EFFECT on a larger, more diverse population of patients also called Proof of Principle, pivotal efficacy studies explore less frequent adverse effects, drug interactions subjects: volunteer patients inclusion/exclusion criteria are less strict: elderly and children, people with different severity of the disease, people suffering from other diseases can be included subgroups can be later analyzed separately number of subjects: 1000<, depending on the prevalence of the disease 14
Phase III clinical trials: therapeutic confirmatory studies duration of the study: if a chronic disease is studied, at least 6 months, but can be years trial site: a multicenter, multinational trial the site can be a hospital ward or even a policlinic: but patients are not hospitalized, only make periodical visits for check-ups principal investigator: a specialist in the area of the intended indication, with GCP training Phase III clinical trials: therapeutic confirmatory studies trial design: randomized, doble-blind, placebo- or active control, or add-on trial dosing: preferably one dose which was selected in Phase II/b trials the formulation of the investigational drug must the the final form which is intended to be marketed 15
Phase III clinical trials: therapeutic confirmatory studies Statistical analysis due to the long duration of the trial, a high percentage of patients might not finish the study Intention-to-treat analysis: each subject is included whether they finished the trial or not Per protocol analysis: only subjects who completed the trial are included Phase IV clinical trials: post-approval studies the purpose is to gather more information on the drug: - to optimalize its use, analyze risk/benefit ratio - explore very rare adverse effects - compare it to other treatments can include randomized, open or double-blind studies (e.g. comparison to a competitor s drug) non-interventional studies: patients are only subjects to tests which are included in routine check-ups in Hungary: NOT considered as phase IV studies, but still need authorization! 16
Bioequivalence studies purpose: to compare plasma concentration-time curves of a generic drug to the original generics contain the same compound but the formulation might be different they are required to prove equivalence in order to market their product referring to the originator s clinical trial results bioequivalence: if plasma concentration-time curves are not significantly different, the two drugs are considered equally effective Bioequivalence studies subjects and trial site: similar to Phase I trials healthy, male volunteers OR patients number: 18, 24 or 36 tested at a Phase I Unit design: - usually a two-period, cross-over design, with a wash-out period of min. 5xT 1/2 - parallel, multiple period design if the compound has a long half-life or variable pharmacokinetics 17
dosing: Bioequivalence studies single dose is usually enough multiple dose steady-state: if PK parameters change with dose or time course of the study: all the factors which could influence absorption are standardized! e.g. GI motility (transit time ) absorption GI blood flow absorption GI secretions (local concentration ) absorption standard food and drinks, physical activity, body position is regulated blood samples are taken at exact time points drug concentration measurement Bioequivalence studies The main pharmacokinetic parameters C max, t max, AUC t (until last blood sample) and extrapolated AUC are determined AUC t must be at least 80% of AUC Statistical comparison: the two drugs are bioequivalent if the confidence interval of 90% of C maxgen /C maxorig and AUC Gen /AUC Orig are between 0.8 and 1.25 in the case of narrow therpeutic index drugs it can be stricter (0.9-1.1), while in the case of drugs showing large variability of PK parameters the criteria can be more permissive (0,75-1,33) 18