3 การวิจัยยาทางคลินิกในระยะต่างๆ Investigational new drug application (IND)Phase IVFDAApprovalNew drugapplication (NDA)Phase IIPhase IIIPhase IAnimal and/orLaboratorystudies
4 Phase I: human pharmacology trial The first stage of testing in human subjects.Designed to assess: drug’s toxicity, pharmacokinetics (absorption, distribution, metabolism, excretion), duration of action, drug-drug interaction or food-drug interactionSmall (20-50) group of healthy volunteers will be selected, except highly toxic drugs (e.g. chemotherapy) will be tested in patients.Higher risk trials are those categorized as ‘first-into-human trial’ or ‘dose escalating trial’
5 Case studyTGN1412 (monoclonal antibody) is an immunodomulatory drug intended for the treatment of B cell chronic lymphocytic leukemia (B-CLL) and rheumatoid arthritis.In March 2006, The previously healthy young men were being paid (up to £150/$330 a day) to take part in its first human trial.The subjects was administered at a sub-clinical dose of 0.1 mg per kg – 500 times lower than the dose found safe in animals.Within hours of their first injection, six volunteers suffered from multiple organ failure and were put in intensive care. The two men receiving placebo are fine.The problems resulted from "unforeseen biological action in humans".
6 Lesson learned from the event Note for bioequivalence trialsLesson learned from the eventCalculation of initial and subsequent doseUsing sequential dosingOne participant dosed on day one, and the rest dosed after a review and a go-ahead decision by data safety monitoring committeeFirst dose in the morning (e.g. 8:00 am)Using dedicated hospital ward or ICU for high risk trialsDoctor standby during the first 24 hours of the trialEstablishment of independent data safety monitoring committee to assess the data safetyGuidelines from European Medicine Agency (EMEA),Association of the British Pharmaceutical Industry (ABPI)
7 Phase II: Therapeutic exploratory trial Aim to show ‘proof-of-concept’, surrogate endpoints can be usedExplore therapeutic efficacy in small target patients (20-100)Sometimes divided into Phase IIA and IIB.Phase IIA: designed to assess dosing requirements (how much drug should be given).Phase IIB: designed to study efficacy (how well the drug works at the prescribed dose).
8 Phase III: Therapeutic confirmatory trial Randomized controlled multicenter trials on large patient groups (300–3,000)Aim to demonstrate or confirm the therapeutic benefit, important clinical endpoints are used, in comparison with current 'gold standard' or placebo treatment.
9 Karlberg and Speers, Reviewing Clinical Trials: a guide for the Ethics Committee, 2010
10 Phase IV: Therapeutic use trial Phase IV trial is also known as Post Marketing Surveillance Trial.Aim to study the effectiveness of treatment after approval to support use under the approved indication e.g. safety, drug-drug interaction, dose response.It is also critical for exploring new use for a therapyHarmful effects discovered by Phase IV trials may result in a drug being no longer sold, or restricted to certain uses: recent examples involve cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).
13 Phase 0: micro dosing trial Phase 0 is a new exploratory, first-in-human trials.Phase 0 trials include the administration of single subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the drug’s pharmacokinetics (how the body processes the drug) and pharmacodynamics (how the drug works in the body).Phase 0 is conducted based on the US FDA 2006 Guidance on Exploratory IND Studies.
14 Dilemma of Phase 0Drug development companies use Phase 0 studies to rank drug candidates in order to decide which has the best pharmacokinetic parameters in humans to take forward into further development (using human models, instead of relying on inconsistent animal data).A Phase 0 study gives no data on safety or efficacy because the dose is too low.Prediction of Phase 0 may be incorrect.Are Phase 0 trials useful, ethically acceptable, feasible, speed up the drug development process or save money?
15 Criteria for EC approval of research Risks are reasonable relative to benefitsRisks to subjects are minimizedAdequate protection of subject privacy & confidentialityAdequate safety monitoring planWritten informed consent obtained (unless waived)Appropriate consent elements are presentSubject selection is equitableAdditional safeguards for vulnerable populationsOther ethical & compliance issues (e.g. conflict of interest, quality of investigator/trial management etc.)45 CFR , OHRP: common Rule & 21 CFR , FDA
16 Consideration for reviewing clinical trials Science* - clinical trials with one standard!EthicsQuality assurance‘Clinical trial with poor science, poor ethics or poor data quality puts participants at unnecessary risk of harm and is likely to be rejected by regulatory authorities or international biomedical scientific community.’†‘Trials that do not add any new information to our body of knowledge put participants at risk without any reason.’†* Declaration of Helsinki and the ICH GCP guideline†Karlberg and Speers, Reviewing Clinical Trials:a guide for the Ethics Committee, 2010
17 Example of ‘unsound’ protocols - unethical Lack of sufficient pre-clinical research informationNo obvious clinical value:The trial will not advance knowledge, put risks to participants and consume financial & human resource for no reasonUsing incorrect endpoint, too small sample size, no controls, no randomization, no blinding when it could be utilizedMajor considerations for trials with confirmatory nature.Using a drug that is manufactured without evidence of good manufacturing practice (GMP)Using placebo control group inappropriately – withholding standard treatment
18 Things to remember when writing a protocol Clinical rationaleWhat is (are) the expected benefit(s) of the drug in normal clinical care?Study objectivesIs (are) objective(s) clearly stated?Study outcomes:Is the study exploratory or confirmatory in nature?Is the primary outcome a clinical or surrogate outcome?Is the outcome the valid internationally accepted outcome?Sample size:Has a proper assumption & sample size calculation been made?If randomization is used, how will this be performed?
19 Ethics consideration in clinical trials Risk benefit balance“In medical research involving human subjects, the well-being of the individual research subject must take precedence over all other interests.”“Medical research involving human subjects may only be conducted if the importance of the objective outweighs the inherent risks and burdens to the research subjects.”Declaration of Helsinki
20 Consideration for risks & benefits Risks of harmPhysical harm (bodily harm or inconvenience)Psychological harm (emotional suffering or breach of confidentiality)Social harm (employment or social discrimination)Economic risks (financial costs related to participation)Potential benefitsPhysical benefit (improvement of disease)Psychological benefit (comfort from suffering or feeling of helping others in the future)Economic benefit (financial benefits related to research participation)Benefit to science/society (general knowledge, effective treatment in the future)
21 Risk benefit balance in Phase I trial Safety concern is immediate serious adverse reaction:Sufficient preclinical safety dataProposed dosing from the relevance animal modelSequential manner (for high risk or first-into-human trial)Appropriate clinical facilitiesConducted by trained investigators & experience medical staffNo benefit for participants (either healthy or patients)This should be clearly stated in the informed consent.Volunteer often get compensation for discomfort.Payment is not benefit!Payment should be appropriate, pay per performance (not at the end) and clearly stated in the informed consent.Evidence of product manufacturing and safety (GMP)European Medicines Agency, 2007
22 Risk benefit balance in Phase II/III trial Inclusion/exclusion criteriaInclude subjects most likely to yield an answerInclude subjects equitably (vulnerable subjects get benefit?)Exclude subjects who could predictably confound the answerExclude subjects who might be at increased risk in a researchNot expose subjects to excessive, unnecessary risksAppropriate risk managementAppropriate frequency to monitor risk/benefitAdequate risk monitoring and stopping rules for subject with worsening conditionIf placebo is justified, rescue medication should be availableHas independent data monitoring committee (if appropriate)Subjects are properly informed of the risks involved
23 Quality assurance of clinical trials EC partially responsible by reviewing:EC applications & protocolQualification of investigatorsAmendmentsAdverse event reportsContinuing progress reportsFinal reportsCompliance issuesRoutine or ‘for cause’ site visits
24 Case scenario 1Phase I trial เป็นการศึกษา pharmacokinetics และ pharmacodynamic parameters ของยาใหม่ในการรักษามะเร็ง small cell lung cancerต้องการเจาะเลือดผู้ป่วยในระยะ advanced จำนวนไม่เกิน 800 ml ในช่วงเวลา 2 สัปดาห์ข้อมูลเบื้องต้นต้องศึกษาในผู้ป่วยมะเร็งเนื่องจากเป็นยาที่มีความเป็นพิษสูง
25 Case scenario 2การศึกษาผลของสารสกัดโสมเข้มข้นในการเพิ่มคุณภาพชีวิตในผู้ป่วยสูงอายุข้อมูลเบื้องต้นมีการใช้โสมเป็นสมุนไพรมาเป็นเวลานาน และยังไม่มีรายงานอาการไม่พึงประสงค์ที่ร้ายแรงยังไม่เคยมีการใช้ในรูปสารสกัดเข้มข้น
26 Summary: Ethical considerations for clinical drug trials Scientifically sound protocolRisk benefit balanceRisks are reasonable relative to benefitsAppropriate risk managementAdequate safety monitoring planSubject selection in equitableAdditional safeguards for vulnerable populationsAppropriate consent elements are presentQuality assuranceQualification of investigatorsContinuing progress reportSerious adverse event reportCompliance issues