Ethical considerations in clinical trials: Drug trials รศ.ภญ.นุจรี ประทีปะวณิช จอห์นส

ประเภทของการทดลองยาทางคลินิก ยาใหม่ ยาที่ยังไม่ได้ขึ้นทะเบียนยาในประเทศไทย ยาที่ขึ้นทะเบียนแล้ว แต่ทดลองใช้ในขนาด/วิธีการใช้/กลุ่มตัวอย่าง ที่ต่างจากที่ขึ้นทะเบียน ยาผลิตในประเทศ ทดสอบเปรียบเทียบกับยาต้นแบบ (bioequivalence)

การวิจัยยาทางคลินิกในระยะต่างๆ Investigational new drug application (IND) Phase IV FDA Approval New drug application (NDA) Phase II Phase III Phase I Animal and/or Laboratory studies

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 interaction Small (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’

Case study TGN1412 (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".

Lesson learned from the event Note for bioequivalence trials Lesson learned from the event Calculation of initial and subsequent dose Using sequential dosing One participant dosed on day one, and the rest dosed after a review and a go-ahead decision by data safety monitoring committee First dose in the morning (e.g. 8:00 am) Using dedicated hospital ward or ICU for high risk trials Doctor standby during the first 24 hours of the trial Establishment of independent data safety monitoring committee to assess the data safety Guidelines from European Medicine Agency (EMEA), Association of the British Pharmaceutical Industry (ABPI)

Phase II: Therapeutic exploratory trial Aim to show ‘proof-of-concept’, surrogate endpoints can be used Explore 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).

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.

Karlberg and Speers, Reviewing Clinical Trials: a guide for the Ethics Committee, 2010

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 therapy Harmful 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).

ในทางปฏิบัติ งานวิจัยทางคลินิกมีหลายวัตถุประสงค์ร่วมกัน จึงอาจพบ phase IA, phase IB, Phase I/II หรือ Phase II/III เป็นต้น

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.

Dilemma of Phase 0 Drug 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?

Criteria for EC approval of research Risks are reasonable relative to benefits Risks to subjects are minimized Adequate protection of subject privacy & confidentiality Adequate safety monitoring plan Written informed consent obtained (unless waived) Appropriate consent elements are present Subject selection is equitable Additional safeguards for vulnerable populations Other ethical & compliance issues (e.g. conflict of interest, quality of investigator/trial management etc.) 45 CFR 46.111, OHRP: common Rule & 21 CFR 56.111, FDA

Consideration for reviewing clinical trials Science* - clinical trials with one standard! Ethics Quality 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

Example of ‘unsound’ protocols - unethical Lack of sufficient pre-clinical research information No obvious clinical value: The trial will not advance knowledge, put risks to participants and consume financial & human resource for no reason Using incorrect endpoint, too small sample size, no controls, no randomization, no blinding when it could be utilized Major 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

Things to remember when writing a protocol Clinical rationale What is (are) the expected benefit(s) of the drug in normal clinical care? Study objectives Is (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?

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

Consideration for risks & benefits Risks of harm Physical 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 benefits Physical 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)

Risk benefit balance in Phase I trial Safety concern is immediate serious adverse reaction: Sufficient preclinical safety data Proposed dosing from the relevance animal model Sequential manner (for high risk or first-into-human trial) Appropriate clinical facilities Conducted by trained investigators & experience medical staff No 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

Risk benefit balance in Phase II/III trial Inclusion/exclusion criteria Include subjects most likely to yield an answer Include subjects equitably (vulnerable subjects get benefit?) Exclude subjects who could predictably confound the answer Exclude subjects who might be at increased risk in a research Not expose subjects to excessive, unnecessary risks Appropriate risk management Appropriate frequency to monitor risk/benefit Adequate risk monitoring and stopping rules for subject with worsening condition If placebo is justified, rescue medication should be available Has independent data monitoring committee (if appropriate) Subjects are properly informed of the risks involved

Quality assurance of clinical trials EC partially responsible by reviewing: EC applications & protocol Qualification of investigators Amendments Adverse event reports Continuing progress reports Final reports Compliance issues Routine or ‘for cause’ site visits

Case scenario 1 Phase I trial เป็นการศึกษา pharmacokinetics และ pharmacodynamic parameters ของยาใหม่ในการรักษามะเร็ง small cell lung cancer ต้องการเจาะเลือดผู้ป่วยในระยะ advanced จำนวนไม่เกิน 800 ml ในช่วงเวลา 2 สัปดาห์ ข้อมูลเบื้องต้น ต้องศึกษาในผู้ป่วยมะเร็งเนื่องจากเป็นยาที่มีความเป็นพิษสูง

Case scenario 2 การศึกษาผลของสารสกัดโสมเข้มข้นในการเพิ่มคุณภาพชีวิตในผู้ป่วยสูงอายุ ข้อมูลเบื้องต้น มีการใช้โสมเป็นสมุนไพรมาเป็นเวลานาน และยังไม่มีรายงานอาการไม่พึงประสงค์ที่ร้ายแรง ยังไม่เคยมีการใช้ในรูปสารสกัดเข้มข้น

Summary: Ethical considerations for clinical drug trials Scientifically sound protocol Risk benefit balance Risks are reasonable relative to benefits Appropriate risk management Adequate safety monitoring plan Subject selection in equitable Additional safeguards for vulnerable populations Appropriate consent elements are present Quality assurance Qualification of investigators Continuing progress report Serious adverse event report Compliance issues

Thank you for your attention