PHARM4813 Lecture - Clinical Trials 1 (PDF)

Medication Access Pathways Dr Fiona Warner Clinical Pharmacist How is this lecture relevant?... Pharmacy Learning Domain 2 Ability to engage in research and scientific endeavour, and critically examine scientific evidence – both quantitative and qualitative – in order to arrive at evidence-based co...

Medication Access Pathways Dr Fiona Warner Clinical Pharmacist How is this lecture relevant?... Pharmacy Learning Domain 2 Ability to engage in research and scientific endeavour, and critically examine scientific evidence – both quantitative and qualitative – in order to arrive at evidence-based conclusions. o Understand pathways for medication supply in Australia o Evidence based medicine and Good clinical practice- Clinical evaluation of new and existing drugs and medicines, and post marketing surveillance. o Prospects for new approaches in therapeutics.  Bench to Bedside New Drug Entity Serendipity? Second generation therapy? Target therapy? Process for introduction of new drugs into practice Clinical trials (pre and post registration) Registration Early clinical experience Costs/who pays Issues for pharmacy services and pharmacist training Drugs in Clinical Practice TGA Registered Compassionate/Alternate Special Access Scheme Access Supply Clinical Trials Personal Importation Registered Medications Therapeutic Goods Administration (TGA) Australian Register of Therapeutic Goods (ARTG) Safe and effective for a specified indication Legal to market, prescribe, dispense Availability according to Schedule S2, S3, S4, S8 Off label’ use – non approved indication Status of Drugs in Clinical Practice Pharmaceutical Benefits Schedule Origins Purpose o Section 85 and Section 100 (National Health Act 1953) Process Criteria for subsidy o Why are some drugs listed and others not? Pharmaceutical Benefits Scheme TGA registration requires evidence of SAFETY and EFFICACY PBS listing also requires COST EFFECTIVENESS An acceptably cost-effective medicine can be recommended for listing if: It treats or prevents significant medical conditions that are not covered, or only partially covered, by currently listed drug(s); It is more effective and/or less harmful than a currently listed drug; or It is as effective and safe as an existing listed drug. Pharmaceutical Benefits Scheme (PBS) Drugs registered by TGA Only approved for a TGA approved indication National Medicines Policy Quality Use of Medicines Framework based on partnerships between Governments, health educators, pharmaceutical industry and health practitioners TGA – quality and safety of products PBS – access (subsidy) Pharmaceutical Industry – innovator/manufacturer of drug product Health Practitioners – prescribing habits Viable Industry Drugs in Clinical Practice Medication Access Pathways Unapproved medication pathways Registered Special Access Personal Scheme (SAS) Clinical Trial Importation Alternate/Compassionate Supply Status of Drugs in Clinical Practice Personal Importation Individuals can legally import most therapeutic goods (except controlled substance) for personal use under the Personal Importation Scheme. Personal importation occurs when: o Upto 3 months of an unapproved medication o An individual arranges from within Australia for a therapeutic good to be sent to them from an overseas supplier or family/friend; and o The goods are to be used by that individual or a member of his/her immediate family and are not sold or supplied to any other person. https://www.tga.gov.au/personal-importation-scheme Drugs in Clinical Practice Medication Access Pathways Registered Special Access Personal Scheme (SAS) Clinical Trial Importation Compassionate Status of Drugs in Clinical Practice Special Access Scheme Provides import and supply of an unapproved therapeutic good to a single patient on a case by case basis.  Special Access Scheme Categories Notification for a patient defined Category A as seriously ill Category B Application pathway Notification of use of specified Category C therapeutic goods https://www.tga.gov.au/form/special-access-scheme Status of Drugs in Clinical Practice Clinical Trials - Unapproved unregistered drug Animal and Human ethics approval Requires apply to the TGA Clinical Trial notification (CTN) scheme register the clinical trial with the TGA Allow importation of the unapproved drug for the trial Evaluation of New Drugs Clinical Trials Pre-evaluation Early pharmacological Studies Clinical Evaluation – HUMAN studies Pre-registration Post-registration Phases of Clinical Trials  Involves: Evaluation of a new chemical entity Identification code or generic name given Application for a patent by the sponsor Preclinical Evaluation Preclinical research studies can include: toxicology screening in vitro cell lines pharmacogenomic probes in vivo animal studies  Preclinical Studies Animal studies require animal ethics approval and safety processes Aim: To predict clinical (human) effectiveness and toxicity Design human clinical trials Pre clinical safety evaluation is essential for a safe starting dose for phase I studies and identification of potential adverse effects that may occur Studies include: single dose toxicity studies repeat dose toxicity studies safety pharmacology studies pharmacokinetic and toxicology studies local tolerance studies genotoxicity and carcinogenecity studies reproductive toxicity studies Phases of Clinical Trials Registration with TGA Phase I studies First in man Small numbers (10-50) of participants (cohorts) Highly monitored, specialist units These studies are investigating Safety Toxicity Maximum tolerated dose Pharmacokinetics/pharmacodynamics Highly pretreated patients OR young healthy volunteers Single ascending dose (Phase 1a) or Multiple ascending dose (Phase 1b) Phase II studies Early phase 100s rather than 10s patients Early pharmacology/efficacy Dose finding Toxicity monitoring Patient in whom no alternative treatment is available Phase III studies Comparative studies 1000-5000 patients Randomised clinical trials (RCT) Test hypothesis Difference between two treatment arm Investigational agent vs gold standard comparator Design Strategies: Blinded, parallel or crossover design Trial Design Randomisation In clinical trials, participants are generally allocated to different arms of the trial (for example, to receive the study medicine or the placebo) randomly. Each participant has an equal chance of being in any of the arms of the trial. It is an important method to reduce the risk of bias in the outcomes of the trial.  Blinding Blinding is a procedure in which one or more parties in a trial are kept unaware of which treatment arms participants have been assigned to Blinding is an important aspect of any trial done in order to avoid and prevent conscious or unconscious bias in the design of a clinical trial. Comparator A comparator may be on a placebo or on an active treatment Placebo Control A placebo is a fake or sham treatment specifically designed without any active element. Active Control An active control is an established treatment that is known to have efficacy and is an alternative to a placebo control Placebo Effect The placebo effect is a psychosomatic effect brought about by relief of fear, anxiety or stress because of study participation Phases of Clinical Trials Registration with TGA Phase IV Often after registration (i.e post marketing approval) postmarketing surveillance Controlled cohort trials vs ‘real world’ experience 10,000-millions New toxicities/adverse reactions (rare) identified Human subjects in clinical trials: Ethical considerations and concerns Hippocratic Oath “ First do no harm”  Autonomy – respect for the patient’s right There to self-determination are Beneficence – the Four Pillars four duty to ‘do good’ Non-Maleficence – of Ethics ‘pillars’ the duty to ‘not do of bad’ Justice – to treat all ethics: people equally and equitably What is a safe drug? Examples of Examples of a an ‘unsafe safe drug? drug’ ?  ALL RESEARCH, INCLUDING TRIALS, REQUIRE ETHICS COMMIT TEE Ethics Approval APPROVAL Ethics Committees (hospital, Committees university or both) Statutory constitution Researchers Clinical practitioners Science training Lay persons Minister of religion Human Purpose of ethics review is to Research advocate for Scientific merit and integrity Ethics Ethical framework Committees Risks and benefits (HREC) Adherence to international and national guidelines Ensure participants of the clinical trial: Give informed consent (written) under no duress Provided appropriate information about risks, benefits, procedures…  Guideline for Good Clinical Practice International conference on harmonisation (ICH) of technical requirements for registration of pharmaceuticals for human use Clinical Trials International ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Primary aim is to protect and preserve human rights.  National Health and Medical Research Council (NHMRC) National Statement on the Ethical Conduct of Human Research The National Statement requires many types of human research to undergo ethics review. It also sets out the requirements for an HREC’s establishment, operation and membership. https://www.nhmrc.gov.au/about-us/publications/national-statement-ethical-conduct-human-research-2007-updated-2018  The Therapeutic Goods Act 1989 requires an HREC to review and monitor all clinical trials of unregistered therapeutic goods. Scientific and Ethic review processes Sponsor (industry) Clinical Trials Clinicians Investigators Pharmacy Ethics committee review Governance National Statement Values and Principles in Ethical Conduct Themes in Research Ethics: Risk and Benefit, Consent Section 3-ETHICAL CONSIDERATIONS IN THE DESIGN, DEVELOPMENT, REVIEW AND CONDUCT OF RESEARCH 3.1 Elements of research 3.2 Human biospecimens in lab based research 3.3 Genomic research 3.4 Animal to human xenotransplantation Section 3 ELEMENTS OF RESEARCH …LOOK AT ‘KEY THIS WILL BE IMPORTANT QUESTIONS’ IN THE CLINICAL TRIALS WORKSHOP Ethics What is an ethical trial? What is ethical research? Informed consent Placebo Randomisation and blinding  Clinical Equipoise provides the ethical basis for clinical research that involves assigning patients to different treatment arms of a clinical trial… …it is not known which of the interventions/drugs is better, or different remember the research question and aim It may be the null hypothesis being tested-for difference, or a study design may test for non-inferiority or superiority Nardini, C. (2014) ecancer 8: 387 https://ecancer.org/journal/8/full/387-review-the-ethics-of-clinical-trials.php Accessed 2/7/19 Harmon A.. New York Times. September 18, 2010. http://www.nytimes.com/2010/09/19/health/research/19trial.html?_r=0. Accessed October 7, 2015. Where are clinical trials conducted? Depending on clinical setting hospital clinical trials specialist unit community setting university research institutions Key Players in Clinical Trials Trial sponsors (Pharmaceutical Principal Clinical Research company, Investigator Associate (monitor) university, hospital) Study Coordinator Patient Pharmacy?  What is the role of pharmacists in clinical trials? Design Monitoring Coordination Review/ Drug supply Patient follow Approval and Auditing up procedures Inventory dispensing accountability per tablet/vial New Drugs – impact on profession ‘New’ Pharmacology How do pharmacists and other learn about new products/therapeutic targets? Role for understanding research steps (opportunity for direct involvement) EVIDENCE BASED MEDICINE – evidence based decisions on drug therapy – rationale for drug use AS PHARMACIST WE NEED TO UNDERSTAND AND CRITICALLY EVALUATE LITERATURE Workshop Workshop You will work in groups and evaluate a Each group will outline their trial design, PHASE III clinical trial: explain its features and any ethical considerations relating to their specific disease or cohort to the workshop participants How will you do this in a scientifically valid, clinically reasonable and ethical way? Issues to Consider Who are your study participants? How did you recruit them? What are the ethical issues? (hint-read Section 3 the National Statement on the Ethical Conduct of Human Research) Did you need their consent? What data did you collect to demonstrate the superiority of your drug in its indication? How much data did you collect? What happens at the end of the trial?