PHARM4813 Lecture Notes - Clinical Trials PDF

Medication Access Pathways Romana Cecchele Bsci (MedChem), Mpharm, GradDip ClinPharm, MSHPA, FANZCAP (Leadership,Clintrials) Senior Pharmacist- Investigational Drugs Unit Acknowledgment: Dr Fiona Warner How is this lecture relevant?... Pharmacy Learning Domain 2 Ability to engage in research and...

Medication Access Pathways Romana Cecchele Bsci (MedChem), Mpharm, GradDip ClinPharm, MSHPA, FANZCAP (Leadership,Clintrials) Senior Pharmacist- Investigational Drugs Unit Acknowledgment: Dr Fiona Warner 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 (overview) New Drug Entity Serendipity? Classical (forward) pharmacology Reverse pharmacology (targeted) Process for introduction of new drugs into practice Clinical trials (pre and post registration) Early clinical experience Registration Costs/who pays Access to Drugs in Australia TGA Registered Special Access Scheme Authorised Prescriber Clinical Trials Personal Importation Access to Drugs in Australia TGA Registered Special Access Scheme Authorised Prescriber 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 Unapproved drugs cannot be advertised Status of Drugs in Clinical Practice Pharmaceutical Benefits Scheme Origins Purpose o Section 85 (General Schedule) 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. S19A section 19A of the Therapeutic Goods Act 1989 temporary approvals to import or supply a medicine that is not registered on the ARTG https://www.pbs.gov.au/info/browse/section-19A SSSI Serious scarcity substitution Instrument Allows for Schedule 4 medications to be substituted Lower or higher strength IR vs SR Different salts Pharmaceutical Benefits Scheme Drugs registered by TGA Only approved for a TGA approved indication Non PBS example 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 Access to Drugs in Australia TGA Registered Special Access Scheme Authorised Prescriber Unapproved Therapeutic Goods Clinical Trials Personal Importation Access to Drugs in Australia TGA Registered Special Access Scheme Authorised Prescriber Clinical Trials Personal Importation Personal Importation Importing unapproved therapeutic goods for personal use or use by someone in your immediate family The following must be met: The goods are an individual or the treatment of immediate family that you are travelling with (such as a parent travelling with their child’s medicine). They are not sold or given to another person Where possible, the medicines are kept in their original packaging The goods are not restricted under Customs or quarantine rules The goods do not contain a controlled substance The total quantity of the goods imported within a 12-month period does not exceed 15-month’s supply If the goods are medicines in Schedule 4 or 8 of the Poisons Standard, a prescription from an Australian-registered MP is held You cannot import more than a 3‐month supply per order. If you wish to bring more than 3‐month supply into Australia, an Australian‐ registered doctor will need to apply for SAS approval. https://www.tga.gov.au/personal-importation-scheme Access to Drugs in Australia TGA Registered Special Access Scheme Authorised Prescriber Clinical Trials Personal Importation 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 Access to Drugs in Australia TGA Registered Special Access Scheme Authorised Prescriber Clinical Trials Personal Importation Authorised Prescriber To apply for an individual patient  (SAS). For multiple patients with the same condition  Authorised Prescriber. Requires endorsement from the local human research committee (HREC) for those goods not on the established history of use list Involves reporting on: Any suspected adverse events or product defects Number of patients treated every 6 months Only available to medical practitioners Can only prescribe once formal approval letter is received Who can prescribe? Access to Drugs in Australia TGA Registered Special Access Scheme Authorised Prescriber Clinical Trials Personal Importation Clinical Trials Approvals required:  Animal or Human Ethics Research Approval (HREC)  TGA Clinical Trial notification (CTN) scheme (allows importation)  Or CTA (uncommon)  Governance approval  Drug Committee approvals  MOH equivalent health department approval  OTGR approvals  IBC approvals The Australian Clinical Trials Handbook  Important points to note…. Conduction a trial still has to comply with: Australian laws Therapeutic Goods Act 1989 Therapeutic Goods Regulation 1990 State based Medicines, Poisons and Therapeutic Goods Act 2022 Poisons and Therapeutic Goods Regulation International guidelines PIC/s annex 13 ICH GCP Local policies Advanced therapeutics policy Medication handling policy SUSMP PBS Drum this slide into your memory, particularly if you move interstate. To run a study you must comply with many laws and policies. You have, Australia laws, state based laws, international guidelines Local policies If you go and run trials in other states or organisations, do not start a trial up and be ignorant to the fact that each organisation has different rules. Unfortunately in Australia, the way the healthcare system is funded, and broken up means EVERY site has different rules, funding models and supply strategies. NSW/ACT did not sign onto be a PBS reformed state. Everyone else did. Our state based supply laws are different, our scripts are different, how we handle S4, S4B, S4D, S8s is different  Evaluation of New Drugs Clinical Trials Pre‐evaluation Early pharmacological Studies Clinical Evaluation – HUMAN studies Pre-registration Post-registration So were now going to start looking more closely at how we evaluate new drugs We’ve brought a new drug into Australia, we want to generate evidence to bring into broad usage, and this requires a lot of steps that can take 10-15 years Process will start with pre evaluation. Early pharmacological studiers. Looking at MOA, how it works, at specific receptors, signaling pathways. From here use these early studies to move into human studies. When we talk about pre and post registration we talk about what happens pre and post registration with the governing body  Phases of Clinical Trials This slide is a nice summary of the phases of CT Preclinical studies or lab studies. Take bulk of our time, several years to complete. Gaining early information about dose and toxicity of drug Only if we are confident the new drug entity has relevance in humans do we move to human studies Phase 1, usually first in human. Evaluate safety, gather information If these are successful, progress to phase 2. Safety and dosing in particularly indication. Looking for SE, dose and efficacy Phase 3 is strongest type of CTR and will generate most data for registration. Looks at efficacy, still safety, but main difference to other phases, these studies are done in comparison with a gold standard or placebo Post registration, we have post marketing surveillance of drug. It monitors every day use  Preclinical Evaluation Involves: Evaluation of a new chemical entity Identification code or generic name given Application for a patent by the sponsor Preclinical research studies can include:  toxicology screening  in vitro cell lines  pharmacogenomic probes  in vivo animal studies We have preclinical evaluation. This involves evaluation of new drug entity We've created a new drug, or isolated an extract and now we want to give it a name. A number or its generic name From here the sponsor is trying to generate information and patent the drug They look at toxicology, they start in invitro cell lines Then we move into animals  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 Animal studies are very important before we move into humans. But at the same time, we don’t want to have to use them, so using animals requires approval from an ethics committee. And there are safety processes in place to protect the animals They give us some idea of the starting dose in humans, and AE There are many types of studies. Single dose, repeat dosing, pharmacology studies looking at targets, safety, look to see what drug does to the body through pharmacokinetics, and how body processes the drug. Local tolerance. What dose can we give animals before we see serious AES And most importantly, does it have genotoxicity. Will it cause fetal abnormalities, cancer Good example where these were missed is our thalidomide case. The sponsor falsely marketed the drug as safe for a multitude of illnesses, including morning sickness, despite not having conducted studies on humans. Doctors began to question the effects of this drug, including an Australian obstetrician, William McBride, who noted that limb deformities were more common in women who used this drug. This case led to guidelines on how CT are performed  Phases of Clinical Trials Registration with TGA Moving onto phase 1  Phase I studies First in man Human pharmacology Small numbers (10-100) 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) Looking at phase 1 studies. These are usually the first in human. They are small, usually 10-100 participants broken into cohorts They are performed in highly monitored units ie hospital or specialised facility that have emergency and ICU facilities because were putting a new drug into a patient. These will study safety, toxicity, but also understanding max dose we can use on these drugs in humans. Usually healthy young volunteers, usually males. Cohorts tightly regulated and homogenous so they can focus on studying drugs Other groups are highly treated patients ie refractory disease, no other medication options. We see this a lot in haematology and oncology where it would be unethical to give healthy patients a new chemotherapy drug for instance knowing the toxicity profile could be quite severe General study designs are single ascending dose phase 1a, or multiple dosing ib. In single ascending dose studies, they use a single dose in increasing amounts to check basic PK and PD To note, early phase trials are no longer defined as traditional phase 1 trials Early phase trials can be broadly defined as non-therapeutic, exploratory trials in human participants who may be healthy volunteers or have a specific disease. These studies look like this. So look at this trial, The protocol has 5 cohorts, each with 8 participants (40 all up). They start at cohort 1, and 6 participants get 30mg sc, 2 get placebo If every single patient in that cohort tolerates the dose without any side effects, the trial can proceed to cohort 2 Then the next 8 participants will enter and have 90mg sc or placebo and so on. The dose will increase until a dose is given to a cohort where the dose is not tolerated and adverse events (Ae’s) start appearing and this is considered the maximum tolerated dose. When we talk about an multiple acceding dose scheme, cohort 1 might get 30mg for 4 doses, then after 4 doses, if group had no ae’s, the patient themselves move up to new cohort. So same patients move through the cohorts. The advantage of doing multiple doses is that the drug can reach steady state in the body and look at long term effects  Phases of Clinical Trials Registration with TGA Next phase, once we have mtd, we move to phase 2.  Phase II studies Early phase Therapeutic exploratory 100-300 Early pharmacology/efficacy Dose finding in an indication Toxicity monitoring Patient in whom no alternative treatment is available Still an early phase study This might involve 100-300 participants How it differs from phase 1 is we are looking at optimal dose in specific indication. Ie optional dose of insulin in diabetic patients. No longer healthy individuals without disease People who tend to participate are refractory patients, and they have no other treatment and willing to participate Usually efficacy is an endpoint. They use them to resolve uncertainties regarding the design and conduct of subsequent trials. And we see this a lot. Studies with very poor design, and it’s because of our feedback they make the phase 3 trials more simplified, like less vials, or they might have better stability Phases of Clinical Trials Registration with TGA  Phase III studies Comparative studies Therapeutic confirmatory 300-3000 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 Then we move to phase 3. These are important as they generate the most data for the registration studies They are usually comparing drugs to a gold standard or a comparator like a placebo. They can include thousands of patients They are called randomized controlled trial (RCT) because they are being randomised into the different arms. They are trying to test a hypothesis and see if there is statistical significance between the arms. So you need large numbers of patients. This is because humans, unlike animals, have varied genetic backgrounds. They can have different comorbidities, disease state, environmental factors. There are a number of strategies used to make the data powerful including blinding patient and dr to treatment, design can be varied and can be performed in parallel, so might mean there are 2 arms a and b. Patients will be randomised to either arm, but run in parallel at same time and conditions so data can be compared Some cases they use cross over design. Use A, then washout period, and receive B. In this way patient acts as own control.. These are to complete the cleanest data Therefore RCT double blind are considered gold standard, and if well designed they provide strongest evidence 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. So when I use the terms randomisation, we’re taking a cohorts of patients, and randomly placing them into a defined group. If we do this randomly, usually by a computer, but sometimes still enveloped, patient has an equal chance of being placed into an arm. This is the best way of removing bias  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. The other term you will hear is blinding Blinding is the process where one or more parties are kept unaware of tx arm participant is assigned to. It’s also a way of preventing conscious and unconscious bias There is single blind, which might mean the patient, or doctor, or person processing the data is not aware of the arm, More likely the better design is double blind., where the patient and the doctor are both blinded. So they doctor cannot influence outcome of study Someone who is not blinded, is called unblinded. Pharmacy staff are often unblinded which means we know what the patients are on. Usually this is because or study design where sponsors are trying to cut costs by not making matched placebos, hence resource cand cost shifting onto us. We are seeing this a lot more and it really puts a strain on our ability to resource trials.  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 So when we use the term comparator, it can be the placebo, or active treatment. Ideally we’d like to sue the placebo. Which is a fake or sham treatment specifically designed without an active element. It looks like the active in every way. Where it doesn’t, we use further masking techniques, like covering bags and lines in amber tape to ensure the patients don’t know what is being administered. When use of a placebo is deemed unethical, for example where with- holding treatment from a patient could produce irreversible harm, an active control is used. An example could be a trial studying a new HIV treatment. Patient are randomised 1:1 to either the new treatment or an active treatment as the comparator. It would be unethical to deny treatment to a HIV patient. However, as the effect of both treatments may be due to a placebo effect it is necessary that the new treatment must be shown to be better than the active control. Advantage of using placebo, is we can attribute all the new effects to the drug, not to the old drug In the second half of the lecture, I will cover further ethics considerations made when designing clinical trials  Placebo Effect The placebo effect is a psychosomatic effect brought about by relief of fear, anxiety or stress because of study participation Did you know..placebo’s are considered unapproved drugs? Using a placebo also allows for exploring the placebo effect, which is the psychosomatic effects brought on by involvement in the study. A participant might experience a SE but be on placebo, so you know that that SE is not from the drug itself, and the data can be reviewed accordingly No treatment is not the same as placebo treatment There is no entry for ‘placebo’ in the ARTG. Therefore, a placebo is considered to be an ‘unapproved’ therapeutic good and a CTN or CTA must be in place before a placebo can be supplied for use in a clinical trial. This is the case even if the investigational product(s) are already included in the ARTG.  Trial design: manufacturing and labelling Therapeutic Goods Act 1989 Investigational agents MUST be produced under GMP Exemptions to part 3-3 Pharmacists who manufactures in a pharmacy and goods are provided to the public Pharmacist employed by a public hospital who manufacture for supply in that organisations for use within the same state or territory A person who applies supplementary labelling to a manufactured product Labelling has to be PIC/s annex 13 complaint TGO 69, TGO 91 and TGO 92 do not apply to investigational agents I just wanted to touch on the manufacture of trial medications as this, again, is something I see investigators and sites struggle with day in and day out in the set up of their trials, which I believe is through lack of knowledge. There is no excuse now as I am telling you what has to occur, Remember how I said that there were a number of laws and policies and guidelines that we must follow? Well in Australia, therapeutic Goods must adhere to Part 3-3 of the therapeutic Goods Act 1989. This means manufacturers of investigational products must hold a valid TGA licence that specifically authorises that site for the manufacture of clinical trial products in Australia. This means the manufacture of a product from discover to labelling must be GMP compliant through a TGA licensed facility OR an equivalent regulated manufacturer if being prepared overseas There is one exemption to this, and that is when goods are prepared for initial experimental studies ion human volumeters ie phase 0 or 1 specified in item 1, section 7 of the therapeutic goods regulatio0ns 1990 Persons exempt from the operation of Part 3-3 of the Therapeutic Goods Act 1989 include: pharmacists who manufacture therapeutic goods in a pharmacy where the pharmacist practices and the pharmacy is open to the public and the goods are supplied from those premises and meet the requirements of item 2, Schedule 8 to the Therapeutic Goods Regulations 1990 ((this states they are provided for supply other than by wholesale) which means off a script pharmacists employed by a public hospital or public institution who manufacture therapeutic goods for supply in hospitals and public institutions in the same state or territory and meet the requirements of item 3, Schedule 8 to the Therapeutic Goods Regulations 1990 a person who applies supplementary labelling to a manufactured product, where the supplementary label contains only a name and address, the registration or listing number of goods, or the biological number of a biological as specified in item 5, Schedule 8 to the Therapeutic Goods Regulations 1990 Refer to Schedule 8 of the Therapeutic Goods Regulations 1990 for the full list of exemptions. The labelling therapeutic goods orders TGO 69, TGO 91 and TGO 92 do not apply to investigational medicinal products. Instead, labelling requirements are specified in Annex 13 of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products. This document outlines the information to be included on labels, unless its absence can be justified. Now PIC/s just got a huge overhaul, which I need to check. These are the items in the regulations that I mentioned above  What this translates to in real life: Pharmacists cannot produce goods for supply via wholesale Ie Pharmacists can only supply PER patient off a script Pharmacists cannot make bulk products to ship across state borders This would be wholesaling Supplementary labels should be added at point of dispensing. Labelling in bulk requires a GMP licence All other pharmacy laws and regulations around supply are applicable An exemption DOES NOT mean a site has capacity or is willing to take on the risk of phase 1 studies outside of GMP We require the product to be GMP compliant regardless of phase Read slide  Phases of Clinical Trials Registration with TGA Last phase is phase 4. These occur after the drugs are registered on the ARTG.  Phase IV Often after registration (i.e post marketing approval) postmarketing surveillance Therapeutic use Controlled cohort trials vs ‘real world’ experience 1000’s New toxicities/adverse reactions (rare) identified It’s called post marketing surveillance These are important to continue to review as we’re moving out of being controlled and patients are careful; selected, and now going into real world experiences. They may have other coomorbidities, other drugs. We’re seeing the drugs being used in big cohorts Great example of this is covid vaccinations. When you went for them, you signed a consent form. And from those vaccinations being given all around the world, we were able to identoi9fy all the AES such as the clotting with the AZ, or myocarditis with Pfizer vaccine. This produced some very powerful information  Access to Drugs in Australia TGA Registered Medication Access Special Access Scheme Programs Authorised Prescriber Clinical Trials Personal Importation https://catag.org.au/resource/manag ing-medicines-access-programs/ I just wanted to touch on a other term you might hear called Medication Access programs or MAPS. This is an umbrella term for programs offered by pharmaceutical companies (sponsors) to facilitate deferred cost, cost-free or subsidised access to medicines for patients before subsidised medicines are available. MAPs may include, but are not limited to, the following: Compassionate Use (non medicare card holder supplying a HIV medication where they might otherwise not be able to afford it) Extended access programs (usually drugs coming off clinical trial, and before PBS registration) Product familiarisation programs (usually drugs awaiting PBS registration) Cost share programs (allow access at a reduced cost) These usually involve medications that are registered, but might not be on the PBS, or marketed for a alternative indication, or using SAS drugs which are not available in Australia, but the company will supply at no cost into the Australian market.  Brain break slide Just a quick brain break  Human subjects in clinical trials: Ethical considerations and concerns We’ll move onto the ethical consideration, in particular protecting the rights of humans participating in trials  Hippocratic Oath “ First do no harm” First we’ll touch on the Hippocratic oath This is the oath of ethics taken by physicians. Origins are Greek, 400bC. Required a new physician to sear to goods to uphold ethical standards including 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 There are 4 main pillars Autonomy- basis of what we know as patient consent to treatment, confidentiality Beneficence- duty to do good, basis of negligence law Non maleficence. Not do bad. Basis of criminal law Justices- to treat all people equal and equitable- anti discrimination law  What is a safe drug? Examples of Examples of a an ‘unsafe safe drug? drug’ ? So what is a safe drug? No drug is safe, depends on how it’s used. Every drug has potential to be a poisons Some have good safety profiles, some need monitoring Ie clozapine one of our oldest drugs, but best antipsychotic. But must have close monitoring  ALL RESEARCH, INCLUDING TRIALS, REQUIRE ETHICS Ethics Approval COMMIT TEE APPROVAL It’s for this reason medicines used in humans need oversite Protocol needs to be reviewed and approved by ethics committee  Ethics Committees (hospital, Committees university or both) Statutory constitution Researchers Clinical practitioners Science training Lay persons Minister of religion It’s an independent body made up researchers, practitioners, lay persons, Can be national, private, public hospitals There are also have multi hrecs which means you can apply to one and it assess across multi sites. practically this means we sometimes run into problems because different states have different laws  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… Ethics committee has the responsibility to ensure protection of rights, safety and wellbeing of participants and ensure public of the protection Operates to express opinion on CT protocol, the investigators on the trial, the methods and documents to be used to informed trial participants. Look to see what is being provided to patients if they would like to participate. Must have informed consent What trial is about, risk and benefits, what procedures, how many appointments, how long will the trial be for,  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. There are a number of national and international guidelines produced to harmonise how CT are performed in countries and across the world. They provide clear scientific proof. They consider risk over benefit of protocol. There to protect rights of human subjects ICH GCP It was designed to bring together trials across the world This document did not come into play until 1997. But what led to it being put in place was dating back to WW2, by German clinicians and nazi research which led to the establishment of the Nuremberg code in 1949 Universal declaration of human rights as a result of the inhumane trials conducted by WW2. So together with this information, and incidents like thalidomide, this led to this document  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) Clinicians Clinical Trials Investigators Pharmacy Ethics committee review Governance Advertising of any agent not on ARTG is an offence Ads reviewed by HREC In Australian we have the therapeutic Goods Act which requires HREC to review and monitor all CT A Number of people that are responsible for looking after CT includes Sponsor (manufacturer) protocol, and financing it. Sponsor will approach clinicians to be investigators of their trial at a specific site. Usually, there is a principal investigator at a site, and many sub investigators delegated to the study. They usually recruit a small number at each site to get a cross section of different patients Pharmacy plays a role, because most hospitals all medications must come through pharmacy. While doctors are authorised to posses the drugs under our state law, the governance of medications in NSW places the responsibility largely within he hands of pharmacy, particularly in the hospital system. Labelling also has to be complaint. Fun fact, you know when people get samples from their doctor that are unlabelled? That’s not actually complaint with legislation. Products have to be labelled in line with the SUSMP, or for trials with Annex 13 You also have the Ethics committee review. I sit on a subcommittee in our hospital that just looks at drug trials before it goes to the full ethics committee And governance. Every institution will have a governance body ie anniversary, hospitals. These are looking at the legal aspects of the trial. Does the hospital have indemnity and insurance to cover the cT and compensate patients would there be any issues To note, unregistered drugs cannot be advertised under the TG Act., While a sponsor can promote their trial in the public dominion, they cannot mention the name of the agent being used in the trial. Any advertisement for a CT must be approved by a HREC  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-2023 Australia has a national statement for the conduct of human research. It is used to inform design and ethical review of human research. Sets out national standard for instructions and organisations, including how they should operate and the membership This was updated this year. What we’d like you to look at is section 3. It identifies common ethical issues that arise, and the level of oversite that is required. You’ll be using this document in your tutorials  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 As I mentioned, please look at section 3 as you will need this for the tutorial.  Section 3- the HOW of conducting a trial ELEMENTS OF RESEARCH …LOOK AT ‘KEY THIS WILL BE IMPORTANT QUESTIONS’ IN THE CLINICAL TRIALS WORKSHOP Look at the elements of research Look at the questions it’s asking So when you look at CT design can you answer those questions  Ethics What is an ethical trial? What is ethical research? Informed consent Placebo Randomisation and blinding So what is an ethical trial What is ethical research? We need to consider the design of the trial. Need to obtain informed consent to therapy. Must be voluntary. Participant should be adequately informed Participant cannot proceed if they have not provided informed consent. This includes use of an official translator, not family members Placebos are interesting, and this was touched on before. If you have a condition, and going on a placebo means treatment is withheld, is that ethical? Randomisation and blinding. Protect integrity of data, but are they fair? You might receive the lowest dose, not the optimal one? Is that ethical? These are the considerations we need to make when designing the trial It’s a fine line between producing data and possibility of harm to participants and that’s why these guidelines exist I’ve also included a pyramid to show the level of evidence. Important as pharmacists to distinguish a level of evidence when we read about new drugs. The best being a meta analysis, which is when someone has come together and done a systematic review of RCT in that therapeutic area. Cochrane reviews are a database of these meta analysis. These would be the one presented to governing body for registration  Clinical Equipoise Provides the ethical basis for clinical research that involves assigning patients to different treatment arms of a clinical trial There is no “better” intervention present during the design of the RCT A true state of equipoise exists when one has no good basis for a choice between care options Ensures that treatment arms (including placebo) of a trial have equal therapeutic merits Regular interim data analysis and safety monitoring is required 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. So it is often asked is it ethical to treat patients with the same disease with different treatment arms This is where the concept of clinical equipoise came about Clinical equipoise is the assumption that there is no “better” intervention present during the design of the RCT A true state of equipoise exists when one has no good basis for a choice between care options When a doctor places their patient onto a CT they actually believe that the patient will benefit from either arm of trial Patients are unlikely to participate in trials where perceived or actual risks outweigh the benefits, and clinicians will not enrol patients to trials where they believe the participants may be randomized to receive inferior therapy. Clinical equipoise can address this by ensuring that treatment arms (including placebo) of a trial have equal therapeutic merits and randomization can become less unappealing. Clinical equipoise should be maintained throughout the duration of a trial. In large adaptive multi-centre, multi-arm trials that are ongoing over a number of years, there is a need for regular interim data analysis and safety monitoring. Monitoring of data and safety information in this way facilitates accelerated progression of promising therapeutic agents and early discontinuation of inefficacious treatment arms, reducing the number of participants exposed to unsuccessful or toxic treatments. There have been examples of trials where the design resulted in ethical discussion, including the one published in the new York times (attached). This one was where they used dacarbazine to treat melanoma for soc vs new drug PLX4032 (vemurafenib). It showed an 81% improvement in an endpoint on an earlier study. So there were 2 groups, one saying it was unethical to give the SOC, but the other saying they needed the RCT to test other endpoints  Where are clinical trials conducted? Depending on clinical setting hospital clinical trials specialist unit community setting university research institutions CT can occur in a number of places Hospitals, specialist units, community setting, New drugs will usually be in a hospital because the PI will be a doctor, and in terms of safety, patients are within an emergency setting. Later phase may work their way into the community setting. In saying that though, about once a year I’ll see a study that a sponsor wishes to run in the community setting. I am always sceptical that they know all the rules around supply, and sadly, I’m usually right because unless you are heavily exposed to the procedures or have first hand experience being mentored by someone, it’s actually really hard to know all the ins and outs of how to run a trial. If you are in a community setting, an are approached to run a study, get in contact with a pharmacy that has a speciality unit, usually your local public hospital  Key Players in Clinical Trials Trial sponsors (Pharmaceutical Principal Study Coordinator company, Investigator university, hospital) Clinical Research Patient Pharmacy? Associate (monitor) The stakeholders in CT: We have the trial sponsor, supplies drug, they pay for medical tests, appointments, staff time Principal investigator, usually a doctor, is the person who is incharge of the trial at a particular site. They run and recruitment of the trial at the site - The study coordinator, usually a nurse but not always, helps the PI with the day to day conduct of the trial. Booking appointments, patient visits, Assist the principal investigator in the conduct of the clinical trial at the site - May be involved in research activities like organising submission paperwork, preparing budgets - Undertake screening and recruitment activities - Ensure compliance with the protocol. - Booking patient appointments CRA is a representative of the trial sponsor. - Go out to each site and monitor and audit how the trial is being conducted - They look at how drugs are being stored by the site, if they are dispensed correctly - Ensure data entered is clean - Ensure compliance with the protocol - Assess suitability of clinical trial sites and identify investigators - Running source document verification - Setting up and closing down CT sites The patient (obvious reasons) And the pharmacy. Yes, we are heavily involved in the conduct of the trial and we play an important role! We’re often unblinded. We have units set up specifically for how to handle these drugs. We maintain trial drug under strict conditions. How it is to be stored, temperature excursion, dispensed in a certain way with certain labelling conditions.  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 What does this mean for you? There's lots of roles for pharmacists outside of conventional roles. You can be involved in the industry, you could be a CRA auditing and monitoring, you can work for the PI coordinating CT at the site, you could be in ethics or governance level You could be in the CT pharmacy You could end up in pharmacovigilance post marketing.  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) As a pharmacist we need to understand and critically evaluate literature So how does this impact our profession? We do need to keep UpToDate as pharmacists with new therapies Until you work in the research space, I don’t thi9nk people truly understand the resourcing that goes into getting a drug to market. The trials process is very intense and highly regulated. As pharmacists, we need to understand how to use evidence as the basis for our decisions 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?