Guidelines For Phase I Clinical Trials 2018 Edition
Guidelines forPhase I clinical trials2018 edition
Guidelines for Phase I clinical trials 2018 editionPrefaceThe first edition of these ABPI guidelines was published in 19701. Since then theguidelines were revisited on a few occasions and in 2007, underwent a major revisiontaking into account the many changes that had taken place in the two decades since the1988 edition.However, developments in the regulatory arena are movingThis new 2018 edition reflects the current EU legislationat a fast pace and a considerable amount of what previouslyfor the performance of Phase I clinical research as setconstituted guidance has now become a legal requirement.down in the EU Clinical Trials Directive2. Until the ClinicalMoreover, an impressive range of guidance documentsTrials Regulation EU No 536/2014 becomes applicable,dealing with various aspects of conducting clinical trials hasall clinical trials performed in the European Union arebeen published by Health Authorities and other stakeholderrequired to be conducted in accordance with the Clinicalorganisations around the world in recent years. However,Trials Directive.many readers still feel the benefit of a comprehensive,In addition to regulatory changes, this new edition now alsolargely jargon-free document that outlines the frameworkincorporates the previous ABPI First in Human Studieswithin which Phase I research is conducted and providesguidelines with the aim of compiling all the different aspectspointers for further, more in-depth reading. In 2012, the ABPIof conducting Clinical Pharmacology Phase I trials into atherefore released an updated version of the 2007 edition.single document.This edition was extremely well received and became auseful guide not only to sponsors and investigators but alsoUpdated and edited in 2018 on behalf of and with the ABPIto ethics committees and trial subjects, read by people wellExperimental Medicine Expert Network by: Eric Helmer,beyond the borders of the United Kingdom.Oliver Schmidt, Jo Collier, Juliet McColm and Odile Dewit.Acknowledgements:We thank the many stakeholders from industry, regulators and professional organisations who provided feedback in responseto our consultation on the previous revision.2
Guidelines for Phase I clinical trials 2018 editionContents1Developing a new medicine71.1 First-in-Human trial (Phase I exploratory trial)91.2 Subsequent parts/studies (clinical pharmacology trials)92Regulations103MHRA123.1 Clinical Trial Authorisation (CTA) application123.2 Protocol amendments123.3 Inspections123.4 Breaches of GCP or trial protocol124Research Ethics Committee135Risk assessment135.1 All IMPs135.2 Higher risk IMPs135.3 Other factors13Risk management146.1 Choice of population146.2 Study design considerations166.3 Starting dose – FIH trials176.4 Increasing the dose – single or multiple ascending dose trials186.5 Administration of doses196.6 Facilities and staff196.7 Procedures207Safety record of Phase I trials218Protocol229Contracts2363
Guidelines for Phase I clinical trials 2018 edition10 Trial subjects2410.1 Recruitment2410.2 Monitoring overexposure2510.3 Special populations2510.3.1 Women2510.3.2 Children2510.3.3 Elderly2510.3.4 Vulnerable subjects2610.3.5 Patients2610.4 Obtaining informed consent2610.5 Screening2710.6 Timing of recruitment and screening2710.6.1 Panel2710.6.2 Specific trial2710.7 Identification2710.8 Informing the subject’s General Practitioner2810.9 Safety2810.10 Follow-up2811 Pharmacy2911.1 Premises, facilities and equipment2911.2 Storage2911.3 Staff3011.4 Types of work3012 Qualified Person3112.1 Requirements3112.2 Responsibilities3112.3 Releasing IMP prepared by the pharmacy3112.4 Manufacture of IMP3212.4.1 European Union or European Economic Area3212.4.2 Third country: importing an IMP3213 Investigational medicinal products3313.1 Manufacture3313.2 Documents and records3313.3 Supplying the investigator3313.4 Transport to the trial site3313.5 Accountability at the trial site3313.6 Retention of samples3413.7 Randomisation3413.8 Emergency unblinding3413.9 Quality management344
Guidelines for Phase I clinical trials 2018 edition14 Biotechnology products3514.1 General3514.2 Proteins and monoclonal antibodies3514.3 Gene therapy3514.4 Genetically modified micro-organisms (GMM)3515 Radioactive substances3615.1 General3615.2 Microdose/microtracer trials3615.3 Premises, facilities and equipment3615.4 Staff3715.5 Trial subjects3716 Non-investigational medicinal products3817 Resuscitation procedures, equipment, medicines and training3817.1 General procedures3817.2 Resuscitation equipment and medicines/antidote3917.3 Resuscitation training3918 Confidentiality4018.1 Sponsors4018.2 Trial subjects4018.3 Data Protection Act4018.4 Human Tissue Act4019 Compensation, indemnity and insurance4119.1 Compensation4119.2 Payments4119.3 Indemnity4219.4 Insurance4220 Pharmacovigilance4321 Pathology laboratory4421.1 General4421.2 Premises, facilities, equipment and procedures4421.3 Staff4422 Data management, statistics, report and publication4522.1 General4522.2 Data management4522.3 Statistics4522.4 Report and publication policy4622.5 Staff465
Guidelines for Phase I clinical trials 2018 edition23 Essential documents, trial master file and archiving4723.1 Trial master file4723.2 Quality of documents4723.3 Storage of documents4723.4 Duration of storage4723.5 Disposal of documents4724 Project management and monitoring4825 Quality management4925.1 Quality system and quality control4925.2 Auditors4925.3 Audits4926 Health and safety5027 References5128 Websites58Appendix 1: Qualifications relevant to Phase I trials59Diploma in Pharmaceutical Medicine59Diploma in Human Pharmacology59MSc59Pharmaceutical Medicine Specialty Training59Appendix 2: Challenge agents60Appendix 3: Abbreviations61Appendix 4: Glossary of terms63Appendix 5: Consultation responses706
Guidelines for Phase I clinical trials 2018 edition1 Developing a new medicineThe pharmaceutical industry is the main sponsor of new medicines research in theUK. Sponsors have to demonstrate the safety, quality and efficacy of a potential newmedicine – called an investigational medicinal product (IMP)3 – through a series ofrigorous trials in humans in order to obtain a licence, so that doctors can give themedicine to patients.However, before an IMP can be given to humans, sponsorsAfter the pre-clinical studies, there are four phases of trialsmust first test it thoroughly in animals and/or in vitro/ex vivoin humans, which in practice often overlap and which canmodels. The main aims of these pre-clinical studies are:be sub-divided. Phases I to III are done before a licence isgranted and Phase IV is done after authorisation to market to find out the effects of the IMP on body systemsthe drug. The phases are different in terms of the number(pharmacodynamics) and thereby to provide translationaland types of subjects studied, and the questions asked, asinformation supporting the hypothesis that the IMP couldoutlined in table 1.be effective in humansClinical trials of an IMP that do not benefit subjects – to study the blood levels of the IMP and how it iswhether they are healthy subjects or patient subjects – mayabsorbed, distributed, metabolised and eliminated afterbe called Phase I or non-therapeutic trials3. The premisesdosing (pharmacokinetics)where these trials are conducted are often (but not always) to find out if some of the doses of the IMP, up to manycalled Phase I units, or simply units. People who take part intimes higher than those intended for use in humans, areclinical trials are called subjects3: healthy subjects when theytoxic to animals4 and if so, to identify the target organsare truly healthy, and patient subjects when they have theand the margin of safety in terms of (a) the no-observed-disease for which the IMP is being developed.adverse-effect dose level (NOAEL) relative to bodyweight and (b) IMP exposure - the concentration of IMPin the bloodstream over a dosing interval, e.g. 24 hours(toxicokinetics)5, and to make a formulation of the IMP, extravascular orintravascular, suitable for early studies in humans.7
Guidelines for Phase I clinical trials 2018 editionTable 1. Clinical trial phases and questions they intend to answerPhaseINumber and type of subjectQuestionsApprox. 50 200 Is the IMP safe in humans?subjects (either healthy or patients) What does the body do to the IMP? (pharmacokinetics)who are not expected to benefit from the What does the IMP do to the body? (pharmacodynamics)IMP (except for life-threatening diseases) Might the IMP work in patients?Approx.100 400IIpatients with the target disease Is the IMP safe in humans? What does the body do to the IMP? (pharmacokinetics) What does the IMP do to the body? (pharmacodynamics) Might the IMP work in patients?Approx.1000 5000IIIpatients with the target diseaseMany thousands or millionsIVpatients with the target disease Is the IMP really safe in patients? Does the IMP really work in patients? D oes the IMP seem to work better than other medicines for thesame disease? J ust how safe is the new medicine? (pharmacovigilance) D oes the medicine work in the real world? (real world datacollected to demonstrate value) H ow does the new medicine compare with similar medicines?The numbers in the table are indicative only and can varyPhases are also often subdivided. A small-scale, exploratoryThe past decade has seen the introduction of exploratoryefficacy study in a limited number of patients may bestudies that are performed prior to the traditional Phasereferred to as ‘Phase IIa’. In contrast, slightly larger trialsI Single-Dose Escalation (also referred to as Singlethat test the efficacy of a compound at different dosesAscending Dose, or Single Rising Dose). These studies(‘dose-range finding’ studies) might be designated ‘Phase IIb’.allow early exploration of potential drugs in humans, toevaluate, for example, human PK, and therapeutic targetPhases I to III can take up to 10 years or more for arelevance to disease. These studies involve exposure of asuccessful IMP. However, many IMPs are withdrawn fromlimited number of subjects to a much-reduced dose (alsodevelopment 6, mainly because: referred to as a micro-dose) of a novel compound, havethey are not well-tolerated or safe enough in humans, orno therapeutic or diagnostic intent, and are not intendedto examine the maximum tolerated dose. Guidance on their pharmacokinetic (PK) or pharmacodynamic (PD)this type of study can be obtained from the Food and Drugprofile in humans is disappointing, orAdministration (FDA) as well as the European Medicines they do not work or do not work well enough in patientsAgency (EMA) 4.with the target disease.While the categorisation of human drug development trialsIn reviews of the historical clinical success of IMPs 7, 8, onlyinto distinct phases implies chronology, in practice there60–70% progressed from Phase I to II, and a mere 10–15%can be considerable overlap. A range of Phase I studiesbecame a marketed product. Phase I trials can identify IMPsare performed when the IMP is already in a more advancedwith potential for success as well as excluding failures andstage of development.thereby preventing unnecessary exposure of the IMP tomany more subjects.8
Guidelines for Phase I clinical trials 2018 editionA Phase I study (exploratory or clinical pharmacologyThe following are key aspects for a FIH study:studies) is typically defined as non-therapeutic. This choice of study populationtherapeutic trials. study design considerationsThe primary parameters tested in Phase I studies (which selection of an appropriate study site and principalcontrasts with Phase II, III or IV clinical studies which areinvestigator (PI)can involve single or multiple doses of the IMP) are: safety and tolerability formulation and site pharmacy considerations PK starting dose, and dose escalation decisions PD (including biomarkers). informed consent considerations.Traditionally there was a range of distinct Phase I studies,These aspects are all considered in Section 6 on riskeach of which was designed to address a particular questionmanagement.or set of questions. In recent years, there has been a trend1.2 S ubsequent parts/studies(clinical pharmacology trials)to combine these studies into larger multi-part studies,where the data in the early parts influences the doses andprocedures in the later parts.After the FIH trial, the next study (or next study part ifThe building blocks of a Phase I programme areincluded in a single protocol) is usually an exploration ofdiscussed below.multiple ascending doses, which is still exploratory.1.1 First-in-Human trial(Phase I exploratory trial)Examples of other clinical pharmacology Phase I trials (whichcontribute to further characterise the IMP are listed below: the effects of potential influences, such as food,First-in-Human (FIH) clinical trials are part of the exploratorygender, age and genetic/ethnicity differences, on thephase of drug development and represent a significantPK of the IMPmilestone in the clinical development of new medicines. the relationship between dose or blood concentrationAt this stage, only pre-clinical data are available to guideof the IMP and the body’s response – for example,dose selection, population, study design, safety monitoringby measuring biomarkers16 or using challenge agentsand appropriate expertise, and all of these are critical to(Appendix 2)maximise the safety of the study subjects and the quality the possible interaction of the IMP with marketedof the data4. The new compound is first tested in cohorts ofmedicines (Drug-Drug Interactions)healthy volunteers or – with increasing frequency – patientsat increasing single doses (single ascending dose study). the absorption, distribution, metabolism and elimination(ADME) of a radiolabelled IMPThere has been intense focus on the risks of FIH clinicaltrials since the TeGenero TGN1412 incident in 2006 and the bioavailability of the IMP (how much of the IMP ismore recently since the Bial incident in 2015, and much hastaken up by the body) or bioequivalence (how similarbeen published on the evidence and recommendations10–14.does a generic compound behave to the brandedThe EMA’s Guideline on strategies to identify and mitigateoriginal brand)17, andrisks for FIH and early clinical trials with IMPs provides an the effect of the IMP on the electrical activity inexcellent overview of points to consider. However, vigilancethe heart as measured by the QT interval of theis still warranted in view of the fatal serious adverse event inelectrocardiogram (ECG)18.the recent trial BIA-102474-101 clinical trial14.9
Guidelines for Phase I clinical trials 2018 editionAs stated above there is an increasing tendency forWhile it is customary to refer to PK studies as ‘Phase I’, thissponsors to combine the first single ascending dose andis not very helpful and might lead to confusion. In general,multiple ascending dose trials of an IMP, and even includethese studies form part of a set of trials classified as ‘clinicalthe effect of food or age, so that the FIH trial is actually apharmacology studies’, expanding from FIH through to‘bundle’ of parts, the first part of which is the FIH evaluation.registration (and beyond). Together they make up Section2.7.2 of the common technical document (which is a set ofSome of these trials, such as the drug-drug interaction trials,specifications-for-application dossier for the registration ofADME and QT-interval trials, may be conducted during anymedicines across Europe, Japan and the United States).stage of development of an IMP.2 RegulationsIn recent years, many changes have been made to the regulatory aspects of clinicaltrials. Most changes stem from the introduction of Good Clinical Practice (GCP), GoodManufacturing Practice (GMP) and the European Clinical Trials Directive, which isbased on GCP and GMP.All clinical trials performed in the European Union are required to be conducted in accordance with the ClinicalDirective 2005/28/EC on GCP29 Governance Arrangements for Research EthicsTrials Directive until the new Clinical Trials Regulation (CTR)Committees (GAfREC)30EU No 536/2014 becomes applicable. Both the Directive Standard Operating Procedures (SOP) for Researchand Regulation apply to all phases, including Phase I,Ethics Committees (REC)31regardless of the trial population. European Medicines Agency, Committee for MedicinalThe new Clinical Trials legislation, which was adopted on16 April 2014 and entered into force on 16 June 2014, hasProducts for Human Use (CHMP), July 2017. Guideline ontaken the legal form of a Regulation.strategies to identify and mitigate risks for first-in-humanand early clinical trials with investigational MedicinalThe main regulatory documents are:Products [EMEA/CHMP/SWP/28367/07 Rev.1])15. International Conference on Harmonisation (ICH)The Clinical Trials Directive was implemented in the UKGuideline for GCP19through the Clinical Trials Regulations3 in May 2004 (also European Union (EU) Clinical Trials Directive2001/20/ECknown as Statutory Instrument (SI) 2004/1031). The SI hassince been amended on an annual basis. The Directive’s20aims were: ICH M3 (R2) Non-clinical safety studies for the conductof human clinical trials for pharmaceuticals4 to simplify and harmonise clinical trials across Europe ICH S6 (R1) Preclinical safety evaluation ofbiotechnology-derived pharmaceuticals to give better protection to subjects who take part inclinical trials, and21 ICH S9 Nonclinical evaluation for anticancerpharmaceuticals to enforce by law the principles of GCP and GMP.22In addition to the Clinical Trials Directive, the European GMP for Medicinal Products. EudraLex Vol. 423, 24 andAnnexes, especially Annexes 1, 13 and 16Commission has published a set of guidelines covering arange of clinical trial aspects (EudraLex, Vol. 1023). EudraLex25–27is a 10-volume body of regulations and guidelines governing Directive 2003/94/EC on GMP for Medicinal Productsmedicinal products in the European Union.and IMPs2810
Guidelines for Phase I clinical trials 2018 editionThe scope of the Clinical Trials Directive is wide; it coversHealth Research Authorityall commercial and academic clinical trials of IMPs andHRA requirements on clinical trials transparency can bemarketed medicines, apart from trials using marketedaccessed via the HRA website33.medicines prescribed in the intended way.In particular, HRA transparency requirements for Phase IThe types of IMP are:studies34 can be accessed via the HRA website regarding chemical entitiesinformation on Phase I trial registration and publication of biotechnology productsresearch summaries and the HRA Registration Deferral cell therapy productsPolicy and Procedure including for the publication of gene therapy products plasma-derived productsABPI Code of Practice other extractive productsFollowing a change to the ABPI Code of Practice inresearch summaries35. immunological products, such as vaccines,201236, companies must disclose details of clinical trialsallergens and immune serain accordance with the Joint Position on the Disclosure of herbal productsClinical Trial Information via Clinical Trial Registries and homeopathic products radiopharmaceutical products.Databases37 and the Joint Position on the Publication ofClinical Trial Results in the Scientific Literature38.Companies are obliged to:In addition, a placebo, or a marketed product used or publicly register trials within 21 days of initiation ofassembled in a way different from the approved form,patient enrolment; andis an IMP when used as a comparator. post results within 12 months of completed trials forClinical trial transparencymedicines licensed for use and commercially available inEU-CTRfor non-interventional studies).at least one country (completed on or after 1 May 2011When the European Union Clinical T
Guidelines for Phase I clinical trials 2018 edition 1 Developing a new medicine 7 1.1 First-in-Human trial (Phase I exploratory trial) 9 1.2 Subsequent parts/studies (clinical pharmacology trials) 9 2 Regulations 10 3 MHRA 12 3.1 Clinical Trial Authorisation (CTA) app
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