Clinical Development - Regulations, Ethics and Adverse Event Reporting

?
  • Created by: LBCW0502
  • Created on: 28-01-20 10:09
Describe features of the regulatory environment - underpinning legislation (1)
Directive 2001/20/EC:The implementation of Good Clinical Practice in the conduct of clinical trials on medicinal products for human use
1 of 85
Describe features of the regulatory environment - underpinning legislation (2)
Directive 2003/94/EC: - Principles and guidelines of good manufacturing practice for medicinal products for human use and for investigational medicinal products for human use
2 of 85
Describe features of the regulatory environment - underpinning legislation (3)
The Medicines for Human Use (Clinical Trials) Regulations 2004.
3 of 85
Describe features of the regulatory environment - underpinning legislation (4)
Directive 2005/28/EC › Principles and guidelines of good clinical practice for clinical trials investigational medicinal products for human use
4 of 85
Describe features of the regulatory environment - underpinning legislation (5)
The Human Medicines Regulations 2012 (SI 2012/1916), - Consolidates and modernises medicines legislation. It replaces most of the Medicines Act 1968 and over 200 statutory instruments
5 of 85
Describe features of the regulatory environment - underpinning legislation (6)
Clinical Trials Regulations on Medicinal Products for Human Use - replace directive 2001, delegated EU regulation on GMP for IMPs/MPs EU
6 of 85
What are the legal requirements for clinical trials in the UK involving IMPs? (1)
The Medicines for Human Use (Clinical Trials) Regulations 2004. Most highly regulated environment. Clinical trial authorisation (CTA, for phases I-IV studies). Approval required for every study. Excluded non-interventional trials
7 of 85
What are the legal requirements for clinical trials in the UK involving IMPs? (2)
EU GCP/EC review and approval legally mandated. Import authorisation required when sourcing IMPs from a third country. EU GMP/QP release required for IMPs. GCP (every 3 years), GMP (every 2 years), regulatory inspections
8 of 85
What are the legal requirements for clinical trials in the UK involving IMPs? (3)
Sites - sponsor, sponsor subcontractor and investigator. Non-EU sponsors require legal representation within the EU
9 of 85
Describe features of clinical trial authorisation (1)
EudraCT number (EMEA). Application to the MHRA –Clinical Trials Unit. Validation of application 3-5 days. Review period for Phase 1, 14 -21 days from receipt of valid application
10 of 85
Describe features of clinical trial authorisation (2)
Review period for Phases 2 and 3, up to 60 days from receipt of valid application-in practice 35 days. EC and regulatory authorisation can be submitted in parallel
11 of 85
What are the documents to be submitted for clinical trial authorisation? (1)
Completed and signed CT application form- Annex 1. Final protocol and summary in English. Outline of all active trials with same IMP. IMP Dossier and Investigators Brochure (only on request)
12 of 85
What are the documents to be submitted for clinical trial authorisation? (2)
GMP documents -Import authorisation, Manufacturing Authorisation or QP declaration of GMP equivalence to EU GMP, label for IMP. Copy of EC approval
13 of 85
Describe features of the IMPD (1)
Summaries of quality, manufacture and control of the drug substance and all IMPs included in the application. Summaries of non-clinical pharmacology and toxicology studies
14 of 85
Describe features of the IMPD (2)
Summaries of all available human data. Overall risk /benefit assessment and guidance to investigators. Reference list of studies conducted or appropriate literature references. Updated on each submission
15 of 85
Describe features of an investigator brochure (1)
Summaries of non-clinical pharmacology and toxicology studies. Summaries of all available human data. Overall risk /benefit assessment and guidance to investigators
16 of 85
Describe features of an investigator brochure (2)
Reference safety information. Reference list of studies conducted or appropriate literature references. Updated annually
17 of 85
What are the principles of GCP? (1)
GCP - an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects.
18 of 85
What are the principles of GCP? (2)
Compliance with this good practice provides assurance that the rights, safety and well-being of trial subjects are protected, and that the results of the clinical trials are credible and accurate
19 of 85
What are the principles of GCP? (3)
Clinical trials should be conducted in accordance with ethical principles and regulatory requirements. Anticipated benefits must justify any risk
20 of 85
What are the principles of GCP? (4)
Rights, safety, well being of trial subjects should prevail over the interests of science and society. Freely given informed consent should be obtained from all trial subjects
21 of 85
What are the principles of GCP? (5)
Available non clinical and clinical information should be adequate to support trial. Clinical trials should be scientifically sound and described in a clear, unambiguous detailed protocol
22 of 85
What are the principles of GCP? (6)
A trial should only be conducted in compliance with a protocol that has received a favourable ethics and regulatory opinion. Medical care of subjects should be the responsibility of an appropriately qualified physician /dentist
23 of 85
What are the principles of GCP? (7)
Each individual involved in a clinical trial should be appropriately qualified by education, qualification, training and experience. All clinical trial information should be handled in a way that permits accurate reporting, interpretation/verified
24 of 85
What are the principles of GCP? (8)
Confidentiality of subjects records should be protected in accordance with applicable regulatory requirements. IMPs should be manufactured, handled stored in compliance with applicable GMP, used only in accordance with the protocol
25 of 85
What are the principles of GCP? (9)
Standard operating procedures which assure the quality of every aspect of the trial should be implemented
26 of 85
Describe features of GMP compliance (1)
GMP - part of quality assurance which ensures that medicinal products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorisation (MA) or product specification
27 of 85
Describe features of GMP compliance (2)
GMP is concerned with both production and quality control
28 of 85
Describe features of IMPs (1)
Manufactured in compliance with EU GMP. Manufacturer within in the EU requires manufacturing authorisation which is process specific not product specific. Regulatory GMP inspections every 2 years. All IMPs require QP release
29 of 85
Describe features of IMPs (2)
Import of IMPs from third country require import authorisation. Audit to assess compliance to EU GMP at non EU site and re-testing on import - QP responsibility
30 of 85
Describe features of IMPs (3)
Technical agreements required to cover all manufacturing activities. Challenge agents not regarded as IMPs. Radio-labelled compounds involve both GMP and GLP processes
31 of 85
State features of the clinical trial regulations on medicinal products for human use (1)
Five major areas of impact. Scope and definitions modified for low interventional trials and auxiliary medicinal products. New authorization process –single RA and EC submission process via EMA portal
32 of 85
State features of the clinical trial regulations on medicinal products for human use (2)
Increased consistency for safety reporting requirements and expansion of Eudravigilance. Increased transparency requirements. Increased notification requirements
33 of 85
Outline the history of research ethics (1)
1948 Nuremberg Code (freezing and high altitude experiments, sulfanilamide and other drugs for wound infection, injected pathogenic organisms (Typhus , cholera, smallpox ) to test effectiveness of vaccines)
34 of 85
Outline the history of research ethics (2)
First international document which advocated voluntary participation and informed consent
35 of 85
Outline the history of research ethics (3)
Declaration of Helsinki 1964 - established by World Medical Association, governs international research ethics and defines rules for research with clinical care and non- therapeutic research, forms basis of good clinical practices
36 of 85
Outline the history of research ethics (4)
Research with humans should be based on credible laboratory and clinical results. Research protocols should be independently reviewed. Informed consent is necessary from research participants. Risk should not exceed benefits
37 of 85
Outline the history of research ethics (5)
Research should be conducted by medically/scientifically qualified individuals. Every clinical trial protocol will refer to the Declaration of Helsinki
38 of 85
Outline the history of research ethics (6)
Tuskegee Syphilis Study USA (1933-1972) - 400 -infected with syphilis- not told of diagnosis. National Research Act 1974-USA- Required biomedical research to be conducted in accordance with basic ethical principles
39 of 85
Outline the history of research ethics (7)
Belmont report 1979-USA - established three basic ethical principles (respect for persons, beneficence, justice). Research on vulnerable groups very strictly controlled (prisoners, mentally infirm)
40 of 85
Outline the history of research ethics (8)
Code of Federal Regulations 1981 and extended in 1991, USA. ICH GCP 1995. 2001/20 EC and SI 1031 (UK)
41 of 85
What are the required elements for informed consent? (1)
Involves research. Purpose. Treatments and probability for randomisation to each treatment. Procedures including all invasive procedures. Subject's responsibilities. Any experimental aspects. Reasonably foreseeable risks/expected benefits (or not)
42 of 85
What are the required elements for informed consent? (2)
Alternative treatments. Compensation details. Payment (if any) to subject). Expense (if any) for subject. Voluntary participation and freedom to withdraw. Direct access to medical records. Confidentiality of identity of subject
43 of 85
What are the required elements for informed consent? (3)
Relevant information made available to subject. Person(s) to contact for further information. Foreseeable circumstances under which the subject's participation may be terminated. Expected duration of subject's participation
44 of 85
What are the required elements for informed consent? (4)
Approximate number of subjects involved
45 of 85
Describe features of the legal aspects (1)
Prescribed by the EU Directive. Legal requirement. Review process to be conducted by a legally established ethics committee (EC). Under EU directive: process can take up to 60 days. EC have a defined constitution, modus operandi and SOPs
46 of 85
Describe features of the legal aspects (2)
EC is responsible for the protection of the rights, safety and well being of the study subject. Care of subject must be the responsibility of an appropriately qualified Doctor or Dentist
47 of 85
Describe features of the UK ethics requirements (1)
United Kingdom Health Research Authority (HRA). National Research Ethics Service (NRES). Co-ordinates, maintains, manages and develops operational systems for Research Ethics Committees (REC) and authorised ethics committees
48 of 85
Describe features of the UK ethics requirements (2)
The National Research Ethics Service will protect the rights, safety, dignity and well-being of research participants, whilst facilitating and promoting ethical research.
49 of 85
Describe features of the UK ethics requirements (3)
Composition of REC, up to 18 members. One third lay members of which one third must have had no previous exposure to working in healthcare
50 of 85
Describe features of the UK ethics requirements (4)
Research Ethics Committees (REC). Type 1 (Recognised for review of phase 1 CTIMPs in healthy volunteers only). Type 3 (Recognised for review of CTIMPs (other than phase 1 trials in healthy volunteers)
51 of 85
Describe features of the UK ethics requirements (5)
All other research taking place in more than one domain anywhere in the United Kingdom. They are also authorised to review other research.
52 of 85
Describe features of the UK ethics requirements (6)
Application via The Integrated Research Application System (IRAS)
53 of 85
Describe features of the UK ethics requirements (7)
Single online system for applying for permissions and approvals for health and social care/community research in the UK
54 of 85
Describe features of the UK ethics requirements (8)
Complete IRAS form and attach required documents (protocol, all subject facing materials, insurance , investigator CV etc )
55 of 85
What is an adverse event?
Any undesirable event occurring to a subject during a clinical study whether or not related to the investigational product
56 of 85
What is an adverse drug reaction?
Any unwanted or harmful reaction experienced following the administration of a drug or combination of drugs under normal conditions of use and suspected to be related to the drug
57 of 85
What is causality?
The probability that a particular medicine is responsible for an isolated effect or ADR.
58 of 85
What is a signal? (1)
Reported information on a possible causal relationship between and adverse event and a medicine, the relationship being previously unknown or incompletely documented
59 of 85
What is a signal? (2)
Usually more than one signal report is required to generate a signal, depending on the seriousness of the event and the quality of the information
60 of 85
What is a serious adverse event? (1)
Any untoward adverse event which a subject suffers during the course of the study which: results in death, is life threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation
61 of 85
What is a serious adverse event? (2)
Results in persistent/significant disability/incapacity, is a congenital anomaly/birth defect, other serious important medical events
62 of 85
What is a SUSAR?
Suspected Unexpected Serious Adverse Reaction. Includes all SAEs but is attributable to the IMP. Reportable to regulatory authorities and ethics committees
63 of 85
What is a type A ADR? - most common
Predictable – from the drug’s pharmacological actions. Pharmacodynamic (e.g bronchospasm from beta-blockers). Toxic (e.g. deafness from amino-glycoside overdose)
64 of 85
What is a type B ADR? - most common
Bizarre–not expected from the drug’s pharmacological actions. Medicine-induced diseases (e.g., antibiotic-associated colitis). Allergic reactions (e.g., penicillin anaphylaxis). Idiosyncratic reactions (e.g., aplastic anemia with chloramphenicol)
65 of 85
What is a type C ADR?
Chronic-effects occurring only after prolonged treatment. Osteoporosis with oral steroids
66 of 85
What is a type D ADR?
Delayed- effects occurring many years after treatment or in the children of treated patients. Teratogenic effects with anticonvulsants or lisinopril
67 of 85
What is a type E ADR?
End-of-treatment- effects which occur when the drug is stopped suddenly. Withdrawal syndrome with benzodiazepines
68 of 85
What is a type F ADR?
F - Failure of efficacy - no response. Resistance to antimicrobials
69 of 85
Which factors are involved in ADRs? (1)
Patient factors (intrinsic - age, gender, genetic abnormalities, previous drug reactions, organ dysfunction, personality/habits, extrinsic - environment, malnutrition, diet). Prescriber factors (incorrect drug/combination/ROA/dose/therapy duration)
70 of 85
Which factors are involved in ADRs? (2)
Drug factors (drug-drug interactions, pharmaceutical - batch problems, shelf-life, incorrect dispensing)
71 of 85
Describe the frequency of ADRs
Very common >= 1/10 (>= 10%). Common >= 1/100 (1% and < 10%). Uncommon >= 1/1000 (0.1% and < 1%). Rare >= 1/10,000 (0.01% and < 0.1%). Very rare < 1/10,000 (< 0.01%), (limitation of clinical studies - need large sample size to detect ADRs)
72 of 85
Describe features of post-marketing surveillance (1)
Pre-marketing phase of drug development is incomplete with regard to possible ADRs. Tests in animals are insufficient to predict human safety.
73 of 85
Describe features of post-marketing surveillance (2)
Patients used in clinical trials are selected and limited in number, the conditions of use differ from those in clinical practice and the duration of trials is limited
74 of 85
Describe features of post-marketing surveillance (3)
By the time of licensing exposure of less than 5000 human subjects to a drug allows only the more common ADR to be detected
75 of 85
Describe features of post-marketing surveillance (4)
At least 30,000 people need to be treated with a drug to detect one patient with an ADR which has an incidence of 1 in 10,000 exposed individuals
76 of 85
Describe features of post-marketing surveillance (5)
Information about rare but serious adverse reactions, chronic toxicity, use in special groups (such as children, the elderly or pregnant women) or drug interactions is often incomplete or not available
77 of 85
Describe features of spontaneous reporting
Core data-generating system of international pharmacovigilance. Rely on HCPs to identify/report suspected ADRs to MHRA (under-reporting - main weakness). Yellow card system (encourage community pharmacists to report ADRs to MHRA)
78 of 85
Describe features of international collaboration
International collaboration - WHO international drug monitoring programme, report to Uppsala Monitoring Centre and WHO international database
79 of 85
Describe features of pharmacovigiliance
A clinical science whose objectives are surveillance, evaluation and signalling of the undesirable effects of pharmaceutical products used for medical therapy and whose major sources of new information are spontaneous notification/reporting effects
80 of 85
What are the investigator responsibilities? (1)
All SAEs (unless otherwise specified in the protocol) require immediate reporting to the Sponsor orally or in writing. Following the immediate report the Investigator shall make a detailed written report to the Sponsor
81 of 85
What are the investigator responsibilities? (2)
If a death occurs - Supply all relevant information to Sponsor and EC as requested. All other AEs to be reported in accordance with the protocol
82 of 85
What are the sponsor responsibilities? (1)
SUSARS-Suspected unexpected serious adverse reactions. Fatal and life threatening to be reported to competent authorities (e.g. MHRA) and EC within 7 days and within a further 8 days report all other additional relevant information
83 of 85
What are the sponsor responsibilities? (2)
All other SUSARS -15 days. Mandated electronic reporting format - EuDRACT. Unblinded reports required
84 of 85
State features of the pharmacovigilance in Europe and the USA
Europe - EudraVigiliance (co-ordinated with EMA). USA - relies on the Adverse Event Reporting system (AERS) to flag safety issues and identify pharmaceuticals or therapeutic biological products (blood products), for further epidemiological study
85 of 85

Other cards in this set

Card 2

Front

Describe features of the regulatory environment - underpinning legislation (2)

Back

Directive 2003/94/EC: - Principles and guidelines of good manufacturing practice for medicinal products for human use and for investigational medicinal products for human use

Card 3

Front

Describe features of the regulatory environment - underpinning legislation (3)

Back

Preview of the front of card 3

Card 4

Front

Describe features of the regulatory environment - underpinning legislation (4)

Back

Preview of the front of card 4

Card 5

Front

Describe features of the regulatory environment - underpinning legislation (5)

Back

Preview of the front of card 5
View more cards

Comments

No comments have yet been made

Similar Pharmacy resources:

See all Pharmacy resources »See all Clinical Development - Regulations, Ethics and Adverse Event Reporting resources »