General Flashcards
Who does GCP apply to?
Only technically applies to CTIMPs = with drugs
CTIMP = Clinical trial of investigational medicinal products
Who provides GCP training?
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)
What can CTIMPS be testing?
Efficacy
Safety
Absorption, distribution, metabolism, excretion
Who regulates CTIMPs
Medicines and Healthcare products Regulatory Agency (MHRA)
What guides Non-CTIMPS?
UK Policy Framework for Health and Social care Research
Describe the following roles of sponsor, CI and PI
Sponsor
Initiation, management and financing of study
Ensure insurance, approvals and registrations in place
Can be an organisation
Retains overall responsibility
May outsource functions to CI, contact research organisation (CRO) or clinical Trials Unit (CTU)
Chief Investigator
Responsibile for conduct of study
Management and oversite
Extensive and found in UK Policy Framework for Helth adn Social Care
Principal Investigator
At site, takes responsibility for initiation anf conduct e.g recruitment,
Make a delegation of futies log - who is doing what and are they competent?
Mainatian recordds
Where to go for CTIMP ethical approval?
Health Research Authority, part of DoH.
MHRA also
What does the HRA do?
protect and promote interest of patients and public, provide national governance system
Governance of health research
Decision tool to tell you if ou need approval from NHS research ethics committee
(REC).
Check compliance with legislation, exit strategy, funding, insurance.
What is a REC used for?
REC needed for almost all research. Also for change of protocolos
What does a site file keep?
Site file keeps all neccessary doccuments
Delegation of duties and/or authorisation logs
What safety issues are recorded?
Safety of individual prevail over science and society
Safety monitioring needed of everything that happens to a participant
Anything that MAY have been caused
Also serious or unintended consequences
Explain some of the principles of GCP
1.Clinical trials should be conducted in accordance with the ethical principles that have their
origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable
regulatory requirement(s).
2. Before a trial is initiated, foreseeable risks and inconveniences should be weighed against
the anticipated benefit for the individual trial subject and society. A trial should be initiated
and continued only if the anticipated benefits justify the risks.
3. The rights, safety, and well-being of the trial subjects are the most important considerations
and should prevail over interests of science and society.
4. The available nonclinical and clinical information on an investigational product should be
adequate to support the proposed clinical trial.
5. Clinical trials should be scientifically sound, and described in a clear, detailed protocol.
6. A trial should be conducted in compliance with the protocol that has received prior
institutional review board (IRB)/independent ethics committee (IEC) approval/favourable
opinion.
7. The medical care given to, and medical decisions made on behalf of, subjects should always
be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.
8. Each individual involved in conducting a trial should be qualified by education, training, and
experience to perform his or her respective task(s).
9. Freely given informed consent should be obtained from every subject prior to clinical trial
participation.
10. All clinical trial information should be recorded, handled, and stored in a way that allows its
accurate reporting, interpretation and verification.
11. The confidentiality of records that could identify subjects should be protected, respecting
the privacy and confidentiality rules in accordance with the applicable regulatory
requirement(s).
12. Investigational products should be manufactured, handled, and stored in accordance with
applicable good manufacturing practice (GMP). They should be used in accordance with the
approved protocol.
13. Systems with procedures that assure the quality of every aspect of the trial should be
implemented.
14. Provision has been made for insurance or indemnity to cover the liability of the Investigator
and Sponsor, which may arise in relation to the clinical trial
What guides CTIMPS
GCP
UK Policy Framework for Health and Social care Research 2017
Medicines for Human Use (Clinical Trials) Regulations 2004
Give some principles of consent
Need a patient information sheet approved by research ethics committee
Is a process
Receive not take
Person taking consent should be part of medical team
Within Integrated research application system IRAS, if data is accessed without consent outside of the clinical team then a confidentiality advisory group (CAG) may be required.
Willingness to participate should be continually checked throughout the study
What is source data? What is sent to sponsor?
Source data (original form) gets transcribed to case report forms to send to sponsor.
How does sponsor insure quality of data control?
Sponser appoints monitor at each site who ensures quality – performs source data vertification
What if protocol is not adhered to?
Need to keep a study deviation log- when protocol is not adhererd to or diaviated form
What is a serious breach of the study protocol?
likely to effect significatly:
Safety or physicla or mental integritiy of subjects or
Scientific value of the study
What should happen if there is a serious breech?
Reported to REC
What is a Serious adverse event?
Result in: Death Life threatening Hospitalisation disability or incapacity (persistent Congenital abnormality/birth defect
Is it attributable to intervention
How do you know if adverse event is unintended or not?
Look at the Investigator Brochure, provided by sponsor, all known clinical info about non-licenced medicine
Summary of product characteristics, as above but if licenced
Then, expected or unexpected according to reference safety info (RSI), in protocol
What is a likelihood ratio
Independent of prevelance
Single figure from sensitivity and specificity
LR = how many times more (or less) likely a positive test result is ti be found in disease vs non diseased
Positive = Probability of having disease with a positive test result
Negative = probability of having disease with a negative test result. (so want to be low)
So both you take probablity of (either +ve or -ve) with disease/ probability without disease
Postiive = sensitivity/ (1-specificity)
Sensitivity = % true positive Specificity = % true negative 1-Specificity = % false postive
Neative =false negative/ true negative
=1-sensiitvity/ Specificity
Therefore
Postivie liklihood ratio = probability of true positive/ false positive
What is a meaningful likelihood ratio result
For positive (ruling in disease) then >1 For negative (ruling out disease) then <1
What is pretest probablility
Be subjective or objective.
Can use prevelence of disease in age group
How to work out pretest odds vs pretest probability
Pretest prob/ 1-Pretest prob (chances you do/ chances you dont)
Posttest odds?
Accounts for prevalence (pretest prob) and for liklihood ratio of test.
= pretest odds x likelhood ratio
Posttest probablility
Postest odds/ (1+postest odds). This makes sense because in betting odds if its 1 in 4 chance, then (simplified) 0.25/1 = 0.25 then 0.25/ 0.25 +1
What is a confusion matrix
For regression. HOw many were and wernt correctly classified based on regression,
Can be used to calculate specificity and sensitivity
Explain why ROC graphs are needed.
For a test you always need a cut off. Increasing threshold decreases true positive but also false positive i.e. less sesnitive but more specific. Decreasing threshold decreases false negative but also true negative - more sensitive but less specific. SO how do you deside threshold? ROC curve`
Axis of ROC
Sensitivity (True pos rate) = y
1- Specificity (False pos rate) = x
What does x=y signify on ROC curve
True postive = false postive
What does left/above ROC curve mean
True pos >false positive
How to tell what threshold is best from ROC curve?
Furthest from x=y (depends how many false pos you will to accept or consequences of false neg)
i.e. more serious things such as Ebola you want higher sensitivity.
Whats the use of AUC in ROC?
Allows you to compare one test with another. The higher the AUC, the better the test.
how may ROC change for rare diseases
May use PPV (or precision) instead of 1-specificity (false pos rate) as accounts for prevalence
What is PRISMA
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
Key benefits from cryptogenic stroke audit
Adherence was really bad. No patients received stages 2 or 3. 5/23 not even followed up. To discuss with consultants - a few found to have cancer, ICD, CSF and toxicology. Clarify guidance.
Non malefice in research
Difficult as potential to harm Harm is monitored Continual monitoring Safety reporting GCP principles that the benefit should outweigh harm
Benefice in research
Of science and society
Of individual - not society. Dec of Hel “responsible for health of patient”
Autonomy
Consent stuff Refuse consent Patinet info sheet approved by ethical team, ask if they still want to continue at every contact Recieve consent Continual process
Justice
Clinical professionals taken
Dec of Hel - equal representation
Rights - Data protection
Not unfair - protocol stuck to for everyone.
Transparency - documentation. - deviation log from protocol
Stages of systematic review?
1: Who should do search
2: Aims and purpose
3: Prep e.g. where and how far - nonpublished vs published, abstract etc
4: Search strategy
5: Search bibliographic database search
6: Supplementary searching (no agreed way to do)
7: Managing references (e.g. remove duplicates/ tools)
8: Reporting searching process (PRISMA)
https: //bmcmedresmethodol.
biomedcentral. com/articles/
10. 1186/s12874-018-0545-3
positives and negatives to non-supplementary searches
Positive: Prevent publication bias
Negative: Introduce bias from non0published works.
How will bioinformatics and platform science change research?
From hypothesis testing to computers finding associations in big data.
New variables - genes (become cheaper to study)
Lots of variables - confounders
Allow for precision medicine through determining specific treatments based on lots of bioinformation.
Why do I want to do platform science?
x
Barriers/ difficulties to bioinformatics and platform science?
Practical:
4 Vs
volume - a lot
Velocity - knowledge and amount of information increasing rapidly
Variety - different databases, can work together?
Value - difficulty in developing and interpreting software - technical mathmatical/statistical skill needed, is data collection valid? Is data tracible? Is it accessible
Scientific
Multiple testing - bonferroni may be too conservative - this gets more with signature (combination of genes) testing.
Overfit - Can get computer models to predict random data if enough variables - needs testing on independent sample.
Batch effects - relevant to genomics but with data collection over time and large volume are methods equal?
What is platform science
Study of infrastructure that can hold vast amounts of fata and generate new knowledge
Talk about CPRD
Sponsered by MHRA and NIHR
50million longitudinal primary care records
Retrospective and prospective
Interventions - ID potential patietns, long term follow up, lots of variables
Vision or EMIS
Linkage to secondary care and other health databases
Which project would I like to do
Project 2, Prof Malanie Davies, designing a pilot for an RCT using GLT + lifestyle intervention with primary outcome of improved mood.
Reasons 1: New skills - after AFP will have experience with pre-collected data/ bioinformation. Want experience stages of RCT - PPI, Focus groups, intervention mapping, literature review, protocol, ethics, recruitment, analysis, publication, grant application.
Reason 2: Set up for PhD
Reason 3: Well-placed candidate - Sports science and medicine.
Reasons 4: Passionate about this project for 2 reasons - that PA can help. 1-2 hours could prevent 44% depression vs none. More of a reason to benefit that general pop: a) higher risk of depression, b) improvement in physical function and benefit to disease burden likely to increase it’s benefit. RCT Mild-moderate depression, evidence that PA is better than pharmacotherapy at one year after baseline. Something I made a video on, I have been a guest on a podcast talking about mental health. Gave a speech at the mental health ball. Lancet, people that exercise have 43.2% fewer days of mental health. Intrigued by
- Reason I want to go into diabetes and lifestyle is because of the potential for improvement, holistic change. Interventions benefit a range of systems. Biggest potential for change as have poorest outcomes. one patient in particular, 55 misable, blind, toe amputation, CKD.
Also: Prof Davies is lead…
How is the project I want to do related to platform science and bioinformatics
- Bioinformatics - needed for tailored intervention . UK biobank has lifestyle info - food recalls at multiple time points, accelerometers in 100,000, questionnaires, DEXA. data… what to do with it.
- Research ongoing to know how to perform a tailored lifestyle intervention.
Why do I want Diabetes Centre and prof Davies as supervisor?
World renound
been a few times - CCD for WfH
Meeting this year
Everybody is friendly, large research environment
Spoken to people that have worked there, Prof Davies in particular spoken highly of. CBE, NIHR senior investigator. Similar research interests, pharmacological RCTs, inertia, lifestyle, fruit and veg, sedentary behaviour, education.
What is intervention mapping?
A protocol for developing effective behaviour change interventions.
6 steps from problem identification to problem solving/mitigation.
Establish problem, expected outcome, select determinants of behaviour and environment
What would be perfect lifestyle intervention
Mindfullness
Physical activity
Simple nutritional intervention - NOT aimed at weight loss e.g. fruit and veg consumption.
How to tailor… clinician contacts if acceptable and agreeable to aim for increased targets across all three fields.
Other project that interests me
Multimorbidity in early-onset adult type 2 DM: incidence, prevalence, association with long-term outcomes.
CPRD and National diabetes Audit (NDA)
Characterise RF and clusters of multimorbidity
Differences between early onset T2DM and later-onset in RFs and outcomes
Issue with lifestyle interventions in T2Dm in real world
Insurance
Cost-effectiveness
Participation.
Main barriers of clinical inertia and poor adherence.
Addressed with Diabetes Prevention Programme
Benefits of lifestyle over GLT
Broader benefit
Microvascular good
Macrovascular - ACM, stroke minimal MI/CHD
Leicester biomedical research centre
4 themes CVD, Respiratory, Lifestyle, Precision medicine.
My project fits under two of them.
What is bioinformatics?
Bioinformatics is an interdisciplinary field of science, combining computer science, statistics, mathematics, and engineering to manage and make use of biological data. This can improve both the safety profiles and the effectiveness of treatments. Major drives such as the 100,000 Genomes Project, of which Leicester is a centre, exemplify the role of the UK in leading the development and implementation of precision medicine for improved healthcare on a national and international scale.
Future of T2DM research
Lancet 2017 paper Technology - Pumps, glucose monitors Bioinformatics - including genetics Stem cells Novel drugs e.g. Lifestyle! Getting research into practice
Describe use of OR verses IRR verses HR
RR can be used to describe either.
OR more useful as used in regression so account for confounders
IRR cant
HR also accounts for time
OR “with exposure is x times as likely to develop disease than y”.
What are teh types of categorical variables
Nominal - unrelated
Dichotomous - two categories e.g. gender
Ordinal - Ordered or ranked.
Difference between parametric and nonparametric
Parametric - must be normally distributed
Non-parametric tests can be anything
parametric test good because: Confidence intervals, estimate parameters, confounding (regression), Higher power than non-parametric
Define screening
The systematic testing in an easy and cheap way to distinguish between apparently well people who probably have the disease and probably do not.
List the criteria for implementing a screening programme
Disease
Test
Treatment
Programme
List the criteria for implementing a screening programme Disease/ condition
Must be important prob
Well understood eitiology and natural history
Early detectable stage
Primary prevention must have been tried
List the criteria for implementing a screening programme relating to the test
Acceptable to patient Cheap and effective Simple and safe Precise and valid An agreed cut off Agreement on who to investigate further Specificity, sensitivity, PPV, NPV
Issues with false positives and false negatives
Stress and anxiety of diagnosis. Invasive tests. may affect future uptake of screening
List the criteria for implementing a screening programme relating to the treatment
Inappropriate reassurance, may delay actual diagnosis
List the criteria for implementing a screening programme relating to the programme
Evidence based treatment available
Early treatment must be beneficial
Agreed policy on who to treat
Optimise management before screening
Briefly list the disadvantages of screening
1 Alteration of doctor-patient contract. Normally patient indentifies themselves, not the other way around
2 Complexity of screening programs. Is it working? Overdiagnosis? Psychological impact?
3 Evaluation of screening
Based on good quality evidence. Lag time bias - (early diagnosis so appear to survive longer?) and length time bias (only slow ones detected so sees better outcomes) Selection bias - healthy volunteer effect
4 Limitations of screening
False post and neg. May not fully treat. Informed choice as it may harm
5 sociological critiques
Describe the sociological critiques of screening
Victim blaming
Individualising pathology
Populations increasingly subject to surveillance
Screening is a form of social control
Health and illness practices can be seen as moral through social relationships..
Screening targeted at women than men
Steps to complete when thinking about funding
Research Design Service advice
Advice from academic supervisor
PPI, focus groups, faesibility data
Idea of cost of research
How is research funded
commercial funders, including industry and private companies
non-commercial funders such as government departments, research councils, charities, National Institute of Health in USA (NIH) and the European Commission.
How can you show that you can balance research and clinical time
Last year through multiple audits, writing stuff, squash.
Don’t always get things right: Not great at saying “No” - learning to change.
Leadership: Led many things, videos, student societies, data collection on crypto audit, WFH. Learning not great at delegation. GF was looking at leadership styles: Autocratic: “classical leader, individual decisions, responsibility, work on task at hand rather than development” Beurocratic “share decisions, give feedback and consult but delegate tasks” as a) save time b) more effective output from team c) team members develop
What makes a good academic?
Organisation - can balance clinical and non-clinical time
Knowledgable - can ask key quesitons, design and implement robust research
Comunication - verbal, work with large MDT, leader, written - applying for grant funding etc.
Describe your experience in research so far
Lboro - research skills broad
Specific - lit review, statistics, writing, through projects
Critical thinking JC
AFP - thinking about research questions , systematic review.
Talk about number of patients and conditions and BMJ editor.
Richard Smith 2018 “Doctors and patients heading in opposite directions”, half of patients have 2 or more disorders, by 80 90% patients have 1 or more disorders. Doctors becoming more specialist.
Tuskegee trial
African american men monitored syphillis natural hisotry 1930s, told “bad blood” and given placebo. Prevented to get penicillin. Even in 50s and 60s noone got penicillin.
