clinical practice & drug discovery Flashcards
1
Q
what is a clinical trial?
A
- Clinical trials are medical research studies involving people
- They can be used for many different reasons :
–> prevent disease and reduce the number of people who become ill
–> treat illness and improve or increase the number of people cured
–> improve the quality of life for people living with illness (i.e. reducing symptoms or side effects)
–> for disease diagnosis and health problems
–> not always about new medicines but could ‘interventions’
to modify lifestyle or behaviour
2
Q
brief history of clinical trials - the bible
A
- Evidence of clinical trials been known for centuries
- Recorded in the ‘’Book of Daniel’’ in The Bible
- King wanted people to only eat meat and win but some objected as they were vegetarians
–> king allowed them to eat beans, peas, chickpeas, lentils and water for 10 days - at this point the vegetarians appeared better nourished than the meat eaters
- Although not a clinical trial first example of human experiment guiding a decision about public health
–> human intervention to create two groups and compare them
3
Q
first clinical trial - 1747
A
- James Lind
- Scurvy trial
- Scurvy was a terrible disease that effected sailors on ships
- Lind thought it was related to diet
–> he had 12 sailors with scurvy and treated them with separate food supplements - the two sailors who had oranges and lemons recovered very quickly and a third who had cider was the next best
- Not only first description of a controlled trial but also a systematic review of previous literature on scurvy
4
Q
Edward Jenner 1700s
A
- rural GP
- noticed milk maids didn’t have deadly symptoms of small pox
–> however they did all have mild symptoms of cow pox - May 1796, Jenner performed the first vaccination on 8 year old boy
–> boy hadn’t had small pox yet, was injected with cow pox and then exposed to small pox - it worked
- shaped modern vaccination
- his paper was rejected and told to gather a larger sample
–> he did this, but was still wildly ridiculed in society
5
Q
vaccination need robust testing
A
- in the 1800’s several major hospitals across Europe started to do studies (‘clinical trials’) that Jenner’s vaccination method could be robustly assessed
- this led to the development of modern vaccination we see today and also laid down the foundations for the rigorous clinical trials we see around the world
- Jenner’s legacy was huge (think of polio, AID’s, MMR all the way up to COVID19)
6
Q
Placebo
A
- first seen and defined in 1800s
- Hoopers Medical Dictionary of 1811:
–> placebo = ‘’An epithet given to any medicine more to please than the benefit of the patient’’ - 1863 : USA Medic Austin Flint first used a placebo in a clinical study
–> he gave a ‘pleceboic remedy’ for rheumatism to patients
–> all reported positive effects
–> even though the remedy did nothing to treat the disease
7
Q
double blind controlled trial - 1943
A
- Patulin (related to penecillin for common cold)
- Carried out by the Medical Research Council
- Recruited over a 1000 subjects from British offices and factory workers suffering from the common cold
–> difficult in wartime - Both the Dr’s and patients were blinded to the treatment
–> unfortunately the results failed to show an effect
8
Q
1946 - first randomised curative trial
A
- using Streptomycin to treat tuberculosis
–> again carried out by the MRC - Patients had systematic and randomised enrolment rather than alternating as used in previous studies into treatment and control groups
- Dr’s looking at the x-ray results were blinded to the different patient groups
- This study set the ground work for the basis of clinical trials we see today
–> this included the establishment of national and international regulatory frameworks across the globe
9
Q
why are clinical trials important?
A
- Health professional need evidence for the best way to compare different approaches
- Without clinical trials :
–> patients cold be given medicines that do not work
–> wasting resources
–> medicine could even make the patient worse
10
Q
who is in control of the clinical trial process?
A
- Generally designed by doctors and other specialists but involve a wide variety of people :
–> doctors, nurses, patients, statisticians, trial managers and representatives from pharmaceutical companies to design the best possible trial - Designed to offer the least risk to the patient but maximum potential new treatment or intervention being tested
11
Q
how do clinical trials begin?
A
- systematic review of previous trials performed in the same area of disease of using similar drugs
–> to assess firstly whether this research has already been done
–> therefore no need for the trial - Based on all of this information all the involved parties get together and design the trials protocol
–> this will then go onto the next stage
12
Q
gaining ethical approval
A
- trial protocol is sent to research ethics committee
- Independent group of people that includes doctors, nurses, other medical staff, members of the public and sometimes lawyers
–> they decide whether the trial is ethical - they focus on:
–> so the potential benefits of the treatment/intervention out way the costs
–> that information provided to the participants who may take part in the trial is clear and satisfactory
–> that will people will be approached in an appropriate way
–> is compensation in place for patients if something goes wrong
–> travel expenses (are they in place)
–> the trial can only start once ethical approval is in place
13
Q
sponsors in clinical trials
A
- In the context of NHS research :
–> sponsor : Individual, company, institution or group of organisations that takes on responsibility for initiation, management and financing of the research
–> all research falling under the remit of Secretary of State for Heath must have a formal sponsor - Sponsorship of involving medicines
–> it is a legal requirement for any clinical trial of an investigational medicinal product (CTIMP) to be sponsored
–> this includes provision for insurance in case things go wrong
14
Q
how stages of clinical trials?
A
4
15
Q
phase 1 of a clinical trial
A
- Early Stage
- Generally small groups of healthy subjects but sometimes patients
- Used to test how safe the treatment is
–> are there any large side effects?
16
Q
phase 2 of a clinical trial
A
- By this stage a lot more is known about the treatment
- This will now be tested in a larger group of people to asses safety and side effects in greater detail
- For the first time to see if the treatment has a positive effect in patients
17
Q
phase 3 of a clinical trial
A
- Moves up to hundreds if not 1000s of people often international groups of people
- Compare the new drug to a standard treatment
- How well drug works and how long the effects last for
- Finds out more about any serious side effects and how long they last for
18
Q
phase 4 of a clinical trial
A
- The drug is now licensed and being used as a treatment
- Gets stats on how well the drug is working on a large population
- Any long term risks and benefits
- Rare side effects
19
Q
controlled trials
A
- Designed to compare different treatments
- Usually trial groups trials group who are given new treatment
- Control group given standard treatment
- Where there is no standard treatment:
–> the control group may not be given any treatment or may be given a placebo
20
Q
blind trial
A
- Participants are not told which group they are in
- Some trials are double blinded
–> this means participants and teams treating them do not know which group they are in
–> takes away any bias toward of the team treating the patient in terms of hoping that its going to work - Really important for all groups not to know or guess which one they are in
–> treatments must look identical
21
Q
randomisation
A
- essential and usually assigned by a computer
- ensures their are no biases and groups have a similar mix of ages, sec and state of health
- with random allocation:
–> if one group does better than the other
-> it is likely that it is the treatment that is working - If it were left to the doctor to assign then they might be influenced by putting patients they think will respond into the treatment group
–> biasing the outcome
22
Q
informed consent
A
- A doctor, nurse or other researcher should always ask your permission to enter you into a clinical trial
- You cannot be entered into a trial without consent
- There are a few exceptional circumstances where the consent process is different where people may be entered into a trial without their consent, for example :
–> treatment of head injuries
–> dementia - In these examples relatives or other legal representatives of the participant will play a key role to safeguard for their role
23
Q
informed consent - children
A
- The process involving children is again different and the has to be fully explained by the person recruiting to the trial
- In all these cases the participant or representative has to be told
–> the aim of the study / what it is trying to find out
–> how you will be treated
–> what you will need to do
–> what the possible risks and benefits are - Enough information is needed to allow a decision to be made and to give your informed consent
- Questions should be encouraged and time given to make the decision
24
Q
what happens during a trial?
A
- As well as test to assess whether the treatment is working the researchers will also assess:
–> any potential side effects
–> any new symptoms
–. wider effects of treatment such as quality of life, day to day activities
–> your mental state is the treatment making you happy, sad, anxious or depressed?
–> cost effectiveness of treatment (are you able to work, how often you need to visit the doctor)
25
Q
what happens at the end of the trial?
A
- normally trials can last for many years (although the process can be dramatically speeded up)
- all participants will have access to the results of the trial if they want them
- they will also be published to help other researchers in the field and allow advancements to be taken up by everyone
- in some instances the treatment used as part of the trial may not be available on the NHS
–> at the end of the trial you will be given the standard treatment - in some cases you may be able to buy the new treatment
- all your information will be kept confidential
–> a key requirement of the trials process
26
Q
what happens if something goes wrong?
A
- Before the start of any trial, arrangements need to be put in place in case something goes wrong and people are harmed
–> ethics committees can refuse permission if this is not in place - Important for participants to know that insurance is in place before the trial starts
27
Q
case of thalidomide: 1960s
A
- really bad point of pharmaceutical research history
- drug was marketed as a mild sleeping pill safe even for pregnant women in the late 1950’s
–> As it seemed to reduce morning sickness, many pregnant women took it - However, it caused thousands of babies worldwide to be born with malformed limbs
- during the testing process on animals
–> no tests were included to look at the effects on pregnancy - The damage was revealed in 1962
–> before then every new drug was seen as beneficial - Frances Kelsey
–> despite huge pressure from the pharmaceutical industry refused a license
–> John F Kennedy praised her as a national heroine
28
Q
cost and success rate of clinical trials
A
- Clinical trials are expensive
- It was calculated that the average cost of a 5.5 year (non-pharmacological) clinical trial involving collecting data across 20 centres in the UK (stage 2 or 3) would cost on average ~£1M to administer
- Staff needed were the highest costs, including :
–> Managers
–> Researchers
–> Statisticians
–> ~30% costs for non-staffing expenses such as ethical approval - In the UK the actual price of taking a drug from development to the market is £1.1 Billion
- Only one in 10 drugs make it through to stage 4 in clinical trials
- Partially explains why drugs that developed are so expensive because the companies have so many failures
29
Q
link between drug discovery and clinical trials
A
- drug discovery is just as expensive as the clinical trials that follow them and also has a high failure rate
- this process of going from drug discovery to developing a new medicine has been termed the valley of death
29
Q
valley of death
A
- basic science research
- translation to human
- translation to patients
- translation to practice
- translation to community
- overall message = translation from basic science to human studies
29
Q
valley of death continued
A
- academia
–> basic research
–> clinical research
–> patient care - education
–> translation research
–> academic drug discovery centers
–> business incubators / accelerators
–> academia / industry consortia - industry
–> drug discovery
–> drug development
30
Q
steps in the drug process - discovery
A
- Typically researchers discover new drugs through:
–> new insights into a disease process that allow researchers to design a product to stop or reverse the effects of a disease
–> many tests or screening of compounds to find the possible beneficial effects against any of a large number of disease
–> existing treatments that have an unexpected effect against a new disease (often called re-purposing or orphan drugs)
–> new technologies, such as those that provide new ways to target the medicine to specifics sites within the body (i.e. across the blood brain barrier)
–> at this stage thousands of compounds my be potential candidates for development
–> after early testing only a small number of compounds will look promising and call for further study
31
Q
High throughput screening (HTS)
A
- 100,000s of compounds
- miniaturisation of screening
32
Q
steps in drug discovery process - development
A
- Once researchers identify a promising compound for development, they conduct experiments to gather information on :
–> how it is absorbed, distributed, metabolised and excreted
–> its potential benefits and mechanisms of actin
–>best dosage
–> best way to give the drug (such as by mouth or injection)
–> how toxic is the drug
–> how it interacts with other drug and treatments
–> how it compares to existing drugs
33
Q
development: in vitro and in vivo testing
A
- before testing the drug in people researchers must find out whether it has the potential to cause serious harm, also called toxicity
- two types of pre-clinical research are
1. in vitro
2. in vivo - There are strict guidelines for pre-clinical laboratories to adhere to often referred to as Good Laboratory Practices (GLP)
- GLP aims to standardise approaches and method
34
Q
in vitro testing
A
often looking at how cells in a test tube are effected by the treatment
35
Q
in vivo
A
- often involving small animals usually mice
- but for some studies, especially brain diseases, non-human primates may be used in the later stages
36
Q
good laboratory practice
A
- GLP sets minimum basic requirements for:
- study conduct:
–> personnel
–> training of staff - facilities:
–> equipment (safe and rigorously checked)
–> written protocols for all experiments
–> standard operating procedures (minimising experimenter error)
–> clearly writing study reports
–> quality assurance oversite for each program of work (essentially ethical approval) - Usually, pre-clinical studies are not very large
- However, these studies must provide detailed information on dosing and toxicity levels
- After pre-clinical testing, researchers review their findings and decide whether to proceed to clinical trials
37
Q
why do clinical studies fail? stroke example
A
- Accurate and repeatable strokes can be caused in rodents
- However as systematic review of the literature showed that
–> over 800 drugs have been tested on animal models
–> 500 of these work in reducing the effects of the stroke
–> 100 went to clinical trials - only one drug has become a treatment
- researchers who randomised and blinded the experiments had less favourable results
- of 100 studies looked at in a separate study, only 36% were randomised and 11% were blinded
–> these are routine in clinical trials
38
Q
why do clinical studies fail? Alzheimer’s disease
A
- Despite billions of pounds in investment
–> no disease modifying Alzheimer’s drug has been developed - Could be the wrong target
–> most studies focus on Beta Amyloid plaques
–> it could be something else
–> e.g. the blood supply - Interventions might be too late
–> the damage is already done
Early biomarkers needed
–> existing treatments could be re-examined - Clinical trials often less than 5 years
–> for Alzheimer’s this might not be long enough
–> however a longer trial is far more expensive - Not easy problems to solve
- Large cohort human studies may help especially in early biomarker detection
39
Q
era of big data
A
- we entering the era of big data and the power it can bring
- many large cohort studies underway
- one of the largest is = Alzheimer’s disease neuroimaging initiative (ADNI) in the USA
40
Q
the Alzheimer’s disease neuroimaging initiative (ADNI)
A
- large cohort study
–> largest of them all - astronomical budget
–> budget so far $218M for multi-modal data from elderly controls and AD patients - tests include:
–> Detailed history of each patient and assessment of health and education
–> Neuropsychological tests
–> Genetic testing for risk factors :APOE4
–. Lumbar puncture :CSF measurement
–> MRI both structural and function scans
–> PET for glucose consumption (Tau and Beta Amyloid)
–> Post mortem histology
41
Q
is the ADNI approach working?
A
- Currently 3393 papers have been published from ADNI studies and it keeps growing
- appears to be working over tome
–> more biomarker availability
42
Q
Iturria-Medina (2016)
A
- moved from theoretical to measured responses
- took advantage of vast amount of ADNI data to look at late onset of Alzheimer’s disease (LOAD)
- It produced a measured, not theoretical time line of disease
- The cerebrovascular system goes first
- Therefore this might be an early biomarker
–> allows drugs to be used earlier
43
Q
clinical trials in the future
A
- All about increasing the efficiency of all the steps in the process
–> even if only a small increase in each step
–> will save millions and importantly time - looks for marginal gains
- want to increase trial success as much as we can
–> increases chances of drugs getting into human population - use of AI is likely
- using more targeted approaches to select more targeted patient populations
–> Genome studies
–> Electronic medical record (EMR)
44
Q
how can the clinical trial process by sped up?
A
- e.g. COVID-19
- Standard protocol of developing a vaccine takes 10 years
- Pre COVID19 this was a real challenge
- Answer:
–> finance and parallel infrastructure development
–> doing steps simultaneously will dramatically reduce time
–> as going through the trials, start mass producing
–> if it succeeds, drugs are already being made, but if it fails, production is wasted
–> finance was the limiting factor
–> a fantastic success story for science and should make us better prepared for pandemics in the future
45
Q
COVID-19 approved vaccines
A
- 14 vaccines approves and in use
- 30vaccines in stage 3 clinical trials
- new technology is being rolled out for many diseases
–> Malaria
–> HIV
–> Cancer
46
Q
summary
A
- long history is development of clinical trials
–> we often learn from mistakes - clinical trials are internationally accepted
as way of developing medicine and human treatment - very strict criteria and ethical approval needed and safeguards in place before a clinical trial can take place
- very expensive and takes a long time with a very high failure rate
–> new emerging technologies could help - drug discovery again very expensive
–> valley of death linked to development of medicine - academia and drug development companies are now working more closely together to reduce this failure rate
