clinical practice & drug discovery

Question 1

what is a clinical trial?

Answer 1

• 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

Question 2

brief history of clinical trials - the bible

Answer 2

• 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

Question 3

first clinical trial - 1747

Answer 3

• 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

Question 4

Edward Jenner 1700s

Answer 4

• 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

Question 5

vaccination need robust testing

Answer 5

• 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)

Question 6

Placebo

Answer 6

• 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

Question 7

double blind controlled trial - 1943

Answer 7

• 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

Question 8

1946 - first randomised curative trial

Answer 8

• 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

Question 9

why are clinical trials important?

Answer 9

• 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

Question 10

who is in control of the clinical trial process?

Answer 10

• 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

Question 11

how do clinical trials begin?

Answer 11

• 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

Question 12

gaining ethical approval

Answer 12

• 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

Question 13

sponsors in clinical trials

Answer 13

• 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

Question 14

how stages of clinical trials?

Answer 14

4

Question 15

phase 1 of a clinical trial

Answer 15

• 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?

Question 16

phase 2 of a clinical trial

Answer 16

• 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

Question 17

phase 3 of a clinical trial

Answer 17

• 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

Question 18

phase 4 of a clinical trial

Answer 18

• 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

Question 19

controlled trials

Answer 19

• 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

Question 20

blind trial

Answer 20

• 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

Question 21

randomisation

Answer 21

• 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

Question 22

informed consent

Answer 22

• 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

Question 23

informed consent - children

Answer 23

• 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

Question 24

what happens during a trial?

Answer 24

• 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)

Question 25

what happens at the end of the trial?

Answer 25

• 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

Question 26

what happens if something goes wrong?

Answer 26

• 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

Question 27

case of thalidomide: 1960s

Answer 27

• 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

Question 28

cost and success rate of clinical trials

Answer 28

• 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

Question 29

link between drug discovery and clinical trials

Answer 29

• 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

Question 29

valley of death

Answer 29

• basic science research
• translation to human
• translation to patients
• translation to practice
• translation to community
• overall message = translation from basic science to human studies

Question 29

valley of death continued

Answer 29

• 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

Question 30

steps in the drug process - discovery

Answer 30

• 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

Question 31

High throughput screening (HTS)

Answer 31

• 100,000s of compounds
• miniaturisation of screening

Question 32

steps in drug discovery process - development

Answer 32

• 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

Question 33

development: in vitro and in vivo testing

Answer 33

• 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

Question 34

in vitro testing

Answer 34

often looking at how cells in a test tube are effected by the treatment

Question 35

in vivo

Answer 35

• often involving small animals usually mice
• but for some studies, especially brain diseases, non-human primates may be used in the later stages

Question 36

good laboratory practice

Answer 36

• 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

Question 37

why do clinical studies fail? stroke example

Answer 37

• 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

Question 38

why do clinical studies fail? Alzheimer’s disease

Answer 38

• 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

Question 39

era of big data

Answer 39

• 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

Question 40

the Alzheimer’s disease neuroimaging initiative (ADNI)

Answer 40

• 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

Question 41

is the ADNI approach working?

Answer 41

• Currently 3393 papers have been published from ADNI studies and it keeps growing
• appears to be working over tome
  –> more biomarker availability

Question 42

Iturria-Medina (2016)

Answer 42

• 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

Question 43

clinical trials in the future

Answer 43

• 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)

Question 44

how can the clinical trial process by sped up?

Answer 44

• 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

Question 45

COVID-19 approved vaccines

Answer 45

• 14 vaccines approves and in use
• 30vaccines in stage 3 clinical trials
• new technology is being rolled out for many diseases
  –> Malaria
  –> HIV
  –> Cancer

Question 46

summary

Answer 46

• 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