Neuroscience; week 9; clinical trials and drug discovery

What is a clinical trial? and what can they be used for?

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 –

• reducing symptoms or side effects

• For disease diagnosis and health problems

• Not always about new medicines but could ‘interventions’ to modify lifestyle or behaviour

A brief history of clinical trials:

Evidence of clinical trials been known for centuries

Recorded in the ‘’Book of Daniel’’ in The Bible

King Nebuchadnezzar ordered his people to

eat only meat and drink only wine – to keep them strong

Several young men of royal blood objected as they only ate vegetables

The king allowed them to eat legumes (beans, peas, chickpeas, lentils) and water  for only 10 days

After 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

1747 Scurvy trial by James Lind

First clinical trial in the modern era

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.

Wrote ‘’Treatis on Scurvy’’ published in 1753 : Not only first description of a controlled trial but also a systematic review of previous literature on scurvy.

It took the British Navy 50 years to adopt these findings in full!

Edward Jenner 1700’s side stepped the process:

Jenner was a rural GP in England – for years he had been taking notes and making observations from his local patient population.

He noticed that all the milk maids on the farms did not contract the deadly small pox disease. However all milk maids reported that they had all previously caught a similar disease called cow pox – which was a lot milder with no lasting effects

In May of 1796 – Jenner performed the first ever experimental vaccination on an 8 year old boy called James Phipps. He had escaped small pox so far, Jenna infected him with cow pox then exposed him to small pox

The experiment worked : If this was done today, the scientist would face jail, However, it is argued this experiment led to Modern vaccination

However when Jenner presented his findings he was rejected and told to collect a larger sample data set. Which he did including his own son.

Finally published : Inquiry into the Causes and Effects of Variolae Vaccinae (1798)

But the finding was still wildly ridiculed in society especially among religious groups

Vaccination needed robust testing

It was only in the 1800’s that 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)

He did give James Phipps a house!

A brief history of clinical trials: Placebo

Into the 1800’s first emergence of a really important term

Plecebo

irst defined in the early 1800’s

Hoopers Medical Dictionary of 1811

‘’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.

1943- trial

1943 :  The First double blind controlled trial – 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 and effect

1946- trial

1946 : First Randomised curative trial – 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.

Why are clinical trials important?

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

Who is in control of the clinical trial process?

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. 

Generally start with 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

Gaining ethical approval

The trial protocol is then sent to a 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 will focus on:

Do 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

The Clinical trial also needs a sponsor- in the context of the NHS

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.

Clinical trials can be split into 4 distinct phases

Phase 1 : 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

Phase 2 : By this stage allot 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

Phase  3 : 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.

Phase 4 : 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. 

Controlled trials

Designed to compare different treatments

Usually two groups – trials group – given new treatment

Control group given standard treatment –

Where no standard treatment  - the control group may not be given any treatment or may be given a placebo

What happens during a trial?

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

What happens at the end of a trial?

Normally trials can last for many years (although as can be seen with COVID19 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 you information will be kept  confidential : a key requirement of the  trials process.

What happens if something goes wrong in the clinical trial?

Before the start of any trial arrangements need to be put in place in case something goes wrong an 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.

Thalidomide: 1960s

One of the darkest episodes in pharmaceutical research history

The 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, may 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

However, Thalidamide has been shown to reduce the symptoms of leprosy and is still being used to treat the condition. 

In the USA : the boss of the Federal Drug Administration - Frances Kelsey – despite huge pressure from the pharmaceutical industry refused a license – John F Kennedy praised her as a national heroine.

Cost and success rate of clinical trials

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 expensive because the companies have so many failures.

Drug discovery

Inextricably linked to clinical trials is another process called

Drug Discovery  - this aspect 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

The valley of death

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  - could be a quick route to the clinic as often these drugs have been safely tested already) – this is true for potential treatments of COVID19 – vaccines methods that are already proved to be safe.

New technologies, such as those that provide new ways to target the medicine to specifics sites within the body – ie 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

Example of a method of drug screening

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 action

The best dosage

The 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

Development: In Vitro and in vivo testing

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

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

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

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

Good and important laboratory practice

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.

Why do clinical studies fail? Example from stroke research

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 blinding 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

Why do clinical studies fail? Example from Alzheimer’s

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 to 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 co-hort  human studies may help especially in early biomarker detection

Co-hort studies- alzheimers

There are many large co-hort studies underway one of the largest is ALZHEIMERS DISEASE NEUROIMAGING INITIATIVE (USA)

Budget so far $218M : 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

BUT is this approach working?

This theoretical figure is what should be produced by all the ADNI studies a complete time line  of disease progression and potential to detect early biomarkers and critical time points for intervention

Currently 3393 papers have been published from ADNI studies and it keeps growing

Now moving from theoretical to measured responses

Clinical trials in the future

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 will save time

Using more targeted approaches to select more targeted patient populations: genome studies

The case of COVID 19- how can the process be speeded up?

Standard protocol of developing a vaccine takes 10 years

Pre COVID19 this was a real challenge.

Answer : Finance and parallel infrastructure development

By doing steps simultaneously will dramatically reduce time

Finance was the limiting factor

A fantastic success story for science and should make us better prepared for pandemics in the future

This new tech is being rolled out for many disease- malaria, HIV and cancer

There are 14 vaccines approved and in use, 30 vaccines in stage 3 clinical trials