Lecture 2: Investigational new drugs and clinical trials Flashcards
What is meant by the following statement - Most discovery programmes begin after a ‘thinking forwards, working backwards’ exercise?
Thinking forwards – what would this medicine do and how would it be used?
- Defined in documentation called the ‘product profile’
- Identifies disease indication(s)
- What existing treatments or unmet needs exist?
- Describes ideal pharmaceutical presentation(s)
- Aspirational marketing claims
Working backwards – having defined the ideal product, how do we get there?
What is a product profile?
Decision making template and evolves with the programme
The route to a new medicine is full of hurdles and success in discovery does not guarantee development.
What determines whether something is going to be developed?
Safety
Quality
Efficacy
Clinical cost effectiveness
Affordability and impact on services
Appropriateness
Corporate Risk Management is another hurdle in developability, describe how risk is assessed?
For example, if we want to have the safest option we will take a program that has precedent chemotype and precedent mechanism in disease – then enhance some of its properties to get differentiation from what is already present tin the market —-> this is the lowest risk possible
So, drug companies don’t want all their high investment programs in the red box but instead distributed round the quadrant
Marketing authorisation depends on 3 principles.
What are they & How is the case for them presented?
A drug regulator is interested in:
- Safety – determines the relative risk for use and handling
- Quality – that the drug is manufactured in a strictly controlled way and can be stored stably
- Efficacy – that the drug produces a beneficial effect
Satisfying the drug regulator is what is needed to get marketing authorisation
The case for these is submitted as a comprehensive dossier of data involving studies done in vitro, in animals and in healthy volunteers and in patients
What does preclinical development include?
[Preclinical Development]
Chemical scale-up and good manufacturing practice (GMP) final method of manufacture
- How can this drug be made safely and economically on a large scale?
- Medicinal chemistry work on mgàg scale and the industrial process needs to produce the active pharmaceutical ingredient in Kg scale (which can be unfeasible).
DMPK/ADME
- How is the drug absorbed, metabolised and excreted (animal studies)?
Safety pharmacology
- Defines any effects on major physiological systems (animal studies)
- Usually uses 2 species one large and one small animal
Acute toxicology
- 2 animal species chosen on the basis of metabolic routes being similar to humans
- Duration of the toxicology studies determines duration of initial clinical trials (Phase I and II).
Pharmaceutics
- Determines the best dosage formulation
Why are Safety and Toxicity Studies important in Drug Development?
[Preclinical Development]
Studies in vitro and in vivo (bacteria, animals, people) determine if the new drug:
- Damages genes, cells or organs
- Alters behaviour
- Produces symptoms (e.g. vomiting, incoordination, breathlessness)
- Alters function (e.g. production of blood cells)
- Damages mother’s eggs or father’s sperm
- Damages developing baby
- Causes development of cancers
Describe how the duration of in vivo toxicology studies depends upon duration of intended clinical trial and phase of development?
[Preclinical Development]
Duration of initial clinical trials (Phase I and II) = Duration of the toxicology studies
Duration of initial clinical trials (Phase III) = 2 x Duration of the toxicology studies
How is the legal requirement in safety assessment for in vivo studies, different for inhaled drugs?
[Preclinical Development]
For inhaled drugs the safety assessment is highly specialised because Irritancy is a common cause of failure in inhaled drug programmes – due to it being an unpredictable property
The main difference between a Multiple Ascending Dose (MAD) study and a Single Ascending Dose (SAD) study is…
[Clinical Development]
The main difference between a Multiple Ascending Dose (MAD) study and a Single Ascending Dose (SAD) study is:
The number of doses given to individual study subjects.
Subjects in a MAD study receive multiple doses of the study drug.
Once there is confidence from a SAD study we move to a MAD study.
Describe how clinical Development Sequential Progression Builds Confidence in Efficacy and Safety?
[Clinical Development]
Requires approval by the:
- EU Clinical Trial Directive
- Ethics Committees
Phase 1
- Healthy volunteers; open design
- To assess the tolerability and side-effects (single ascending dose (SAD) and MAD studies)
- Initial human ADME (pharmacokinetics)
Phase 2
- Controlled trials to explore efficacy and dosage in patients (PK-PD)
- Animal and other safety studies for chronic/specialised toxicology
Phase 3
- Large scale controlled clinical trials: Clinical Proof of Concept
- Collation of data for Regulatory Approvals (for marketing authorisation application).
What are some considerations to have during Phase III Clinical Trials? How does this affect their success?
[Clinical Development]
- Best kept as simple as possible because these are typically large multi-centre trials
- Straightforward objectives
- Simple dose regimen
- Few, well-accepted endpoints
- Double blind parallel groups if possible: EU prefers comparison with gold standard treatment, US prefers placebo comparisons
- Reduce potential for errors (false positive/negatives)
- Only consider doses relevant to final product
- Select a number of patient participants which gives statistical power and confidence in safety balanced against ethical constraints
Give an example of a Post-Marketing Surveillance that lead to discovery of deadly consequences of a drug?
What are some recent controversies (refer to research articles)?
[Post-Marketing Phase]
- Thalidomide as sedative and in nausea, 1957-61
- Silver linings – thalidomide in leprosy, multiple myeloma and AIDS
- 1964- present; pomalidomide approved by FDA in 2013
Recent controversies: COX-2 inhibitors; Avandia
Using Nurofen (ibuprofen) as an example describe how success of a drug is very delicate?
[Post-Marketing Phase]
Ibufenac, not Ibuprofen, was the first-choice development compound but had to be withdrawn shortly after launch due to adverse events (toxicity in the liver) the difference was a single methyl group
How can people report an adverse event in the UK?
[Post-Marketing Phase]
In the UK, anyone may file an online report concerning a suspected adverse event using the yellow card system – now available as a phone app too
