Principles of drug development

Question 1

Describe the use of safety, quality and efficacy when providing market authorisation of drugs? How are these measured before they reach shelves?

Answer 1

Safety - Determines the risk for use and handling

Quality - Ensure the drug is manufactured in a strictly controlled way and can be stored stably

Efficacy - Ensure that the drug produces a beneficial effect

The case for these principles is submitted as a comprehensive dossier of data involving studies done in vitro, in animals, in healthy volunteers and in patients.

Question 2

How can new drugs be discovered?

Answer 2

• Chemical synthesis
• Biotechnology
  
  • Some medicines discovered by this methods include pacific yew, paclitaxel and industrial plant cell culture
• Nature
• Rational modification of known drugs

Question 3

How do drugs become medicines? Describe each stage

Answer 3

Discovery phase - Target validation - Hit identification, lead identification and optimisation, candidate drug

Preclinical development - ADME- Safety pharmacology, short-term toxicology, chemical scale-up and pharmaceutics.

Clinical development - Phase 1 ADME - Tolerability and side effects (healthy volunteers). Phase 2 - Long-term toxicology - Efficacy and Dosage Trials (patients), specialised safety screens. Phase 3 - Large-scale clinical trials - Clinical proof of concept.

Marketing authorisation

Post marketing surveillance

Question 4

Describe the discovery phase of identifying new drugs

Answer 4

Discovery phase may take 10- 12 years and costs £12 billion
average with 95% failure rate – new drug approvals in 2016 = 22, 2017 = 46

Basic research identifies targets

Virtual and physical chemical libraries are screened for ‘hits’ against target

Hits are optimised into ‘drug-like’ leads, leading to formation of a candidate drug

• Screening many 1000s substances requires
  automation = robots set up assays on microplates and move
  microplates for analysis
• Advanced studies require in vitro experiments
• From validated target takes 3 years and costs several million
• High failure rate due to:
  
  • Target process to be
    unimportant
  • Target important but
    biological redundancy operates (other receptors can do same effects)
  • Target not ‘druggable’ (potency, selectivity, pharmacokinetics problems

Question 5

Describe the preclinical development stage of drug development (These are the tests done preclinically)

Answer 5

• Chemical scale-up and GMP final method of manufacture - How can this drug be made safely and economically on a large scale?
• ADME - How is the drug absorbed, metabolised and excreted (animal studies)?
• Safety pharmacology - 2 animals species: Duration determines max length of initial clinical trials
• Pharmaceutics - Determines the best dosage formulation

Question 6

Describe the clinical development stage of drug development (These are the clinical tests)

Answer 6

• Requires approval - clinical trial directive, ethics committees
• Phase 1 - Healthy volunteers; open design, tolerability and side effects, Initial human ADME, Can sometime be used to gain early efficacy indicators
• Phase 2 - Controlled trials to explore efficacy and dosage in patients. 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

Question 7

What do safety and toxicity studies in drug development look for?

Answer 7

Post marketing surveillance:
Post marketing surveillance, things can go wrong e.g. thalidomide

Studies in vitro (outside living organism) , in vivo (inside living organism) and in silico (bacteria, animals, people, computational models) determine if the new drug:

• Damages genes, cells or organs
• Alters behaviour
• Produces symptoms (e.g. vomiting, inco-oordination, breathlessness)
• Alters function (e.g production of blood cells)
• Damages mother’s eggs or father’s sperm
• Damages developing baby
• Causes development of some cancers