Pharma lecture 3

What major tragedy led to the passing of the Medicines Act in 1968 in the UK?

The use of Thalidomide (a sedative used for morning sickness), which caused severe birth defects.

What are the two main regulatory bodies controlling drug regulation in the UK and Europe?

• UK: MHRA (Medicines and Healthcare Products Regulatory Agency)

• Europe: EMA (European Medicines Agency)

What are the two basic reasons drugs fail in clinical trials?

1. They don't work (lack of efficacy).

2. They are unsafe (toxicity).

What are the three main types of functional proteins that serve as drug targets?

1. Receptors (44% - e.g., GPCRs, ion channels)

2. Enzymes (29% - e.g., protein kinases, proteases)

3. Structural proteins (15%)

What is the aim of "Target Validation" in drug discovery?

To identify the most useful target and ensure that the target protein is instrumental in a given disease (determining its role in the disease before seeking drugs to act against it).

Name three approaches used for Target Validation.

1. Genetic manipulation (e.g., CRISPR, shRNA to knock out/down genes).

2. Antibodies (to block the target).

3. Chemical genomics.

What is "High-Throughput Screening"?

An automated assay system used to test thousands of compounds for specific activities (e.g., cell-free enzyme assays, membrane binding) to identify "hit" compounds.

What is the aim of "Lead Optimisation"?

To increase the potency of the compound, optimize selectivity (binding), and improve metabolic stability. Also involves checking for toxicity and determining the best route of administration.

What are the two main types of Preclinical Research?

1. In Vitro: Cell culture, enzyme assays, bacteria, isolated tissues.

2. In Vivo: Testing in live animals.

What three types of licences are required under the UK Animals (Scientific Procedures) Act 1986?

1. Personal licence

2. Project licence

3. Establishment licence

What are the "3Rs" of animal research?

• Replacement: Using non-animal alternatives where possible.

• Reduction: Minimizing the number of animals needed.

• Refinement: Improving living conditions and minimizing suffering.

What is the main aim of a Phase I clinical trial?

"First in Man." Performed on 20-80 healthy volunteers to check pharmacokinetics (absorption, half-life, dose) and side effects (tolerability).

What is the main aim of a Phase II clinical trial?

"Proof of Concept." Performed on 100-300 patients to test for efficacy in the clinical situation and establish the correct dose for Phase III.

What is the "Placebo Effect"?

A psychological and physical response where an inert treatment (sugar pill, sham injection) produces a real effect. It works in about 30% of people.

What is the "Nocebo Effect"?

Negative side effects reported after taking a placebo, caused by negative expectations, past experiences, or anecdotes. (Example: Men told Finasteride causes ED reported it at higher rates).

True or False? The colour of a placebo pill affects how well it works.

True. Studies show yellow pills work best for depression, red pills increase alertness, green pills ease anxiety, and white pills soothe stomach ulcers.

What does "Double-Blind" mean in a clinical trial?

Neither the patient nor the investigator knows which treatment (test drug or control/placebo) is being used. This avoids bias.

What is "Randomisation" in a clinical trial?

The random allocation of patients to the test or control treatment group to ensure equivalent distribution of age, sex, disease severity, etc., and avoid bias.

What is the main aim of a Phase III clinical trial?

Definitive double-blind, randomised trials on thousands of patients (multicentre) to compare the new drug with commonly used alternatives or placebo.

What percentage of compounds entering Phase I are eventually approved for marketing?

Only 10% of compounds entering Phase I are eventually approved.

What is the main purpose of a Phase IV clinical trial?

Post-marketing surveillance. Designed to detect any rare or long-term adverse effects in the "real world" with thousands of patients of varied ethnicity and underlying diseases.

What is the "Yellow Card Scheme"?

The UK system for adverse event reporting. Doctors fill out an Adverse Event Report (AER) form (Yellow Card) to report suspected side effects to the MHRA. Safety monitoring continues for the life of a drug.

Why is "Compliance" (taking the drug as prescribed) a major issue in clinical trials, and give an example of a solution?

Many drug trials fail due to lack of drug compliance. Example: The Breelib nebuliser (for Iloprost) uses Bluetooth and a phone app to monitor compliance via a colour-changing mouthpiece.

What is "Good Clinical Practice" (GCP)?

An international, unified quality standard (produced by the ICH) to maintain the quality, safety, and efficacy of clinical trials, minimizing risk to participants.