Exam style questions

Compare novel psychoactive substances (NPS) with conventional medicinal products

What is the first step of drug discovery?

The first stage of the drug discovery process involves selection of disease and identification of an unmet clinical need. Once you have selected the disease, you will identify your target such as a receptor or enzyme and validate how target modification will lead to therapeutic benefit.

What is the second step of drug discovery?

The second stage of the drug discovery process following identification of the target is hit identification which uses high throughout screening to give rise to the lead compound. the lead compound will be modifed by medical chemists to optimise potency, selectivity, and safety profile.

What is the third step of drug discovery?

The optimised lead compound then becomes the drug candidate which will be used in pre-clinical studies such as in-vitro and in-vivo animal studies. In-vitro studies include the use of cell lines for example, whereas animal studies will take place as animal testing. Good Laboratory Practice in clinical trials usually involves the use of 2 studies. Pre clinical data allows us to gather information regarding: toxicology e.g. single / repeated dose-toxicity, genetotoxicity, carciongenicity etc.

What is the fourth step of drug discovery? - stages of clinical trials

Once successful in preclinical studies and there is an acceptable risk-benefit profile, the drug candidate moves to clinical trials, which are conducted by the MHRA, FDA, EA etc. There are 4 stages of the clinical trials:

Stage 1 - Safety and pharmacokinetics in healthy volunteers - usually involving 10-100 people - dose escalation

Stage 2 - Efficacy and dose findings in 100-300 patients - this is a randomised-control double blinded study

Stage 3 - Safety and efficacy profile in larger population - 1000-10000 patients

Stage 4 - Post-marketing pharmacovigilance

Once phase 3 is successful, approval for the use of the drug will be granted clinical use but continued post-marketing surveillance

What is meant randomised-controled double blinded study?

randomised - participants are randomly selected a treatment group

controlled - treatment or placebo group

double-blinded - meaning both participants and investigators do not know whether they are in the treatment or controlled group

How long does the whole drug discovery process take?

Between 10-15 years

Out of how many drug candidates does a drug successfully go through clinical trials?

1 in 10,000 drugs will reach the market

Before a new drug reaches humans, what studies are required before hand?

Before a new drug reaches administration in humans, extensive pre-clinical studies are required. Firstly, the compound’s activity is confirmed in vitro assays to assess potency and selectivity against the target. It is then tested in animal models to demonstrate efficacy. Pharmacokinetic studies are preformed to determine absorption, distribution, metabolism and excretion while toxicokinetic studies measure exposure using parameters such as Cmax, Tmax and AUC.

Safety studies include:

• single and repeated dose toxicity

• genotoxicity studies

• safety pharmacology studies assessing cardiovascular, respiratory and CNS effects

• reproductive toxicity and carcinogenicity where appropriate

What is different about phase 1 oncology studies in comparison to other drugs?

whereas in other clinical trials, phase 1 would usually involve the safety and pharmacokinetic research to be conducted in healthy volunteers, in oncology studies we conduct phase 1 clinical trials in cancer patients rather than health participants.

Using data generated in the practical classes, explain how lead compounds are selected and optimised.

Successful hit identification will give rise to a lead compound. The selection of a lead compound is based on a combination of potency, selectivity and drug-like properties. Compounds with the lowest IC50 will usually be considered the most potent. However, potency alone is not sufficient and the ideal lead should also demonstrate:

• selectivity for the target

• Good solubility and permeability

• Metabolic stability

• Minimal toxicity

• Synthetic feasibility and patentability

Medicinal chemists will analyse structure-activity relationships (SAR) to identify structural features and improve activity. Functional groups may be modified to improve potency, reduce off-target effects and optimise pharmacokinetics.

Compounds are then retested until a candidate meets the target product profile

lipinskis rule of 5 can be used to determine if a drug would be a succesdful oral drug candidate/ therapeuticaly active once administered orally (molecular weight of less than 500, logP less than 5, 5 or less hydrogen donars, 10 or less hydrogen acceptors

Discuss the challenges associated with translating pre-clinical findings into successful medicines

• Animal models do not always predict human efficacy or toxicity accurately. Species differences in metabolism and disease biology can limit extrapolation.

• Poor pharmacokinetic profile, such as low bioavailability or rapid clearance, may prevent adequate exposure in humans. Toxicity may also emerge despite favourable early data

• Clinical trials are expensive and time-consuming, and unexpected adverse effects can lead to termination

• Commercial issues, including inadequate patient protection and competition, may halt development

• successful translation requires balancing efficacy, safety, pharmacokinetics, regulatory requirements and commercial viability.

What 3 key parameters are measured in toxicological studies?

• Cmax - maximum concentration of drug achieved in the plasma following administration

• Tmax- Can be useful for predicting “peak” time for clinical effects

• AUC - Exposure to drug (over time interval), relationship to dose and accumulation ratio

What t is ICH?

Formed by regulators from FDA, MHRA, EA etc and produce guidlines for ensuring quality, safety, and efficacy of medicines. Enables harmonised regulatory requirements across regions

Before a new drug can be tested in humans, it must undergo preclinical studies - how are these studies regulated to ensure scientific quality and animal welfare?

GLP - Good Laboratory Practice - Regulators such as the MHRA, FDA and EA ensure that preclinical studies are conducted under good laboratory practice to ensure data is reliable, reproducible and traceable. To ensure clear documentation and standard operating procedures.

Animal studies must be regulated to ensure ethical requirements are met e.g. complying to the 3R’s principle - Replacement (use non-animal alternatives where possible), reduction (use the minimum number of animals as necessary and refinement (modify procedures to minimise pain, suffering and distress

Clinical trials must be conducted in line with…

Good clinical practice (GCP) to ensure the safety, welfare and rights of the participants. It ensures that participants have voluntarily consented to the trial (obtain informed consent), and ensures the trials comply with ethical standards. It ensures data is accurate, and that participant data is confidential

What is GMP?

Good Manufacturing Practice is a system of quality assurance that ensures medicinal products are manufactured and tested consistently according to predefined specifications and regulatory requirements

Outline the 5 stages of drug development

1) Drug discovery

2) Preclinical development

3)Clinical trials (phase I-III)

4)Marketing authorisation

5)Phase IV/ Pharmacovigilance

Outline the key pre-clinical activities after identification of a therapeutic target

• target identification and validation

• Hit discovery

• Lead optimisation

• In vitro testing

ALLOWS FOR → Selection of a drug candidate

What are we testing during laboratory and animal testing?

• pharmacokinetics

• pharmacodynamics

• Toxicology - single/repeated dose toxicity

• Safety pharmacology

• Genetotoxicity - e.g. congenital malformations / teratogenicity

What does phase 4 marketing authorisation include?

Following stage 3 of clinical trials, an application is submitted to the MHRA/ FDA for use in the public/clinical use

What is post-marketing surveillance?

Continuous safety monitoring - allows for yellow card reporting, risk minimisation

GLP applied to which part of the drug-development process?

Applies to non-clinical studies - ensures the integrity and traceability of laboratory safety data and covers SOPs, QA audits and raw data archiving

Which part of the drug discovery process does good clinical practice relate too?

Applies to human clinical trials - protects participants and ensures reliable data (key principles → informed consent, ethics approval, qualified investigators and accurate documentation)

Which part of the drug discovery process does good manufacturing practice relate too?

Applies to medicine manufacturing. Ensures medicines are consistently produced to quality standards