pharmaceutical medicine roadshow

Question 1

What is the purpose of non-clinical testing?

Answer 1

Non-clinical testing starts before humans are exposed to determine the safety and efficacy of a new molecule.

Question 2

What are the requirements before administering a dose in humans?

Answer 2

Two species toxicology testing is required, involving one rodent and one non-rodent species. The species are determined based on evidence that the new molecule binds to the same target as in humans.

Question 3

What factors are considered when conducting toxicology testing?

Answer 3

The testing should ideally be conducted using the intended route of administration in humans, and histological examination of all major organs, including reproductive organs, should be performed. Pharmacokinetic (PK) studies are conducted to define the No Observed Adverse Effect Level (NOAEL) and assess ADME (Absorption, Distribution, Metabolism, and Excretion) properties.

Question 4

What additional studies are conducted during non-clinical testing to support drug registration?

Answer 4

Depending on the duration of drug administration in humans, longer-term mammalian toxicity studies may be required if the drug will be dosed for more than 6 months. Reproductive toxicity studies are conducted to evaluate the effects on women of child-bearing potential and male sperm. Carcinogenicity studies are generally required, except for medicines such as chemotherapy or short-duration drugs where genotoxicity data is sufficient. Specific studies may also be determined based on safety findings in clinical trials or similarities to drugs with a similar mechanism of action.

Question 5

What are the different phases of clinical trials in human drug development?

Answer 5

The phases of clinical trials are as follows: Phase 1, Phase 2, Phase 3, and Phase 4

Question 6

What does Phase 1 trials provide information on?

Answer 6

Phase 1 trials provide information on safety and tolerability, including laboratory tests, electrocardiograms (ECG), vital signs (blood pressure, heart rate), and adverse events.

Question 7

What type of data is collected during Phase 1 trials?

Answer 7

Phase 1 trials collect data on pharmacokinetics (PK), including parameters such as Cmax (maximum concentration), tmax (time to reach maximum concentration), AUC (area under the curve), t1/2 (half-life), clearance, and dose proportionality. They also gather data on pharmacodynamics (PD), such as biomarkers, and investigate the relationship between PK and PD.

Question 8

What is the purpose of Phase 1 trials?

Answer 8

Phase 1 trials help guide the determination of the therapeutic dose. They also assess the effects of the drug in special populations, such as individuals with renal or liver impairment. Furthermore, Phase 1 trials evaluate drug-food interactions, determining whether the drug should be taken under fed or fasted conditions, or if it does not matter. They also investigate the potential for drug-drug interactions (DDIs) and assess the drug’s potential to cause QT prolongation.

Question 9

What are some considerations when selecting the trial population for Phase 1 trials?

Answer 9

Considerations include choosing between healthy volunteers and patients, considering factors such as age, gender (contraception requirements), concomitant medications or diseases (special populations with renal or hepatic impairment), and even lifestyle factors such as alcohol, cigarette smoking, or grapefruit juice consumption. Phenotypes and genotypes may also be considered.

Question 10

When is the use of healthy volunteers considered unethical or inappropriate in Phase 1 trials?

Answer 10

The use of healthy volunteers is generally considered unethical or inappropriate in Phase 1 trials involving cytotoxic anti-cancer agents, some immunological agents, or when the biological drug target is only expressed in patients with the disease. Additionally, gene therapy studies may also require the inclusion of patients.

Question 11

What are some considerations in Phase 1 trial design and logistics?

Answer 11

Considerations include choosing between parallel group and cross-over designs, determining whether to administer single or multiple doses (taking into account PK and PD considerations), establishing the starting dose, forming a dose escalation committee, and defining stopping rules. Placebo-controlled trials or active control groups may be used, such as in QT studies where “moxifloxacin” is often used as a positive control. Endpoints should be evaluated based on complexity and invasiveness to the subjects. Intense PK sampling should follow ethics approval, and trial sites should have specialized units, necessary equipment, and 24/7 emergency coverage staff.

Question 12

What are the considerations in a Phase 1 food interaction trial?

Answer 12

In a Phase 1 food interaction trial, no food interaction is observed if the 90% confidence intervals for PK parameters (Cmax and AUC) after food compared to fasting fall within the 80-125% range. These trials typically use a randomized cross-over design with a standardized fast or high-fat meal consumed 30 minutes before dosing. The trial involves a single dose administration, followed by a 4-hour period without further food intake.

Question 13

What are the considerations in Phase 1 drug-drug interaction (DDI) trials?

Answer 13

In Phase 1 DDI trials, the test drug can either be a victim (acting as a substrate of CYP P450 enzymes) or an aggressor (acting as a CYP P450 inducer or inhibitor). CYP P450 inducers speed up drug metabolism, resulting in lower plasma levels, while CYP P450 inhibitors slow down drug metabolism, leading to higher plasma levels. Regulatory agencies provide guidance on specific drugs to be used as known substrates, inhibitors, or inducers, such as midazolam for substrate, itraconazole/clarithromycin for inhibitors, and rifampicin for inducers.

Question 14

What happens if drug-drug interactions (DDIs) are observed in Phase 1 trials?

Answer 14

If significant interactions are observed in Phase 1 DDI trials, dose adjustment or avoidance may be necessary to address safety concerns. The test drug is typically evaluated in combination with an oral contraceptive pill to assess potential interactions.

Question 15

What is the purpose of Phase 2 trials in clinical drug development?

Answer 15

Phase 2 trials aim to demonstrate proof of principle or proof of concept in patients. These randomized clinical trials (RCTs) compare several doses of the test drug against a comparator (placebo or active control or both) and take into account various considerations such as patient population, duration of treatment, and standard of care.

Question 16

What does Phase 2 trial data enable in the drug development process?

Answer 16

Phase 2 trial data helps in selecting the appropriate dose(s) for Phase 3 trials. Typically, one dose (sometimes two doses) is taken forward into Phase 3 trials, considering factors such as sample size, complexity, and cost.

Question 17

What is typically required for Phase 3 trials and registration of a new drug?

Answer 17

Usually, at least two randomized controlled trials (RCTs) are conducted, although a single large-scale trial may be acceptable. These trials are often international and multicenter, involving data monitoring and adjudication committees. Eligibility criteria are defined to determine the patient population for the drug’s license Summary of Product Characteristics (SmPC). Endpoints in these trials require regulatory acceptance, with primary endpoints often focusing on mortality or morbidity. Safety assessment is essential, and patient-reported outcomes (PRO) are evaluated for quality of life measures. Health care resource utilization is assessed for economic evaluations, such as Health Technology Appraisals.

Question 18

What regulatory agencies are involved in the registration process of new drugs?

Answer 18

The Medicines and Healthcare products Regulatory Agency (MHRA) in the UK and the European Medicines Agency (EMA) are responsible for the approval of drugs. The typical approval process takes around 210 days, with accelerated approval granted for drugs intended to treat life-threatening or orphan conditions. Promotion of the drug is allowed only after approval.

Question 19

What is the purpose of Phase 3b/IV studies?

Answer 19

Phase 3b/IV studies are conducted after registration and serve to provide additional scientific data. These studies may focus on efficacy or safety objectives. For example, new diabetes drugs may need to demonstrate “no harm” on cardiovascular mortality or morbidity. Real-world evidence is often collected through disease registries. If there are new disease indications, the drug may need to undergo further Phase 3 or Phase 2 studies, especially if new dose-finding studies are necessary. Additionally, all new drugs need to be developed in the pediatric population (0 to <18 years) unless a waiver is granted.

Question 20

What is the purpose of Phase 4 trials?

Answer 20

Phase 4 trials are conducted post-approval of a medicine and provide further understanding of the medication in a specific disease area. These trials help gather additional real-world data and assess the long-term safety and effectiveness of the medicine.

Question 21

What is the impact of TNF inhibitors in inflammatory diseases?

Answer 21

TNF inhibitors (also known as anti-TNFα drugs) have had a significant impact on various inflammatory diseases, including Rheumatoid Arthritis, Psoriasis, Psoriatic Arthritis, Ankylosing Spondylitis, Crohn’s disease, and Ulcerative Colitis.

Question 22

How are TNF inhibitors administered?

Answer 22

TNF inhibitors are biological drugs that are typically given by injection.

Question 23

What precautions should be taken when using TNF inhibitors?

Answer 23

Since TNFα plays an important role in immunity, TNF inhibitors should not be given to patients with active infections. They should be used with caution in patients with a history of chronic infections.

Question 24

What was the target selected in the development of a new class of drug mentioned in the reference?

Answer 24

The target selected was amyloid protein, which is one of the diagnostic features of Alzheimer’s disease.

Question 25

What were the results of the drug-in-development for Alzheimer’s disease?

Answer 25

The drug-in-development showed promising results in removing amyloid protein in a dose-dependent manner, as observed in brain scans where amyloid was visualized as yellow/red areas.

Question 26

Is amyloid protein considered the correct target for Alzheimer’s disease?

Answer 26

Although the drug study yielded tantalizing results, there is ongoing debate as to whether amyloid protein is the correct target for Alzheimer’s disease.