TPP, clinical trials and economics

What does TPP stand for?

Target product profile

Factors included in TPP

Nature of infection

Age group of target patients

Minimum clinical efficacy

Safety/tolerability

Chemical stability

Route of admin

Dosing frequency

Cost

Phase 1 clinical trial

Dose-ranging

20-100 healthy volunteers

Subtherapeutic/ascending doses

Aim: is it safe and what dose?

Phase 2 clinical trials

Efficacy, side effects

100-300 with specific infection

Therapeutic dose

Phase 3 clinical trials

Efficacy, safety and comparison to SoC (is it as good as standard tx)

300-3000 with specific disease

Therapeutic dose

Phase 4 clinical trial

Long term effects

Post marketing surveillance

Therapeutic dose

Key points for clinical trials

Know what success looks like for this drug (TPP nb)

Be ambitious and inventive (have plan B, plan C, etc)

Have clear go/no-go criteria at every step (cannot keep recruiting patients if drug is definitely failing)

Talk to regulators asap

Key populations to keep in mind for clinical trials

The elderly: drug-drug interactions; may represent many with target infection; safety profile may be less favourable in them

Paediatrics: Consider early; need to discuss Paediatric Investigation Plan or prove that it won’t be used ever in children

Pregnant women: generally excluded from trials, need to figure out how to capture data for this population

Overview of single ascending dose phase I trial (phase Ia)

Single dose given, observed

If all ok, dose increased and more people added

Continue until pre-calculated PK safety levels are reached, or intolerable side effects start showing up

Maximally tolerated dose = when 1/3 of participants experience unacceptable toxicity

Overview of multiple ascending dose for phase I (phase Ib)

Group of patients receive multiple low doses of drug, while samples are collected at various time points

Analysed for PK/PD information

Dose subsequently increased for further groups, up to a pre-determined level

Difference between superiority vs non-inferiority trial

Superiority: goal is to show new agent is measurably superior against existing treatments/placebo

Non-inferiority: show that the agent has efficacy similar to that of existing treatments

Why are non-inferiority trials conducted?

Unethical to withhold active tx from patients with serious condition

How are anti-infectives valued?

Drug cost / QALY (quality adjusted life years)

What is the net present value?

A method of calculating return on investment for a project

What are push and pull incentives?

Push: grants etc to generate and push a product into the market. Aim is to get through clinical trials

Pull: ensure that product is established at the market (eg government paying fixed price for so long). Aim is to keep drug on the market. De-linkage model0 separating sales from costs