FDA report showed that most drugs are effective in only 25-62% of the patients. That probably make you wonder why they are approved and prescribed to patients? The answer to this question is not simple. Many approved drugs have a range of therapeutic dose which could be prescribed to the patients which allows clinicians to adjust the dose based on patient response and toxicity.
This variation of efficacy is another argument in support of precision medicine where patients are assessed based on their medical history, genetic background and other information in order to be provided with the optimal dose and the most adequate treatment for their condition.
What are the disadvantages of current clinical trial designs when it comes to dose individualisation?
Some small size clinical trials in specific indication like blood pressure, blood sugar, pain, seizure and coagulation could use different dose titration models to identify the best dose for the patients. However, large clinical trials often use fixed dose in their research.
Statistical model using data from clinical trials shows that in large clinical trials with fixed dose the response rate can vary between 20 and 80% while clinical trials with individually adjusted dose have much higher response rate.
Why cannot we simply use individualised dose instead of fixed dose?
While no doubt having option to adjust doses as per individual response would be the best solution to the problem there are some complications that prevent this.
- For example if the drug is eliminated by kidneys and patient has renal function impairment they should be treated with lower dose to reduce the toxicity. And while this sounds like a logical decision the risk of giving the patient sub-optimal dose should also be considered.
- This could not be done in oncology trials because the dose calculated is the maximal tolerated dose which is selected to maximise the effect.
- Dose reduction is not an option for HIV drugs because of the high risk of drug resistance.
- Drugs for slow progressing disease which require extended treatment also cannot be assessed adequately for efficacy.
- Acute conditions which require one-off treatment cannot use dose titration.
There are several considerations for cases where dose titration is possible:
- The condition has to be stable to allow efficacy assessment.
- The drug should rapidly achieve steady pharmacokinetic and pharmacodynamics state otherwise the clinical trial will be very long considering the patients have to take more than 1 dose.
- Efficacy and toxicity should be quantifiable and relevantly stable once steady state is reached.
- The response to the drug should have quick onset and offset to avoid washout period.
- There should be an upper limit of dose-escalation to ensure patient safety.
- Subtracting the response of placebo – for example, patients could expect better response at higher doses and this could increase the efficacy of placebo arm.
- The treatment duration will be longer because patients will need more than one dose and this could increase the risk of drop out.
While dose titration has its challenges it has future in precision medicine and it is a logical option when assessing patients’ treatment.
Published on 1 Aug 2019
Author: Olga Peycheva, Director at Solutions OP Ltd. Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe