After a new compound is discovered, a series of pre-clinical and clinical studies need to be conducted to identify the suitable dose for clinical trials. Rigorous steps are taken to ensure that the safe dose is used in clinical trials. There are multiple FDA guidelines (some adopted from ICH guidelines) discussing the dose selection issues:
- FDA Guidance for Industry (2010) M3(R2) Nonclinical SafetyStudies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals
- FDA Guidance for Industry (1997) S6 Preclinical Safety Evaluation of Biotechnology-DerivedPharmaceuticals
- FDA Guidance for Industry (2008) S1C(R2) Dose Selection for Carcinogenicity Studies
- FDA Guidance for Industry (2005) Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers
- FDA guidance (1994) Dose-Response Information to Support Drug Registration
Drug development is a stepwise approach: from pre-clinical testing to identify the ED50, NOAEL to first-in-human clinical trial to identify MTD and RP2D to phase 2 dose-response study or dose-ranging study to identify MinED. Here are various terms used to describe the doses.
NOAEL (No Observed Adverse Effect Level): The highest dose tested in animal species that does not produce a significant increase in adverse effects compared to control group
ED50 (Median Effective Dose): a pharmacological term for the dose or amount of drug that produces a therapeutic response or desired effect in 50% of the subjects taking it. In a more extreme case, the term LD50 is used for the median lethal dose.
ED50 (Median Effective Dose): a pharmacological term for the dose or amount of drug that produces a therapeutic response or desired effect in 50% of the subjects taking it. In a more extreme case, the term LD50 is used for the median lethal dose.
MRSD (Maximum Recommended Starting Dose): the dose for first-in-human clinical trials of new molecular entities
in adult healthy volunteers.
HED (Human Equivalent Dose): a dose in humans converted from the NOAEL identified in animal studies by applying a conversion factor or scaling factor. See FDA Guidance for Industry (2005) Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers for details on how to calculate the HED from NOAEL.
MTD Maximum Tolerated Dose (or Maximum Tolerable Dose): it is usually identified through the first-in-human trial designed as a dose-escalation study (such as 3+3 study design commonly used in oncology studies). The study will include multiple ascending doses with a predefined algorithm for the dose increase to the next cohort. The study will be stopped at a cohort with a dose-limiting toxicity (DLT) rate crossing the pre-specified boundary. The MTD is then the dose one level below.
RP2D recommended phase II dose: This is the term specifically used in oncology clinical trials. he primary goal of phase I cancer clinical trials is to identify the dose to recommend for further evaluation (the recommended phase II dose [RP2D]), while exposing as few patients as possible to potentially sub-therapeutic or intolerable doses. In oncology, the RP2D is usually the highest dose with acceptable toxicity, usually defined as the dose level producing around 20% of dose-limiting toxicity. In North America, the MTD is the RP2D, whereas in the rest of the world, the MTD is considered the dose level above the RP2D.
Minimum Effective Dose (MinED or simply MED) and Maximum Useful Dose: a concept derived from dose-response studies with placebo control and derived based on the efficacy signal (instead of safety/DLT). The terms were mentioned in FDA guidance "Dose-Response Information to Support Drug Registration "... the concepts of minimum effective dose and maximum useful dose do not adequately account for individual differences and do not allow a comparison, at various doses, of both beneficial and undesirable effects. Any given dose provides a mixture of desirable and undesirable effects, with no single dose necessarily optimal for all patients."
RP2D recommended phase II dose: This is the term specifically used in oncology clinical trials. he primary goal of phase I cancer clinical trials is to identify the dose to recommend for further evaluation (the recommended phase II dose [RP2D]), while exposing as few patients as possible to potentially sub-therapeutic or intolerable doses. In oncology, the RP2D is usually the highest dose with acceptable toxicity, usually defined as the dose level producing around 20% of dose-limiting toxicity. In North America, the MTD is the RP2D, whereas in the rest of the world, the MTD is considered the dose level above the RP2D.
Minimum Effective Dose (MinED or simply MED) and Maximum Useful Dose: a concept derived from dose-response studies with placebo control and derived based on the efficacy signal (instead of safety/DLT). The terms were mentioned in FDA guidance "Dose-Response Information to Support Drug Registration "... the concepts of minimum effective dose and maximum useful dose do not adequately account for individual differences and do not allow a comparison, at various doses, of both beneficial and undesirable effects. Any given dose provides a mixture of desirable and undesirable effects, with no single dose necessarily optimal for all patients."
According to FDA's Good Review Practice: Clinical Review of Investigational New Drug Applications:
"Inclusion of a placebo group in a dose-response trial can provide critical information in interpreting trials in which all doses tested resulted in indistinguishable outcomes, usually because the doses are all above the minimum effective dose (on the plateau) or because the doses are too close together. Without the presence of a placebo group, it may be impossible to tell whether any of the doses were effective at all in the trial. In such a case, the trial provides no evidence of effectiveness and no useful dose-response information. With a placebo group, the trial can provide evidence of effectiveness and, if efficacy is seen, may be able to identify where on the dose-response curve of the examined doses fall."
MFD (Maximum Feasible Dose): a concept from ICH M3(R2) "Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals" derived from animal studies.
MSD (Maximum Safe Dose): an approved maximum prescribing dose restricted by the product label, in other words, the highest approved dose.
References:
- Stuart Bailey Beyond MTD: Integratingnon-safety endpoints into Oncology dose-finding
- Tourneau (2012) Efficiency of New Dose Escalation Designs in Dose-Finding Phase I Trials of Molecularly Targeted Agents
- Buckley and Dorato (2009) High dose selection in general toxicity studies for drug development: a pharmaceutical industry perspective
- NAITEE TING (2017) PHASE I/II CLINICAL TRIALDESIGN AND DOSEFINDING
- Fan et al (2018) Phase I–II clinical trial design: a state-of-the-art paradigm for dose finding
- Vikram Sinha "Dose Response Assessments: Guidance,Experience, Expectations"
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