CRED Understanding Clinical Development 2024

11/10/2024

Design and Guidelines for First in Human Studies

Healthy

Patients

Pros

Faster recruitment More intense PK and PD sampling Better control of population Better control of con meds Use of placebo Not related to disease Not possible for toxic drugs Requires more extensive preclinical information SAD – single ascending dose MAD – multiple ascending dose

Actual disease – can start evaluation of the drug efficacy

Possible for toxic drugs if benefits outweighs risks Meaningful biomarkers

Cons

Longer recruitment Placebo may not be possible – at least standard of care Comorbidities and con meds

Dosing

Mostly MAD

Disease

NA

Phase I – can be all comers or wide range of conditions such as all solid tumors

The Organisation for Professionals in Regulatory Affairs

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Starting Dose Considerations

• No observed adverse effect level (NOAEL) in the most relevant and sensitive animal species is used to identify the equivalent exposure for humans (HED – human equivalent dose) through modelling and and/or using allometric factors.

• Minimal anticipated biological effect level (MABEL)

• Pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD)

• Any safety factors used should be justified and detailed in the IB and protocol

⚫ When the methods of calculation (e.g., NOAEL and MABEL) give different estimations of the starting dose for humans, the lowest value should be used, unless justified ⚫ In healthy volunteers, the starting dose should ideally result in an exposure to a subject that is below that which would be expected to produce a PD response

The Organisation for Professionals in Regulatory Affairs

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