Are You Ready for a Phase I, First in Human Safety Trial?

So, you have a novel drug ready for Phase I First in Human safety trial.  What dose should you start with that will be reasonable and acceptable to the FDA?  The answer revolves around safety for the individual subject.  For example, despite relatively innocuous findings in the animal testing stages, you will not have a clue that the drug produces headaches in a person.  

Here are the steps to evaluating proper dosing levels:

1. First review this FDA document: Industry Guidelines Entitled: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers.

2. A thorough review of the findings in the animal studies, including behavior and laboratory findings in addition to the pathology examinations, is necessary.  With this information, you must be careful to examine fully any potential adverse effect as early as possible in humans, i.e., at a low dose.  This will allow you to reduce the dosing even further or terminate the trial before irreversible damage to the subjects is done.

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3. Your review of the toxicology findings will give you the No Observable Effect Level (NOEL) for the animal species. This is the dose per kilogram that does not produce any behavioral, laboratory or histologic abnormalities.  The animal NOEL will be converted to the Human Equivalent Dose (HED) based on the relationship of weight to surface body area of the test animal and humans.  Within the guideline, there is a useful conversion table for numerous animal species to humans.

4. The guidelines will provide a sound way to convert the NOEL doses to human equivalent doses.  With this dose, you must then reduce it to one-tenth or one-twentieth of the NOEL for your initial single dose study.

5. For safety, start at a very low dose that may give you a tip that the drug poses problems in humans not elicited in the animal toxicology studies as noted above for headaches, etc.

6. After the single dose study is completed, move on to a higher single dose study.  When you have reached or surpassed your estimated therapeutic dose, you will be ready to embark on multiple dose studies, usually lasting a week, starting again at a low dose and then escalating to higher doses. 

7. Successful completion of these studies will then enable you to start Phase II with the disease that your drug is targeted for.

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