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Dear all,
I am helping one of my client companies with designing a first in human study for a drug candidate (NCE). The IND will be submitted to the Division of Anesthesia, Analgesia and Rheumatology Products in FDA and I'd like to know of other people's experiences in these type of studies with the division. The general design I have in mind is an alternate dosing with no subject receiving more than 2 doses of the active compound. I am also thinking of spacing the dose administrations between the subjects in the first cohort by at least 1-2 hours with an start dose of several times lower than that allowed by the FDA guidelines. Furthermore, the second cohort will be dosed 2-3 weeks after the first one in order to get a good understanding of the safety and PK of the drug. The expected half-life of the compound in humans is around 1 day.
Any comments that can help me get a well-designed study are welcome!
Toufigh
Toufigh Gordi, PhD
Clinical Pharmacology, PK/PD analysis consultant
www.tgordi.com
E-mail: tg.-at-.tgordi.com
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The following message was posted to: PharmPK
In reply to Toufig's question, we often used 3 doses per subject
rather than 2 (plus a placebo) partly because you get a dose response
and secondly because its origin was I believe 1 day's testing often
requires 3 doses. In that way we found that 2 groups taking alternate
doses gave us a 6 dose range, a useful safeguard against poor
absorption, with wider within-subject doses to increase the chances of
seeing a dose-related effect and longer duration gaps between
individual doses for increased safety.
There are other logistic advantages such as requiring fewer subjects,
which reduces the recruitment time and costs. The extra dose also
gives volunteers more cash!
Andrew Sutton
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Toufigh,
A good design will achieve the desired objective. What is your objective?
IND submission is not the objective that will lead you to a good design.
You need to think what you are trying to find out from this study. Is it learning or confirming?
Nick
--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
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Dear Toufigh:
I have seen a change in the way first in human studies are conducted in healthy subjects since the 2006 incident with Tegenero's TGN1412 and would like to comment on your proposed stagger, both with subjects within a cohort and the stagger between cohorts. Previously it was common for all subjects in a cohort to be dosed on the same day, with a stagger of a few minutes between doses, to allow the staff to manage the blood sampling and safety evaluations such as ECGs and vital signs at each scheduled time point. More commonly now, all the subjects in a cohort are not dosed on the same day - but I have no idea whether FDA has been requiring this, or whether sponsors and Phase 1 units are just more cautious.
Your suggestion to space the dose administrations by at least 1-2 hours in the first cohort can result in a long day of dosing, and if the Tmax (of parent drug or an important metabolite) is late, at least a few of the subjects may have already been dosed in the event of a safety issue becoming apparent in the first subject. Dosing in each subject will also be at a totally different time of the day, and may have a different relationship to meals (either of which may or may not affect the PK). As an alternative to this, I have seen, for example, a cohort of 8 subjects (6 randomized to active and 2 to placebo) with 2 subjects dosed on the first day, one randomized to active and the other to placebo. They can be dosed with a few minutes stagger, as only one is randomized to active drug. Assuming no safety issues in these subjects, the remaining 6 subjects (5 active and 2 placebo) are dosed the second day, with a relatively short stagger between them - alternatively, if another placebo subject
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The following message was posted to: PharmPK
Hi Nick,
The company I work on this project with is actually very open to the idea of learning and confirming, and a model-based drug development in general. This is the first in human study so at this moment we are just learning about the drug, mainly how safe and tolerable it is but also its PK properties will be investigated.
I don't really think about IND or not IND when designing a study. IND is just an application and does not dictate how the main design elements of your studies will look like. There are, however, a few regulatory check-points that one needs to pass before getting to start a first in human study. (I must admit that I don't mind this at all. I look at it as a collaborative effort to dose subjects in a manner that gathers enough information about the drug while the "big brother" tries its best to make sure nobody is harmed.) The issue I think I am facing on this particular project is that different divisions within FDA might have different approaches on how a first in man study should start and proceed and since I have never worked with this division at such an early stage program, I want to make sure that my proposed protocol is in line with the minimum safety precautions they may have. Nobody likes unnecessary delays and extra work (e.g. in form of extra
communications with the agency), if simple changes in the early stages of the first study in humans can be tailored in a way to meet the objectives of all parties involved.
Toufigh
Toufigh Gordi, PhD
Clinical Pharmacology, PK/PD analysis consultant
www.tgordi.com
E-mail: tg.aaa.tgordi.com
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