Early phase dose finding studies - inviting perspectives on 3+3 versus dose titration

3+3 dose level groups versus individualized dose titration:

Which approach maximizes the prospect for clinical benefit (a core principle for ethical clinical research) – arguably, in my view, the reason most patients take part.

Which approach best protects the study participants from harm?

Are there preferred methods to find the recommended dose (or range of doses) for different classes of study drugs?

What language is needed to inform participants about possible side effects and the potential for benefit for the competing methods in dose finding studies? For example, should the consent document explain that there’s a risk of receiving sub-clinical doses of the study drug in the 3+3 design - if you are assigned to an early dose level groups?

Should the consent explain (in plain language of course) absorption, distribution, metabolism, and excretion (ADME), and how ADME can vary among individuals, and how this can influence both the risk and the potential for meaningful activity of the drug?


all good Qs. Off the top of my head id suggest the paper published by an expert group formed by the RSS after the london phase I disaster: https://rss.onlinelibrary.wiley.com/doi/full/10.1111/j.1467-985X.2007.00481.x See section 4.2.1 re informed consent


Thank you for your interest and for the reference. Off the top of it, prompting another question:

"In March 2006 a first-in-man trial took place using healthy volunteers involving the use of monoclonal antibodies. Within hours the subjects had suffered such adverse effects that they were admitted to intensive care at Northwick Park Hospital. "

Q: What role does the disease prognosis (healthy volunteers - urgent need / terminal) in choosing a dose finding study method?

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Note: I appreciate that the purpose of clinical research is to advance the science - in the case of phase I research to identify the dose that has therapeutic activity with acceptable toxicity.

But there is also an ethical obligation to minimize the risk of harm and to optimize the prospect for benefit. When the design choices are made are these ethical principles in focus, or do they take a back seat to expediency and habit?

Are well-informed patient representatives involved in the decisions? What should advocates understand about the merits and liabilities of the different approaches? Since 3+3 is the default, this advocate wants to understand why.

Unfortunately, I do not have access to the full text.

“Classical 3 + 3 design” versus “accelerated titration designs”: analysis of 270 phase 1 trials investigating anti-cancer agents


The number of patients treated at each dose-level in dose seeking phase I trials is arbitrarily established. The most frequently used design is the “classical 3 + 3 design (3 + 3D)”.

Recently, Simon et al. had introduced several “accelerated titration designs (ATD)”. In the present analysis, we compared the performance of these two types of designs in 270 recently (1997–2008) published phase I trials. ATD had been used in only 10% of the recent studies.

ATD had permitted to explore significantly more dose levels (seven versus five, p = 0.0001) and reduced the rate of patients treated at doses below phase-2 recommended dose (46% versus 56%, p = 0.0001).

Nevertheless, ATD did not allow a reduction in the number of enrolled patients, shorten the accrual time nor increase the efficacy of phase I trials. These data support that ATD as an effective clinical trial design over a standard 3 + 3 dose escalation design.

i think it’s an area that received much attention over the last 15 years, until today. I’m sure someone presented on the topic at the recent pharma stats conference. But i havent kept up with that research, certainly bayesian approaches have been described with an R package available: CRAN - Package dfpk Stephen Senn added about 10 pages to his dose finding chp in the 3rd ed v 2nd ed of stat issues in drug development, i must read it …

edit: Davd Norris made this handy app: Predict Risks of High-Grade Toxicities in Dose-Escalation Trials

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The question of therapeutic intent is everything to me. My past 4+ years’ work in oncology dose-finding methods has been totally predicated on the therapeutic intent of these trials. I would argue that healthy-volunteer and phase 1 oncology trials have almost nothing in common. In fact, I consider healthy-volunteer studies to be inherently unethical, and have absolutely no interest in even discussing them, other than possibly refering to them as an instructive contrast.

One reason this vast gulf between healthy-volunteer vs oncology phase 1 studies is not appreciated, is that current designs for the latter type do not — and cannot, given the methodological frameworks they are constructed in — acknowledge their full ethical and decision-theoretic context.


There’s a cool website where you can access paywalled papers like that … Sci-Hub | “Classical 3 + 3 design” versus “accelerated titration designs”: analysis of 270 phase 1 trials investigating anti-cancer agents. Investigational New Drugs, 27(6), 552–556 | 10.1007/s10637-008-9213-5

As we’ve discussed elsewhere, therapeutic intent is controversial in phase 1 studies and for good reason. I think it’s important to inform patients that dose finding studies are only a first step in clinical research. Participants can benefit but historically the probability of benefiting is low because of the unknowns:
if the target is relevant,
if the side effects offset the activity of the study drug against the disease.
If activity even translates into living longer or better.
if the active dose is a safe dose

What appeals to me about titration is that the participants have a better chance of receiving a dose with meaningful activity against the disease. Because this is why (from impression and from personal experience) many persons with terminal disease take part, phase I studies should more routinely adopt titration and avoid 3+3.

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