Study design and subject safety are of the utmost importance in a Phase 1 study. It is also important to be wary of pitfalls as you plan your clinical trial. Based on our extensive experience in clinical pharmacology, some of the challenges that we have come across include:
- Selecting the wrong doses.
- Failing to record actual times of PK sample collection and dose administration.
- Selecting the wrong blood sampling schedule for PK/PD.
- Lack of or inadequate controls.
- Failure to assess biomarkers.
- Failure to assess for clinical metabolites in early phase clinical development.
- Conducting a Phase 1 study without considering the overall impact on your drug development strategy.
1. Selecting the wrong doses.
In a Phase 1 study, it is critical to assess doses that may achieve target drug exposures (i.e., ideal drug concentrations) in patient populations that are relevant to the development program. Ideally, the doses used in a clinical dose escalation study should result in drug exposure ranges that have some overlap, but that are different enough to allow for the collection of PK and safety data over a wide range of exposures. It is important to consider model-based methods to predict likely exposures based on simulated dose levels.
If ideal dose ranges are not explored in a Phase 1 clinical study, it could result in PK data that does not cover your target therapeutic window. This will make dose justification difficult for a proof of concept Phase 2 study or a pivotal Phase 3 study. It could also result in selecting the wrong dose for these pivotal efficacy and safety studies. Additional clinical pharmacology Phase 1 dose-ranging studies may be necessary if the ideal dose is not explored early on.
By thoughtfully predicting the ideal dose ranges for a Phase 1 study, you can mitigate the risk of testing doses that add little value to the development program. You may also avoid the need to repeat studies due to insufficient data or a failed Phase 2 or Phase 3 study because inadequate doses were explored in Phase 1.
2. Failing to record actual times of PK sample collection and dose administration.
It is important to emphasize collection of the actual time at which a PK sample is collected or the actual time a dose is administered. Many times, people focus on the PK collection window and lose sight of getting the actual time a PK sample was collected. Strict PK collection windows do not add value to a Phase 1 study because actual times will be used to estimate PK parameters. Instead, the site should simply write down the time at which they collected the sample. See our past blog post on “Record actual times instead of relying on a window.”
3. Selecting the wrong blood sampling schedule for PK/PD.
We see a tremendous number of Phase 1 studies, and it is surprising how often a sponsor has selected the wrong or inadequate sampling schedule for PK/PD analysis. This is fundamental to the success of a Phase 1 study and takes such little effort for a trained pharmacokineticist to evaluate the appropriateness of a sampling schedule that this should be an easy pitfall to avoid. Along with blood, other matrices may include: urine, cerebral spinal fluid (CSF), saliva, etc.
4. Lack of or inadequate controls.
We have often heard the question: “Do I need a placebo control in my Phase 1 study?” Yes, it is often recommended to include a placebo or active control in Phase 1 studies like first-time-in-human (FTIH) studies. Placebo controls may help counter unexpected anomalies in the study data (such as unexpected adverse events). For example, we had a subject in a Phase 1 study that demonstrated a significant increase in premature ventricular contractions (PVCs) post-dose compared to pre-dose and it appeared to be a drug-related adverse event. The subject was actually on placebo and had an underlying condition that was not observed due to limited pre-dose ECG sampling; pre-dose ECG sampling was expanded in future cohorts. Had the subject received active drug, it could have been a very significant mark against the drug. Depending on the nature of your drug and the excipients in the formulation, a risk-benefit assessment would be wise to consider whether the use of a true placebo, a vehicle control, or possibly both, is warranted.
5. Failure to assess biomarkers.
Although it may not be required in your Phase 1 study, you may want to consider preliminary assessment of appropriate biomarkers. For example, if your targeted indication has a qualified biomarker that can be assayed in a healthy population, then comparing the biomarker response between your investigational drug and an active comparator in Phase 1 can help to establish preliminary targets for a therapeutic window and ideal dose ranging for future studies. If a biomarker isn’t qualified, it is possible that the endpoint could be co-developed as a validated marker for use in later stage development and a comparative response to an appropriate and accepted therapy may be useful. In this case, it is best to start collecting data as early as possible.
6. Failure to assess for clinical metabolites in early phase clinical development.
Metabolite identification of your drug from clinical samples is important to determine early in a development program. Human metabolite profiles may differ from animals and active metabolites may impact efficacy and safety in your development program. A few blood or urine samples collected from a limited number of subjects in your FTIH study (or subsequent Phase 1 study) are all that is needed.
7. Conducting a Phase 1 study without considering the overall impact on your drug development strategy.
As you consider your next Phase 1 study, it’s important to ensure that the design of each study provides the maximum value to and overall impact on your drug development strategy. This common-sense statement isn’t necessarily ignored by sponsors who believe that their Phase 1 study is being considered in the context of the overall development program. However, it’s more problematic when sponsors conduct a Phase 1 study without knowing all the clinical pharmacology options available to them (i.e., taking the wrong step or missing a step). Each study should begin and end with a review of a global clinical pharmacology plan to think through questions such as the following:
- Is the Phase 1 study designed to provide the right information to make informed decisions for the next step in the development program?
- What can we do in this study to capture clinical pharmacology data that sets up Phase 2 and Phase 3 efficacy/safety studies for success?
- How can a Phase 1 study de-risk certain parts of a development program to facilitate your regulatory strategy or exit strategy (IPO, partnering, acquisition, marketing authorization)?
- Can the study be designed in a way that helps to avoid conducting other clinical pharmacology Phase 1 studies (e.g., avoiding hepatic, renal, drug-drug interaction, or thorough QT studies, etc.)?
- What clinical pharmacology/PK/PD investigations will be required to support an NDA or BLA?
In the end, a fast and cheap study may be costlier than a well-designed, purposeful, and thorough study. Careful planning with the help of a clinical pharmacologist or pharmacokineticist can avoid missteps in your Phase 1 clinical studies and overall clinical pharmacology program.