An adaptive study design can be used to combine a Phase 0 (also known as early Phase 1) and Phase 1 clinical trial. In a combined Phase 0/I trial, first the biodistribution and pharmacokinetics can be evaluated before safety and dosing are studied. How does such a combined Phase 0/1 adaptive trial design compare to two separate clinical trials in terms of regulatory submission, preclinical requirements, and study design? In this article, we answer that question and discuss the factors that determine whether a single trial submission or separate submissions would be the preferred approach.
Highlights
- Drug developers can choose Phase 0 or Phase 1 as the first-in-human (FiH) study.
- Both approaches can be combined with an adaptive clinical trial design: a Phase 1 trial with a Phase 0 sub-study.
- There are advantages and disadvantages of combining both studies.
Short explanation of Phase 0 and Phase 1
Phase 0 and Phase 1 can both be the first in-human study, but they are different in many ways.
What is a Phase 1 trial?
The purpose of a Phase 1 clinical trial is to determine dosing regimens and safety at therapeutic levels. Although usually conducted in healthy volunteers, Phase 1 studies may also be conducted in patients. Choice of subjects is defined in Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products, section 8.2.3 [1]. A Phase 1 clinical trial design can consist of a single ascending dose (SAD) study and a multiple ascending dose (MAD) study. The first establishes baseline safety, and the latter determines optimal dose and dose regimens. The two studies, and additional studies such as food-effect or drug-drug interaction, may often be combined in an adaptive trial design.
What is a Phase 0 clinical trial?
A Phase 0 study is an assessment of the new drug at a subtherapeutic level in a small cohort, typically between 10 and 15 patients or healthy volunteers. By using a microdose, preclinical requirements are lowered to a minimum. A Phase 0 study can therefore be initiated much sooner than a Phase 1 trial. For nuclear imaging, such as, Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) imaging, a labeled microdose of the drug is sufficient for accurate visual and quantifiable data. The study has no therapeutic intent and has no safety evaluation. Instead, it delivers data on biodistribution (BD) and pharmacokinetics (PK) that can be extrapolated to therapeutic levels.
Relationship Phase 0 and Phase 1
With a Phase 0 imaging study, you predominantly measure BD, PK, and on/off-target binding. This data can be relevant for your Phase 1 study, namely:
- When labeling the drug with a radionuclide for nuclear imaging, dosimetry data demonstrate the exposure of the drug at the target and in non-target organs.
- By performing multiple scans (dynamic PET), you can get a time-activity curve.
- If you have multiple undifferentiable preclinical candidates, a Phase 0 trial offers the opportunity to compare compounds and select a lead compound for your Phase 1 study.
- A Phase 0 basket trial, especially useful for oncology studies, can be used to select a lead indication from multiple suitable indications.
- With extrapolation of Phase 0 microdose study data, a more accurately defined starting dose and the chance of adverse events can be determined.
- Promising results can attract investors for your Phase 1 study.
When is a Phase 0 imaging study most relevant?
Are phase 0 trials mandatory? No, they are not mandatory, but they do offer valuable information or are a better alternative to the classical development pathway. Below, we list specific scenarios and the main reasons to conduct Phase 0.
You have not yet completed your preclinical requirements for a Phase 1 study.
A Phase 0 microdose study can already be conducted after an extended single-dose toxicity study in rodents. In addition, you don’t need a Good Manufacturing Practice (GMP) grade starting material. When labeling the drug under GMP conditions, your Good Laboratory Practice (GLP) grade drug substance is sufficient.
You don’t have the funding yet for Phase 1, large animal studies, and GMP production.
The costs of a Phase 0 trial are generally lower than those of a Phase 1 trial, particularly due to reduced preclinical work and manufacturing requirements of the starting material. Therefore, Phase 0 offers smaller pharmaceutical and biotech companies the possibility to generate FiH data on a smaller budget, with the potential of attracting more investors.
You have multiple compounds with similar preclinical profiles.
If you have undifferentiable preclinical candidates, human data can be decisive for which compound progresses into Phase 1. At TRACER, we’ve seen that similar preclinical compounds can yield completely different results in humans.
You are not sure which indication will be the lead indication.
Especially in pan-cancer targets, selecting a lead indication from preclinical data alone may be challenging. In a Phase 0 study design, it is possible to include various patient populations and use those outcomes to select a lead indication for your Phase 1 study.
You have low translational certainty
Low translational certainty (i.e. the confidence that preclinical research accurately predicts clinical outcomes) comes from differences between animal models and humans. Situations associated with low translational certainty are first-in-class programs, drugs with a target for which little to no in-patient research exists, and drugs that need to cross the blood-brain-barrier. For these types of programs, validation in the patient population prior to further preclinical and clinical research can be beneficial.
Your preclinical data is conflicting or not consistent
When preclinical data are conflicting or not consistent, in-human or in-patient data can be used to validate animal models.
Phase 0 and Phase 1 as separate or one adaptive study
Phase 0 can influence the design of Phase 1 and subsequent studies. Both studies can always be conducted as separate clinical trials, meaning for each study, a study design is made, protocols are written, and regulatory approval needs to be obtained. In certain cases, both studies can be combined in an integrated adaptive Phase 0/1 design. An adaptive design may take more time upfront, but can save time compared to two separate studies. You only have one study submission and review of your Clinical Trial Application (CTA) package, and only one study start-up. That said, changes that lead to substantial amendments will reduce the time saved from using a single, integrated protocol.
More information on criteria for integrated protocols
- The investigational compound needs to remain the same throughout the entire protocol.
For example, if the Phase 1 study evaluates an antibody-drug conjugate (ADC), but the Phase 0 imaging study uses a radiolabeled version of the compound, a combined protocol is not feasible. The same applies when the labeled compound used for Phase 0 is intended to be used unlabeled in your Phase 1 study.
- Radioligand therapies are suitable candidates for a combined protocol, especially since the Phase 0 imaging data can inform a patient-specific therapeutic dose.
- Radioligand therapy can use a single nuclide for imaging and therapy or separate nuclides, which affects the choice for separate studies or combined protocols
- Your intended use of the data needs to have the same goal/purpose.
- You don’t intend to change the compound based on the Phase 0 data, as is the case with ADCs
- You need to be certain of your Phase 1 study design
Learn if and how Phase 0 can be integrated into your Phase 1.
Schedule a meeting with TRACER.
Regulations combined/adaptive protocols
An adaptive study design, such as a combined Phase 0/1 protocol, for FiH studies needs to contain a very extensive protocol. The information from one study needs to be analyzed and assessed in a short timeframe before a decision can be made about the second study. The entire study design and decision criteria, that will be used to decide to progress to your Phase 1 study, need to be described in detail. Based on the information present at the time, you need to describe the likelihood of protocol modifications. When a change in the study protocol was not described in the protocol, it needs to be submitted and approved as a substantial amendment, which is still faster than a separate CTA.
“All parts, and the criteria to move from one part to another, should be predefined within an integrated protocol, as should possible modifications, based on the totality of available information and the related uncertainty.”
– Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products, Section 8.2.2, EMA, 2017 [1]
Study design with a unifying hypothesis and without unnecessary complexity
ICH E8 states that protocols need to remain operationally feasible in order to achieve practical and meaningful study designs.
- the scope is well-justified based on a single hypothesis;
- the adaptive study design avoids unnecessary complexity;
- each factor contributing to the overarching research question is clearly described.
Reasons for disapproval of clinical study design
- Insufficient definition of in/exclusion criteria
- Insufficient or a lack of stopping rules
- Lack of interim safety and PK data before starting subsequent parts of the trial in dose escalation studies
- Unclear or insufficient justification of dose selection
- And insufficient exposure/safety margins based on non-clinical data for dose escalation parts
In other words, based on the currently available information and the expected outcomes of the first study, all decision criteria should be predefined to minimize substantial amendments as much as possible and avoid disapproval from the competent authorities.
Pros and cons of both approaches
The main advantage of an adaptive trial is to save time compared to separate studies. The main advantage of a separate Phase 0 and Phase 1 study is the ability to start Phase 0 much sooner and prepare Phase 1 simultaneously. Below is a pros and cons list to assist you in your decision.
Adaptive study design
Pros
- A seamless clinical trial design can save time (1 – 6 months compared to single protocols), resources, and total costs.
- One regulatory step.
- Reaching the effective dose in patients earlier.
- Potential for faster recruitment of study subjects. Read the FAQ on recruitment.
- Integrated protocols generally need fewer substantial amendments, assuming that the protocol is well-established.
Cons
- Longer preclinical development, all requirements for Phase 1 should be met before a seamless clinical trial design can be initiated.
- You need full GMP-grade material of the precursor.
- More complex protocol development, which requires a more complex ethical approval.
- Adaptive designs usually require more substantial amendments compared to single protocols, but they are processed more quickly.
- Difficult handling of informed consent, data management and analysis, and reporting.
Separate study submission
Pros
- For a Phase 0 study, there are less preclinical requirements upfront. This means you could start Phase 0 already while preparing Phase 1.
- There is an easier regulatory/ethical framework upfront.
- Less complex study design.
- A clear go/no-go moment.
- Lower initial investments due to non-GMP material and limited toxicity studies.
- Results from Phase 0 can be used to attract extra investors.
- You can change your Phase 1 study design if unexpected outcomes occur. In a combined protocol, these changes will typically result in a substantial amendment, which is generally faster than the submission of a complete protocol. However, if the proposed modifications are too extensive, submission of a new protocol may still be necessary.
Cons
- Double administrative labor due to submission/protocol development/contracting
- Renegotiating contracts
- Extended timelines due to an interim period of data analysis and study submission
- Costs can increase due to this duplication of work
Preclinical requirements Phase 0 vs Phase 1
|
Phase 0 |
Phase 1 |
|
|
Preclinical requirements |
Limited, variable; depends on extent of exposure to the test article and experimental goals |
Full requirements |
|
In vitro models |
Full requirement |
Full requirements |
|
Toxicology |
14-day extended single-dose or 7-day repeated dose |
Full requirements |
|
Genotoxicology |
None or limited |
Full requirements |
|
GMP |
Flexible, depending on available preclinical information and route of administration (e.g., sterility ensured for i.v. route) |
Full requirements |
Considerations for choosing the right approach
Whether it is useful to submit your study in one adaptive trial design or two individual studies depends on various factors.
The main goal of your program
If your compound, study subjects, and indication stay the same throughout the entire project, an adaptive trial design can be used. This would be beneficial for umbrella or basket trial designs. If your end goal is to reach a fast Proof of Concept (PoC), for instance, to attract more investors, individual submissions would be more useful.
The status of your preclinical work
If your preclinical work already meets the requirements for a Phase 1 study, it may be beneficial to submit your study in a single application. In this case, if you have multiple compounds that have completed full Phase 1 preclinical requirements, you could use a Phase 0 imaging study with multiple compounds to find a lead compound. If your preclinical work does not yet meet the requirements of a Phase 1 study, it is more beneficial to submit your study separately. You could already start your preclinical studies required for Phase 1 in parallel with the clinical Phase 0 studies, saving time.
Translational certainty
The degree of translational certainty reflects the confidence that preclinical research accurately predicts clinical outcomes.
If preclinical research is indecisive or there are no appropriate animal models, a separate Phase 0 study prior to Phase 1 is useful. This provides clear in-human PK and BD data to validate animal studies and decide on further development.
Even with high translational certainty, a Phase 0 study is still valuable. It allows for obtaining proof of concept with first in-human data. Even when animal models seem highly representative of human pathogenesis, in-human data can still show unexpected differences, as we’ve seen in our case studies. In such cases, lead candidate selection and Phase 1 study optimization are possible in a combined protocol.
Conclusion
To summarize, Phase 0 imaging studies can offer valuable insights for drug developers to inform their Phase 1 study design. Phase 0 can be conducted separately or as integrated part of the Phase 1 trial. An integrated protocol requires an extensive protocol with clear, predefined decision criteria, making regulatory approval more complex. On the other hand, if done correctly, a single protocol can save time, resources, and costs. Choosing a single or separate submission ultimately depends on your end goal, the status of your preclinical work, translational certainty, and budget.
FAQ
An adaptive clinical trial design offers many possibilities in various phases of drug development. However, setting up and preparing such a study often requires specialized knowledge. Below, we’ve provided brief answers to a few questions on this topic. For more information or answers to other questions, please feel free to contact us.
What is, for both phases, the influence on participant recruitment?
On the subject of patient recruitment, Phase 0 and Phase 1 both have advantages and disadvantages.
- For Phase 0, the non-therapeutic dose may disadvantage recruitment speed because patients won’t receive a therapeutic effect.
- For Phase 1, in certain indications, only patients who have exhausted all treatment options can be included.
Effect of combined Phase 0/1 study on patient recruitment
When combined in one protocol, the possibility of efficacy in the Phase 1 part of the study can benefit recruitment for Phase 0.
- Study subjects who have participated in the Phase 0 study can often re-enroll in the Phase 1 study. An advantage of this approach is that the potential benefit of a therapeutic effect in the Phase 1 study might make recruitment for a Phase 0 study easier, as Phase 0 does not have a therapeutic effect, which may affect recruitment speed.
- When the same patients are intended to participate in both study parts, it is important to consider the timeline of the study and the expected life expectancy.
- However, Phase 1 is generally still only conducted in patients without further treatment options. Also keep in mind, in Phase 0 the microdose does not affect their active treatment, but for Phase 1 their treatment should have ended.
Why is a single protocol less suitable for ADCs but possible for radiotherapy?
For ADCs, you remove the radionuclide and replace it with a drug after the Phase 0 imaging trial. This means you change the compound and, therefore, possibly the efficacy and dosing. This makes a single protocol commonly less suitable. For radiotherapy, you change the imaging radionuclide for a therapeutic one. In such a case, you can still use a single protocol.
Can you skip dosimetry studies in Phase 2 when they have already been conducted in Phase 0 or 1?
When you conduct a dosimetry assessment in Phase 0 or a combined Phase 0/1 design, you may skip dosimetry in Phase 2. To do so, you need to have enough patients per population; three is often not enough. You’ll then need to expand your cohort during the study.
Are additional toxicity studies always required for Phase 1?
The limited requirements for Phase 0 toxicity studies are related to the low dosage used. A higher clinical dose means an increase in the required toxicity studies. As long as you stay within the microdosing range, you might not need additional toxicity tests for Phase 1 either. For trials with oncology patients, you have more flexibility, including which toxicity test you need. However, the GMP standards are somewhat stricter in that case.
Is a microdose always suitable?
In many cases, a study with a microdose has been shown to be a clear predictor of higher dosage. Based on your preclinical data, you can estimate how accurate a microdosing study will be. When your compound is already being metabolized extensively in the liver during your preclinical studies, it might not be practical to conduct a microdosing study. The liver might absorb the very low dose. In such a case, you would need to start with a higher dose right from the beginning of your Phase 0 or 1 trial. You can ask TRACER to help you assess the feasibility of an imaging (sub)study for your drug development program.
Abbreviations
| ADC | Antibody-Drug Conjugate |
| BD | Biodistribution |
| CA | Competent Authority |
| CTA | Clinical Trial Application |
| EMA | European Medicines Agency |
| FiH | First-in-Human |
| GLP | Good Laboratory Practice |
| GMP | Good Manufacturing Practice |
| ICH | International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use |
| MAD | Multiple Ascending Dose |
| PET | Positron Emission Tomography |
| PK | Pharmacokinetics |
| PoC | Proof of Concept |
| SAD | Single Ascending Dose |
| SPECT | Single Photon Emission Computed Tomography |