Zero to hero

Phase 0 is a designation for optional exploratory trials, originally introduced by the FDA’s 2006 Guidance on Exploratory Investigational New Drug Studies, but increasingly adopted as standard practice in drug development. They aim to learn more about new drugs without exposing subjects to their full, potentially toxic, effects.

In a traditional phase 0, often designed as ‘microdosing’ studies, subjects take a subtherapeutic dose of an experimental drug, usually for no more than a week.

The aim is to provide pharmacokinetic data on how a drug candidate behaves in the human body at an early stage, before planning more extensive and costly phase 1 studies. They involve subtherapeutic doses of the drug candidate, typically around 1/100th of that used in later phases.

‘Phase 0’ can also describe window of opportunity trials in neuro-oncology, where patients receive a full therapeutic dose of a drug, typically for no more than a week, before a scheduled tumour resection surgery.

Researchers then measure whether the drug penetrated the blood-brain barrier and reached the desired target. For tough-to-treat conditions like glioblastoma (GBM), this data can help decide whether a new drug is worth testing further.

• Gather early data on how a drug candidate behaves in humans without exposing participants to high doses
• Short duration, lasting a few days or weeks
• Involve a small group of around 10–15 often healthy volunteers, but increasingly also patients
• Investigate pharmacokinetics, drug metabolism and sometimes initial biological effects of the drug at low doses
• Not designed to test efficacy, but how a drug candidate is absorbed and processed, and if it behaves as expected, based on preclinical data
• Originally introduced to assist drug candidate selection, based on clinical pharmacokinetic data – when either candidate molecules were too similar, or there was a theoretical pharmacokinetic risk.

Phase 0 studies provide early, human-specific data on drug candidate behaviour that is not always fully predictable based on animal models. This can help determine how it behaves in humans, including potentially in patients, and avoids wasting resources on those unlikely to succeed in later trials.

Assessing early data, such as drug absorption, metabolism and elimination can actually help speed up the overall drug development process.

Understanding a drug candidate’s pharmacokinetics in humans early can provide better safety assessments. Potential toxicity issues, side effects and other safety concerns can be predicted and managed – helping prevent costly later-stage failures.

Phase 0 study data can also help optimise dosing for later phases, resulting in more efficient and effective phase 1 and 2 trials with better informed dosing strategies. It can also help inform dose escalation and patient selection decisions in later stages.

The drive towards better cost and time efficiency is increasing the adoption of phase 0 studies, where critical data can be provided early in the development process, helping avoid expensive failures in later stages.

Advances in precision medicine mean that some drugs are increasingly tailored to specific patients. Phase 0 studies can provide insight into how a drug candidate behaves in a particular population, helping select the right drugs for the right patients at an early stage.

As drug development shifts toward more complex drugs and targets including biologics, gene therapies and precision therapies, phase 0 data is an important indicator of how new drug candidates behave in humans, especially when targeting novel mechanisms or rare diseases.

Regulators such as the FDA and EMA are increasingly open to reviewing phase 0 data as part of the development process – particularly in fast-track approval processes for drug candidates targeting critical or unmet medical needs. This is highlighted in a recent post-COVID 19 review.

Oncology drug development, especially targeting novel pathways or specific genetic mutations, could benefit from phase 0 studies to understand how drug candidates interact with tumour tissue. Targeted radiotherapy in particular has used phase 0 studies effectively for first-in-human studies of new compounds.

For drug development in rare diseases, phase 0 data in a limited number of patients can reduce the risk of investing heavily in a drug that may not work. Lysosomal storage disorders such as Gaucher disease have benefited from early studies assessing CNS delivery methods.

Phase 0 studies could also provide some mechanistic insights into how immunotherapies interact with the human immune system, before moving on to actual pharmacodynamic and efficacy testing.

Complex gene therapies and biologics benefit from early understanding of their behaviour in humans. For example, phase 0 window of opportunity studies have been used effectively in monoclonal antibody treatments for cancer.

Phase 0 studies can also play a useful role in neurodegenerative diseases. For conditions like Alzheimer’s or Parkinson’s, where targeting the brain with new treatments requires careful dose management, early data may help ensure better pharmacokinetic understanding, improving dosing in later stages.

Phase 0 studies only use small numbers of volunteers or patients. This can make it difficult to generalise the results to larger or more diverse populations, especially in terms of adverse reactions or drug responses.

The use of subtherapeutic doses, along with their limited size and duration means that phase 0 studies cannot produce reliable safety data. If early safety data is required, a traditional GLP toxicology data set would be needed, meaning that phase 0’s ‘data light’ package is not helpful in that instance.

Being typically focused on pharmacokinetics, phase 0 studies lack detailed pharmacodynamic data, meaning that the mechanism of action and therapeutic potential may not be fully understood until later phases of clinical trials.

Some also question the ethical implications of administering drugs to humans, particularly patients, with no direct therapeutic benefit.

Data from phase 0 studies may also not always predict how the drug will perform in later phases, especially its effects at higher doses. This could lead to overconfidence in the drug’s safety profile.

Adding another step to the already lengthy and expensive process of drug development may not be helpful for all drug candidates, especially those with an already established safety profile or well-understood pharmacokinetics.

Phase 0 studies are an increasingly accepted and important part of modern drug development. They can provide early, human-specific data to streamline the development process, identify potential issues and optimise dosing strategies for future trials.

However, this data is limited in terms of understanding the full safety and efficacy profile of a drug. Additional studies can also be an unnecessary step for more established drug candidates, adding time and expense.

However, as drug development becomes more targeted and precise, the use of phase 0 is likely to grow, especially in complex fields like oncology, rare diseases and gene therapies. Here, it can play a valuable role in improving the efficiency and safety of bringing new treatments to patients.