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Flexible Study Designs

Phase 1 studies can be tailored to the needs of the specific compound and conducted more efficiently using combination, flexible protocols. The time-savings, compared to conducting several separate protocols, can greatly reduce costs and the overall development timelines.

Phase 1 marks a significant milestone in the development of any new medicinal product. A target has been identified, a compound has been discovered that hits the target, and has been refined to ensure it has good properties for development. In vivo safety pharmacology and toxicology studies have been conducted and the compound has been tested in preclinical models of the disease.This process will have taken many years.A multi-disciplinary team has evaluated all the data, and has decided to take the plunge and invest in clinical development. And now, the drug is ready to be tested in humans.

The objectives of the Phase 1 development plan are diverse. In addition to establishing the safety, tolerability and pharmacokinetics (PK) of single and multiple doses in humans, and ascertaining the maximum tolerated dose, it is also important to consider the effect of food on exposure, potential drug-drug interactions, gender and/or age effects, alternative formulations and pharmacodynamic (PD) effects. Traditionally, this has led to sizeable Phase 1 packages with multiple studies that take many months to complete. However, with careful planning and protocols that are written flexibly, many objectives can be addressed under one protocol (often with many parts), which can improve efficiencies in the drug development process and speed up the time to becoming Phase 2 ready.This article will illustrate some of the ways in which this can be achieved.

Phase 1 Clinical Development

Planning To maximise efficiency in Phase 1 development, the clinical development plan must first be considered as a whole before considering the details of the individual studies. Some questions will need to be considered; for example, what are the objectives of Phase 1 for the compound in question; and what data do the team require before they can proceed to efficacy studies in patients? Also, are there any potential issues from preclinical development that need to be addressed (for example, QT signal, potential for drug-drug interactions)? Once all the questions have been identified, the clinical team can then plan which studies need to be conducted in order to answer them, look for specific ways to minimise the time taken, as well as aim to maximise the value of each study.

It is becoming increasingly common to combine single dose ascending (that is, first-in-human) and repeat dose studies under one protocol (1).With a single protocol written in a flexible way, this can save considerable time by cutting out the period between the end of the single dose study and the writing of the repeat dose protocol, and the time for regulatory review of the second protocol. In these combined designs, it is typical for the clinical development team to be unblinded, while the subjects, investigator, all staff at the study site (other than the pharmacist) and study monitors to remain blinded to treatment allocation.

The clinical development team will carefully review any issues of poor tolerability or adverse events at the individual level, and thus need to be fully unblinded in order to make an informed choice of doses for the repeat dose phase while the study is ongoing. Provided an efficient process is in place for the transfer of samples between the study site and the bioanalysis laboratory, and of electronic data between the study site and the study statistician and pharmacokineticist, statistical summaries of pharmacokinetic and safety data can be provided quickly throughout the course of the trial, which will assist the clinical development team at each dose escalation or key decision stage.

Additional objectives can often be easily incorporated into a combined single and repeat dose study.The possibilities here are almost limitless, but some common examples for an orally administered drug primarily aimed at a broad cross-section of the population include:

  • Assessing the food effect on the PK of a selected dose
  • Assessing the relationship between PK and PD effects (for example, on QT interval)
  • The assessment of a potential drugdrug interaction (for example, the effect of drug A on drug B, effect of drug B on drug A, or both)
  • The assessment of the effect of gender and/or age on PK (if applicable to the target population)
  • The assessment of therapeutic effect, if an appropriate PD measure is available (for example, fMRI, EEG, blood biomarker or relevant rating scales)

If the protocol is written in a flexible way, some of these may be incorporated in an opportunistic manner. For example, if the dose escalations stop earlier than planned (due to reaching the maximum tolerated dose, or achievement of higher PK exposure than anticipated), one or more of the remaining periods can be utilised to assess, for example, the food effect on a dose that has been established as being well tolerated earlier in that cohort. Optional cohorts may also be included to allow exploration of higher doses where appropriate (for example, if the planned doses are well tolerated and there are appropriate safety margins, the PK exposures are lower than anticipated). Assessments of PD effects, or drug-drug interactions, can often be built into the design of the planned cohorts, obtaining more information using the same set of subjects.

Study Considerations

Before a study can be carried out, there are some important steps to bear in mind, including designing a thorough protocol, deciding on how the data is to be captured, and scheduling review meetings.

Protocol
When planning a combination study with many objectives such as those illustrated above, care must be taken to ensure that all optional aspects are explained clearly. Stopping rules at the individual, cohort and study level, as well as the decision rules for selection of doses and for proceeding, or not, with the optional parts of the study should be outlined.The maximum number of subjects to be included should be stated, and there must be no compromise to subject safety through the flexible nature of the study design. Ethics committees and regulators will be particularly concerned that there is an appropriate data review process in place for each key decision stage.

There may be a greater lead time required between the initiation of protocol development and the first subject visit (due to study complexity), but provided this time is built into the development plan, it is easily accommodated. In fact, overall there will be a reduction in the development time of the drug (due to efficiencies gained by only having one protocol to review, time savings between cohorts, as well as in the data management, statistical and reporting processes). Other data analysis activities (for example, population PK) will benefit too from having data consolidated onto one database.

Data Capture
It is important that the data required for in-stream decision-making (that is, while the study is ongoing) can be available for review and analysis very quickly – perhaps even within 24 hours of the assessments being performed. Therefore, some means of electronic data capture is necessary. With a multi-part study, which may include a mixture of cross-over and parallel group cohorts, the structure of the database must be carefully considered to ensure that the data from any part of the study can be extracted separately as required for reporting.Where possible, data checks should be built in at data-entry to ensure high quality data are available for in-stream decision-making, which will occur prior to database lock.

In-Stream Monitoring
During the course of the study, there are likely to be several data review meetings to determine the dose level or other design aspect, for the next cohort(s) of subjects. These meetings need to be planned from the start and incorporated into the study schedule. Key points to identify include:

  • What data are required for decisionmaking (PK, adverse events or lab results, for example)?
  • How much time needs to be built in for sample analysis and data transfer?
  • How much time is required by the pharmacokineticist, statistician and other study team members to analyse and report the data to the rest of the team?

If appropriate measures are in place, it can – in most cases – be possible to complete the last two key points within a week of the last data point being recorded. Dose escalation decisions are usually made jointly between the clinical development team and the investigator, therefore during review meetings care must be taken so that any information that might ‘unblind’ the treatment allocations are not shared with the investigator or other study site personnel.

The points mentioned above highlight the fact that planning is key. Once everything is in place, the study can proceed efficiently through the various cohorts to completion. The resulting time saving compared to doing several separate protocols can have high impact in terms of reducing cost and overall development timelines.

Conclusion

The aim of this article was to provide an overview of some of the ways in which Phase 1 packages can be tailored to the needs of the specific compound and conducted more efficiently using combination, flexible protocols. Considerations that need to be made at the planning stage have been outlined and the practicalities discussed so that best use can be made of emerging PK and safety data to enable informed decisions regarding study progression.

Apart from combination studies, the novel statistical designs can also be used to improve Phase 1 or other clinical pharmacology studies. For example, the use of incomplete block designs (where each subject receives a subset of the treatments under study) can enable more treatments to be tested within a cross-over study than might otherwise be thought practical. This may arise in situations where different formulations of the same compound are to be evaluated. Factorial designs can also be used to help explore several factors simultaneously in one study (for example, for ascertaining the optimal dose levels for a combination product). For compounds where the expected variability of the pharmacokinetic parameters is high, resulting in a large sample size, the use of interim analysis or sequential designs can offer the opportunity to complete the study more quickly with fewer subjects, if the primary objective has been reached or the study looks as if it will fail to achieve it.

In summary, the use of combination studies, flexible protocols and novel statistical designs can significantly improve Phase 1 and clinical pharmacology packages, with benefits both in terms of timelines and costs.

Reference

  1. Guidelines for Phase 1 clinical trials, Association of the British Pharmaceutical Industry, www.abpi.org.uk/publications, 2007

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David Underwood is CEO and Chairman of Quanticate. He has been in the pharmaceutical industry for over 30 years, starting his career at GlaxoSmithKline as a statistician. David started his own company 15 years ago to provide specialist biometrics services and fully understands that data and their interpretation are the final product of clinical trials and their importance cannot be overstated. Part of this remit is the provision of statistical consultancy expertise to the industry. He is delighted to present this paper on behalf of the statistical consultancy team on the use of flexible methods in Phase 1 clinical studies. Email: david.underwood@quanticate.com
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