Smarter designs, faster: Accelerating decision-making in early-phase development

By Dr Matthias Kruse , Vice President Technical Clinical Pharmacology, Parexel Consulting; Amy Roach , Vice President, Clinical Pharmacology Unit Head, Parexel; and Christian Wagener , Ph.D., Vice President, Early Phase Project Management Office, Parexel

In early-phase clinical development, time is money. To arrive at go/no-go decisions faster, biotech organizations can combine sequential early-phase studies into a single protocol, safely bringing patients into research much sooner than traditional designs allow.

Integrated early-phase protocols are a scientifically sound way to reach proof of concept as efficiently as possible, without shortcuts. Parexel ’s internal research, however, shows that biotech organizations are often hesitant to use this approach. This may be because combined protocols are more complex than traditional designs and therefore more challenging to operationalize or because they’re perceived to have greater risks. But integrated designs have been used safely and effectively for years, and for good reason.

In our experience, combined protocols help biotech organizations reduce development costs and earn the confidence of investors through early patient data. This is particularly important for a capital-intensive sector like biotech in which investor funding is essential but competition for it is fierce. Organizations with early proof-of-concept data can offer more compelling value stories, improving their chances of winning financial backing.

An accelerated approach to early data collection

In an early-phase study, data enables:

• Pharmacokinetic-pharmacodynamic (PK/PD) analysis, which allows researchers to better understand the relationship between dosing and absorption and pharmacologic effect, particularly among patient subpopulations.
• Meaningful exposure-response relationship analysis, which leads to insights on safety events and clinical responses.

The sooner developers can conduct these analyses, the sooner they can make informed go/no-go decisions.

Every development program is unique and developers will always need to assess the safety and feasibility of acceleration for their specific compounds. Barring exceptional circumstances, however, it is almost always possible to use protocol integration in early-phase development. For example, developers design studies that combine single ascending dose (SAD) studies and multiple ascending dose (MAD) studies with both healthy volunteers and patients. As an organization, we’ve also had considerable success running these studies with other important assessments such as food-effect and drug-drug interactions under a single protocol.

In partnering with a client to study a compound for a respiratory condition, for example, we conducted SAD and MAD studies in parallel with healthy-volunteer cohorts, then added a proof-of-concept cohort of patients with asthma immediately following completion of MAD assessments. This design shortened the study by six months.

In a study of an investigational compound for dyslipidemia, Parexel conducted concurrent studies of healthy volunteers and patients — a design that saved 11 months as compared to a traditional design. In this case, results from two cohorts of healthy-volunteer SAD assessments informed MAD assessments in patients, which launched at the same time as a third healthy-volunteer SAD assessment. In total, we conducted five SAD assessments with one additional optional assessment and three MAD assessments with one additional optional assessment.

In addition to timeline reduction, an integrated protocol can also result in cost savings as the approach streamlines protocol design, study reporting, clinical database setup, and regulatory submissions.

Designing and operationalizing combined protocols

Because it is more complex than a traditional study, an integrated study will require careful planning. Developers will need to:

• Earn stakeholder buy-in. As you begin designing a combined protocol, ensure that you have the input and support of key stakeholders, including experts in translational science and clinical pharmacology as well as the operational experts: the principal investigator and clinical site professionals. Stakeholders should reach consensus on a clear decision tree for dose escalation decisions. This will help avoid amendments, which increase costs and delay timelines.
• Engage early with regulators. Consult with authorities about your planned study design as soon as is reasonable. The protocol design you present needs to be precise enough to satisfy regulatory requirements but flexible enough to allow researchers to apply what they learn from cohorts to successive steps. For the FDA, we recommend discussing integrated protocols at the pre-IND meeting or even earlier at an INTERACT meeting. Historically, the FDA accepts well-planned integrated protocols with clear and scientifically sound decision matrices. A partner like Parexel can help you prepare for these agency meetings to maximize the benefit of your time with regulators.
• Consider investors. As biotech organizations seek funding, they will need to demonstrate how they will derisk the development process through data generation. Ultimately, investors want early-phase study designs that lead to multiple data points. Investors will also want assurance that developers will use capital efficiently.

Once the combined protocol is written, developers will need a clear plan for operationalizing it. Because of the relative complexity of an integrated-design study, it is important for developers to:

• Collaborate with the right sites. Only select sites with proven experience in phase I, first-in-human environments. Because safety is the primary endpoint of any early-phase study, these sites must be thoroughly familiar with dose escalation methods, stopping criteria, intensive PK analysis, and continuous monitoring. The schedule of coinciding events in integrated studies will require investigators and sites to manage intensive procedures in a timely manner, quickly assessing safety data and remaining in close communication with developers and their partners.
• Target the most advantageous patient populations. An integrated design requires parallel enrollment of both healthy volunteers and patients—overlapping cohorts that will allow researchers to maximize both safety and scientific learning. The compressed timeframe can make recruitment more challenging and study designers must avoid making inclusion/exclusion criteria so stringent that sites struggle to enroll adequate populations. To maximize recruitment efforts, developers will likely benefit from using sites in multiple locations.

To best navigate the complexity of early-phase research and take advantage of strategies for its acceleration, many biotech organizations choose work with a partner like Parexel. We can support integrated phase-I and phase-II protocols through four hospital-based research units in the U.S. and Europe with access to more than 60 million healthy volunteers and patients. We also have experts in translational science, patient engagement, regulatory strategy, and market access strategy — specialized functions that may not be internally available to many biotech developers.

At Parexel , we see integrated early-phase development as one facet of a comprehensive strategy to address scientific, clinical, regulatory, and commercial considerations within your development program. As we collaborate with you to create and execute that strategy, Parexel amplifies your team's expertise, putting your compound on the surest path to success. Ready to learn more? We’re always available for a conversation.