With patient safety paramount, the high cost of running trials and the large risk of failure of taking drugs to market, sponsors have historically erred on the side of caution when it comes to clinical trial methods.
But this is changing. Indeed, the industry has reached a “tipping point, where the need for flexibility is outweighing the need to be conservative and risk-averse in this highly-regulated environment” Rob Campanella, director of DevOps at 4G Clinical, writes.
The focus now for pharma companies is to build flexibility into trial designs. This is not straightforward, of course, and this post will highlight why flexibility is essential for success and how to go about achieving it.
How Clinical Trials Have Been Designed Traditionally
Clinical trials have always been set up in the basic format: the trial is designed and conducted, then the data analyzed according to the prescribed plan.
But researchers at BMC Medicine note the inflexibility of this design. What about changes that arise during the study?
This is why more trial managers are looking to adaptive designs that would increase flexibility. It is wise to think about this approach as “insurance against assumptions” the researchers write.
In the past, trial managers would have had to implement necessary changes on an ad hoc basis. However, this is costly and can threaten the integrity of the data. Adaptive designs, on the other hand, include planning for potential changes so they can be implemented according to predetermined rules.
The result is greater flexibility and more efficient use of resources. It can also be a more ethical approach as it allows for drug treatments to be rolled out more quickly and often requires fewer participants.
Despite these advantages, the researchers suggest that uptake of adaptive designs has been slow. They posit that this is due to a general lack of awareness of the approach within the clinical trial community.
Additionally, many incorrectly regard the term adaptive design as a label for trials that have been wrongly implemented.
Why the Move to Increased Flexibility?
According to the FDA, the prevailing notion is that a randomized trial is best as it provides “conclusive evidence about the relative benefits of treatments.”
However, with rare diseases and emergency breakouts of epidemics, the length of time associated with randomized trials is not only infeasible, but can even be unethical in delaying the provision of treatment.
This is why flexibility and adaptive features of clinical designs are vital for testing new treatments.
To achieve such adaptivity, maximizing the use of master protocols requires collaboration between pharma companies, Janet Woodcock, M.D. and Lisa LaVange, Ph.D., at the Center for Drug Evaluation and Research (CDER), argue.
This approach may require more time and resources upfront, but ultimately allows for faster and more efficient approaches to answering study questions.
Adaptive, Umbrella and Basket Designs
The traditional approach to trial design has worked well for the past 60 years but times and demands have changed, Frank Hermann, M.D. at Molecular Partners, says.
Cancer, for example, is now thought about less in terms of body area and more in terms of specific genetic changes in tumors of patients. The traditional approach too inflexible to deal with these nuances.
Hermann refers to the three trial designs as ways of overcoming these challenges:
- Umbrella studies can test “different drugs on different mutations in a single type of cancer (‘under the umbrella of one disease’),” he writes. This means patients are chosen for particular treatments based on the most prominent genetic mutation of their tumour.
- Basket studies are used to test the effects of “a single drug or drug combinations on a specific mutation in a variety of cancer types (‘baskets’).”
- Adaptive studies are flexible unlike traditional designs which have specified treatment arms that correlate to predetermined treatments for patients over a certain time period. Adaptive designs, which incorporate umbrella and basket studies under the broader theme of flexible design, allow researchers to change study features based on patients’ responses to treatment.
Adaptable Design Features
In traditional studies, once a study has begun, the main features of a study protocol cannot be altered, the team from Venn Life Sciences explains.
However, collecting data during interim analyses can provide some flexibility. These adaptive trials enable some of the design features to be amended.
Analyzing data as it is gathered enables trial managers to alter certain study aspects as the trial continues. A caveat is that these amendments are only possible if they were “prospectively planned” and processes put in place to protect data against operational biases and statistical inferences.
The following design features can be adapted: subject eligibility criteria; randomization ratio; treatment arms; and endpoints.
Adaptable Design Is Better For Patients
A major advantage of adaptable design is that multiple treatment types can be included under one design as “different arms of the study.”
Patients can be shifted between these arms if a particular treatment type is not working for them, Rose Wu at The Institute of Cancer Research writes. This also means shorter trials and quicker routes to market for trial drugs.
Potentially important consequences of adaptable design is that the target population could shift or the clinical research question asked at the beginning of the study could change.
Wu refers to her colleague Paul Workman, Ph.D., chief executive and president at ICR, who says that adaptive design means trials are smarter and “patients get the drugs that are best suited to them, and can be switched to an alternative treatment more quickly when there are signs that a drug isn’t working.”
Competitive Edge of Flexible Designs
What happens if a competitor drug is approved mid-development? According to Andrew Zupnick, Ph.D., VP Oncology Strategy at Novella Clinical, a sponsor that adopts a flexible design approach can adapt the course of the trial and mitigate the economic repercussions of not being first to market.
Rather than see the planning, time and resources invested in a trial lost without any value, a flexible design allows sponsors to shift research directions.
This happened to Novella Clinical, which added an arm to study “its drug candidate as a second-line of therapy,” Zupnick explains.
The result was Novella Clinical averted directly competing for a rare patient population and sped up the time-to-market as a second-line therapy, which is often approved faster. The company could then focus on a first-line competitive edge later after conducting more research on the competitor drug.
Software to Enhance Flexibility
Software can be used to enhance adaptable designs. Nirav Gokani at Daily Industry Reports explains how the market for EDC software in particular is set to expand steadily until 2025. Part of the driving factor in the software’s appeal, he argues, is that it facilitates adaptive trial design, offering greater flexibility to trial managers.
ClinPlus’ own software makes technical requirements easier to manage and provides more solutions to trial managers. Our EDC, CTMS, IWRS and eTMF functionality, for instance, are all included one one platform to make operations more flexible and efficient and adapt to the evolving needs of trials.
It’s important that the chosen software provides robust and accurate manual and electronic data capture and management, accommodates adverse event coding, generates reports and includes statistical consultation.
Regardless of the decision as to which software is best suited to assist trial designers, incorporating flexibility is key. Pharma companies that can employ adaptable designs will become industry leaders, leaving traditional competitors behind.