How Janssen Applies Innovative Trial Designs for Patient Flexibility and Efficient Drug Development
Janssen Research & Development has been embracing innovative clinical trial designs to improve overall efficiencies. Daniel Millar, MBA, Sr Director, Strategic Business Transformation, shares how innovative trial designs are helping his team find the most efficient and most patient-centric way to develop assets.
Why do you believe master protocols are so important to the future of clinical research?
A master protocol approach can provide inferential benefits and operational efficiency. Clinical development is costly; we want to make sure that trials are as efficient as possible to generate high quality evidence of drug safety and efficacy. On top of that, especially in a rare disease setting or special populations such as pediatrics, it may be difficult to find enough eligible patients interested in participating in a clinical trial. This makes efficiency important not only financially, but also to ensure that the clinical trial can produce timely and reliable evidence.
If you had two different therapeutic interventions, the traditional method would require setting up two clinical trials in parallel: selecting a number of sites for each, training everyone involved, recruiting patients and then dismantling the clinical trial infrastructure at the end. And, in each trial, a percentage of the participants would be randomized to standard of care or placebo. Imagine if you could step back and say, “Can't we share that site infrastructure? Can't we share the placebo data?” Then we can still draw conclusions that are statistically valid (with proper statistical approaches) for each of the interventions that we're trying to test.
What are the key benefits of using a master protocol?
One benefit is that you have a long-term relationship with the sites with whom you are working. You do not need to go back, with every new asset, to a different collection of sites to contract, or train investigators on operationalizing the protocol. In a master protocol, many of the procedures will be the same irrespective of which intervention is being investigated. Any needed procedures specific to a particular investigational intervention could be added, if required. Since many of the clinical trial procedures are common, sites gain experience performing these procedures over time which can enhance quality.
Another benefit is recruitment. Over time you have very experienced sites, who know where the patients are. Recruitment is always a big challenge, and it's an even bigger challenge in rare diseases. As new therapeutics are available to be evaluated in a master protocol study, new patients can decide whether they would like to participate.
How does an innovative trial design do better on behalf of patients?
The patient's perspective on this is very important. We don't introduce statistical innovation for the sake of making things complicated or interesting. We do it because it's the right thing to do for patients and it creates efficiency in the drug development process. It's about people's lives, the lives of people participating in clinical trials, and how we must be good stewards of the willingness of patients to participate in clinical research.
Patients also appreciated that master protocols can remove redundancies built into the clinical research system. Randomizing patients to an investigation therapy or stand-of-care/placebo is important to be able to make statistically valid conclusions about safety and efficacy; however, we may be able to reduce the number of patients in the standard-of-care/placebo group in a master protocol study. In turn, this reduces the total number of patients required allowing those financial resources and time of patients participating to be re-invested in answering the next set of research questions leading to new medicines.
"We don't introduce statistical innovation for the sake of making things complicated or interesting. We do it because it's the right thing to do for patients."
What have you seen from industry sponsors in willingness to pursue master protocols?
It can be challenging for some sponsors. There are still complexities, particularly in a setup with multiple drug development companies participating in the same infrastructure. Companies still need to compete to bring the best therapies to patients, but pre-competitive spaces have been successfully established in many other areas. Think back 15 years prior to TransCelerate – it was very difficult to share anything across companies, and now, we have common templates and standards, like a protocol template, which all companies can leverage.
A clear legal framework is required to ensure that intellectual property is attended to and all parties meet their regulatory obligations. Successful case studies such as I-SPY2 in breast cancer and the HEALEY trial in ALS demonstrate that the key challenges can be overcome. Companies with a rich portfolio of assets in a particular area have also elected to set up their own master protocol studies. This allows them to achieve some of the benefits of a master protocol, while still retaining regulatory and trial operations responsibilities.
What has been your experience with master protocols?
At Janssen, we have been able to use master protocols and innovation in study design in several places. First, we have applied these approaches to our own portfolio in early development in disease areas where we have multiple assets to evaluate. Second, we have participated in multi-company, master protocol-driven clinical trials focused on developing COVID-19 therapeutics during the pandemic. And third, we are taking an active role in the EU PEARL public-private consortium focused on ensuring these efficient, patient-centric clinical trials can be implemented in Europe with support from the Innovative Medicines Initiative. Common across each of these engagements is the need to educate stakeholders on innovations in trial design, and work together across stakeholder groups to address the challenges.
How do you address uncertainties in drug development when pursuing a master protocol?
One of the challenges is that the future is not always clear where things will go. Maybe you have one asset today, and over time you might hope to have a collection of assets. But there's attrition; you may not yet have identified the next mechanism to investigate, etc.
But if you think you could be in this line of research for the longer term, the question becomes how to build for the future while addressing the needs of today. We want to think beyond a single asset and a single trial. Instead, if there is a longer-term perspective, the first trial and its asset becomes the first intervention guided by the master protocol. And then in due time, when there is a new asset or a new development in standard-of-care, the master protocol study provides the flexibility to not start a completely new trial and set up the infrastructure to do that, but drop in that next investigational arm into the infrastructure and begin studying the next intervention in parallel to what we have already started.
How do you account for the need for flexibility in protocol design?
To start, we need to consider upfront the current state of clinical development in a given disease area and how we could reasonably expect this to evolve over time. We can then anticipate that some factors will need to change over time, and we need to account for this in designing a platform trial. The general idea of adaptive designs is that you pre-specify how you will adjust the clinical trial based on emerging data. That allows you to maintain statistical rigor – in this case the ability to make regulatory and clinical decisions based on the data generated – while also adding some flexibility.
For example, you might pre-specify that you will check part-way through a trial for futility where you say, “Based on everything that we have seen so far, do we have reason to believe that the therapeutic being tested could be successful?” If not, it's time to terminate the trial and allow patients to move on and allow the clinical development investment to move to another approach also. Alternatively, we may see overwhelming efficacy and good safety, which gives us great confidence to say the effect size is so large, the right thing to do is to accelerate here. Either way, you must pre-specify where you're going to do these adaptations so that you don't introduce bias. In practice modeling and simulation is used to evaluate the operating characteristics, such as control of Type I error, of designs being considered.
"It’s important that innovation in trial design is not only embraced by FDA but that the methodologies are well understood by other global regulators."
What can you tell us about the FDA and their thoughts on master protocols?
FDA has taken several steps to spur innovation in clinical trial design. FDA and other global regulators have an important responsibility to ensure that medicines are safe and effective. Making this determination is best done when there is timely and reliable evidence to inform the decision. Therefore, there is a shared objective across patients, regulators, drug development and clinical investigators to ensure that clinical trials are designed to provide this evidence.
For master protocols, the New England Journal paper in 2017 by Dr. Janet Woodcock and Dr. Lisa LaVange, “Master Protocols to Study Multiple Therapies, Multiple Disease, or Both,” was an important signal from leaders within FDA. The paper was followed by formal guidance from FDA on Master Protocols. In addition to the publications, FDA’s Complex Innovative Designs Pilot Program was another important accelerator for design innovation. The program allowed FDA to discuss innovative trial proposals with sponsors and share the non-proprietary learnings from these case studies more broadly.
Do you have any final thoughts to share?
It’s important to remember that drug development takes place at a global scale – we need to run global studies to achieve recruitment objectives and ensure that clinical trial participation aligns with the target patient population. Therefore, it’s important that innovation in trial design is not only embraced by FDA but that the methodologies are well understood by other global regulators. We have worked through EU PEARL, a public-private partnership supported by the Innovative Medicines Initiative, to help build that experience within the European context. The global response to the COVID-19 pandemic, including several important master protocol studies, also accelerated learning about master protocols, by necessity.