Five strategies for success in complex, innovative rare disease trials

By Martin Roessner, Corporate Vice President, Biostatistics
Jamie Pierson, Project Leader, Parexel International

7 min

Five strategies for success in complex, innovative rare disease trials

Randomized, controlled trials (RCTs) can measure the efficacy of a single treatment in a single disease indication with maximum rigor and minimum bias. However, RCTs are often impractical for rare and ultra-rare diseases: only a small number of patients are available, the condition may be highly variable or poorly understood, and using placebo controls for rapidly progressive fatal illnesses is not ethical.

By contrast, a complex, innovative trial design (CID) can answer multiple questions about one or more compounds in one or more conditions or patient subgroups. Prespecified, “adaptive” modifications of the trial protocol can allow changes during the study based on interim data analyses. These adaptations can include sample size adjustments, dropping arms because of futility or safety findings, or enriching the target population. 
CIDs are well suited to rare diseases. They are efficient (enroll patients quickly), informative (yield more data about a treatment’s effects), and ethical (patients may be less likely to receive a placebo). They are also more complicated, costly, logistically challenging, and at greater risk of operational and analytical bias. 

At Parexel, we’ve found that innovative trial designs with adaptive elements are a demanding team sport. They require tight collaboration between biostatisticians, clinical operations, data management, medical experts, and project leadership. We’ve conducted dozens of CIDs, including more than 30 “basket” trials (which test one drug in multiple conditions), and we’ve learned from experience what works and what doesn’t. While some of our advice is common sense, many companies and clinical research organizations (CROs) struggle to execute these best practices with consistency and discipline.  Here are five of them:

Review risks for each cohort and across cohorts weekly

A master protocol can evaluate more than one drug in more than one patient population, and a basket trial can include several studies in one. But the risk management plan must be tailored to each indication or cohort. For example, if one arm enrolls pediatric or elderly patients, it will have risks specific to that cohort. A complex design involves running several trials simultaneously rather than sequentially, and it complicates risk review logistics exponentially.

At Parexel, a dedicated project risk lead oversees initial and ongoing risk management activities using a system-based risk assessment and categorization tool (RACT). The initial assessment identifies Critical to Quality (CtQ) factors essential to data integrity and patient safety for each trial cohort. Some CtQ metrics are specific to adaptive trial designs. For example, if the early withdrawal rate escalates, it can compromise the sample size and render results uninterpretable. If one or more cohorts of a trial expand to enroll more patients, there is a risk that newly enrolled patients won’t meet the inclusion criteria.  

Once risk metrics are defined, we develop an integrated risk management and mitigation plan that looks at each cohort separately and then at the overall picture. The centralized statistical data analysis plan focuses on key risk indicators (KRIs) and quality tolerance limits (QTLs) for adaptive trials. Risk management proceeds on a set schedule throughout the trial, and the RACT includes prespecified remediations if a risk emerges. Though the frequency of review is set at the study start, there is room for re-evaluation and flexibility. For adaptive and rare disease trials, reviews are typically performed at least once per week and more often, if needed, for each cohort and for the entire trial.

Clean data continuously

We’ve found that the traditional approach to data handling, which involved gearing up the analyst team to “clean” data before the database lock, is obsolete for CIDs. Trials with adaptive elements require precise planning for the data that will be needed at each stage. That data must be monitored, analyzed, and cleaned on an ongoing basis. Throughout these trials, sponsors must communicate with independent data monitoring committees (IDMCs) so that they can review the data and make timely decisions about stopping, modifying, or expanding the study to a new indication or patient population.

Continuous data cleaning requires tight coordination between data teams and clinical teams. At Parexel, we have adopted a data-cleaning approach that can deliver interim analyses to IDMCs with a minimal lag time after the last patient’s assessment. We have learned by experience that this is a prerequisite for IDMCs to make timely decisions. Smaller companies sometimes underestimate the data monitoring requirements of running an adaptive trial, and the frequent need for data cuts can quickly overwhelm their in-house staff. 

At Parexel, we find that only about 3% of data needs correcting or changing due to the source verification, data cleaning, and query process. Rather than deploying resources and expending effort on all the data, Parexel’s risk-based approach to data monitoring concentrates on critical factors, such as the project-specific QTLs and KRIs defined at the study’s start. We continually interrogate the data to spot emerging risks, mitigate them, and make decisions to protect the integrity of the dataset. 

Give sites comprehensive and dedicated support

Trials involving multiple cohorts can be challenging for sites. We provide considerable logistical and emotional support to study staff when they are enrolling many cohorts for one trial at a single site. This support requires extra time from our clinical research associates and project leads. Complex trial designs demand a more complex project management structure from sponsors and CROs.

For example, one Parexel client—a gene therapy company running a complex study in a rare disease—recently chose to retain an extra study coordinator assigned full-time to a single site to support the staff and avoid delays. As a result, they completed their study on time.

Before a CID trial begins, we determine what each site will need and set up a logistical infrastructure to give it the training and support for a successful trial. For example, one site might enroll pediatric and adult patients in separate arms in a rare disease multi-cohort study. The risks, doses, data collection schedules, informed consent materials, and other study documents will differ between the arms. We recently ran a trial with 14 cohorts, all of them in different cancer indications. Sites had to accommodate the different assessment schedules and dosing regimens while administering different standards of care based on the condition. Each arm of the trial had a specific risk management plan, and sites received support tailored to the cohort (or cohorts) they were enrolling and treating.

Closely track and manage patient onboarding

Patients with rare diseases often have rapidly progressive, terminal conditions. They are motivated to participate in a trial as soon as they qualify. For many, the trial represents the only treatment and follow-up care they will receive. And due to the small patient populations in rare disease trials, every patient’s data is much more valuable. Sponsors cannot afford to let problems with paperwork, site training, translation services, or study supplies disrupt patient enrollment and treatment. Knowing when you can onboard each patient into the study is critical, and there should be no delays.

At Parexel, we track the allocation of patient “slots” in each trial to achieve a streamlined progression from qualification to informed consent to the first treatment. We liaise with sites to project the timing accurately. We always have backup patients ready to fill in if a patient or site must change the schedule. In this way, we avoid disappointing patients and principal investigators (PIs), who have likely made promises to their patients about when they can join the trial.

We recently worked on a Phase 1 trial with three patient slots available for the first cohort. The sponsor and primary PI did not obtain Institutional Review Board approval on time at the site slated for the third and final slot. The patient lined up to take that slot was thus unable to enroll, and a patient from a different site enrolled instead. To address the PI’s and patient’s frustration and maintain a good relationship with the site, we rearranged the slot assignments and placed the site in line for the fourth patient slot in the trial once the IRB approval was in hand. It is critical to have the paperwork done on time and plan carefully to solve problems as they arise. 

Plan enough drug supply for every protocol permutation

Adapting a protocol to include a new arm or expand an existing arm can cause drug supply shortages, especially for expensive products with complex manufacturing procedures or limited supply. Recently, we conducted a trial in which a sample size re-estimation added 20 percent more patients. Unfortunately, the sponsor had not arranged for a sufficient quantity of drug to be available, and it was impossible to expand the trial immediately.

Frequent protocol changes require flawless supply chain logistics to avoid delays and disruptions in patient recruitment due to inadequate drug supplies. At Parexel, we scrutinize the drug supply plan of every protocol to ensure that, before the first patient enrolls in a trial, the drug supply will be adequate to cover every potential adaption of the protocol.

Recent FDA guidance documents and resources for complex, innovative trials

Topic Document
Extension of Complex Innovative Trial Design Program (October 2022) Complex Innovative Trial Design (CID) Paired Meeting Program
Final Guidance on Master Protocols (March 2022) Master Protocols: Efficient CLinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics
Extension of COmplex innovative Trial Design Program (October 2022) Expansion Cohorts: Use in First-in-Human Clinical Trials To Expedite Development of Oncology Drugs and Biologics

Emerging biotechs often struggle to execute CIDs in rare diseases

Locating and enrolling enough patients. Providing realistic development timelines to investors. Running out of money to fund the entire trial. These are some of the challenges emerging biotech companies often face in executing CIDs. The solutions to these problems require expert planning. At Parexel, we’ve helped clients design trial protocols with interim analyses at predetermined milestones to allow further fundraising for the next milestone. We’ve also helped them estimate how many patients with rare or ultra-rare diseases they must enroll to meet the regulatory requirements for evidence generation. And, based on our experience designing and running CIDs, we’ve helped create data-driven projections of study start-up, enrollment, treatment, and follow-up times for companies that must gain approval from a Board of Directors or Scientific Advisors.

Almost nothing we have described in these best practices is brand new. But in the exceptionally challenging environments of rare diseases and complex, innovative trials, errors, and oversights can quickly compound into costs, delays, and disappointments. These five strategies, effected by an experienced team with discipline and rigor, can keep a trial on track.

Contributing Experts