Shifting Paradigms in PAH Clinical Trials: 7 Key Takeaways for Success

PAH research is shifting from development of drugs for symptomatic treatment to those that focus on disease-modifying medications. Clinical trials must adapt.

Pulmonary arterial hypertension (PAH) is a progressive and fatal lung disease that is caused or influenced by multiple factors. Historically, the available drugs and U.S. Food and Drug Administration (FDA)-approved therapies for treating PAH were primarily vasodilators, designed to overcome the imbalance between vasoactive and vasodilator mediators and to restore endothelial cell function. Though they do positively impact patients’ quality of life and hemodynamic parameters, these treatments — prostacyclin analogs and receptor agonists, phosphodiesterase 5 inhibitors, endothelin-receptor antagonists, and cGMP activators — have shown limited beneficial effects on survival and disease progression. None offers a cure for PAH.

Where the historical goal was to delay progression of the disease, more recent research focuses on new medications and disease-modifying therapies with potential for generating clinical improvements and, ultimately, reversal of the disease. Novel investigational medicinal products that target the underlying cause of disease induction and progression are fueling advancements in the treatment of PAH, with extensive work underway in several areas, including:

• Stem cell-based therapies
• Gene transfer
• Altered glucose metabolism
• Tyrosine kinase inhibitions
• Signaling pathways associated with disease-causing gene mutations (e.g., bone morphogenic protein receptor 2)
• Inflammation and immunomodulation, including the effects of mesenchymal stem cells and the extracellular vesicles they secrete
• Epigenetic modifications, including the roles of micro RNAs, DNA methylation, histone acetylation and transcription factors that modulate pulmonary vascular remodeling

Composite endpoints can compound complexity

Every clinical trial needs to define a certain number of critical endpoints to achieve adequate statistical power for a compelling assessment of a drug’s efficacy and safety. However, it is often the case that the smaller marginal benefit of new treatments leads to a reduction in relevant outcomes that can be used as endpoints. As a result, researchers now often use composite endpoints in lieu of the customary single primary endpoint.

Among the benefits of composite endpoints are smaller sample sizes and shorter follow-up periods needed to demonstrate effectiveness. Although statistically treated like a single primary endpoint, composite endpoints do provide unique challenges for patient care and can ultimately be detrimental if used or interpreted incorrectly.

Because there are no generally accepted standardized approaches to interpretation of composite endpoints, and one cannot simply evaluate a composite endpoint as if it were a single primary endpoint, it is critical that sponsors, clinicians and contract research organizations (CROs) devote adequate attention to defining these endpoints at the outset of the trial. Composite endpoints might include factors such as hospitalization, transplantation and worsening of clinical outcomes. Their early definition — as well as plans for recording and tracking — is a major factor in a trial’s success.

Six-minute walk distance and other factors

From a regulatory standpoint, some of the factors that are expected to be addressed in PAH trials include:

• Hemodynamic effect or the distribution of pressure and flow within the pulmonary system
• Objective assessment of functional exercise capacity, such as with the commonly used six-minute walk distance (6MWD)

In patients with PAH and other lung conditions, the absolute 6MWD and any change in the 6MWD are predictive of morbidity and mortality. And while 6MWD may compare well against cardiopulmonary exercise stress testing that requires complex equipment or technical expertise, this safe, low-complexity test can nevertheless be challenging to administer and assess. Measuring and tracking hemodynamic effect, meanwhile, is even more invasive as it requires right heart catheterization (RHC).

Global expertise and 7 key lessons learned

The PPD™ clinical research business of Thermo Fisher Scientific has extensive history working with PAH clinical trial sites globally (more than 3,500 sites across 53 countries in the past five years). The clinical sites working on these trials are highly experienced and have a deep understanding of the complexities of successfully running PAH clinical trials. As your CRO partner, we deliver equally dedicated and experienced teams that understand this disease and the range of assessments used for collecting endpoint data in PAH clinical trials.

The partnership between the sponsor and CRO should start as early as possible to align on study design and incorporate lessons learned. Work with sites should start during the feasibility stage, when focused, protocol-specific outreach assesses a site’s experience, access to relevant patient populations, competing trials and interest in participating. This can be accomplished in part with site-selection questionnaires designed to include sufficient detail to:

• Enable site teams to make an informed decision on trial participation
• Gather feedback to support the site selection process

With the advances in novel treatments for PAH and the associated development of novel endpoints, it is important to ensure that selected sites are familiar with the protocol requirements, study drug mechanism of action, and have the necessary experience and equipment to complete the required assessments.

We have a record of success with sites that have performed strongly on previous PAH studies, both in terms of recruiting and in generating high-quality endpoint data. From that experience, we offer seven key takeaways.

1. Complexity: PAH trial sites are complex and require highly experienced clinicians, researchers and support staff. By partnering with an experienced provider of clinical research solutions, you gain expertise built on decades of successful trials across the spectrum of infectious and respiratory diseases – giving your trial the know-how needed to forge ahead.

2. Composite endpoints: The use of composite endpoints reduces sample size and shortens timeframes, but interpreting the results can be difficult. To avoid misleading conclusions, it is important to carefully substantiate details such as clinical importance, frequency of events and the effect of the intervention on each component of the composite endpoint.

3. 6MWD: Successful collection of 6MWD data can be achieved by implementing robust assessment training that ensures consistency across sites, and by performing ongoing reviews of data to ensure quality is maintained throughout the trial. Periodic checks during trial conduct of site’s procedure/facilities for collecting 6MWD data will ensure ongoing confidence in data quality.

4. RHC: Right heart catheterization presents various challenges that can be addressed through specific solutions. For example, the interpretation of RHC data is complex and requires expertise. A preferred solution is to incorporate an over-read process, where experienced clinicians review and verify the data to ensure accuracy and consistency. Another challenge is the integration of RHC with echocardiography to obtain a comprehensive assessment of cardiac function. This can be addressed by implementing protocols that combine both procedures, allowing for a more comprehensive evaluation of the patient’s hemodynamics and cardiac structure/function. Additionally, it is essential to provide training and oversight of health care professionals performing RHC. Employing standardized training programs, certification processes and regular quality control measures ensures that personnel possess the necessary skills and adhere to established protocols. A trusted CRO partner enables you to navigate these challenges and improve the reliability and validity of right heart catheterization in clinical practice and research.

5. Cardiac MRI: Cardiac MRI poses certain challenges in PAH clinical trials, including the need for specialized equipment, expertise and patient cooperation. Obtaining high-quality images in PAH patients can be challenging due to factors such as right ventricular enlargement, motion artifacts and limited breath-holding capacity. Radiation exposure is another concern, especially when repeated imaging is required in longitudinal studies. Researchers can address these challenges with advanced imaging techniques, such as respiratory gating and image post-processing methods, to improve image quality. Minimizing radiation exposure can be achieved by utilizing low-dose protocols and considering alternative imaging modalities, such as echocardiography, when possible. Ensuring patient comfort and cooperation through proper education and communication is also crucial for obtaining reliable and meaningful cardiac MRI data in PAH clinical trials.

6. Patient recruitment: The rarity of the disease and the specific eligibility criteria make recruitment a challenge for PAH clinical trials. Strategies for successful recruitment include collaboration among multiple research centers and working with patient advocacy groups and health care providers to identify and refer potential participants. Additionally, leveraging technology and online platforms can reach a wider pool of eligible patients. Changes in the clinical trial landscape, such as the recent approval of new treatments, have led to increased awareness and interest among patients and physicians. This has facilitated recruitment efforts as patients are more likely to consider participating in trials to gain access to potentially life-changing therapies. To better attract and retain patients, regulatory agencies and research organizations are actively working to streamline trial processes, reduce administrative burdens and enhance patient engagement. These efforts collectively contribute to improving recruitment for PAH clinical trials and advancing the development of new treatments.

7. Investigator grant: It is important to ensure that investigator sites are properly recognized for the work done in compliance with applicable laws, regulations and ethical guidelines while working on complex protocols in a rare disease population. Maintaining open communication and promptly addressing any payment-related queries or concerns fosters a positive working relationship with the investigators. Adherence to internal financial controls and procedures, along with regular monitoring and audit processes, also ensures the appropriate allocation and management of funds for investigator grants in the PAH clinical trial.

When specialized respiratory expertise is a must

The success of PAH trials depends on the consistent and accurate collection of data to support the primary protocol endpoints required to support approval by regulators. Key endpoints in PAH trials include a variety of composite endpoints, including labor-intensive 6MWD and invasive RHC procedures — all of which require significant training and experience. The PPD clinical research business keeps pace with changing research landscape to ensure that your studies are put upon a path towards success and to overcome even the toughest challenges.

Understanding the nuances and complexities of respiratory research is vital for success. Our proven track record of success with PAH clinical trials is just one example of our deep expertise in respiratory research. Partner with us to gain access to our subject matter experts across a broad range of respiratory disease indications. Our end-to-end global capabilities — including site networks and investigators, regulatory support, integrated laboratory services, patient access, and digital and decentralized solutions — support your study from Phase I through peri-and post-approval.