Trial Better: A Clinical Trials Podcast

Introduction [00:55]

Nadeeka Dias and Chris Watson from ERT discuss the race for a coronavirus vaccine and take a deeper dive into how sponsors and CROs can use technology to address the unique challenges of vaccine trials.

What are the specific challenges sponsors face in trying to create a COVID-19 vaccine? [02:10]

The real challenge is that the threat is now, so time is not on our side. However, good clinical research takes time. Because there are currently no approved vaccines or treatments for COVID-19, researchers are working on two types of trials: trials to test treatments for patients who already have the disease and trials to test a COVID-19 vaccine.

Even though these vaccine trials are accelerated and researchers and the FDA are moving quickly, it’s still going to take a lot of time to find a vaccine that works. While collecting data in a COVID-19 vaccine trial is going to be similar to any other vaccine trial, patient recruitment will be harder and sponsors will have to ensure that patients who are enrolled aren’t asymptomatic.

What are the challenges that are unique to vaccine trials? [04:21]

Vaccine trials are often developed in response to a new plague. Because of this, clinical development teams need to collaborate quickly to mitigate trial risks and delays. These studies also require a lot of physician oversight of patient safety and adverse events. Additionally, because vaccine trials often enroll large numbers of healthy volunteers across diverse demographics, it’s important to be mindful about how sponsors will effectively collect a very large volume of data. Lastly, sponsors should consider how they can keep their patients engaged, especially as the vaccine trial transitions into a more observational phase.

What are the challenges of using paper in vaccine trials? [06:05]

Because paper is a quick way to respond to the needs of vaccine studies, paper has always been the default option for data collection in these trials. What isn’t always taken into account is the volume of data that will need to be transcribed from paper into a repository; a typical vaccine trial can produce millions of data points. This volume of data should convince sponsors to contemplate using electronic data collection.

What advice would you give sponsors still using paper in their vaccine trials?[07:27]

It’s important to consider the impact of still using paper not just on data collection but on data analysis. If all of the data is regularly uploaded into an electronic database, the sponsor will likely be able to get results quicker and achieve database lock sooner compared to using paper. An electronic platform also provides real-time access to patient data, making it easier for clinicians to monitor patient safety.

How can sponsors already using a digital solution improve their data collection?[08:45]

Electronic always gives you better data quality, but to maximize it, you need to remember the end user: the patient. Engage with patients and facilitate their journey within the clinical space so ultimately they’re providing the quality data you need to determine the results of the study.

Flexible provisioning or BYOD is an electronic solution that makes electronic data capture very affordable for vaccine studies and integrates well into the everyday lives of patients.

How can a sponsor get started with electronic data collection?[10:59]

If sponsors have reservations about starting to collect data electronically, they can always run a small pilot study in one particular territory using these techniques. Comparing the results in that territory to results in the others should make it clear whether or not a sponsor should pursue electronic data collection in their studies.

Once this data is collected, what tools are out there for sponsors to use to help them analyze and visualize the results?[12:15]

Instead of putting data into the system at the end of a study (as is done with paper data collection), data is added to the system throughout the study. A strong reporting platform that can support analysis of millions of data points and give you early insights into how the vaccine is progressing is critical.

What are the ways we can use digital to keep healthy volunteers engaged in vaccine trials?[13:25]

Incorporating technology into a well-thought-out study design can improve long-term patient engagement. A key motivator for patients is knowing that a clinician is reviewing the information they’re entering in their diaries. A digital solution can be beneficial here; concerning data can be quickly flagged and sites can easily maintain communication with patients.

Any final thoughts?[15:15]

The circumstances we’re in are...

What trends have you seen in respiratory in 2019?

In previous years, there were a number of blockbuster drugs developed for conditions like asthma and COPD. However, these drugs are beginning to move off-patent, so the industry is beginning to see studies for generics taking place. Because these blockbuster drugs are still on the market, sponsors are instead looking for new indications to apply these treatments to, where they might achieve small benefits. In order to find these incremental effects, the size of the study must increase. However, respiratory trials are not immune from the industry-wide patient recruitment issue. Additionally, these new products are fairly niche and respond to a small subset of patients; as drug companies are testing a lot of the same mechanisms, this leads to more competition for an already small patient population. The shift in clinical research towards personalized medicine continues to exacerbate the problem. Finally, this new search for small treatment effects requires very accurate data.

What do you anticipate respiratory drug development looks like in 2020 and beyond?

The key change is going to be a stronger focus on data quality and the importance of understanding exactly how the drug works in every individual patient. In order to do this, the challenge of data variability needs to be addressed by a shift towards research-grade quality lung function testing. This will allow the data to reflect small treatment effects. The updated ATS/ERS guidance published in October 2019 recognizes the importance of reducing data variability.

How does this new guidance and focus on reducing data variability affect the industry in general?

High quality data often comes with a higher cost but the potential rewards are huge, because data variability has an impact on every phase of development and can compromise decision-making and revenue potential. We’ve learned that the results of a trial can be undermined even if only 10% of the data is corrupt.

How did you end up in patient advocacy?

At the time of her first diagnosis, Deb was a computer company executive. Along with her husband (also a cancer survivor), she got involved with an oncology patient advocacy group. This was in the early 1990s when very little was known about effective cancer treatments, and she felt that this was important to change

Can you explain the role of a patient advocate?

A patient advocate contributes in a dramatic way to improve the experience of patients they don’t know through direct patient support, political advocacy, fundraising, and watchdog advocacy. A research advocate takes a long-term partnership approach. They focus on improving and speeding research results and ensure patient results and things that are important to the patient community, not just the scientific community, are a major focus.

Why do you believe it’s so important to speak up for the patient in clinical research?

Typically research has been all about science, product development, and regulatory compliance. No one has truly focused on the patient experience or the fact that the patient is the true end-user. This needs to change, and clinical research should set goals for finding better treatments, not just more, that give patients the improvements they’re looking for.

Do you find there’s usually a difference between the answers patients are looking for vs. answers sponsors are looking for?

While they are different, they can be considered together so we can get to the answer we’re all looking for. Companies may be focused on getting label approval from regulatory agencies, rather than the usefulness of this product and how it can fit into the rest of a patient’s life. This is where the patient voice is crucial, because it helps us complete the picture and cover aspects that are actually important to the patient community.

What are the risks of a lack of patient focus in clinical trial design, or in the industry at large?

Not recognizing the patient as the end-user can negatively impact the results patients get from a treatment. By involving patient advocates in the trial design process, sponsors can avoid or eliminate barriers that prevent individuals from enrolling in a clinical trial. Sponsors can also turn to adaptive trial design, which celebrated its 50th anniversary in 2019, as a potential way to improve the patient experience.

Does the method of incorporating patient centricity vary based on therapeutic area or indication?

It does vary. In oncology, for example, cancer is very multi-faceted; it can be chronic, life-threatening, acute, and so on). The type of cancer or patient situation can make a big difference in terms of what will be effective.

Currently, the industry approach to “patient centricity” still views the patient as a target to get data from. To address this, we need to start thinking “what’s in it for patients?” instead of “what’s in it for me (as a sponsor)?” Focus on patient needs ensures that regulatory and product concerns will also naturally be addressed.

Are there any advancements that you’ve seen improve the patient experience in the last few years, or any you anticipate to come? How can the industry implement these changes?

Things are definitely improving, and more people are understanding the difference in perspectives among trial stakeholders. However, the scientific and medical communities need to be more in line with the patient perspective of a “cure”. There also needs to be an increased recognition of the fact that clinical research is often an endurance test for patients, particularly when sponsors are looking to address retention or compliance issues.

Can you share an example of a sponsor who experienced some benefit after proactively choosing to keep the patient at the center of their trial?

A breast cancer study funded in part by the National Cancer Institute was the first trial that explored neoadjuvant therapy. Patient advocates were involved in the trial development process from the beginning. As a result, the study recruited patients quicker, required fewer amendments, cost less, and was completed faster. Bringing in patient advocates early was crucial to the trial’s success..

Do you have any final thoughts you’d like to share?

We’ve all heard the terms “real-world data” and “real-world evidence.” The concept is important and has a lot of promise, but we have to think about what’s in it for patients. A shift from real-world data (raw material), to real-world evidence (analytics) to real-world answers is key to addressing what patients, families, and doctors really need and want.

Intro

Dawn Patterson, ERT Director of Respiratory Solutions, is joined by Kevin McCarthy, ERT Clinical Overread Specialist and member of the ATS/ERS 2019 Spirometry Update Task Force. They’ll explore the implications of the October 2019 ATS/ERS update to their pulmonary function testing guidance. ERT was the only data and technology vendor involved in the update.

What are the ATS/ERS guidelines?

These guidelines represent what can be considered as worldwide standards that ensure the quality of pulmonary function measurements. This type of measurement is somewhat unique in that it requires a high degree of patient understanding and cooperation.

When were the ATS/ERS guidelines last updated?

Spirometry standards were first published 40 years ago, and updated approximately every 10-15 years since. The last time they were updated prior to 2019 was 2005.

How did you get involved in the task force that was responsible for updating the guidelines?

I was approached by the ATS/ERS to participate on a committee to develop an accreditation for pulmonary function laboratories. While working on that project, I was asked if I’d be interested in participating on the update task force.

How is this guidance used in clinical research?

Typically, ATS/ERS guidelines are incorporated in testing protocol for clinical trials. This is important in guaranteeing comparability of tests obtained from multiple global testing sites. In the 2019 guidelines, it’s specified that these standards represent the minimum criteria that must be met for clinical spirometry only - not necessarily for research or occupational surveillance. In clinical trials, sometimes the bar should be set higher.

What are the most important changes in the new spirometry guidelines?

One of the most important changes involves the recognition that the forced exhalation could be performed perfectly but still give erroneously low results. The new standards emphasize the need to look at the subject for feedback, and gives detailed guidance to site operators on how to vigorously coach patients to full inflation.

The new standards also stipulate that the procedure does not end with the forced exhalation. At the end of the forced exhalation, the subject is again vigorously coached to full inflation, allowing for a comparison to the FVC that allows operators to verify the forced exhalation started from full inflation.

In recognition that pediatric patients and patients with interstitial lung disease had difficulty in meeting end-of-test acceptability criteria, these acceptability criteria were redefined in a manner that accommodates the lung physiology of these groups.

Finally, the updated standards provide a new letter grading standard for acceptability based on the two main forced spirometry parameters. In the old standards, if an effort failed to meet the start of test criteria, the effort was considered to be unusable for reporting. In the new standards, an effort that is unusable for FEV1 may be acceptable for FVC and vice versa.

Are there any minor changes to the guidance that people need to look out for?

This document makes recommendations to the manufacturers about features that they should provide for the users of their testing equipment. One of the recommendations made was that the manufacturers provide standard lists of operator comments. These lists allow the operator to quickly select a comment from a list (in addition to adding free text) to provide insight and context about quality issues for study teams or physicians.

How will this new guidance impact sites and patients in respiratory clinical trials?

This new update of the spirometry standards will likely reduce the number of times a patient will have to perform the forced expiratory maneuver to achieve acceptability, improve data repeatability and improve data quality by verifying all efforts start from full inflation. This should result in a big win for sponsors, especially in studies involving pediatric patients and patients with interstitial lung disease.

Final thoughts:

There was an increased recognition of the importance of the operator administering the test in getting quality results. Operator training and the attainment and maintenance of competency must be integrated in any spirometry testing service.