By Alycia Shilton-Lloyd, Ph.D., Imago BioSciences
Drug developers often talk about “patient centricity,” but most find it challenging to prioritize a patient-centric research approach in the earlier phases of drug development. While the majority of development teams understand that a patient’s experience living with a disease should inform treatment decisions, it has been challenging to hear directly from patients and incorporate their feedback into trial designs from the outset.
Drug approvals are based on validated measures of safety and efficacy. An effective drug is one that slows, halts, or even reverses clear clinical markers of disease activity. Assessments clinicians use to judge disease activity or progression, such as cardiac ejection fraction or the size of lesions in an image, are obvious measures of disease activity used to evaluate the efficacy of a treatment. But many assessments of disease activity are used because they are easily measured, convenient, cheap, or non-invasive. These metrics may not read directly on disease activity but are accepted surrogates. Further, the great majority of these assessments provide objective, numerical data. These metrics have historically been favored over subjective measures of the patient’s experience with the disease.
Biomarkers may reflect disease activity but often fail to reflect patient experience – this is particularly true for palliative treatments. For example, in patients with myelofibrosis, reduction in spleen volume was presumed to be a proxy for improvement in symptoms. An enlarged spleen, however, is not the cause of most reported symptoms; indeed, neither spleen size nor reduction in spleen size are associated with overall outcomes. It certainly is not useful as a sole measure of the impact of treatment on the patient experience.
This slow but steady evolution toward thinking about “effective” disease management from the perspective of the person living with disease has led to the subsequent creation and adoption of tools designed to measure the impact a drug has on a patient’s life due to a new drug regimen. This is best implemented by assessing clinical outcomes. Clinical outcome assessments (COAs) are questionnaires or diaries that capture how a patient feels and functions. These patient reported outcomes (PROs) can extend to the observer/caregiver of the patient (ObsROs) or a clinician (ClinROs). Innovative drug developers strive to incorporate the COAs that measure the most impactful changes in how a patient feels and functions into their clinical trials. But it has been difficult to generate tools that are validated and reliably measure what matters most to patients. This has led to many PRO assessments, and versions of those PROs, for the same disease state. Licensing and implementing the right PRO is complicated and expensive.
Regulatory authorities are placing greater importance on the patient experience in both trial designs and drug labeling. Use of a patient-centric drug development approach has advanced considerably with the help of the FDA. The FDA, along with input from private and academic groups, has issued guidance detailing how researchers can collect and submit COAs and other relevant information from patients and caregivers in a way that is in alignment with the agency’s regulatory decision-making. This four-part guidance series is intended to facilitate the advancement of patient-focused drug development and has involved the generation of numerous assessment tools designed to measure clinically meaningful changes in all aspects of the patient’s well-being over the course of treatment. The first guidance document was finalized and issued by the FDA in 2020, and the second document followed earlier this year. The agency is currently crafting the third guidance document titled Selecting, Developing or Modifying Fit-for-Purpose Clinical Outcomes Assessments. You can review the draft guidance here. These guidance documents are important as more of the patient’s experience becomes a part of the endpoint in clinical trials. A common theme echoed in workshops and draft presentations of the FDA’s third guidance document nearing publication is the importance of discussing with FDA and implementing patient-centric research practices as early as possible in the clinical study process.
Seeking Patient Perspectives
As discussed in the guidance documents, the perspective of the patient must be sought. The patient is the one best positioned to report on the personal experience of living with a specific disease or condition. Observers will invariably fail to capture the breadth and severity of the signs, symptoms, and other challenges that impact a patient’s life. A preponderance of studies has shown that clinicians underreport both the number and severity of symptoms a patient experiences and often prioritize their management differently than a patient would. For many conditions and disease states, treatment priorities that are most important to the patient have been captured in a Voice of the Patient report. These reports are the results of FDA-led Patient-Focused Drug Development (PFDD) meetings, externally led PFDD meetings, or Patient Listening Sessions for the disease or condition in question. All existing reports can be found on the FDA CDER Condition Specific Meeting Reports page.
A major challenge for drug developers is seeking out patient input early enough in the COA selection process so that the COA tools used capture the outcomes that matter most to the patient. It can be a daunting task to seek assurance from patients that the COAs you have selected are measuring the outcomes that matter most once you are far down the development pipeline – when the machinery of a robust protocol and clinical operation is well established. Using an existing Voice of the Patient report at the earliest stage of clinical development can help ensure you are on the right track in selecting meaningful COAs. If a PFDD meeting or Patient Listening Session has not yet been held for the disease or condition in question, partnering with patient advocacy groups to source this information early will be vital. A patient-centric approach includes both an ongoing dialogue with patients and ongoing research into which COAs are best for a particular upcoming trial.
We have hit a tipping point as an industry. We have access to patient insights, and we have more and more validated tools being developed to both measure these insights and decipher how well our drugs are meeting the patient’s expectations for the management of their disease. As part of this tipping point, we are seeing COAs show up more and more in protocols as co-primary or secondary endpoints with positive results as claims in labels. PROs have now played key roles in drug approvals in therapeutic areas as diverse as oncology, gastroenterology, and neurology. The importance of PROs in regulatory decision-making is crucial in allowing the patient impact of a new medication to be a part of the prescribing information and value story. This alerts the healthcare provider of that impact, facilitating the alignment of the physician’s treatment goals and those of the patient.
Tips for Implementing PFDD
I believe the best way to advocate for patient-focused drug development is to make it easy for others to follow suit. Here are six ways your organization can implement patient-focused drug development practices and begin incorporating COAs into your own trial protocols:
- Focus on treatments that can truly improve the lives of patients. This is an ambitious and challenging goal but consider the development of treatments that carry the prospect of providing significant clinical benefit. The goal should always be to develop medicines that leave a significant and lasting impact on patients. While incremental improvement is good, there are more than enough conditions that desperately need better treatments.
- Listen to your patients’ day-to-day experiences. Patients know what it's like to live with their condition and what they would regard as a clinical benefit. Understand their experiences and employ clinical development tools that measure the major issues affecting patients.
- Patients who feel better take their medicine. Compliance in clinical trials is a major factor in determining efficacy. It is also a major determinant of drug use in the real world. By documenting the improvement of subjective aspects of a trial outcome that reflect patients’ opinions, compliance and the adoption of the treatment will improve. You cannot make claims about what you don’t measure.
- Be open to sharing your insights. Patient-focused drug development is constantly evolving and sharing what we learn from payors, the FDA, healthcare providers, and patients will accelerate that evolution.
- Experiment with different tools. There are many tools one can use. It is not always obvious which ones to employ for a given treatment, a specific population of patients, or a specific trial design. Input from the FDA and other groups dedicated to advancing patient-focused drug development is readily available.
- Make your clinical progress accessible to the patients you are serving. Part of our practice at Imago BioSciences is to render our clinical trial results in plain English for the benefit of interested patients. This invites patients into the drug development process and offers Imago an additional opportunity to get feedback.
By identifying and leveraging patient-reported COAs into trial designs as study endpoints, life sciences companies can do a better job of developing impactful medicines that are truly patient-centric before being launched. A good place to start is by collectively measuring what matters most to patients — and COAs help get us there.
About The Author:
Alycia Shilton-Lloyd, Ph.D., is vice president of medical affairs at Imago BioSciences, a clinical-stage biopharmaceutical company discovering and developing new medicines for the treatment of myeloproliferative neoplasms (MPNs) and other bone marrow diseases. Alycia is leading the company’s patient engagement activities for bomedemstat, their novel LSD1 inhibitor.