On October 1, 2019, FDA issued its second Patient-Focused Drug Development (PFDD) draft guidance – the next in a series of four methodological guidance documents, which discuss the collection of patient experience data to support decision-making related to drug development and approval (see some of our previous coverage of the evolving role of the patient voice over the years here, here, here, here, & here).
The first PFDD guidance more broadly discussed various methods for collecting patient experiences to help ensure they are accurate and representative of the intended patient population. This second guidance provides approaches to identifying what is most important to patients with respect to their experience as it relates to burden of disease and burden of treatment. Eliciting what is important to patients is valuable to drug development, as it is informative to the selection and, if necessary, development of clinical outcome assessments (COAs) for use in clinical trials, as well as determining what represents a clinically meaningful effect. However, it will be in the next two PFDD guidance documents that FDA discusses how to translate this information about what is important to patients to then identify, collect, and analyze data from COAs.
Where to Start?
The draft guidance explains that in order to understand what is most important to patients, you should begin with a good foundation in the disease and in currently available treatments. As such, literature reviews and consultation with subject matter experts can help establish this baseline characterization. Presumably, this includes patient advocates in addition to clinical researchers/KOLs. This informs the selection of the research question(s) and method(s). FDA acknowledges that there is no single preferred method, whether that be a qualitative, quantitative, or mixed-method approach. The draft guidance provides an array of data collection methods within each category, noting those that are most commonly used and providing recommendations for selecting and implementing them.
Recommendations for Qualitative Research
An Array of Qualitative Methods to Choose From
FDA highlights two qualitative methods as being most common: one-on-one interviews and focus groups.
- One-on-one interviews involve a discussion on the topic of interest between a patient or caregiver and a trained interviewer. The benefit is that interviews offer opportunities to explore topics in depth at an individual level using probing questions. They are also useful for exploring subject areas that might be too sensitive for a focus group. Interviews can vary in their degree of structure (i.e., use of predetermined questions and interview guide).
- Focus groups involve a discussion with a group of participants led by a moderator, allowing the exploration of issues both at an individual level and through a discussion among participants. This method allows for an understanding of a range of experiences. Sample sizes of focus groups typically range between 5-10 participants, which reduces the likelihood of multiple, simultaneous conversations occurring that decrease the effectiveness of the session.
A number of additional qualitative methods are described in Appendix 1 of the draft guidance, including:
- Facilitated discussions at patient meetings, similar to focus groups, provide a forum for a moderated discussion with patients and caregivers. The draft guidance specifically calls out the PFDD meeting format as the exemplar of this. While originally run by FDA, the Agency now invites patient organizations to host these meetings (called externally-led PFDD meetings). HP&M’s James Valentine and Larry Bauer have helped plan and moderated over two-thirds (20) of the 28 EL-PFDD meetings to date (see an FDA Law Blog post on learnings from these meetings here).
- Survey instruments with open-ended questions are viewed as a qualitative alternative to quantitative survey instruments that can help obtain answers that were unplanned or more realistic answers (quantitative survey methods discussed below).
Because the data from these qualitative methods can be so voluminous, the draft guidance raises the importance of having a standardized way to analyze and interpret this data in a practical and consistent way. Appendix 4 of the draft guidance discusses the steps for data analysis, including how to use a coding approach for categorizing and aggregating study results. This appendix also recommends that data collection continue until no new or important concepts have appeared, which is known as “saturation.” Once saturation is met, no further elicitation is needed.
What is the right question to ask?
FDA emphasizes the importance of collecting unbiased patient input, which means that it is critical to frame questions in a way that avoids biased or false/misleading responses. In general, the draft guidance recommends spontaneous responses over prompting participants (i.e., stimulating or providing a participant’s memories). However, prompts are viewed as valuable for gaining more information, particularly if the participant does not provide detailed responses. The draft guidance, however, states that prompts should avoiding leading questions, which include or imply the desired answer in the phrasing of the question.
Recommendations for Quantitative Research
FDA focuses on survey research methods as the primary approach to collecting quantitative data from patients and caregivers. Surveys can be interview-administered or self-administered, including by paper, telephone interactive voice response, or by computer. Of note, if a survey instrument is intended to be used to derive a study endpoint for use in a clinical trial, the draft guidance recommends that the two future PFDD guidance documents be referenced.
How to Develop Items for a Survey Instrument?
The draft guidance recommends that steps be taken to ensure survey items are well-understood. This includes assessing appropriateness for literacy of the population, using familiar language used by patients rather than clinical terminology, assessing translatability in multinational and multicultural studies, and testing through interviews of respondents on whether interpretation is as intended. Other recommendations include:
- Simple formatting for ease of use;
- Usability testing if electronic or web-based;
- Scripting to ensure standardization, if interviewer-administered;
- Assessing for potential social desirability bias (i.e., tendency to respond in manner they perceive may be viewed favorably by others);
- Assessing for applicability of the content; and
- Understanding impact of question ordering to avoiding priming by earlier questions.
Tables 3 and 4 of the draft guidance provide considerations for selecting various question types.
The draft guidance sets out a series of reasons that warrant using a mixed methods design:
- Harmonizing and confirming results from different methods;
- Supplementing and clarifying results from one method with those of another;
- Using results from one method to inform the design of another;
- Discovering inconsistencies, contradictions, and new perspectives; and
- Expanding scope of research question in different methods.
Depending on the specific utility of mixed methods, implementation may be either sequential or concurrent.
Eliciting Patient Input During Clinical Trials
While most of the draft guidance is devoted to methods of eliciting what is important to patients generally, FDA calls out one method that can add greater depth to understanding the patient experience during a clinical trial: patient exit interview studies. This innovative approach to using interview (or survey) methods was the subject of a commentary co-authored by HP&M’s James Valentine, published in Advances in Therapy (see an FDA Law Blog post covering this article here). FDA echoes the strengths of patient feedback that can be obtained using this approach, including:
- In rare diseases, contributing to the cumulative understanding of aspects of the patient experience;
- Informing initial development and refinement of COAs if done in early development;
- Adding greater depth to data in rare diseases where stand-alone qualitative studies are less feasible; and
- Obtaining input on meaningful outcomes or meaningful change as defined by the patient.
FDA calls attention to the burden this type of interviewing can be on site staff and patients/caregivers, as well as to the challenges with scheduling this could cause. To overcome these limitations, the commentary recommends utilizing a mobile app-based approach to remote self-interviewing using an embedded interview guide.
Additional Considerations for Specific Populations
One of the more thought-provoking sections of the draft guidance explores special considerations that should be examined when obtaining input from specific populations of patients and caregivers. This includes, but is not limited to, a patient population’s:
- Health status and the impact it may have on participation;
- Limited attention span (e.g., young children) and/or cognitive slowness (e.g., elderly)
- Geographic disbursement and whether to use remote assessment;
- Emotional burden (i.e., potential for heightened emotions, like anxiety);
- Need for stimulation to participate (e.g., asking young children to draw to help elicit concepts); and
- Stage in their disease course, because understanding and acceptance of prognosis change over time.
In addition, where patients can provide reliable self-reporting, the draft guidance states that it is generally preferable for the caregiver to not be present during an interview or, if needed in the room, to sit behind the patient to minimize influencing.
For caregiver reporting, the draft guidance recommends against proxy reporting (i.e., reporting as if they were the patient), but instead eliciting what caregivers observe in patients, including things patients tell them.
Can This Research Be Done on Social Media?
The final section of the draft guidance states that this patient experience data, regardless of method, can be collected using social media. FDA gives greater weight to such research that is conducted with communities that provide personal information (e.g., verified patient communities) to allow verification of personal characteristics (e.g., diagnosis). Other forms of social media lacking verification are open to data integrity and interpretation concerns.