Stakeholders want more clarity on concepts introduced in third PFDD draft guidance
The US Food and Drug Administration (FDA) received a broad range of comments concerning its draft guidance on selecting, developing, or modifying clinical outcome assessments (COA) in patient-focused drug development (PFDD), with most stakeholders wanting to know how new terminology introduced in the guidance would fit in with the agency’s overall PFDD program.
FDA’s draft guidance on COAs for PFDD is the third in a series of four guidances authored by staff members in the Center for Drug Evaluation and Research (CDER). The fourth guidance, currently in the public workshop stage, discusses incorporating COAs into endpoints that meet requirements for regulatory decision making. (RELATED: FDA’s first patient-focused drug development guidance now final, Regulatory Focus 17 June 2020; PFDD: FDA finalizes guidance on identifying what’s important to patients, Regulatory Focus 28 February 2022; PFDD: Draft guidance seeks to demystify clinical outcomes assessments, Regulatory Focus 30 June 2022)
Theresa Mullin, PhD, associate director for strategic initiatives within CDER and leader of the PFDD program at FDA, told attendees at a recent webinar hosted by the Alliance for a Stronger FDA that the intent behind the guidance documents is to “to further expand the opportunity to incorporate patient perspectives in drug development and decision-making and realizing.”
“We think the information in this PFDD series will really help patients, stakeholders and other researchers to address a number of important and challenging issues,” Mullin said in the webinar. (RELATED: CDER official reflects on a decade of patient-focused drug development, Regulatory Focus 19 September 2022)
New PFDD concepts, conflicting terminology
Many stakeholders commenting on the third PFDD draft guidance highlighted that FDA introduced new and overlapping concepts, and wanted more information about whether the agency intends this latest guidance to replace existing guidance such as the patient-reported outcome (PRO) measures final guidance released in 2009.
“We ask FDA to clarify this intent in the final draft of this guidance and indicate whether this will replace or expand upon both the 2009 PRO guidance for medical product development as well as the 2022 medical device-specific PRO guidance,” the Alliance for Regenerative Medicine wrote in their comment.
The draft guidance also caused some confusion for industry stakeholders looking to understand terminology discussed in the guidance. Janssen used the example of the word “measure” in their comment to FDA, which is “often used to mean the tool used to obtain observed data during a clinical trial.” However, the word has also been used as a synonym for “assess” or “evaluate” in other discussions and publications, including the current draft guidance, which can create confusion. “We recommend that FDA review all instances of the word measure(s) in the Draft Guidance and where the intended meaning is assess/assessment or evaluate/evaluation, change the phrasing to ensure consistency of use,” they said.
Pfizer explained that the concepts and terms brought up in the guidance “have been introduced with minimal context” and would benefit from explanation in relation to the existing 2009 PRO guidance.
“In the absence of more context and examples, it will be very challenging for sponsors to understand how to efficiently and effectively incorporate these new considerations into their development programs,” they wrote, recommending the agency elaborate on these definitions in their existing PFDD Glossary. “These enhancements will provide a common level of understanding and accelerate successful implantation of these principles.”
Discussion of digital health technologies
The concept of using digital health technologies (DHTs) to collect COA data were also brought up in multiple comments. Based on the current draft guidance, Advanced Medical Technology Association (AdvaMed) said it unclear whether it applies to DHTs regulated by the Center for Devices and Radiological Health (CDRH) or if it applies to DHTs used to support drug trials.
“Many DHTs are not regulated by FDA, and as such, if this guidance is intended to cover them, that needs to be made clear. Clarity on this point will be essential if the guidance is finalized with devices included,” they wrote.
Novartis wanted to understand how DHTs would be classified, using the example of an actimetry device capturing the mean number of daily steps but not meeting performance outcome standards. “We recommend that FDA consider how DHT and passively collected data can addressed in the COA framework,” they said.
Genentech asked FDA to take this concept a step further and make passive COA monitoring data collection its own COA type. “We believe a clearly defined 5th COA category, ‘Passive Monitoring COA’, will help stakeholders distinguish between the use of digitally captured data for use as a COA from sensor-capture of other measures (i.e., physiological parameters like body temperature) that can provide important evidence of disease status,” the company wrote.
Developing a conceptual framework
Stakeholders also wanted more clarity in the guidance on how to develop conceptual models for COAs.
“The guidance recommends development of a conceptual model for the health condition and a measurement model for the COA,” the International Advisory Committee on Clinical Trials in Multiple Sclerosis wrote. “However, this discussion is not entirely clear and would benefit from additional development and delineation.”
The Alliance for Regenerative Medicine said it’s unclear what FDA meant when they wrote that a conceptual model for a COA should be different from the measurement model. “There are often multiple concepts of interest, with potentially different inclusion in an endpoint hierarchy. A single concept of key relevance may be measured by a single domain of a multi-domain,” they explained. “Guidance is requested on what would be the expected evidence needed to support a single domain within a multi-domain PRO.”
In particular, the National Multiple Sclerosis Society (Society) noted that the agency should inform patients when concepts of interest are not used to develop a conceptual framework. “By not explaining this decision to participants, the sponsor and the FDA are ignoring patient feedback and may be decreasing the trust the participant has in the care they are receiving,” they said.
Use of other COAs
A few stakeholders wanted more information about how to have FDA recognize existing COAs through the agency’s COA Compendium and have sponsors use them in drug development programs.
“We request that FDA provide more information regarding the data that need to be submitted to support the use of an existing COA,” Genentech wrote. “Specifically, we ask whether prior data (e.g., patient interviews, evaluation of measurement properties) that was reviewed by the Agency in the context of a drug development program or through the qualification process would need to be re-submitted to the Agency or if Sponsors can refer to the COA Compendium or other sources.”
“It would be valuable to acknowledge at some point that every disease has organizations that have already, or are in the process of developing COAs to support research and clinical trials. It would be unfortunate for guidance to encourage those starting in a new disease to try to pursue COA development without collaboration with those who have created a foundation,” Boehringer Ingelheim wrote.
COAs for rare diseases
The National Organization for Rare Disorders (NORD) expressed concern that the guidance was too broad for stakeholders developing resources for patients with rare diseases to be effective partners in developing COAs.
“NORD is deeply concerned that this very technical and quite abstract guidance document will be too difficult to understand and implement for most rare disease patient and caregiver groups,” they wrote. “Based on NORD’s long-standing experience supporting rare disease patients, caregivers, and their advocacy organizations with education, research, data collection, and the organization of PFDD meetings and listening sessions, we urge FDA to adopt a multi-pronged strategy rooted in clear communication, implementation support, and educational best practices.”
The National Multiple Sclerosis Society echoed the concept of patients as partners in the COA development process.
“Although the Draft Guidance does a good job of describing how to identify patient priorities, patients come across as individuals to be studied rather than as active partners with regulators, investigators, and industry in the conceptualization, design, conduct, and evaluation of measures to be used in trials along with the design, conduct, and assessment of trials,” they said. “FDA should ensure that sponsors are viewing patients as an integral group instrumental to the success of all phases of a clinical trial. Engaging with patients early and often in the clinical trial development process is essential to understanding what is most important to patients.”
Draft guidance
FDA’s draft guidance on COAs for PFDD is the third in a series of four guidances authored by staff members in the Center for Drug Evaluation and Research (CDER). The fourth guidance, currently in the public workshop stage, discusses incorporating COAs into endpoints that meet requirements for regulatory decision making. (RELATED: FDA’s first patient-focused drug development guidance now final, Regulatory Focus 17 June 2020; PFDD: FDA finalizes guidance on identifying what’s important to patients, Regulatory Focus 28 February 2022; PFDD: Draft guidance seeks to demystify clinical outcomes assessments, Regulatory Focus 30 June 2022)
Theresa Mullin, PhD, associate director for strategic initiatives within CDER and leader of the PFDD program at FDA, told attendees at a recent webinar hosted by the Alliance for a Stronger FDA that the intent behind the guidance documents is to “to further expand the opportunity to incorporate patient perspectives in drug development and decision-making and realizing.”
“We think the information in this PFDD series will really help patients, stakeholders and other researchers to address a number of important and challenging issues,” Mullin said in the webinar. (RELATED: CDER official reflects on a decade of patient-focused drug development, Regulatory Focus 19 September 2022)
New PFDD concepts, conflicting terminology
Many stakeholders commenting on the third PFDD draft guidance highlighted that FDA introduced new and overlapping concepts, and wanted more information about whether the agency intends this latest guidance to replace existing guidance such as the patient-reported outcome (PRO) measures final guidance released in 2009.
“We ask FDA to clarify this intent in the final draft of this guidance and indicate whether this will replace or expand upon both the 2009 PRO guidance for medical product development as well as the 2022 medical device-specific PRO guidance,” the Alliance for Regenerative Medicine wrote in their comment.
The draft guidance also caused some confusion for industry stakeholders looking to understand terminology discussed in the guidance. Janssen used the example of the word “measure” in their comment to FDA, which is “often used to mean the tool used to obtain observed data during a clinical trial.” However, the word has also been used as a synonym for “assess” or “evaluate” in other discussions and publications, including the current draft guidance, which can create confusion. “We recommend that FDA review all instances of the word measure(s) in the Draft Guidance and where the intended meaning is assess/assessment or evaluate/evaluation, change the phrasing to ensure consistency of use,” they said.
Pfizer explained that the concepts and terms brought up in the guidance “have been introduced with minimal context” and would benefit from explanation in relation to the existing 2009 PRO guidance.
“In the absence of more context and examples, it will be very challenging for sponsors to understand how to efficiently and effectively incorporate these new considerations into their development programs,” they wrote, recommending the agency elaborate on these definitions in their existing PFDD Glossary. “These enhancements will provide a common level of understanding and accelerate successful implantation of these principles.”
Discussion of digital health technologies
The concept of using digital health technologies (DHTs) to collect COA data were also brought up in multiple comments. Based on the current draft guidance, Advanced Medical Technology Association (AdvaMed) said it unclear whether it applies to DHTs regulated by the Center for Devices and Radiological Health (CDRH) or if it applies to DHTs used to support drug trials.
“Many DHTs are not regulated by FDA, and as such, if this guidance is intended to cover them, that needs to be made clear. Clarity on this point will be essential if the guidance is finalized with devices included,” they wrote.
Novartis wanted to understand how DHTs would be classified, using the example of an actimetry device capturing the mean number of daily steps but not meeting performance outcome standards. “We recommend that FDA consider how DHT and passively collected data can addressed in the COA framework,” they said.
Genentech asked FDA to take this concept a step further and make passive COA monitoring data collection its own COA type. “We believe a clearly defined 5th COA category, ‘Passive Monitoring COA’, will help stakeholders distinguish between the use of digitally captured data for use as a COA from sensor-capture of other measures (i.e., physiological parameters like body temperature) that can provide important evidence of disease status,” the company wrote.
Developing a conceptual framework
Stakeholders also wanted more clarity in the guidance on how to develop conceptual models for COAs.
“The guidance recommends development of a conceptual model for the health condition and a measurement model for the COA,” the International Advisory Committee on Clinical Trials in Multiple Sclerosis wrote. “However, this discussion is not entirely clear and would benefit from additional development and delineation.”
The Alliance for Regenerative Medicine said it’s unclear what FDA meant when they wrote that a conceptual model for a COA should be different from the measurement model. “There are often multiple concepts of interest, with potentially different inclusion in an endpoint hierarchy. A single concept of key relevance may be measured by a single domain of a multi-domain,” they explained. “Guidance is requested on what would be the expected evidence needed to support a single domain within a multi-domain PRO.”
In particular, the National Multiple Sclerosis Society (Society) noted that the agency should inform patients when concepts of interest are not used to develop a conceptual framework. “By not explaining this decision to participants, the sponsor and the FDA are ignoring patient feedback and may be decreasing the trust the participant has in the care they are receiving,” they said.
Use of other COAs
A few stakeholders wanted more information about how to have FDA recognize existing COAs through the agency’s COA Compendium and have sponsors use them in drug development programs.
“We request that FDA provide more information regarding the data that need to be submitted to support the use of an existing COA,” Genentech wrote. “Specifically, we ask whether prior data (e.g., patient interviews, evaluation of measurement properties) that was reviewed by the Agency in the context of a drug development program or through the qualification process would need to be re-submitted to the Agency or if Sponsors can refer to the COA Compendium or other sources.”
“It would be valuable to acknowledge at some point that every disease has organizations that have already, or are in the process of developing COAs to support research and clinical trials. It would be unfortunate for guidance to encourage those starting in a new disease to try to pursue COA development without collaboration with those who have created a foundation,” Boehringer Ingelheim wrote.
COAs for rare diseases
The National Organization for Rare Disorders (NORD) expressed concern that the guidance was too broad for stakeholders developing resources for patients with rare diseases to be effective partners in developing COAs.
“NORD is deeply concerned that this very technical and quite abstract guidance document will be too difficult to understand and implement for most rare disease patient and caregiver groups,” they wrote. “Based on NORD’s long-standing experience supporting rare disease patients, caregivers, and their advocacy organizations with education, research, data collection, and the organization of PFDD meetings and listening sessions, we urge FDA to adopt a multi-pronged strategy rooted in clear communication, implementation support, and educational best practices.”
The National Multiple Sclerosis Society echoed the concept of patients as partners in the COA development process.
“Although the Draft Guidance does a good job of describing how to identify patient priorities, patients come across as individuals to be studied rather than as active partners with regulators, investigators, and industry in the conceptualization, design, conduct, and evaluation of measures to be used in trials along with the design, conduct, and assessment of trials,” they said. “FDA should ensure that sponsors are viewing patients as an integral group instrumental to the success of all phases of a clinical trial. Engaging with patients early and often in the clinical trial development process is essential to understanding what is most important to patients.”
Draft guidance
link
