1Day has been conducting a transparency experiment with offering a view into our development process for our “Operation Warp Speed 2.0” campaign. (Previous posts in this series here and here. Some more general background on our thinking here). In keeping with that, I wanted to post below a brief draft I put together of what I envision the FDA component of Warp 2 might look like. For background on existing expedited pathways, this FDA guidance document is quite useful. Comments and criticisms welcome!
Regulatory Acceleration of Next-Gen Coronavirus Vaccines
The FDA’s role in accelerating the development of COVID vaccines through Operation Warp Speed has not been properly recognized. Staff worked long hours to prioritize rapid processing of COVID trial submissions. The FDA conducted a streamlined review process, and steps of the process that are normally performed in sequence were parallelized to speed the development timetable significantly.
Summary: This memo assesses how the FDA and civil society groups could accelerate the regulatory consideration of pan-sarbecovirus and intranasal COVID vaccines. It proposes a “Warp 2 Pathway” for these products that includes faster entry into and exit out of Phase 1 and multiple options for proof of surrogate biomarkers to establish relatively narrow emergency use authorization designed to allow for rapid confirmatory trials before broader authorization and licensure. To implement this pathway and reliably approve safe and effective candidates, supporting programs are envisioned including a centralized “Warp 2” office within the FDA featuring greater pay for staff, additional resources for CBER to create advance policy guidance including correlates of protection, and a well-funded process to commission research on regulatory science issues common to multiple candidates such as questions concerning the neurological safety of intranasal vaccines. Finally, assisting outside efforts are envisioned including pseudo-trade associations representing the interests of pan-sarbeco and intranasal developers.
The Warp 2 Pathway
In Operation Warp Speed, initial human testing of candidates was approved on an accelerated basis (often in the absence of animal data) and phase 2⁄3 studies began before a full readout of phase 1 became available. The regulatory bandwidth provided to these studies was massively heightened, with staff working around the clock to review submissions. A Warp Speed 2.0 should imitate this method while building off existing accelerated review pathways and adapting for present circumstances.
Pathway Outline: The process envisioned would include:
Rapid submission response times;
Ability to enter phase 1 with relatively limited pre-clinical data;
Ability to enter phase 2 after presentation of 4-6 weeks worth of phase 1 participant safety data;
Testing larger scale safety (2000-4000 participants) separately from establishing efficacy or surrogate markers of efficacy;
Multiple options to establish sufficient proof of efficacy for emergency use authorization including:
predicted correlates of protection based on pre-clinical and clinical studies;
human challenge studies; and
accelerated phase 2 / 3 study designs;
Design of emergency use authorization in healthcare workers and high risk populations to facilitate rapid confirmatory study designs (including potential integration into the annual flu vaccine process) to rigorously demonstrate efficacy prior to broad rollout; and
Rolling review of submission components.
Supporting Programs within FDA
To safely and effectively execute the steps above, the following options are envisioned:
Specialized Division within CBER: Designating a core team of reviewers devoted to Warp 2 who receive 1.5x their normal pay in exchange for working longer and more flexible hours. Reviewers outside the core team assisting on submissions would also receive 1.5x pay for the hours spent working on these projects.
Expanded Advance Guidance on Key Questions: Increasing funding for CBER’s policy development function would allow for guidance to be published proactively on questions like safety, confirmatory trial designs, and correlates of protection to provide clarity on the vaccine approval process.
Studies to Answer Broadly Relevant Questions: Funding and developing a capacity to commission studies to answer questions relevant to a class of candidates (such as neurological safety of intranasal vaccines or methods) would allow for improved guidance and an economy of scope beyond what individual developers can manage on their own.
Supporting Efforts Outside FDA
Civil society and other governmental entities could assist with inputs into the regulatory process.
Pseudo-Trade Association of Developers: Assembling developers of intranasal and pan-sarbeco vaccines to identify common needs and advocate for solutions.
Target Product Profile: Working with the WHO or another body to publish target product profiles that could provide clarity to developers and regulators on criteria and evidence needed for approval.
Correlates of Protection: Creating a panel of vaccinologists, former regulators, and other scientists to publicly elucidate correlates of protection that could be used for authorization based on pre-clinical and clinical data.
Research Participant Corps: Recruiting a group of highly motivated, well-educated, and pro-social research participants to participate in early trials could bridge uncertainty and potential safety issues with accelerated entry into early phase studies by ensuring informed consent.
Sketch of a Warp 2 Regulatory Pathway
1Day has been conducting a transparency experiment with offering a view into our development process for our “Operation Warp Speed 2.0” campaign. (Previous posts in this series here and here. Some more general background on our thinking here). In keeping with that, I wanted to post below a brief draft I put together of what I envision the FDA component of Warp 2 might look like. For background on existing expedited pathways, this FDA guidance document is quite useful. Comments and criticisms welcome!
Regulatory Acceleration of Next-Gen Coronavirus Vaccines
The FDA’s role in accelerating the development of COVID vaccines through Operation Warp Speed has not been properly recognized. Staff worked long hours to prioritize rapid processing of COVID trial submissions. The FDA conducted a streamlined review process, and steps of the process that are normally performed in sequence were parallelized to speed the development timetable significantly.
Summary: This memo assesses how the FDA and civil society groups could accelerate the regulatory consideration of pan-sarbecovirus and intranasal COVID vaccines. It proposes a “Warp 2 Pathway” for these products that includes faster entry into and exit out of Phase 1 and multiple options for proof of surrogate biomarkers to establish relatively narrow emergency use authorization designed to allow for rapid confirmatory trials before broader authorization and licensure. To implement this pathway and reliably approve safe and effective candidates, supporting programs are envisioned including a centralized “Warp 2” office within the FDA featuring greater pay for staff, additional resources for CBER to create advance policy guidance including correlates of protection, and a well-funded process to commission research on regulatory science issues common to multiple candidates such as questions concerning the neurological safety of intranasal vaccines. Finally, assisting outside efforts are envisioned including pseudo-trade associations representing the interests of pan-sarbeco and intranasal developers.
The Warp 2 Pathway
In Operation Warp Speed, initial human testing of candidates was approved on an accelerated basis (often in the absence of animal data) and phase 2⁄3 studies began before a full readout of phase 1 became available. The regulatory bandwidth provided to these studies was massively heightened, with staff working around the clock to review submissions. A Warp Speed 2.0 should imitate this method while building off existing accelerated review pathways and adapting for present circumstances.
Pathway Outline: The process envisioned would include:
Rapid submission response times;
Ability to enter phase 1 with relatively limited pre-clinical data;
Ability to enter phase 2 after presentation of 4-6 weeks worth of phase 1 participant safety data;
Testing larger scale safety (2000-4000 participants) separately from establishing efficacy or surrogate markers of efficacy;
Multiple options to establish sufficient proof of efficacy for emergency use authorization including:
predicted correlates of protection based on pre-clinical and clinical studies;
human challenge studies; and
accelerated phase 2 / 3 study designs;
Design of emergency use authorization in healthcare workers and high risk populations to facilitate rapid confirmatory study designs (including potential integration into the annual flu vaccine process) to rigorously demonstrate efficacy prior to broad rollout; and
Rolling review of submission components.
Supporting Programs within FDA
To safely and effectively execute the steps above, the following options are envisioned:
Specialized Division within CBER: Designating a core team of reviewers devoted to Warp 2 who receive 1.5x their normal pay in exchange for working longer and more flexible hours. Reviewers outside the core team assisting on submissions would also receive 1.5x pay for the hours spent working on these projects.
Expanded Advance Guidance on Key Questions: Increasing funding for CBER’s policy development function would allow for guidance to be published proactively on questions like safety, confirmatory trial designs, and correlates of protection to provide clarity on the vaccine approval process.
Studies to Answer Broadly Relevant Questions: Funding and developing a capacity to commission studies to answer questions relevant to a class of candidates (such as neurological safety of intranasal vaccines or methods) would allow for improved guidance and an economy of scope beyond what individual developers can manage on their own.
Supporting Efforts Outside FDA
Civil society and other governmental entities could assist with inputs into the regulatory process.
Pseudo-Trade Association of Developers: Assembling developers of intranasal and pan-sarbeco vaccines to identify common needs and advocate for solutions.
Target Product Profile: Working with the WHO or another body to publish target product profiles that could provide clarity to developers and regulators on criteria and evidence needed for approval.
Correlates of Protection: Creating a panel of vaccinologists, former regulators, and other scientists to publicly elucidate correlates of protection that could be used for authorization based on pre-clinical and clinical data.
Research Participant Corps: Recruiting a group of highly motivated, well-educated, and pro-social research participants to participate in early trials could bridge uncertainty and potential safety issues with accelerated entry into early phase studies by ensuring informed consent.