HHS “Operation TrialBlazer”: FDA Moves to Accelerate and Modernize Clinical Development

On June 22, 2026, the U.S. Department of Health and Human Services (HHS) announced the launch of Operation TrialBlazer, a coordinated effort across multiple HHS agencies and divisions aimed at strengthening American leadership in clinical research. The initiative responds to the growing migration of clinical research, particularly early-stage research, to locations outside the U.S., including China. A Roadmap published the same day emphasizes the importance of making the U.S. a more attractive location for clinical research and describes how HHS plans to address the “unnecessary delays, redundant requirements, and regulatory ambiguity that currently slow and disincentivize U.S.-based development.”

As part of Operation TrialBlazer, FDA announced a number of actions intended to streamline and modernize drug development across the development continuum, from Investigational New Drug (IND) submission to late-stage pivotal trials. These actions, consistent with the goals of Operation TrialBlazer, are aimed at “eliminating unnecessary regulatory burden, clarifying phase-appropriate requirements, and building partnerships with government, academic medical centers and the private sector.” Key FDA actions across the clinical development lifecycle include:

1. Proposed Expedited IND Pilot Program: FDA proposed and seeks stakeholder feedback on a voluntary pilot program, where drug sponsors would partner with third-party “qualified research institutions” in developing Phase 1 IND submissions, using a rolling IND submission platform, with the goal of improving IND submission quality and speeding authorization to proceed to clinical trials.
2. Phase 1 IND Chemistry, Manufacturing, and Controls (CMC) Flexibilities: FDA posted a webpage clarifying its expectations on what CMC-related data are required for Phase 1 INDs, and what information can be provided later in development, with the goal of speeding time to IND submission by helping sponsors avoid unnecessary generation and submission of CMC data to support the application.
3. Phase 1 Contact Center: FDA established a contact center to which sponsors can submit early-phase trial questions, and specialists will respond in real time and facilitate connections to agency subject matter experts as necessary.
4. Draft Guidance on Dose Selection for First-In-Human (FIH) Clinical Trials: FDA published draft guidance addressing use of a quantitative systems pharmacology approach to select an appropriate dose for FIH Phase 1 trials.
5. Revised Draft Guidance on Substantial Evidence of Effectiveness: FDA issued significantly revised draft guidance on substantial evidence, clarifying the circumstances in which drug developers may be able to rely on one adequate and well-controlled clinical trial plus confirmatory evidence to support approval.
6. Revised Draft Guidance on Master Protocols: FDA published revised draft guidance providing recommendations on designing, analyzing, and submitting trials conducted under a master protocol, such as basket trials, umbrella trials, and platform trials.

In addition to the actions announced by FDA, the HHS Roadmap accompanying Operation TrialBlazer lists future FDA initiatives that the biopharmaceutical industry should keep on its radar, including:

• Plans to make the IND clinical protocol amendment process more transparent and efficient, including by implementing a real-time status tracker so that sponsors can view the status of protocol amendments submitted to FDA;
• A potential rulemaking to require a single Institutional Review Board (sIRB) to serve as the “IRB of record” for multi-site cooperative studies in order to streamline and harmonize IRB review without reducing oversight; and
• Future collaboration with other government agencies and relevant stakeholders to make it easier for patients and clinicians to participate in clinical trials, including by continuing to advance guidance on embedding randomized controlled trials (RCTs) into routine clinical care (a topic on which FDA released draft guidance in 2024, which we discussed in a previous Alert).

This Alert provides details on FDA’s actions to date as part of Operation TrialBlazer, focusing on key issues for sponsors, contract research organizations, clinical researchers, investors, and other stakeholders in the drug development process.

For more information on the HHS Roadmap and actions undertaken or planned by other HHS agencies besides FDA, see our companion Alert.

Expedited IND Pilot Program

On June 24, FDA published a Request for Information (RFI) in the Federal Register describing and seeking stakeholder input on its proposal for an “expedited IND” pilot program. Under the proposed pilot, FDA would establish a network of Qualified Research Institutions (QRIs)—including academic medical centers, health care networks, contract research organizations, regulatory advisors, and other research or third-party review organizations—to serve as “expert partners” for participating drug sponsors to improve the quality of IND submissions for Phase 1 FIH clinical studies. QRIs would assess and make recommendations for the pharmacology and toxicology, clinical, and CMC components of the IND submission. In addition, QRIs would support participating sponsors in initiating clinical trial initiation activities, such as IRB review and clinical trial site activation, in parallel with the IND process to facilitate timely trial initiation.

QRIs would serve in a purely advisory capacity during the pilot. Sponsors would maintain ownership of their IND submission, and FDA would remain solely responsible for all regulatory decision-making regarding INDs. FDA would, however, have visibility into QRI recommendations. As part of the pilot, FDA plans to implement a rolling submission platform, which would enable FDA to review QRI recommendations on completed individual IND components prior to submission of the entire IND. Although the 30-day IND review clock would begin only after submission of all IND components, FDA posits that rolling review may expedite FDA’s decisions on Phase 1 FIH INDs and reduce the likelihood FDA would need to impose a clinical hold. It would also allow FDA to monitor QRI performance, which would inform development of a potential process for QRI certification by FDA following the pilot.

In addition to describing the proposed contours of the expedited IND pilot program, FDA poses numerous questions in the RFI seeking stakeholder input on aspects of the pilot, including QRI qualification and oversight, processes for QRI review of INDs and pre-IND materials, scope and scale of the pilot, feasibility, and risks. FDA also seeks suggestions on potential alternative approaches to accelerate Phase 1 FIH IND study initiation in the U.S. The RFI is open for public comment until July 22.

At this point, the specifics of the expedited IND pilot program and how it would be implemented are unclear. For example, there is very limited detail on how FDA proposes to select or qualify QRIs for participation in the pilot, how many QRIs may participate, or how their performance would be measured. The ultimate benefits of the proposed expedited IND program may also be fairly limited depending on how it is implemented. If rolling review is only available to sponsors who work with QRIs, for example, then there would be little benefit to biotech companies that choose not to work with QRIs (e.g., because they have sufficient internal expertise to support IND development). Further, for those sponsors that do work with QRIs, the potential time savings provided by rolling review must be weighed against the potentially longer pre-IND process, including the time and cost to engage and participate in collaborative review with a QRI prior to undergoing FDA review.

Notably, in its April budget request to Congress for FY2027, FDA proposed creating an “optional, risk-based Expedited IND pathway for certain Phase 1 clinical trials where there is existing preclinical data that can potentially satisfy the regulatory standard with validated new approach methodologies.” The proposal envisions Congress amending Section 505 of the FDCA to create this new pathway. The proposed pilot program and the budget request use the same “expedited IND” terminology. However, the descriptions of the two programs are markedly different, and it is not clear if (or how) the two proposals are connected.

Phase 1 IND Clarifications and Flexibilities

In addition to the proposed expedited IND pilot program, FDA also took several steps to clarify its current expectations and processes for Phase 1 FIH INDs. These actions include updating the FDA webpage addressing CMC requirements for CDER-regulated drugs, consolidating information on Phase 1 IND requirements on a new “Phase 1 IND Navigator” webpage, and creating a new Phase 1 Contact Center within FDA to answer sponsor questions about clinical protocols, regulatory requirements, and other early-phase trial considerations.

FDA’s updated CMC webpage may serve as a particularly useful resource for sponsors planning and preparing INDs. Specifically, the webpage now spells out FDA’s expectations and flexibility regarding CMC requirements for Phase 1 FIH IND applications, with the goal of helping companies generate and submit only the data that are needed. FDA asserts that this is key to expediting development, because sponsors often submit more CMC information than is necessary at the FIH Phase 1 IND stage. FDA estimates that focusing on minimum requirements to ensure phase-appropriate CMC information is provided could reduce application development time by 6-12 months.

FDA highlights several examples of CMC clarifications and flexibilities that could help expedite time to Phase 1 FIH IND for sponsors, including:

• Stability data from the specific clinical lot to be used may not be required.
• The initial stability data may not need to cover the full duration of the proposed clinical studies.
• Analytical method validation data are not expected.
• Process controls that are not directly related to product safety are not expected to be specified.

The webpage includes two detailed charts describing CMC regulatory flexibilities and clarifications for small molecule drug products and recombinant biological products. For each regulatory requirement, FDA describes its general expectations and lists specific CMC flexibilities and CMC information generally not needed at the time of FIH Phase 1 IND.

The CMC webpage represents a continuation of FDA efforts to clarify CMC requirements and regulatory flexibilities, including through guidance released in May 2026 addressing “Chemistry, Manufacturing, and Controls Flexibilities for Developing Human Cellular and Gene Therapy Products for a Biologics License Application.” By clarifying its expectations for CMC information in Phase 1 FIH INDs, FDA hopes to reduce time spent prior to IND submission generating CMC information that could be developed at a later stage, allowing sponsors to submit applications earlier and dose patients sooner, and ultimately accelerating drug development timelines. 

Dose Selection Draft Guidance

Also on June 24, FDA issued new draft guidance, entitled “Quantitative Systems Pharmacology (QSP)-Based Dose Selection for Minimum Anticipated Biological Effect Level (MABEL) in First-in-Human (FIH) Trials.” The draft guidance discusses how sponsors can use a QSP-based approach to help select the appropriate starting dose for FIH clinical trials when a MABEL is recommended. QSP uses mathematical modeling, disease characteristics, and drug-biological system interactions to determine the appropriate dose of a drug given to humans. FDA characterizes the draft guidance as part of its continuing efforts to move away from historical methods of using animal toxicology studies to select the FIH dose and toward drug development informed by quantitative modeling and simulation.

The guidance lays out general principles for using QSP in FIH dose selection (e.g., considering relevant data, accounting for species-specific differences, understanding model uncertainties) and provides recommendations for QSP modeling practices across the model construction, verification, application, analysis, and refinement stages. The guidance is open for public comment until July 24, 2026.

Substantial Evidence of Effectiveness Draft Guidance

Whereas much of HHS’s and FDA’s discussion regarding Operation TrialBlazer focuses on bringing early-phase clinical trials back to the U.S., some FDA actions also are intended to modernize and streamline regulatory requirements for later-stage product development. Significantly, FDA published revised draft guidance on “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products.” The draft guidance revises a 2019 draft and would replace FDA’s 1998 guidance on “Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products.” A separate 2023 draft guidance, entitled “Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence,” remains in place, though it is not cross-referenced in the revised substantial evidence draft guidance, and FDA’s Federal Register notice notes that it may take “further action regarding the 2023 draft guidance” in consideration of stakeholder comments it receives.

The revised substantial evidence draft guidance describes FDA’s thinking on how sponsors submitting drug and biological product applications can satisfy the statutory “substantial evidence of effectiveness” standard necessary for approval.  The draft guidance represents a significant rewrite of the 2019 draft, reflecting recent FDA movement toward considering a single adequate and well-controlled clinical investigation plus confirmatory evidence—rather than two adequate and well-controlled studies—as the norm to satisfy the substantial evidence standard. New introductory content in the draft guidance explains that the updates reflect that “[a]dvances in our understanding of biological processes and the increasing availability of high-quality data have transformed the evidentiary landscape for drug development.” The revisions follow an article published by former FDA Commissioner Martin Makary and former CBER director Vinay Prasad earlier this year in the New England Journal of Medicine, which announced that FDA was “ending the two-trial dogma” and switching to a one trial “default standard” when it comes to drug approval.

The revised draft guidance does not explicitly change the “default” requirement to a one-trial standard. Nonetheless, the increased emphasis on the “one adequate and well-controlled investigation plus confirmatory evidence” approach is significant. The draft guidance now lists this as the first option for meeting the substantial evidence standard and provides more detail on how FDA will assess whether a single trial plus confirmatory evidence is sufficient to support approval. Ultimately, regardless of the number of trials conducted, FDA explains that whether sponsors have satisfied the substantial evidence standard will depend on the strength of the evidence provided. In assessing the strength of the evidence, FDA considers factors such as clinical trial design (e.g., control, population selection, randomization, blinding, endpoints), quality of trial conduct (e.g., completeness of follow-up and missing data), aspects of the trial analysis (e.g., pre-specification, analysis assumptions), the clinical and statistical persuasiveness of trial results, and aspects of the overall drug development program.

FDA expects that a one trial approach to providing substantial evidence will involve either “a highly persuasive adequate and well-controlled trial” or “a source of strong confirmatory evidence,” though the draft guidance notes there may also be specific circumstances where additional regulatory flexibility may be available.

• A highly persuasive trial is one that (i) is designed to provide information that is generalizable and relevant to clinical practice in the United States (e.g., it enrolls a broad and representative population across multiple sites and uses a control arm that reflects current standard of care); (ii) uses a clinically meaningful primary endpoint (e.g., irreversible morbidity or mortality) and has sufficient power to convincingly demonstrate an effect; (iii) generates primary results that are clinically and statistically highly persuasive (e.g., based on magnitude of benefit and p-value), as well as supportive secondary endpoint results and results across important subgroups; and (iv) was well-conducted (e.g., minimal missing data). Where the single adequate and well-controlled trial is highly persuasive, “it is expected that the available early-phase information used to support proceeding to such a trial may be able to provide sufficient confirmatory evidence.”
• Strong confirmatory evidence generally would come from “related adequate and well-controlled trial data, such as trial data in related diseases or conditions or for related products.” FDA acknowledges there may be legal and regulatory concerns with relying on its finding of safety or effectiveness for related products, particularly where the related product is not owned by the sponsor or subject to a right of reference. In the NDA context, such reliance may convert the application to a section 505(b)(2) application. In the biological product context, it would not be possible to rely on FDA’s previous determination of safety, purity, and potency for another product to support approval of a section 351(a) BLA, and the applicant would need to meet applicable requirements under the section 351(k) biosimilar pathway.   
• Regulatory flexibility is discussed at length in the revised draft guidance. Consistent with FDA’s existing practice and the 2019 draft guidance, FDA explains that it exercises flexibility in applying the substantial evidence standard in “certain critical settings,” where “a somewhat greater uncertainty about effectiveness may be warranted when balanced against the risk of rejecting or delaying the marketing of an effective therapy.” FDA goes on to explain that there is no single set of clinical considerations that lead to the application of flexibility, and there is no single definition of what constitutes a flexible approach, but provides familiar examples of each. For example, factors relevant to assessing whether flexibility is appropriate include disease severity, unmet need, and disease rarity. FDA may exercise flexibility both with respect to the single adequate and well-controlled clinical trial (e.g., to accept external controls, primary endpoints that may be more susceptible to bias or difficult to interpret, or a prespecified significance level higher than the common one-sided 0.025 level) and with respect to confirmatory evidence (e.g., to accept sources like mechanistic data and natural history data).

Throughout the revised draft guidance, FDA emphasizes the importance of communication with the agency. FDA recommends that sponsors discuss their planned approach to demonstrating substantial evidence with FDA early in development, such as at a pre-IND meeting, and no later than at an end-of-phase 2 meeting, prior to initiating an adequate and well-controlled trial intended to support approval. 

It remains to be seen the extent to which the policies articulated in the revised draft guidance will ultimately impact FDA’s approach to evaluating new drug and biological product applications. It is possible that the revisions largely reflect what has already become regular FDA practice in recent years, with many novel drugs having been approved by FDA on the basis of a single pivotal trial. And, as with all FDA guidance, the policies are open to interpretation, and whether it will be applied uniformly across FDA reviewers is an open question. Comments on the draft guidance are due by September 22, 2026.

Master Protocol Draft Guidance

A second later-stage trial-focused action was FDA’s issuance of revised draft guidance on “Master Protocols for Drug and Biological Product Development.” The draft guidance significantly revises and expands on draft guidance issued in 2023. A key update is the addition of much more detailed information related to basket trials (i.e., trials that evaluate one drug for multiple diseases, conditions, or disease subtypes), which had been limited in comparison to information on umbrella and platform trials (i.e., trials that involve the evaluation of multiple drugs). In alignment with the objectives of Operation TrialBlazer, FDA touts the potential of master protocols to reduce duplicative clinical trial infrastructure, streamline data collection, and accelerate the generation of evidence needed to support regulatory decision-making.

The draft guidance provides recommendations on the design and analysis of trials conducted under a master protocol as well as guidance on associated regulatory submissions, much of which has been revised and clarified in response to stakeholder comments on the 2023 draft guidance. The focus is on clinical trials utilizing a master protocol design that are intended to contribute to a demonstration of safety and substantial evidence of effectiveness, though FDA notes that the concepts in the draft guidance may also be useful for earlier-phase and post-approval studies conducted under a master protocol. The guidance is open for public comment until August 24, 2026.

Conclusion

The ultimate impact of the actions described in this Alert and future initiatives as part of Operation TrialBlazer remains to be seen. The initiative highlights the growing consensus within FDA and other HHS agencies that regulatory reforms to modernize the U.S. clinical trial infrastructure are critical in an increasingly competitive global environment. Regulatory authorities outside the U.S. are taking similar steps, initiating reforms aimed at making their nations a more attractive location for drug development and clinical research. In April 2026, for example, new regulations in the U.K. entered into force, representing a significant overhaul of the U.K. clinical trial regime. We discussed the U.K. reforms in a prior Ropes & Gray Alert. As the regulatory environment continues to evolve, sponsors and other stakeholders involved in drug development in the U.S. and globally should stay abreast of developments and opportunities to provide input on reform efforts.

Ropes & Gray will continue to closely monitor developments in this area. If you have any questions about Operation TrialBlazer or recent FDA developments, please contact any member of Ropes & Gray’s FDA regulatory or health care practices or your usual Ropes & Gray advisor.