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Off-Script FDA: How Smart Teams Pivot, Escalate, and Progress
Off-Script FDA: How Smart Teams Pivot, Escalate, and Progress
Source: Rachel Sherman, MD, MPH, President of Rachel Sherman Partners, LLC, former Principal Deputy Commissioner of the U.S. Food and Drug Administration.
When the fog of red tape thickens and the path forward turns opaque, one signal still cuts through the darkness: a call to Dr. Rachel Sherman. No drama, no cape – just decades of experience, a mastery of science and law, and an uncanny ability to restore direction when even the best teams lose their bearings.
A former Principal Deputy Commissioner of the FDA and now one of the most trusted regulatory strategists in biopharma, Dr. Sherman is who leaders call when a clinical program hits gridlock. She doesn’t waste time on noise or speculation. Her toolkit? Science, law, and unflinching precision. Her superpower? Translating regulatory opacity into clear, actionable direction when the stakes are highest. Dr. Sherman knows when to pivot, when to escalate, and when to hold the line. More often, though, she doesn’t just solve problems—she prevents them.
“Stick with the science. Don’t be rash. Don’t be timid.”
For teams navigating uncertainty, she’s more than a strategist—she’s the one who sees what others miss, moving programs forward before trouble can take hold.
A New Era of Regulatory Complexity
The FDA is operating under visible strain. A sweeping loss of institutional memory—through retirements, reassignments, and dismissals—has reduced the number of experienced leaders. Junior reviewers now dominate project teams, and even seasoned sponsors are facing regulatory hesitation, inconsistent feedback, and unexpected delays.
“The agency’s been gutted. Leadership overhaul. Staff turnover. Fewer veterans, more rookies. That means you need to do more.”
Sponsors who once relied on institutional expertise must now lead from the front. In other words, make the reviewer’s life easier: Clear, concise submissions. No duplication. No buried leads. “You can’t assume the person reading your submission knows what they’re doing. You can’t rely on precedent. You must guide the process, staying several steps ahead —and you better know the law better than they do.”
This isn’t just internal chatter. Outside voices have corroborated Dr. Sherman’s opinions:
- The New England Journal of Medicine recently observed that the FDA’s staffing changes, leadership transitions, and increased political oversight have created a ripple effect, slowing regulatory reviews and creating uncertainty in agency decision-making.[1]
- Simultaneously, Stat News has reported that the FDA is “operating with limited staffing in critical review divisions,” contributing to longer turnaround times and placing increased pressure on reviewers navigating complex submissions with fewer resources.[2]
A Politicized Landscape
Perhaps the most disturbing shift, Dr. Sherman warns, is the erosion of scientific independence. “Until recently, regulatory decisions weren’t political. That’s changed,” she states.
She cites the Novavax vaccine delay and subsequent post-marketing requirements as an example of unprecedented political interference. “Review decisions used to be made by reviewers. Now we’re seeing decisions shaped or blocked at the highest levels—including the Commissioner, the department of Health and Human services and the White House.
“The implications are far reaching. It creates uncertainty inside the agency. Reviewers start looking over their shoulders; that contributes to the “slow down” and decline in morale.”
Dr. Sherman saw this coming. Years before the current climate of regulatory uncertainty, she issued a Federal Register notice inviting industry leaders to share their experiences with inconsistent or contradictory feedback from different FDA divisions. It was an open call for transparency—a rare opportunity to shine a light on internal misalignments that often stall innovation. But the industry’s response was, in her words, “underwhelming.” Few came forward.
“They finally had the ear of the FDA, and they chose not to bend it,” Sherman recalls, her frustration unmistakable. It was a missed chance to correct systemic issues—and a cautionary tale about the cost of silence when collaboration is on the table.
The result? Growing inconsistency as scientific complexity increases and review teams become not only less experienced but also more siloed. Answers should vary based on data, not on who happens to field the question. However, with sparse mentoring, reduced crosstalk, and fewer opportunities for cohesive interaction, sponsor teams often receive contradictory feedback, even within the same division. This erosion of internal coherence undermines confidence and introduces unacceptable unpredictability into timelines.
Yet despite these challenges, Dr. Sherman is not cynical. “FDA is a public health agency. I believe it’s the premier consumer protection agency in the world,” she says. “The people there are, with a few notable exceptions, dedicated civil servants who still care deeply about getting it right for the sake of patient wellbeing.”
Never, she makes clear that caring isn’t enough. Sponsors must rise to meet the moment with strategic clarity and an unshakeable grasp of fundamentals. Dr. Sherman doesn’t sugarcoat the shift, but she doesn’t flinch from it either. For those willing to adapt, her message is clear: the agency may be changing, but regulatory success is still possible for those who show up prepared, strategic, and sharp.
Real-World Evidence: A Frustrated Frontier
Nowhere is the FDA’s internal inconsistency and the erosion of institutional expertise more apparent than in its handling of Real-World Evidence. Although FDA has approved drugs based on non-concurrent controls since the 1970s, the new label of RWE created expectations the current leadership cannot always support.
“RWE is misunderstood. The name sounds futuristic, but it’s not—FDA has been using these types of data for decades,” Dr. Sherman explains. The term “Real-World Evidence” itself, and its formal regulatory framing, emerged more recently under the 21st Century Cures Act of 2016. That legislation elevated RWE as a strategic priority, triggering new guidance and pilot programs aimed at expanding its role in drug development and approval.[3]
Yet, despite its pedigree, sponsors bringing RWE to FDA appear to be down more often than not. One notable success came in 2019, when the agency approved a label expansion for Pfizer’s Ibrance based solely on real-world data from electronic health records and insurance claims. It was the first time the FDA approved a drug for a new patient population—specifically, men with HR-positive, HER2-negative breast cancer—without requiring additional randomized trials
But not all RWE attempts succeed. Novartis’s 2021 bid to expand Entresto’s indication for heart failure met resistance when FDA reviewers questioned the methodology of the submitted real-world data. The drug was ultimately approved, although with a narrower label than originally requested.[5]
Dr. Sherman’s view? RWE must be presented with methodological rigor and contextual clarity. “Bring someone who understands the field,” she urges, “and know the history of what the agency has accepted—because the burden of proof is always on the sponsor, now more than ever.” FDA has made high-stakes decisions using real-world data for decades—long before the term RWE existed. Landmark approvals such as a beta blocker in the 1970s[6], IV ganciclovir and amiodarone[7] in the 1980s, and early HIV therapies in the 1990s[8] were all supported by nontraditional data. “If you’re walking into that conversation without someone who understands how RWE has worked in practice, you’re already at a disadvantage,” she adds.
“Part of the issue is internal. It appears that, increasingly, sponsors are getting ‘No’ without a rationale or willingness to enter into a conversation, and the agency’s experts in this space are scarce,” she says. Her advice: “Never enter a conversation about RWE alone. Bring someone who understands the methodologies—a statistician, a methodologist, or a consultant who knows what the agency can and has done.”
But Dr. Sherman is equally blunt about what not to do.
In her view, too many sponsors waste valuable time chasing hypotheticals and collecting data “just in case,” slowing everything down and obscuring the real story. The fundamentals still apply, even in a shifting landscape. Her call to sponsors is simple but firm: “Stay grounded. Focus on what truly advances the science and supports regulatory decision-making.” Too many companies lose both time and clarity by over-engineering studies—either in anticipation of future policy changes or by defaulting to outdated guidance or examples because it worked once, even a decade ago. “What worked before may not be relevant now,” she cautions. “Don’t build for what you think FDA might want someday. Build for what the science requires .”
Instead, she urges teams to stay focused on the data that is meaningful and necessary, regardless of external noise. “Stick with what matters. Don’t collect extra data just because you can. Don’t try to guess what new leadership will do. Stick to the science. Stay steady. Build for evidence, not .”
And if there’s one thing sponsors should always do—even in the most uncertain of moments—it’s this: “Pick up the phone and call.”
For Dr. Sherman, it’s more than advice—it’s a conviction shaped by years of experience at the heart of regulatory decision-making. In an environment often clouded by uncertainty, waiting for perfect clarity is a mistake. You make the call. That’s how progress moves forward.
“If you’re getting an answer that doesn’t make sense—not just one you don’t like—you must escalate.”
Escalation: The Power of 10.75
One of the most underused tools in the regulatory arsenal is 21 CFR 10.75; a mechanism that allows sponsors to request a review by more senior FDA officials when they receive a decision that appears flawed or illogical.
“It’s not an appeal,” Dr. Sherman emphasizes. “It’s simply a request for more senior input. And it’s underutilized.”
Unlike formal dispute resolution, which can be slower and is often perceived as adversarial, 10.75 offers a faster, more collaborative path to clarity. But that doesn’t mean formal dispute resolution should be avoided—on the contrary, it remains a vital tool when used strategically. In today’s FDA, where institutional memory is thin and junior reviewers often serve as gatekeepers, sponsors should not hesitate to escalate concerns through any appropriate channel. The key is to choose the right tool for the situation—and to understand that both 10.75 and formal dispute resolution exist to ensure sound, science-based decisions.
“In a climate where more decisions are being made by staff who may not fully be fully cognizant of regulatory or precedent, sponsors need to be proactive,” she says. “If you’re getting an answer that doesn’t make sense—not just one you don’t like—you must escalate.”
Dr. Sherman is clear: escalation is not about confrontation, it’s about strategy. “You don’t need to go in with a battering ram. You need to go in with knowledge.”
Her advice is surgical:
- Use 10.75 early, before confusion into delay.
- Be specific, citing the law, regulations, or guidance the agency may be misapplying.
- Stay factual and respectful—the goal is to realign, not.
Dr. Sherman insists she’s never seen negative consequences from a well-grounded request for additional senior input. On the contrary, it often restores momentum and unblocks stalled progress. “These mechanisms exist for a reason,” she says. “The smartest sponsors know when and how to escalate.”
Reading the Signals: What FDA Is Really Telling You
Dr. Sherman guidance is blunt and tactical: Learn to read the FDA like a seasoned insider, because you can’t afford to miss the signs. “If they’re talking about labeling, that’s a very good sign. It means you’re close to the finish line.”
But what does a sponsor do when communication dries up? “Radio silence is a red flag. Realize they’re short-staffed, but that doesn’t mean you should wait passively.” Inaction is not a strategy. Sponsors must follow up, and it must be done strategically and persistently. As Dr. Sherman puts it, “Silence doesn’t mean nothing is happening. It means you’re not part of the conversation.”
Dr. Sherman drills down further, emphasizing that sponsors shouldn’t just listen to what the FDA says, but analyze how they say it. Tone, precision, and internal consistency all matter.
“All the metrics should tell the same story. When data or review documents send conflicting signals, it may reflect scientific uncertainty or internal disagreement.”
That insight applies to both communication signals and operational metrics. The ability to interpret both is critical to managing risk. Recruitment rates, retention trends, site performance, and ROI per trial location all provide insight into your program’s health and may affect the perception of your submission. But metrics alone aren’t enough.
“If you’re hearing about labeling, that’s your signal. If you’re hearing nothing, that’s your warning,”
Dr. Sherman says.
Data backs up her perspective. A study published in JAMA Network Open found that among FDA approval packages for novel therapeutic agents from 2011 to 2015, 24% contained at least one documented disagreement—often between reviewers or between staff and leadership.[9] This underscores the importance of recognizing conflicting signals as signs of internal discord that sponsors must tactfully address.
“In this new climate, the era of collaboration appears to have ended, and another reality has emerged: your review team may not be the most experienced voices in the room—and often, they never were. Sponsors have always been responsible for bringing deep, cross-functional expertise to the table.
But with turnover high and institutional memory thinning, that obligation is now more urgent than ever. “The people you’re meeting with may be junior and new to the agency,” she says. “Make sure you understand the law, the regulations, and the guidance better than they do.” You can no longer count on the agency to escalate uncertainty internally or provide advice shaped by decades of institutional knowledge. That responsibility now falls squarely on the sponsor.
Dr. Sherman warns that too many sponsors confuse guidance with law—and pay the price. Guidance documents reflect the agency’s current thinking, not binding requirements. Knowing the difference isn’t just helpful, it’s strategic.
“People forget that guidance is not binding. If you know the regs and statutes well, you can say to FDA, ‘You’re wrong, and here’s why.’ That’s incredibly powerful.”
This isn’t rhetorical posturing—it’s a survival strategy. A 2023 RAPS survey found that regulatory teams trained in FDA statutes and procedures saw shorter review cycles and higher approval success rates.[10]
In this environment, regulatory fluency isn’t a luxury; it’s a strategic imperative.
Table 1: FDA Signals and
| Signal | Interpretation | Recommended Action |
| Early engagement by FDA pre-submission | Strong initial interest or priority status | Maintain active communication and transparent updates |
| Request for additional data post-submission | Gaps in evidence or unexpected concerns | Provide requested data promptly and clearly |
| Radio silence from FDA | Possible internal delay or decreased prioritization | Follow up via formal inquiry or phone call |
| Conflicting review comments | Potential internal disagreement or uncertainty | Request clarification or senior-level input |
| FDA begins labeling discussions | You’re nearing approval | Continue to prepare final submission materials |
PDUFA and the Myth of a Two-Tier System
The Prescription Drug User Fee Act (PDUFA) sets standardized fees annually, regardless of sponsor size, and does not grant preferential treatment based on payment amount. While some commentary has suggested that large companies can “buy” faster reviews, that’s a misconception—PDUFA is about timelines, not influence. In fact, small businesses—typically those with fewer than 500 employees and no previously approved product—may qualify for a full exemption from the application fee. The system is designed to be consistent, not tiered.
Dr. Sherman calls the claim of a tiered system factually incorrect. “That’s not how it works. Everyone pays the same for an NDA or BLA—unless they qualify for a waiver, which is clearly defined in statute[11]. There’s a misconception that bigger fees buy faster reviews. That’s just not the case. PDUFA is about timelines, not favoritism. The fee doesn’t buy influence—it funds infrastructure.”
Dr. Sherman emphasizes that the structure of PDUFA is built to ensure fairness and consistency: “There aren’t user-fee reviewers and taxpayer-funded reviewers. All funds support the same .” User fees are pooled into a common account and are meant to supplement—not replace—federal appropriations. “If the FDA doesn’t get enough base funding, it can’t collect user fees. That’s a built-in protection.”
Indeed, the statute includes trigger mechanisms to ensure that the FDA continues to receive baseline appropriated funding. But even these safeguards may soon be stress-tested. According to agency sources cited by Pink Sheet, if the House’s proposed FY 2026 appropriations are enacted, the FDA may be forced to scale back non-user-fee-funded programs just to preserve its authority to collect user fees. Food safety—which receives no user fee support—could face sharp cuts, as could prescription drug functions like surveillance inspections, drug shortage response, and advertising oversight not linked to specific applications. No formal decisions have been made, but the agency’s financial strain is now unmistakable.[12]
These statutory safeguards require that:
- FDA’s direct Salaries and Expenses appropriation meet or exceed 1997 levels;
- Congress specifically authorizes the collection of fees; and
- Appropriated spending on human drug reviews remains at or above the inflation-adjusted 1997 baseline.
If these conditions aren’t met, the FDA may be barred from collecting—or may have to refund—user fees, ensuring that user funding never becomes the agency’s sole financial support.
There are, however, exemptions:
- Orphan Drug Designation: Sponsors with FDA Orphan Drug Designation (ODD) are exempt from PDUFA fees for NDAs/BLAs related to the designated condition.
- Small Business Waivers: Companies with fewer than 500 employees and no previously approved drug product are eligible for a one-time waiver of the application fee.
- Other Exemptions: Government applications, certain blood and allergenic products, and some in vitro biologics are also exempt.
Dr. Sherman’s advice is unwavering: smart sponsors move forward, even when the road looks rough.
“Don’t wait for perfect conditions because they will never exist. If your package is ready, get it in line.”
The bottom line? Set the pace. Be ready. Be early. Be relentless. In this environment, speed isn’t about rushing—it’s about precision timing.
Early, Often, and Honest
Dr. Sherman’s advice is firm and simple: “When in doubt, ask.”
Some sponsors burn time and goodwill trying to reverse-engineer what they think the FDA wants. That approach is a recipe for delays, additional review cycles, or even regulatory mistrust. “I can’t count the number of times a sponsor made a decision based on what they assumed we wanted. And I’d ask them—Why didn’t you just ask?”
The rules of engagement may be more bureaucratic now, but meaningful dialogue is still possible and is even more essential. Despite the red tape, Dr. Sherman insists persistence almost always . “It’s become harder to have the phone conversations but it’s not impossible.” And if an answer from the FDA feels vague, inconsistent, or off the mark? Escalate. “Ask for a more senior-level review. I never saw retaliation or negative consequences from doing that. In fact, it often clarified the path forward.”
Whether it’s confusion or imperfection, Dr. Sherman is clear: don’t bury it—escalate it. “If something doesn’t make sense, escalate,” she says. “And if there’s a flaw, own it.” Trying to finesse problems or downplay risk is a fast track to losing credibility. “Try to hide something,” she warns, “and you’re toast.” Transparency, not perfection, is what builds trust inside the agency—and trust is what keeps your program moving.
“Don’t hide the bad stuff. Acknowledge it, explain how you dealt with it, and show the logic behind your conclusions.”
In Dr. Sherman’s world, honesty isn’t just a virtue, it’s a strategy. reviewers don’t expect perfection. They expect transparency. When sponsors obscure weaknesses, it raises red flags and invites distrust followed by deeper scrutiny. But when they own the challenges and show their thinking, they build trust. “If we thought you were being straight with us—even about the limitations—we were more likely to trust your overall approach,” she says. “That saves everyone time and guarantees a better outcome.”
This philosophy of open, proactive, and honest dialogue underscores what Dr. Sherman sees as the foundation of successful regulatory
“You don’t win points by trying to guess what FDA wants. You win by engaging as partners and being transparent about your science.”
Avoiding Pitfalls: Dr. Sherman’s Tactical Playbook
Dr. Sherman distilled her decades of experience into the following key takeaways for sponsors:
- Stay the course.
Don’t panic or make drastic changes due to short-term uncertainty. - Ask early and often.
Communication with the FDA saves time and money. - Know the rules.
Be more informed about laws and guidance than the people reviewing your application. - Bring reinforcements.
Never attend potentially contentious FDA meetings alone—bring experts who know the data, law, and guidance. - Use 10.75 escalation, or an equivalent, early.
If you receive a response that defies logic, escalate tactically. - Be strategic, not verbose.
Short and sweet. Don’t say anything twice. Don’t bury the lead. - Prepare for review.
Write for the most disinterested reader – because they exist. - Be honest.
Transparent acknowledgment of data flaws builds credibility and trust. - Avoid the ‘fairness’ argument.
Past precedent won’t save you if the science or context has changed. - Don’t wait for calm skies.
If your submission is clean, get it in early. Momentum matters.
AI vs. Experience: Why Human Judgment Still Rules FDA
Artificial intelligence has generated tremendous buzz in regulatory circles, with some hoping it can streamline submissions, automate analysis, and even replace certain aspects of FDA decision-making. But Dr. Sherman remains skeptical.
“AI can help you organize data, find redundancies, or ensure formatting consistency. But it can’t replace human judgment,” she says. ” Sponsors can deploy AI to structure large data sets, validate submission completeness, or flag inconsistencies—but strategic interpretation still demands experienced human eyes. And, she adds, more automation isn’t always better: “Just because you can do something doesn’t mean you should. Like powerful computers before it, AI can generate unnecessary work if not grounded in purpose.”
A real-world example comes from hospitals that adopted Epic Systems Corporation’s AI model for early sepsis detection. While intended to improve response time for a life-threatening condition, the algorithm frequently issued false positives and missed true cases. Clinicians often had to override or ignore alerts to avoid inappropriate treatment. A 2021 JAMA Internal Medicine study concluded that “clinical judgment was often necessary to contextualize or override algorithmic outputs
Dr. Sherman argues that regulatory review is not a data science exercise—it’s a human process rooted in values, experience, and discernment. “These are not faint-of-heart decisions,” she says. “You’re making calls with limited data, patient lives at stake, and political pressure in the background. AI doesn’t do uncertainty. Humans do.
“AI doesn’t understand risk. It can’t calibrate uncertainty the way seasoned regulators do.”
She warns sponsors against overreliance on automation to dictate strategy. “If you’re waiting for a dashboard to tell you the FDA is ready, you’re already behind,” she says. “Momentum matters.” Dr. Sherman emphasizes that sponsors can’t afford to delay action in hopes that AI-driven insights—or a more stable agency climate—will clarify the path forward. “If your package is ready, submit,” she advises. “Waiting for perfect conditions is a strategic mistake. Reviews may be slower, but they’re still happening.”
Looking Ahead
Dr. Sherman doesn’t sugarcoat. Yes, the FDA is strained. Yes, the system is slow. But she’s not interested in excuses. “The machinery is still working… even if it’s slower.”
And yet, despite those concerns, Dr. Sherman believes the agency is well positioned for a meaningful transformation. The FDA may be large and complex, but behind every decision are real people—reviewers, project managers, and leadership—the vast majority of whom want to get it right. And sponsors who show up prepared, clear, and honest can still prevail – in the end that means patients win.
“If you’re ready, submit. There’s nothing to be gained by putting the brakes on.”
And when it comes to FDA communication, she offers a stark reminder: “If the agency is talking about how your product will appear to the public, that means you’re close. But if you’re hearing nothing? Silence isn’t neutral—it’s negative. Don’t ignore it.”
The machine may be strained, but it’s still functioning. “Approvals are still coming out. AdComms (public application reviews) are still being held,” she notes. These formal FDA advisory committee meetings—where independent experts publicly weigh in on high-stakes drug decisions—are a visible sign that the system is still moving. “The system is working. Just more slowly. Your job is to be ready, take on as much of the burden as possible—and push for a timely outcome.”
She points to areas with enormous promise: rare disease programs, real-world evidence, and adaptive trial design as areas ripe for growth; representing tangible opportunities to improve patient outcomes, streamline development, and modernize regulatory science. All spaces where innovation can move fast and evocatively if handled with regulatory savvy.
Engaging early, asking questions, and clarifying expectations can go a long way, especially in uncertain times. “Don’t wait for the agency to stabilize. Lead with clarity. Be precise. Be early.”
The New Team Playbook and the New Path Forward
“Bring experts. Know the law. Know the regulations. Know the guidance—and know all of it better than the reviewers.” For Dr. Sherman, that’s not just preparation—it’s strategy. Success in today’s FDA doesn’t come from hoping the agency will connect the dots. It comes from showing up fluent, focused, and fortified with the right people. The most effective sponsors don’t just speak science—they speak FDA. And they don’t go in alone.
“In today’s FDA, teamwork isn’t just a virtue. It’s a strategy.”
She recalls a pivotal moment when a reviewer didn’t understand the concept of a surrogate endpoint. “You can’t have a rational conversation unless you share a common vocabulary.” That misunderstanding cost the sponsor months of additional analysis and a second meeting to clarify what should have been accepted from the start. She recalls, “It wasn’t a scientific issue—it was a communications .”
Misalignment like that, she explains, isn’t just inconvenient—it can derail promising therapies. That’s why she urges sponsors to approach meetings as strategic engagements, not just regulatory check-ins.
Dr. Sherman hopes to see momentum in the agency’s internal culture shifting more toward the cross-disciplinary collaboration that once was a high priority. She also sees untapped potential in sponsor-agency alliances, when built on transparency, mutual respect, and shared goals. “We need a return to that mindset. We need a team again.” In an agency still recovering from institutional drift, the team you build will matter as much as the data you bring.
She points to the creation of the breakthrough therapy designation as a model for what’s possible. It wasn’t born from legislation—it came from dialogue and a white paper that challenged the status quo. The ability to accelerate development for serious conditions already existed within the agency, but some reviewers needed the knowledge—or the encouragement—to use it. The designation simply formalized what was already possible and made it consistently accessible.
“That didn’t happen because someone followed a rulebook. It happened because smart, committed people worked together to innovatively solve a shared problem,” she says.
Even amid today’s political and operational turmoil, Dr. Sherman is optimistic: “We can shape progress. But we must stick together. This only works if we believe we’re on the same side—because when it comes to public health, we are.”
Dr. Rachel E. Sherman, MD, MPH, FACP