How will the current changes at the FDA affect the standard of evidence it uses for reviewing new drugs and other treatments? With input from two longtime observers of the biopharma industry and its U.S. regulator, this article covers a cross section of opinions regarding trends and proposals for improving the FDA review process. The goal was to have about a half dozen people, representing the range of stakeholders inside and outside of the industry, voice their opinions on current and proposed policies that promise to change the agency’s structure, its organization, and even its core mission of ensuring the safety and efficacy of the industry’s marketed products. Our sample is even smaller than planned, however, because it turns out this is not a subject that currently inspires public comment. Out of more than 30 logical candidates invited to participate, no industry figures chose to take part. Even the FDA turned down the request. Why? “We just have so many competing interests at this time,” said the contact person at the CDER Press Office.
CAUGHT IN CROSSFIRE
The CDER press contact may have been referring only to a short-term rush of media queries, but “competing interests” also stands out as an apt phrase for current conditions at the agency and the wider conflict over so-called FDA reform. A white paper issued early in the Trump administration proposes narrowing FDA’s mission to drugs only and radically expediting approvals. Members of the administration have discussed ideas such as “de-emphasizing” Phase 3 trials and basing drug approvals mainly on safety rather than efficacy. Some in the administration seem to envision ultimately eliminating the agency’s approval authority and making it more like a clearinghouse for drug information. Outside government, patient advocacy groups and free-market think tanks such as the Manhattan Institute push for easier access to new treatments by “streamlining” FDA reviews largely through deregulatory measures.
The biopharma industry may well cheer the promise of faster reviews, but there is rising concern in the medical community, and even among some industry leaders, about some of the streamlining proposed — or already effectively implemented through accelerated review and conditional approvals. The issues around “right to try” persist in the populist notion that the FDA simply stands in the way of needed treatments.
The trend toward less approval and more advice in the agency’s role has shown up in the way it operates, as our expert contributors note below. We asked them to explain whether they believe the FDA is degrading or improving its review of new drugs and devices.
“The pendulum that seems to swing between stricter and looser regulation in the U.S. has been moving to the side of deregulation for the past decade,” says Dr. Arthur Caplan, who heads the Division of Medical Ethics (DME) at NYU Langone Medical Center (LMC). (Kelly McBride Folkers, senior research associate at the DME, assisted with Dr. Caplan’s responses.) He notes the 21st Century Cures Act significantly alters FDA review processes with the goal of streamlining drug and device approvals. It eases requirements for researchers and sponsors in some ways, such as allowing the submission of “data summaries” in the review of new indications for marketed medications and expedited review of cell- and tissue-based technologies through the Regenerative Advanced Therapy designation. “The number of novel drugs approved by the FDA has steadily increased over time, and about half of the novel drugs the FDA approves go through at least one expedited program. Thus, it is fair to say that the FDA is achieving the goal of approving drugs and devices faster.”
Caplan believes it is inevitable some of the expedited therapies will display safety and efficacy concerns post approval, but many may escape regulatory challenge. “The FDA increasingly relies on post-marketing studies to confirm initial trial results, but these studies are often delayed, incomplete, or in some cases, not completed at all. This poses an ethical concern: Many patients are using FDA-approved medications for which insufficient evidence exists to draw conclusions about their safety and efficacy,” he says. “Weakening standards for drug and device approvals without vigorous post-approval monitoring could compromise patient safety or waste scarce financial resources on useless agents.”
Dr. David Gortler, past FDA medical officer who now consults for the group FormerFDA.com, has even stronger words to describe the hazards. “The FDA has made some highly questionable regulatory approval decisions over the past few years, to the point that I hardly recognize the agency where I once worked,” he says. “The FDA’s contentious approvals of flibanserin [Addyi], to improve underactive sexual desire in women, and eteplirsen [Exondys 51], to treat Duchenne muscular dystrophy, illustrate that the FDA is having trouble following its own guidelines for efficacy and safety.”
Gortler believes flibanserin’s approval was marred by its poor safety profile, and the approval of eteplirsen set another bad precedent. “Eteplirsen’s clinical studies were fundamentally flawed — the drug was tested in a mere 12 individuals, with no control group. The drug only increased production of a key dystrophin biomarker protein by less than one percent of normal overall, which is neither clinically nor scientifically meaningful.” Despite the medical review team’s conclusion to the contrary, Janet Woodcock, who heads CDER, overrode their decisions and approved the drug. Then-Commissioner Dr. Robert Califf did not block or take any position on the drug’s approval. In protest, review team member Dr. Ronald Farkas resigned from the FDA.
“Following eteplirsen’s approval, one would think that the ‘new’ way to get a drug approved is to run a trial in a dozen people, generate inadequate and deeply flawed scientifically unsound data, and then militarize patients who understand nothing about the drug-development process to harass Janet Woodcock until it gets approved,” Gortler says. “Just think about what would happen if this type of bureaucratic, subjective FDA approval became contagious.”
MEASURES FOR MEASURES
Not all of the outlook on the FDA is negative. Caplan gives the agency high marks for completing guidelines broadening clinical trial participation to include more pediatric patients, women, and minorities. One important goal is “making access to investigational products more equitable and clinical trial populations more reflective of the population intended to use a product after approval,” he says. “A more diverse population can participate, and companies can gather valuable information on how products work in patients under variable socioeconomic conditions.”
Caplan gives the example of new eligibility guidelines that eliminate the exclusion of patients with liver or kidney disease or HIV and hepatitis infections. “Because these conditions are being controlled with medications in many populations, trial designers can evaluate whether these medications interfere with effects observed in testing new agents.”
One caveat regarding such guidelines: A “competing interest” in fighting the so-called deep state yielded an executive order in October 2019, cutting back the guideline-making authority of federal agencies in general. It also introduced another uncertainty into the future transparency and guidance for industry at the FDA. A good number of industry interests may suffer the effects of that uncertainty — including some of the streamlining proposals discussed further on.
“Recent proposals aimed at weakening the scope of the FDA’s purview are very troubling,” says Caplan. He sees several negative issues with one case in point: the Free to Choose Medicine (FTCM) initiative, a model policy developed by the Heartland Institute and supported by Senator Ted Cruz (R-TX). FTCM calls for expanding the FDA’s parallel track — originally established to allow individuals with HIV/AIDS to access breakthrough drugs prior to FDA approval — to other disease areas such as Alzheimer’s, cancer, and ALS. The proposed model would allow drug developers to make their investigational medical products available for prescription after completing a Phase 1 and at least one Phase 2 trial. It would encourage physicians to record observational data that would be publicly available so that patients and physicians could learn whether the drug is worth trying. Early-use patients could be charged for the products. What could possibly go wrong?
“Observational data recorded in the database that FTCM’s proponents envision would have to be vetted for quality,” says Caplan. “Whether or not patients and physicians can make reliable decisions on which investigational drugs to try, as they might not have the requisite experience to analyze observational data as it relates to investigational products, is an open question.”
Expanded access programs, at the time parallel track originated, were usually based on significant data from late Phase 3 trials. Now, federal regulations permit consideration of Phase 2 data in severe cases, so Caplan says reinstating the parallel track policy is not needed — nor is it wanted. “In the years since parallel track was introduced, drug developers and regulators have not revived the policy because it is virtually the same as operating a large-scale expanded access program,” Caplan explains. “Hundreds or thousands of patients would receive access to an investigational drug prior to regulatory approval if preliminary efficacy data were strong.”
Taking patients’ money for preapproval drugs in the expanded parallel track would be worse than useless, he argues. “It would be ethically dubious, because most safety issues with investigational drugs are revealed in multiple Phase 2 trials. There is no mechanism to ensure data from a single Phase 2 study can show a product is safe for widespread use in a population medically more diverse than the trial population.”
FTCM would establish a “Free to Choose Medicine committee,” which would unilaterally permit certain investigational agents to enter the market after a Phase 2 study is completed. “The creation of such a committee raises the question of which stakeholders the Heartland Institute and Senator Cruz anticipate serving on the committee and why. The potential for conflicts of interest is enormous,” Caplan says.
TIME TO RETOOL?
To some extent, changes in therapeutic technology are driving the proposals for change at the FDA. Janet Woodcock has recently spoken and written about “new efficacy measures” for personalized therapies using genomics and other new tools. “Reformers” say the chasm of differences between small molecule and even conventional biotech drugs on one hand and new approaches such as cell and gene therapies on the other requires new ways of conducting and evaluating clinical development.
"The pendulum that seems to swing between stricter and looser regulation in the U.S. has been moving to the side of deregulation for the past decade."
Dr. Arthur Caplan
Head of Division of Medical Ethics
NYU Langone Medical Center
A rapidly growing list of proposals is driving the bulk of discussion over FDA reform. Where the proposals overlap in purpose, they often differ in their degree of disruption. But some would cause radical transformations in how the FDA reviews new treatments.
One of the more radical ideas is to reduce or eliminate full-scale Phase 3 for many products and rely on Phase 2 data for approvals. The idea seems most popular among lay people in business or stocks, groups of patients grown impatient waiting for help, and a host of startup companies looking for a more expedient path to the market. But medical ethicists, FDA veterans, leading researchers, and drug-development professionals have largely opposed such a change, preferring the gold standard of Phase 3 trials in most cases.
“Reducing or eliminating Phase 3 trials is not in the best interest of patients or the public because these trials serve a vital purpose in establishing whether there is a treatment effect observable across a large group of patients,” says Caplan. “Controlled studies are the fastest way to see efficacy and some safety signals.”
Gortler concurs: “I don’t know of any of my colleagues in investigational medicine at Yale University, Georgetown University, the FDA, or Pfizer who would sincerely advocate eliminating Phase 3 clinical trials. Those who do are people who have never worked at the FDA or in investigational medicine and who don’t fully understand the intricacies and importance of the drug development process.”
Another radical idea — seriously floated by high-placed deregulatory advocates — is to remove the efficacy requirement for approvals, leaving only safety as the sole basis for FDA review. Not surprisingly, people who know drug development tend to reject the proposal.
Caplan says, “The FDA was charged with this mission back in 1962, when the Kefauver-Harris Amendment modified the Food, Drug, and Cosmetic Act to require that the agency review proof of effectiveness of medical products submitted for review. Removing the efficacy requirement for approvals would put many patients in danger of using useless and burdensome agents. Society would be gambling significant amounts of money on paying for drugs that are likely not to work.”
Gortler is a conservative, was a former campaign advisor to Cruz in 2016, and serves as a fellow and policy advisor at the Heartland Institute. He says he is all for freedom and fewer regulations, but he cannot recommend substantially loosening efficacy requirements for approvals. “It would be mayhem if the government simply let market forces dictate clinical pharmacology standards and allow consumers to make their own clinical and statistical decisions about long-term safety and efficacy. The drugs we take and the food we eat are the most regulated things in the United States for good reason: We need expert-level scientists and clinicians to oversee the approval, marketing, and manufacturing of America’s prescription drugs.”
MORE OR BETTER
Short of the radical surgery on the FDA’s basic mission, many of the other ideas advocated for drug reviews involve changes in the standard or nature of evidence required in clinical trials.
Those include using more surrogate markers, observational studies, and real-world evidence (RWE) and relying less on randomized controlled trials (RCTs) as a basis for review and approval. Our experts comment:
“We should integrate high-quality, state-of-the-art surrogate markers as a critical component of a clinical trial, but these should not replace clinical trials themselves,” says Gortler. “Initial ‘real-world’ evidence cannot be obtained without efficacy and safety results from Phase 3 and Phase 4 clinical trials.”
Caplan agrees. “RCTs ought to remain the gold standard for medical-evidence generation because they are the most reliable method that permits the attribution of differences in outcomes among study groups to the investigational intervention.” But RCTs lack “generalizability,” he says. They can only determine whether an effect is observed under ideal conditions. “Patients seen in the clinic, on the whole, have more complex medical situations than those in the trial, and RCTs can’t determine whether a drug will work for an individual patient at a specific point in time.” In Caplan’s view, encouraging RWE use in regulatory decision making would enable the FDA to gain critical information that increases the opportunity to generalize traditional trial results, thereby helping physicians and patients to make more informed choices among available drugs.
“Reliable RWE should mimic the results of a pragmatic RCT, which is conducted in a routine practice setting and often increases the generalizability of results because study groups are reflective of patient populations,” he says. “If RWE generation can perhaps eliminate the need for randomization of patients into placebo or comparator groups in certain circumstances, patients may be more willing to participate in clinical research activities that are observational in nature. The key to appropriate usage of RWE is ensuring that the data source and statistical methods applied to it can answer the research at hand.”
A less radical or disruptive proposal is to allow or encourage the agency to grant approvals based on varying levels of evidence that providers would consult before use, rather than requiring all approvals to be based on Phase 3 data. Gortler rejects the concept for its inherent reliance on small, often unblinded trials: “This is a fundamentally bad idea that no competent clinician who has worked in and understands the sacrosanct science of investigational medicine would agree with. Unblinded patients are not in a position to objectively judge the effectiveness of a drug compared with the untreated control unless the efficacy effect is very large, which is rarely the case.”
But Caplan has a more flexible opinion: “In situations where there are no effective treatments on the market for particularly dire conditions, accepting varying levels of evidence is ethically permissible as this would increase the speed with which patients can get access to a treatment. Treatments and preventive vaccines for Ebola virus disease, for example, would fit these criteria. Setting clear guidelines for when dire circumstances might admit differential evidentiary standards to be invoked is essential.”
It is clear, from quite different perspectives, the two experts who provided us with such valuable input for this article agree in many respects. Both seem open to genuine improvements in the FDA’s drug-review process, but neither favors the radical deregulation of the agency envisioned by its aggressive advocates. From the ethical and clinical perspectives, they believe the world’s leading regulatory body for therapeutics should stick with its gold-standard methods, tools, and mission to ensure the safety and efficacy of new medical therapies. But their recognition of the competing interests now buffeting the agency confirms one other fact — the industry can expect an extraordinary period of risk and uncertainty at the FDA in 2020.