Eds. note, 25 Jun 2021: In the three days since this series posted, Senators Elizabeth Warren (D, Massachusetts) and Bill Cassidy (R, Louisiana) have requested the Senate Finance Committee examine how Aduhelm will affect the Medicare budget. Private insurer Point32Health, a merger of Tufts Health Plan and Harvard Pilgrim Health Care that insures some two million people in New England, said it may not cover Aduhelm unless the cost comes down. Meanwhile, the FDA granted breakthrough therapy status to Biogen’s lecanemab and Eli Lilly’s donanemab, and Lilly applied for accelerated approval. Gantenerumab developer Roche has said it will continue its Phase 3 program unchanged.

 

In the two weeks since the Food and Drug Administration approved a license for Biogen’s Alzheimer’s antibody aducanumab, marketed as Aduhelm, controversy over the decision has continued to build. Industry analysts have written numerous scathing editorials. Critical debate reached the U.S. Congress. A watchdog group called for heads to roll at the FDA, and three members of the agency’s advisory committee quit in protest. On the other side, advocacy groups continue to laud the decision, but even they note qualms about the treatment’s price tag (see Part 2 of this series). Among Alzheimer’s researchers and clinicians, reaction remains mixed. Privately, many express unhappiness with the decision and lament a possible chilling effect on other therapeutic research, as well as the logistical challenge of integrating monthly infusions into clinical practice (see Part 3 of this series). Others view it as a first, if faltering, step toward more disease-modifying treatments. They see a bright future ahead. The debate will likely continue as the field grapples with this disruptive change to Alzheimer’s practice.

  • Three AdComs members resigned in protest of the FDA’s decision.
  • Critics question the use of plaque reduction as a surrogate of meaningful benefit.
  • Plaques may have an indirect effect on cognition, possibly acting through tangles.

Recriminations Swirl in Wake of FDA Decision
The approval process for aducanumab has been fraught from the beginning. After skipping Phase 2, Biogen halted its two Phase 3 trials when they failed a futility analysis, but later announced that additional data rendered one of them positive (Mar 2019 news; Dec 2019 news). None of the members of the FDA’s advisory committee considered these conflicting data sufficient for approval (Nov 2020 news; Nov 2020 news). 

In its June 7 ruling, the FDA acknowledged uncertainties in the efficacy data but based its decision on aducanumab’s robust clearance of amyloid plaques, noting their expectation that this will lead to a clinical benefit. The agency granted a marketing license using its accelerated approval program, which accepts change on a surrogate biomarker as likely evidence of efficacy but requires a post-market study to prove clinical benefit. Biogen has nine years to conduct such a trial (Jun 2021 news), a time span that sparked outrage for its length.

In the industry press, the decision ignited a firestorm of criticism. Observers lamented the lowering of standards and the precedent this might set for other drug approvals (Bloomberg newsAAAS blog). In a poll of 1,400 biopharma executives and staff, 80 percent thought the FDA should not have approved aducanumab, and 70 percent disagreed with the use of the accelerated approval pathway (Endpoints news). 

The FDA’s move led Joel Perlmutter at Washington University in St. Louis, David Knopman at the Mayo Clinic in Rochester, Minnesota, and Aaron Kesselheim at Brigham and Women’s Hospital, Boston, to resign from AdComs (STAT news). Kesselheim later penned a New York Times editorial lambasting the agency. A fourth member, Madhav Thambisetty of the National Institute on Aging in Bethesda, Maryland, felt the need to explain why he was staying on the committee (STAT news). 

The Washington, D.C.-based watchdog group Public Citizen, which had earlier criticized the close collaboration between Biogen and the FDA, went so far as to call for the removal of acting FDA commissioner Janet Woodcock, drug evaluation director Patrizia Cavazzoni, and neuroscience director Billy Dunn (Jan 2021 news; Endpoints news). The issue even reached the halls of the U.S. Congress, where Senator Joe Manchin (D, West Virginia) cited the aducanumab approval in his June 17 letter urging President Biden not to appoint Woodcock commissioner of the FDA. The decision also prompted criticism of the agency in the general media (e.g., The Washington Post editorial). 

Plaque Removal A Surrogate Marker?
In particular, the FDA’s use of the accelerated approval mechanism raised eyebrows. At the AdComs meeting last November 6, FDA officials explicitly said this pathway was not on the table (Endpoints news). The advisory committee was asked to evaluate the drug based on the efficacy data. After receiving a “no,” the agency pivoted to make its decision on a different basis not discussed by the committee. The FDA never consulted the AdComs about the different pathway it had switched to since the meeting.

Lon Schneider at the University of Southern California, Los Angeles, noted that by using this pathway, the FDA in effect declared that amyloid PET functions as a surrogate marker of efficacy in AD treatment. “This perhaps is the most stunning outcome,” he wrote to Alzforum. Normally, the FDA follows a methodical qualification process, whereby it first establishes the validity of a surrogate marker and issues guidance to the whole field, before using the marker as the basis for approving a specific drug. That did not happen here, giving the de facto validation of plaque removal as a surrogate a sense of sleight of hand.

Many others expressed similar surprise. “This [decision] implies that brain amyloid has achieved the status of blood cholesterol for heart disease, and I don’t believe it has,” John Hardy at University College London wrote to Alzforum (full comment below). AdComs member Thambisetty warned that the aducanumab approval could make it easier for other amyloid-lowering drugs to reach the market without proving efficacy. Jörg Schulz, who chairs the neurology department at RWTH University Medical School in Aachen, Germany, asked if a slew of amyloid-reducing agents from the past will now be re-evaluated under the accelerated approval pathway (see full comment from June 14). In a public defense of her agency’s decision on June 22, Woodcock said future approvals under this pathway would be possible if the magnitude of plaque reduction was great enough.

Marsel Mesulam at Northwestern University, Chicago, believes the agency stepped outside of its purview by declaring amyloid reduction a surrogate marker. “Many of us have wondered whether regulators should be in the business of deciding on hope rather than fact, and whether they should be adjudicating on theories of pathogenesis,” Mesulam wrote (comment below). Jason Karlawish at the University of Pennsylvania, Philadelphia, said, “It raises real concerns about what’s going on at FDA and how they are using their regulatory authority.”

Plaque and Cognition, a Hazy Relationship
One reason for some scientists’ reservations about plaque removal as a surrogate marker is that small reductions in amyloid have not led to cognitive benefit in trials of several different drugs. In a recent meta-analysis, researchers led by Edo Richard at Radboud University Medical Center, Nijmegen, the Netherlands, evaluated data from trials of solanezumabbapineuzumab, and low-dose gantenerumab, the latter two of which nudged plaque load but not ADAS-Cog scores (Richard et al., 2021). 

Researchers led by Maria Glymour at the University of California, San Francisco, cast a wider net, including published studies of all drugs purported to lower amyloid plaque, regardless of their mechanism of action. In addition to the trials studied by Richard et al., Glymour et al. analyzed data from bexarotene, semagacestat, verubecestat, lecanemab Phase 1, and aducanumab Phase 1 trials. Their meta-analysis found no correlation between MMSE score and the small amyloid reduction in these studies (Ackley et al., 2021). 

“The idea that we would approve medications on the basis of a biomarker change, i.e., amyloid reduction, when we know that reducing amyloid does not equate to definite benefit for improving people’s lives, i.e., memory and functioning improvements, sets a bad precedent,” Glymour wrote to Alzforum (full comment below).

The connection between amyloid removal and cognitive benefit remains possible, however. These meta-analyses included small trials, e.g. lecanemab; low-dose trials, e.g., gantenerumab; and drugs not primarily designed to lower plaques, e.g., BACE inhibitors, bexarotene. Much more drastic amyloid plaque reduction is being reported for three other anti-amyloid antibodies besides aducanumab. Two of them—donanemab and lecanemab—did tap the brakes on cognitive decline by 20 to 30 percent in well-designed Phase 2 trials, while Phase 3 data on high-dose gantenerumab are expected next year. This renders the agency’s assumption that near-complete amyloid removal may foretell a subsequent cognitive benefit not formally proven but plausible.

And indeed, many scientists focus on the bigger scientific picture in their qualified welcome of the agency’s decision. Bart De Strooper, who leads the U.K. Dementia Research Institute at UCL, thinks it is misleading to set up a dichotomous choice whereby amyloid plaques are seen as either a driver of cognitive decline, or irrelevant to the disease process. “A simplistic cause-consequence relationship between accumulating amyloid and neurodegeneration should have been abandoned more than a decade ago,” he wrote to Alzforum (full comment below). “Amyloid pathology [is] a trigger of a series of disease processes.” In this scheme, often referred to as the amyloid cascade hypothesis, amyloid buildup unleashes tau tangles, which then lead to neurodegeneration and memory problems. Inflammation is an important player, too.

And How About the Tangles?
Takeshi Iwatsubo at the University of Tokyo noted that aducanumab’s effect on tangles may be the key to its apparent slowing of cognitive decline in Biogen’s one positive Phase 3 trial. “The FDA statement emphasized amyloid reduction as a surrogate biomarker, but they should rather have valued the CSF p-tau and tau PET data,” he wrote to Alzforum (full comment below). Biogen ran only tiny substudies on these tau markers; the data they did show indicated normalization in people on high-dose aducanumab.

All four of the anti-amyloid antibodies that clear plaques to below the threshold of brain-wide positivity also seem to dampen tau pathology, as seen by CSF or tau PET. These data often come from substudies and effect sizes are typically small (Mar 2021 conference news; Nov 2018 conference newsApr 2020 conference news). 

For more reaction from Alzheimer’s researchers, see Part 2 of this series.—Madolyn Bowman Rogers

Comments

  1. I think aducanumab had a small beneficial effect on mildly affected individuals. This opinion is weakly held, and I respect the opinion of those who disagree. We await further data for sure, as this did not reach the threshold of “beyond a reasonable doubt.”

    I was surprised by the implicit logic of “it removes amyloid so it must be good.” This implies that brain amyloid has achieved the status of blood cholesterol for heart disease. I don’t believe it has. Still, I am hopeful aducanumab will indeed be the first drug which bends the curve of decline.  

    It will be expensive, and I am not at all sure what this will mean for coverage approvals and for take-up. This is a very difficult issue. A concern I hear is that this will hurt recruitment into other trials of possibly more-effective drugs. I would like to hear from trialists what they think this effect will be.

    On balance, I do think this is the first faltering step in mechanistic therapies, but this conviction, too, is weakly held.

    I have consulted for Eisai, but not on its amyloid program; I consult for Eli Lilly on its Alzheimer’s program.

  2. After 18 dry years, the hunger for a novel Alzheimer’s drug had reached a fever pitch. Everyone was primed to welcome a new addition with loud cheers. This has clearly not been the response elicited by the FDA’s approval of aducanumab (Aduhelm).

    To provide context, it is important to remember that cholinesterase inhibitors have overwhelming proof of at least some clinical efficacy, that they are remarkably safe, and that they are cheap. How does Aduhelm stack up?

    Many of us have wondered whether the regulators should be in the business of deciding on hope rather than fact, and whether they should be adjudicating on theories of pathogenesis. For the sake of our patients, however, let's hope that the FDA will be shown to have acted in response to providential intuition. Until then, the best we can do is to convey the facts in plain language so that our patients and families can effectively participate in the decisions regarding Aduhelm.

  3. The experiments supporting aducanumab were, admittedly, inconclusive regarding its clinical benefit. The FDA points out, however, that the biomarker (amyloid plaques) was convincingly targeted, and this made the FDA believe that the positive clinical effect in one of the two Phase 3 trials was real. The accelerated approval shows that the FDA takes the research in our field seriously and recognizes the huge unmet medical need of Alzheimer’s patients, warranting the accelerated approval track for novel drugs to bring hope to the patients. This decision reminds me of early times in AIDS research, when drugs with minimal clinical benefit were fast-tracked for use in humans. This opened the way for further clinical experimentation and trialing, and brought almost curative therapy to the AIDS field in two decades. In that case, too, patient organizations were lobbying and driving the process.

    The question of the role of amyloid plaques in Alzheimer’s disease is complex. The way the field approaches it is, however, surprisingly simplistic, with debates leaning more toward correct political thinking than sound scientific argumentation. My take is that very good genetic and basic research demonstrates that amyloid peptides and amyloid plaques are not innocent bystanders in Alzheimer’s disease, but that a simplistic cause-consequence relationship between accumulating amyloid and neurodegeneration should have been abandoned more than a decade ago (see Karran et al, 2011). It is therefore remarkable that most of the clinical trialing still tests the concept of amyloid pathology as the driver of disease. Conceptually, it is much more useful to think about amyloid pathology as a trigger of a series of disease processes that evolve over time and lead, only relatively late, to neurodegeneration and dementia (De Strooper and Karran, 2016). 

    Questions like whether a minimal threshold of amyloid pathology has to be reached before disease is initiated, and whether and when disease processes become independent of amyloid pathology, have not, as yet, been answered. Similarly, it remains unclear whether patients with mixed forms of dementia (displaying next to amyloid plaques and tangles also vascular dementia, α-synuclein or TDP-43 inclusions, a.o.) will benefit from a drug that only removes amyloid plaques.

    Most importantly, it takes more than a decade to accumulate amyloid pathology and induce disease, which suggests that it is important when during this process the drug is used. It might also take some time to remove the already accumulated amyloid from the brain to reach a level below the pathological threshold. It might even take more time to see the clinical benefit, as brain function will only restore gradually. While these are logical and not very new ideas, they are not taken into practical consideration when clinical trials are designed in the field.  

    My biggest concern is that the very negative press regarding the approval of aducanumab will lead to half-hearted clinical follow-up. In my opinion, the field now has a great opportunity to test the potential of an anti-amyloid therapeutic in a coherent and refined way. We can now ask long-overdue questions in well-designed clinical trials: Which patient subgroup will see the greatest effect with this drug? At what stage of the disease will maximal cost/benefit be realized? Does it make sense to treat patients in an advanced stage of dementia with a drug that tackles the initial trigger of the disease?

    It seems unlikely that the large group of aged patients with mixed forms of dementia will strongly benefit from a drug that tackles only one aspect of the disease. At least some trials should test carefully selected patients with positive biomarkers but no clinical signs. Those patients should be followed up over years, including a full panel of biomarkers, to see whether early intervention with aducanumab can halt Alzheimer’s disease in its tracks.

    The DIAN cohort is another group of familial Alzheimer’s disease patients who should be tested for beneficial effects of aducanumab in the preclinical phase of the disease. These clinical experiments will allow us to determine definitively the triggering role of amyloid plaques in the cellular processes that eventually lead to Alzheimer’s disease. Only when we know that aducanumab provides a significant benefit in these groups of patients can the field move forward with the necessary conviction that aducanumab also can benefit patients suffering from less-well-defined forms of dementia.

    The expectation is that the effects of aducanumab in mixed forms of dementia and in late stages of AD will be variable and probably minimal. Therefore, if the field leaves the execution of the Phase 4 trial as requested by the FDA to the free market alone, we will see mostly results from a complex patient population, resulting again in blurred and controversial signals. We need well-designed trials that address specific aspects of the remaining questions conclusively by selecting patients and biomarkers in a logical and consistent way.

    Hard proof of efficacy should be sought in rigorously defined Alzheimer’s disease cases, which, of note, are relatively rare in the general population. Aducanumab might later turn out to be also useful in mixed-dementia cases but, almost for sure, mostly in combination with treatments that tackle the other mechanisms of dementia in these patients. 

    In conclusion, our field is not helped with polarized yes-no discussions, which already have paralyzed our field many times in the past. Alzheimer’s disease and dementia are complicated disorders, and it is unlikely that one simple hypothesis and one golden bullet will explain and treat all. Instead of throwing out the baby with the bathwater, we should now try to understand what the experiments are telling us. 

    The field could profit from the enormous chance that the FDA decision provides to learn about novel ways to treat dementia. We should realize the important learning from the aducanumab trials that interim futility analyses appear not very helpful when trying to seriously test a clinical hypothesis. We have now heard that the FDA is ready for the field bringing medication to the patients in accelerated ways, and that good biomarker evidence is critically helpful.

    This is good news not only for amyloid plaques aficionados. It will help many clinical investigators bring their many ideas and drug candidates faster forward into the clinic. I am positive: This approval will initiate an explosion of intense clinical research into Alzheimer’s disease, which will bring light at the end of the very long and dark tunnel of AD research of the last decade. We do not have to deny the problematic aspects of the aducanumab approval to see the golden chance it also hands us. We have the obligation, both basic and clinical Alzheimer’s disease researchers alike, to think positively. We need to help our patients now to use this new drug in a wise and constructive way.

    References:

    . The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011 Sep;10(9):698-712. PubMed.

    . The Cellular Phase of Alzheimer's Disease. Cell. 2016 Feb 11;164(4):603-15. PubMed.

  4. This approval is a big step toward success in disease modification of AD, despite a vigorous controversy on the interpretation of the trial data and regulatory decisions by the FDA. Accelerated approval requiring an additional randomized controlled trial was a difficult choice, made to reconcile the compelling need of a new therapy for patients and family members with the insufficient evidence supporting the regulatory decision. The FDA statement emphasized amyloid reduction as a surrogate biomarker, but it should rather have valued the CSF p-tau and tau PET data as noted in the pharmacodynamics part of the prescribing information.

    This will surely accelerate clinical development of anti-Aβ drugs with similar effects, i.e., gantenerumab, lecanemab, and donanemab, despite the possibility of competition between medications and trials. Hopefully prevention trials using the same set of drugs in preclinical AD will be facilitated.

    In Japan, the mass media enthusiastically reported the news of aducanumab's approval. It is attracting much attention among the general public, especially among the elderly population, with some mixed feelings caused by the negative information on the efficacy, etc. The estimated high cost may be an issue in Japan, where prescription cost, including the excess part for expensive medications, is largely covered by public insurance. We may ultimately need some new strategies to publicly cover the expensive drug costs.

    While the application for approval was submitted by Biogen and Eisai to the Japanese regulatory agency PMDA last December and is still under review, we may have to formulate a guideline for appropriate use of anti-Aβ antibody drugs to ensure that the indication (probably limited to early AD) is strictly observed, and to avoid the waste of precious resources and medical budgets.

    The Japan Society for Dementia Research, a comprehensive research association to which many of the dementia clinical experts of different disciplines belong, is taking the lead for open discussions to prepare for the clinical application of these drugs without confusion in our society. We do feel much is left to be done prior to the implementation of these drugs to clinical practice of dementia and Alzheimer’s disease.

  5. The data did not support this approval. The advisory committee did a thorough and independent review and came to the same conclusion countless independent scientists have also voiced: The clinical efficacy findings are no more convincing than a roll of dice. Within the context of other evidence from previous studies of similar drugs, they are less convincing.

    If accelerated approval meant accelerated finding of a successful drug, it would be a good thing, but in fact it is likely to do the opposite: delay the day we know whether this drug helps people with AD or just helps Biogen's bottom line. Contrary to the label, this may mean deceleration of effective treatments. The idea that we would approve medications on the basis of a biomarker change, i.e., amyloid reduction, when we know that reducing amyloid does not equate to definite benefit for improving people's lives, i.e., memory and functioning improvements, sets a bad precedent. 

    Recruiting for trials of new drugs because people prefer to take an approved drug is a major concern, based on what has happened in the past when there was a popular belief but no convincing evidence that a drug or treatment worked. It took a long time to accumulate the evidence, and during that time, patients suffered from harmful treatments and from lack of progress in finding effective treatments.  

    Sadly, this approval feels like we have failed patients, and failed families. It's our job to wade through the statistics, insist on rigorous evidence, and be honest that drugs without proven benefit that have demonstrable harms should not be approved. The failure is not just the aducanumab decision, which is the culmination of years and years of relentless focus on a single strategy for disease prevention and treatment, despite ever-growing evidence that that strategy will not succeed. We need to invest more broadly, build an innovative and inclusive research program that incorporates new approaches, not dig ourselves deeper into this amyloid hole.

    There are ways to structure the rollout of aducanumab so we can learn more about whether it works, and learn it more quickly than waiting a decade for the confirmatory trial. I hope that the entire ADRD community of people living with the disease, their loved ones, advocates, and scientists, will consider pressing for structures to accumulate the most convincing evidence possible one way or another. Given that the drug has been approved, we need to insist on getting more convincing evidence as soon as possible.

  6. Bart De Strooper's thoughtful and cogent comments provide compelling guidance for the AD field moving forward in our new landscape following the approval of aducanumab. I agree with Bart that the approval of aducanumab will offer new opportunities to explore in clinical and basic AD research. Carefully designed clinical trials of aducanumab in the appropriate participant subgroups will begin providing answers to the questions of who to treat, when to treat, and how much to treat. Secondary prevention trials in people who are amyloid-positive but clinically asymptomatic may show that aducanumab is more effective in this group than in either MCI or mild AD. Primary prevention trials in individuals at genetic risk for AD but biomarker negative may also be considered.

    Finally, AD is a complex disorder in which multiple pathogenic mechanisms manifest, requiring combination therapies that attack different targets sequentially or simultaneously. The approval of aducanumab makes such combination trials more feasible. For example, aducanumab could be used first to clear amyloid from the brain, then aducanumab treatment halted and followed by a safe, low-dose BACE1 inhibitor regimen to lower Aβ production by ~30 percent and maintain an amyloid-free brain.

    Other drug combinations with aducanumab could be envisioned, such as with an anti-tau antibody or ASO, or a γ-secretase modulator. It will also be interesting to test whether individuals cleared of amyloid by aducanumab can have a drug holiday, and if so, for how long. Focusing on the potential opportunities for AD research that the aducanumab approval may present provides a useful and positive path forward.

  7. With regard to this sentence in the story: "These meta-analyses included small trials, e.g. lecanemab; low-dose trials, e.g., gantenerumab; and drugs not primarily designed to lower plaques, e.g., BACE inhibitors, bexarotene."

    We did include small trials (the trial of lecanemab was not a small trial), but they had very little influence on the overall estimate. We didn't just naively "average" across trials, i.e., trials with larger sample sizes and that removed more amyloid had greater influence on the overall estimate. We also stratified by antibody (typically larger trials and more effective at removing amyloid) and non-antibody drugs.

    These are indeed a heterogeneous group of drugs and trials, but no single drug/trial showed a significant effect of amyloid reduction on cognitive decline as measured with the MMSE. Even the one significant estimate for one trial of aducanumab using the ADAS-Cog precluded large clinical benefit.

    "Much more drastic amyloid plaque reduction is being reported for three other anti-amyloid antibodies besides aducanumab. Two of them—donanemab and lecanemab—did tap the brakes on cognitive decline by 20 to 30 percent in well-designed Phase 2 trials, while Phase 3 data on high-dose gantenerumab are expected next year."

    Lecanemab (BAN2401) was already included in the analysis. Also, donanemab removed a great deal of amyloid—more than aducanumab—but did not have a large effect on cognition. See update on the analysis at https://twitter.com/MariaGlymour/status/1389087467928625154

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References

Therapeutics Citations

  1. Aduhelm
  2. Solanezumab
  3. Bapineuzumab
  4. Bexarotene
  5. Semagacestat
  6. Verubecestat
  7. Donanemab
  8. Lecanemab
  9. Gantenerumab

News Citations

  1. A New Era of Alzheimer’s Treatment
  2. Biogen/Eisai Halt Phase 3 Aducanumab Trials
  3. Exposure, Exposure, Exposure? At CTAD, Aducanumab Scientists Make a Case
  4. FDA Advisory Committee Throws Cold Water on Aducanumab Filing
  5. Aducanumab Still Needs to Prove Itself, Researchers Say
  6. Aducanumab Approved to Treat Alzheimer’s Disease
  7. Begone 2020: Despite COVID, Alzheimer’s Research Advanced
  8. Donanemab Confirms: Clearing Plaques Slows Decline—By a Bit
  9. Second Look at BAN2401 Data Still Positive, Despite Snafu
  10. In DIAN-TU, Gantenerumab Brings Down Tau. By a Lot. Open Extension Planned

Paper Citations

  1. . Bayes analysis supports null hypothesis of anti-amyloid beta therapy in Alzheimer's disease. Alzheimers Dement. 2021 Jun;17(6):1051-1055. Epub 2021 May 31 PubMed.
  2. . Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. BMJ. 2021 Feb 25;372:n156. PubMed.

External Citations

  1. requested the Senate Finance Committee
  2. Point32Health
  3. Bloomberg news
  4. AAAS blog
  5. Endpoints news
  6. STAT news
  7. New York Times editorial
  8. STAT news
  9. Endpoints news
  10. June 17 letter
  11. The Washington Post editorial
  12. Endpoints news
  13. public defense of her agency’s decision

Further Reading