The Food and Drug Administration’s conditional approval of aducanumab (Aduhelm) left most researchers and clinicians with a big question: Does the drug really work to slow cognitive and clinical decline? Post-market research will now try to answer this question. At the Alzheimer’s Association International Conference, held July 26-30 in Denver, James Galvin of the University of Miami described one such effort. Galvin introduced an observational study, sponsored by Biogen, that aims to enroll 6,000 people taking aducanumab. It will make a particular effort to recruit minorities, who were under-represented in the clinical trials. The observational study will track the clinical outcomes, blood biomarkers, and safety of aducanumab use. It has no control group.

  • Biogen is running an observational study of aducanumab’s real-world effects.
  • Once it’s clear who pays, the study will enroll 6,000 people, at least 1/6 minorities.
  • It won't gather efficacy data, leaving scientists to brainstorm other ways to do this.

The study is likely to be one of many attempts to determine aducanumab's real-world effects. Researchers have proposed other models for testing how well the drug works, but given the difficulty of finding a true control group now that treatment is approved, some wonder if the field will ever get a definitive answer. Nonetheless, data from such post-market studies will likely influence payers’ coverage decisions (see Part 5 of this series).

This study is separate from the FDA-required Phase 4 trial, on which no information has been made public yet.

ICARE-AD Will Assess Real-World Aducanumab Treatment
At AAIC, Galvin laid out the details of the International Collaboration for Real-World Evidence in Alzheimer’s Disease, suggestively collapsed into the acronym ICARE-AD. Biogen began identifying potential centers for this study before receiving FDA approval for aducanumab. More than 200 are now part of the effort; Galvin said they include academic and memory clinics, but not primary care. Biogen plans to expand the study to other countries if aducanumab becomes available elsewhere. The contract research organization IQVIA, based in Durham, North Carolina, will run the study. ICARE-AD does not have a principal investigator but will be led by a steering committee co-chaired by Galvin.

Participating clinics will recruit patients over the next four years. Of the 6,000 planned enrollees, the goal is that at least 500 be African-American and 500 Latino. This is an effort to remedy the lack of diversity in the aducanumab Phase 3 trials. Galvin said many of the sites for this study are in areas with diverse populations, which should aid in recruiting minorities. For example, Galvin's clinic in Miami serves a local population that is 60 percent Latino.

Importantly, ICARE-AD will relax the inclusion/exclusion criteria typically used in AD placebo-controlled trials, and include more people with chronic medical conditions such as diabetes, heart disease, and cancer. The long list of usual AD trial exclusion criteria is one reason a disproportionate number of minority participants tend to get screened out of participation (Raman et al., 2021). The idea is for ICARE-AD to reflect the U.S. clinic population, Galvin said. This means the ICARE-AD population may be less healthy overall than the ENGAGE/EMERGE populations were. Clinical trials usually try to select participants with relatively "pure" forms of the disease in question who are otherwise in good health.

ICARE-AD will follow each participant for up to five years, collecting data via interviews roughly every six months. Biogen has selected tests it believes will be both easy to administer and reflect change in early stage AD. The primary cognitive measure will be the MoCA version 8.1; the primary functional measure, the Amsterdam Instrumental Activities of Daily Living Questionnaire Short Version; and the main behavioral measure, the Neuropsychiatric Inventory Questionnaire. To assess global functioning, clinicians will administer the CDR at baseline and will track participants with the Quick Dementia Rating System. In addition, centers will use the Functional Activities Questionnaire and Geriatric Depression Scale Short Form.

Because the study has no control arm, there is no built-in way to directly assess how patients would have fared without going on aducanumab. To get at this question, researchers could compare the ICARE-AD treatment outcome data to historical norms, for example from observational studies such as ADNI, AIBL, BSLA or other biomarker-enhanced aging cohorts. Better yet, scientists could use existing disease progression models built from placebo group data (e.g. Jul 2013 news; Conrado et al., 2014). Lilly uses such a disease-progression model to better understand donanemab treatment data (Aug 2021 conference news). DIAN uses one, as well (Apr 2020 conference news). Galvin indicated to Alzforum that he knows of no plans to compare the ICARE-AD outcome data to anything.

The ICARE-AD study will assess participants' quality of life using the Quality of Life–Alzheimer’s Disease scale and the Short Form–12 Health Survey. It will also track caregiver burden and the cost of dementia care; for these outcomes, the measures are the Zarit Burden Interview and the Resource Utilization in Dementia Lite questionnaire, respectively.

Biogen will bank plasma and serum from participants to measure biomarkers, though as of this writing, Galvin did not know which markers would be chosen, nor whether samples would be collected from all participants, or from a subset. In addition, clinicians will track the incidence and severity of adverse events, particularly ARIA. At AAIC, an attendee asked how MRIs would be standardized across centers. Galvin said no attempt will be made to do this; the data will reflect real-world use.

The audience questioned how feasible this study will be, given the current lack of insurance coverage not only for aducanumab, but also for amyloid screening and for the numerous MRI scans to monitor ARIA. Although Biogen will pay physicians for administering outcome measures, and will cover the cost of CSF analysis for patients interested in aducanumab, Biogen will not pay for any other testing, nor the cost of the drug itself. Galvin suggested that amyloid PET scans could be covered under the new IDEAS study instead, i.e., indirectly via Medicare funds (Aug 2020 conference news). Galvin acknowledged, however, that due to the high cost of aducanumab, ICARE-AD will likely get off the ground only after there is more clarity about insurance coverage (Fierce Pharma story).

Between a delayed ramp-up, recruitment, and observation, ICARE-AD will likely take up to 10 years to generate results.

ICARE will not assess aducanumab’s efficacy. Galvin emphasized the definitional distinction between efficacy, which compares effects between people on and off an investigational drug, and effectiveness, which simply measures the effects of a drug in those who take it. ICARE-AD will track effectiveness. To settle questions of efficacy, clinicians will need a placebo-controlled trial.

So What About Efficacy?
The FDA requires Biogen to complete such a trial, and Biogen has promised to do so sooner than the nine years the agency gave it. Thus far, the company has revealed no details.

In the meantime, other researchers have suggested ways to approximate aducanumab’s efficacy. Maria Glymour at the University of California, San Francisco, proposed that researchers exploit the fact that manufacturing delays and logistical challenges mean aducanumab treatment will begin at different times in different places. Researchers could use these staggered start times to perform a quasi-randomized trial, comparing how quickly patients at different clinics progress to mild or moderate dementia as a function of their total exposure to aducanumab. This model would require clinics to coordinate their efforts, whereby they record run-in data for each patient in the months before aducanumab became available for them. Researchers could then compare that progression data to data from people on drug.

“This study design would provide patients and providers with vastly better information than currently available,” Glymour noted in her proposal

Madhav Thambisetty at Johns Hopkins University School of Medicine in Baltimore endorsed Glymour's idea. He noted that it could produce answers much sooner than Biogen’s Phase 4 trial will. He said aducanumab's accelerated approval based on biomarkers means that the thousands of AD patients who will eventually take the drug are in effect part of a huge public health experiment to determine whether aducanumab helps on the outcomes that matter to patients. Given this, Thambisetty suggested that medical centers collaborate to collect data on how their patients fare on this drug. “[Patients’] active participation as citizen-scientists in these post-approval studies is now critical to definitively test whether this medication works or not,” Thambisetty wrote (Endpoints News editorial).

Other analysts, such as Rita Rubin at the American Medical Association, warn that the unusual approval process means clinicians may never get a clear answer on how well aducanumab works. Now that aducanumab is publicly available, who will want to enter a randomized controlled trial where they may get placebo (Rubin, 2021)? Accelerated approval “has too often become essentially a commercial end-run around the [FDA],” wrote Elisabeth Rosenthal of Kaiser Health News (Washington Post editorial).

Biogen has not published the data from its two Phase 3 trials of aducanumab, which were conducted from 2015 to 2019. The company recently withdrew a manuscript describing the data from JAMA after the journal asked for edits (Axios news). On August 12, Biogen is publishing, in Nature Medicine, the data from the trials of its discontinued anti-tau antibody gosuranemab, which were conducted from 2017 to 2019 (Dam et al., 2021).—Madolyn Bowman Rogers

Comments

  1. Numerous pragmatic study options would be possible for ICARE-AD to have a more direct comparison group. Any type of randomized wait list would provide much more rigorous and convincing evidence than historical controls or any version of the Conrado et al. disease-progression model.

    The Conrado et al. disease-progression model was built to evaluate how specific assumptions about disease progression play out over the long run. It does not evaluate those input assumptions, it merely evaluates their long-term implications, taking for granted that the input assumptions about disease process are true. It should not be interpreted as new evidence for treatment efficacy. This is not a criticism of the model, which might be useful for planning a trial, but it seems to have been adopted in some settings as providing an independent source of information on treatment effects.

    An historical-control approach is deeply flawed and will not provide useful information unless the medication is astonishingly good or incredibly harmful. We know from the studies to date that the medication is somewhere in the range of a little harmful to a little helpful. Therefore, we will learn nothing from a study based on historical controls.

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References

News Citations

  1. Will Insurance Cover Aducanumab? Jury Is Out
  2. AD Trial Simulation Tool Receives Regulators’ Blessings
  3. On Donanemab, Plaques Plummet. Off Donanemab, They Stay Away
  4. In DIAN-TU, Gantenerumab Brings Down Tau. By a Lot. Open Extension Planned
  5. IDEAS Finds Small Drop in Hospitalizations, Missing Goal

Paper Citations

  1. . Disparities by Race and Ethnicity Among Adults Recruited for a Preclinical Alzheimer Disease Trial. JAMA Netw Open. 2021 Jul 1;4(7):e2114364. PubMed.
  2. . An updated Alzheimer's disease progression model: incorporating non-linearity, beta regression, and a third-level random effect in NONMEM. J Pharmacokinet Pharmacodyn. 2014 Dec;41(6):581-98. Epub 2014 Aug 29 PubMed.
  3. . Recently Approved Alzheimer Drug Raises Questions That Might Never Be Answered. JAMA. 2021 Aug 10;326(6):469-472. PubMed.
  4. . Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial. Nat Med. 2021 Aug;27(8):1451-1457. Epub 2021 Aug 12 PubMed.

Other Citations

  1. aducanumab

External Citations

  1. Fierce Pharma story
  2. her proposal
  3. Endpoints News editorial
  4. Washington Post editorial
  5. Axios news

Further Reading