Gyawali B, Ross JS, Kesselheim AS.
Fulfilling the Mandate of the US Food and Drug Administration's Accelerated Approval Pathway: The Need for Reforms.
JAMA Intern Med. 2021 Oct 1;181(10):1275-1276.
PubMed.
At the level of dementia care, the accelerated approval of aducanumab, and its enabling of the approval of perhaps three other anti-Aβ antibodies (donanemab, lecanemab, gantenerumab) under the same pathway, promises to have a large impact in countries where the drugs gain approval. Even if only a modest number of prescriptions for aducanumab, and others with the similar mechanism of action, are written, it’s clear that the resources necessary to provide treatment with anti-Aβ antibodies to the right patients with the necessary safety precautions are woefully inadequate.
There are too few dementia specialists, too few neuropsychologists, to collaborate with physicians on the diagnosis of mild cognitive impairment and mild dementia, too few persons with expertise in interpreting CSF Aβ and tau assays. There is complete absence of infrastructure or reimbursement for Aβ PET imaging, and there are too few neuroradiologists with expertise in recognizing ARIA.
Of course, all of those deficiencies are additive (or multiplicative) with the deficiencies in our knowledge of aducanumab’s long-term prospects for benefit. One can only hope that sponsors of the agents in the wings will be responsible citizens and publish, in peer-reviewed journals, their detailed controlled and open-label results. Adding cost considerations into this mix is even more daunting.
It’s too early to tell how soon clinical trial design will change, or be forced to change. Grill and Karlawish, 2021, have written a nice article about this, citing the experience of multiple sclerosis in the post-β-interferon days. β-Interferon and aducanumab make for an imperfect comparison, in that with β-interferon there was a robust clinical signal, i.e., reduced rate of exacerbations, while with aducanumab, there was no consistent clinical outcome signal.
Perhaps one or more of the other anti-Aβ antibodies will find some genuine clinical benefits. A consistent clinical signal with an anti-Aβ antibody will be what drives changes in future trial designs. Trial designs that involve active comparators or background treatment of all participants with an anti-amyloid agent will then become necessary. Such designs are necessarily more complex logistically and more expensive than currently, but such designs are feasible.
References:
Grill JD, Karlawish J.
Implications of FDA Approval of a First Disease-Modifying Therapy for a Neurodegenerative Disease on the Design of Subsequent Clinical Trials.
Neurology. 2021 Sep 7;97(10):496-500. Epub 2021 Jun 4
PubMed.
There has been some confusion and controversy in the field regarding the accelerated (not full) approval of aducanumab. The FDA has used the accelerated approval regulatory pathway since 1992, though primarily for HIV and cancer treatments. It allows a drug to be prescribed based on studies showing a change in a biomarker that is “reasonably likely” to predict efficacy based on clinical outcomes. A requirement is that a subsequent study demonstrate clinical efficacy, and if such a study is negative, the drug can be removed from the market. This situation is quite different from a full approval of a new drug.
In the case of aducanumab, an Advisory Committee meeting was held to discuss full approval and, as has been widely reported, the committee was not supportive. The accelerated approval pathway was not discussed at the meeting.
At the time of this meeting, it was clear that treatment with aducanumab and lecanemab both resulted in substantial reduction in neuritic amyloid plaque load based on PET imaging. The clinical data on aducanumab are much less clear-cut from the Phase 3 ENGAGE and EMERGE trials. The clinical data from the lecanemab Phase 2 trials, while promising, must be interpreted with caution given the complex adaptive study design. Given the mixed clinical data from the Phase 3 aducanumab studies and the Phase 2 lecanemab studies, the argument that lowering of plaque load was “reasonably likely” to predict clinical effects could not be made; hence, the Advisory Committee only discussed full approval.
On March 13, 2021, Eli Lilly and Company announced in a press release, and with a paper published simultaneously in NEJM, that a Phase 2 study of the drug donanemab caused marked reduction in amyloid plaque based on amyloid PET, and also showed statistically significant improvement in the clinical measure that was the primary outcome for the study, the iADRS. With the new data from donanemab, in addition to the data from aducanumab and lecanemab, at that point the FDA apparently felt that plaque reduction did meet the hurdle of “reasonably likely” to predict clinical efficacy. This conclusion by FDA would be consistent with the accelerated approval given for aducanumab on June 7. The FDA is requiring a subsequent study for aducanumab as required by the accelerated approval pathway, but for unclear reasons FDA allowed nine years to complete the study.
Given the precedent for accelerated approval based on plaque reduction established by aducanumab, not surprisingly this pathway is being utilized for lecanemab and donanemab. Discussions with FDA regarding gantenerumab are reported to be underway.
While plaque reduction based on amyloid PET has apparently reached the threshold of “reasonably likely” for the FDA, the fact that other biomarkers might prove even more useful (e.g., NfL, p-tau231) should be noted. Based on available data to date, plaque reduction would also be expected to be accompanied by ARIA, which immediately complicates the assessment of the risk/benefit ratio. With further advances in the field, other biomarkers might reach the threshold of “reasonably likely” to predict clinical efficacy, but without also predicting the occurrence of ARIA.
Like many fields before us, we wrestle with the central question of the validity of a biomarker to be used as a surrogate endpoint in clinical trials. Beyond the vague legal term "reasonably likely" used by the FDA in its texts, numerous methodologists have already tried to answer this difficult question, proposing several scales (Prentice, 1989; Kim et al., 2016; Fleming and Powers, 2012; Ciani et al., 2017). Among them, Ross Prentice's criteria are widely used and cited in the oncology field.
In a recent viewpoint with Vincent Planche (Planche and Villain, 2021), we have detailed how these four “Prentice criteria” would apply to anti-amyloid therapies:
First, before validating amyloid load (measured by amyloid PET) as a surrogate endpoint in clinical trials, a clinical trial of the same drug should have proven to be positive on clinical outcomes. This is arguably the case for anti-amyloid therapies so far.
Second, there should be a statistical demonstration (mediation analysis) that the amyloid load mediates the treatment effect on the clinical outcome. This, to our best knowledge, has never been done so far, beyond the non-significant correlations between amyloid load loss and CDR-SB progression of aducanumab Phase 3 trials and donanemab phase II trial (Liu and Howard, 2021).
Third, there should be a demonstration that the drug has an effect on the potential surrogate marker. This third point is the only one that is not debated regarding aducanumab and the other three other anti-amyloid drugs cited in this article, lecanemab, donanemab, and high-dose gantenerumab.
Finally, amyloid load should be associated with the clinical outcome. In the AD field, the relationship between amyloid and clinical symptoms is highly debated: from the theoretical questioning of the “amyloid cascade” (Karran and De Strooper, 2016), to its implication in the definition of AD (Dubois and Villain et al., 2021).
As a whole, beyond agencies’ definitions, the field should not lightly establish what makes a biomarker “reasonably likely” to be used as a valid surrogate endpoint for future clinical trials. Instead, rigorous methodology should be applied to this key element, as performed in the rest of our work.
References:
Prentice RL.
Surrogate endpoints in clinical trials: definition and operational criteria.
Stat Med. 1989 Apr;8(4):431-40.
PubMed.
Prasad V, Kim C, Burotto M, Vandross A.
The Strength of Association Between Surrogate End Points and Survival in Oncology: A Systematic Review of Trial-Level Meta-analyses.
JAMA Intern Med. 2015 Aug;175(8):1389-98.
PubMed.
Fleming TR, Powers JH.
Biomarkers and surrogate endpoints in clinical trials.
Stat Med. 2012 Nov 10;31(25):2973-84. Epub 2012 Jun 18
PubMed.
Ciani O, Buyse M, Drummond M, Rasi G, Saad ED, Taylor RS.
Time to Review the Role of Surrogate End Points in Health Policy: State of the Art and the Way Forward.
Value Health. 2017 Mar;20(3):487-495. Epub 2016 Dec 22
PubMed.
Planche V, Villain N.
US Food and Drug Administration Approval of Aducanumab-Is Amyloid Load a Valid Surrogate End Point for Alzheimer Disease Clinical Trials?.
JAMA Neurol. 2021 Nov 1;78(11):1307-1308.
PubMed.
Liu KY, Howard R.
Can we learn lessons from the FDA's approval of aducanumab?.
Nat Rev Neurol. 2021 Nov;17(11):715-722. Epub 2021 Sep 17
PubMed.
Karran E, De Strooper B.
The amyloid cascade hypothesis: are we poised for success or failure?.
J Neurochem. 2016 Oct;139 Suppl 2:237-252. Epub 2016 Jun 3
PubMed.
Dubois B, Villain N, Frisoni GB, Rabinovici GD, Sabbagh M, Cappa S, Bejanin A, Bombois S, Epelbaum S, Teichmann M, Habert MO, Nordberg A, Blennow K, Galasko D, Stern Y, Rowe CC, Salloway S, Schneider LS, Cummings JL, Feldman HH.
Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group.
Lancet Neurol. 2021 Jun;20(6):484-496. Epub 2021 Apr 29
PubMed.
Comments
Mayo Clinic College of Medicine
At the level of dementia care, the accelerated approval of aducanumab, and its enabling of the approval of perhaps three other anti-Aβ antibodies (donanemab, lecanemab, gantenerumab) under the same pathway, promises to have a large impact in countries where the drugs gain approval. Even if only a modest number of prescriptions for aducanumab, and others with the similar mechanism of action, are written, it’s clear that the resources necessary to provide treatment with anti-Aβ antibodies to the right patients with the necessary safety precautions are woefully inadequate.
There are too few dementia specialists, too few neuropsychologists, to collaborate with physicians on the diagnosis of mild cognitive impairment and mild dementia, too few persons with expertise in interpreting CSF Aβ and tau assays. There is complete absence of infrastructure or reimbursement for Aβ PET imaging, and there are too few neuroradiologists with expertise in recognizing ARIA.
Of course, all of those deficiencies are additive (or multiplicative) with the deficiencies in our knowledge of aducanumab’s long-term prospects for benefit. One can only hope that sponsors of the agents in the wings will be responsible citizens and publish, in peer-reviewed journals, their detailed controlled and open-label results. Adding cost considerations into this mix is even more daunting.
It’s too early to tell how soon clinical trial design will change, or be forced to change. Grill and Karlawish, 2021, have written a nice article about this, citing the experience of multiple sclerosis in the post-β-interferon days. β-Interferon and aducanumab make for an imperfect comparison, in that with β-interferon there was a robust clinical signal, i.e., reduced rate of exacerbations, while with aducanumab, there was no consistent clinical outcome signal.
Perhaps one or more of the other anti-Aβ antibodies will find some genuine clinical benefits. A consistent clinical signal with an anti-Aβ antibody will be what drives changes in future trial designs. Trial designs that involve active comparators or background treatment of all participants with an anti-amyloid agent will then become necessary. Such designs are necessarily more complex logistically and more expensive than currently, but such designs are feasible.
References:
Grill JD, Karlawish J. Implications of FDA Approval of a First Disease-Modifying Therapy for a Neurodegenerative Disease on the Design of Subsequent Clinical Trials. Neurology. 2021 Sep 7;97(10):496-500. Epub 2021 Jun 4 PubMed.
View all comments by David KnopmanAcumen Pharmaceuticals
There has been some confusion and controversy in the field regarding the accelerated (not full) approval of aducanumab. The FDA has used the accelerated approval regulatory pathway since 1992, though primarily for HIV and cancer treatments. It allows a drug to be prescribed based on studies showing a change in a biomarker that is “reasonably likely” to predict efficacy based on clinical outcomes. A requirement is that a subsequent study demonstrate clinical efficacy, and if such a study is negative, the drug can be removed from the market. This situation is quite different from a full approval of a new drug.
In the case of aducanumab, an Advisory Committee meeting was held to discuss full approval and, as has been widely reported, the committee was not supportive. The accelerated approval pathway was not discussed at the meeting.
At the time of this meeting, it was clear that treatment with aducanumab and lecanemab both resulted in substantial reduction in neuritic amyloid plaque load based on PET imaging. The clinical data on aducanumab are much less clear-cut from the Phase 3 ENGAGE and EMERGE trials. The clinical data from the lecanemab Phase 2 trials, while promising, must be interpreted with caution given the complex adaptive study design. Given the mixed clinical data from the Phase 3 aducanumab studies and the Phase 2 lecanemab studies, the argument that lowering of plaque load was “reasonably likely” to predict clinical effects could not be made; hence, the Advisory Committee only discussed full approval.
On March 13, 2021, Eli Lilly and Company announced in a press release, and with a paper published simultaneously in NEJM, that a Phase 2 study of the drug donanemab caused marked reduction in amyloid plaque based on amyloid PET, and also showed statistically significant improvement in the clinical measure that was the primary outcome for the study, the iADRS. With the new data from donanemab, in addition to the data from aducanumab and lecanemab, at that point the FDA apparently felt that plaque reduction did meet the hurdle of “reasonably likely” to predict clinical efficacy. This conclusion by FDA would be consistent with the accelerated approval given for aducanumab on June 7. The FDA is requiring a subsequent study for aducanumab as required by the accelerated approval pathway, but for unclear reasons FDA allowed nine years to complete the study.
Given the precedent for accelerated approval based on plaque reduction established by aducanumab, not surprisingly this pathway is being utilized for lecanemab and donanemab. Discussions with FDA regarding gantenerumab are reported to be underway.
While plaque reduction based on amyloid PET has apparently reached the threshold of “reasonably likely” for the FDA, the fact that other biomarkers might prove even more useful (e.g., NfL, p-tau231) should be noted. Based on available data to date, plaque reduction would also be expected to be accompanied by ARIA, which immediately complicates the assessment of the risk/benefit ratio. With further advances in the field, other biomarkers might reach the threshold of “reasonably likely” to predict clinical efficacy, but without also predicting the occurrence of ARIA.
View all comments by Eric SiemersSorbonne University - APHP - Pitié-Salpêtrière Hospital
Like many fields before us, we wrestle with the central question of the validity of a biomarker to be used as a surrogate endpoint in clinical trials. Beyond the vague legal term "reasonably likely" used by the FDA in its texts, numerous methodologists have already tried to answer this difficult question, proposing several scales (Prentice, 1989; Kim et al., 2016; Fleming and Powers, 2012; Ciani et al., 2017). Among them, Ross Prentice's criteria are widely used and cited in the oncology field.
In a recent viewpoint with Vincent Planche (Planche and Villain, 2021), we have detailed how these four “Prentice criteria” would apply to anti-amyloid therapies:
First, before validating amyloid load (measured by amyloid PET) as a surrogate endpoint in clinical trials, a clinical trial of the same drug should have proven to be positive on clinical outcomes. This is arguably the case for anti-amyloid therapies so far.
Second, there should be a statistical demonstration (mediation analysis) that the amyloid load mediates the treatment effect on the clinical outcome. This, to our best knowledge, has never been done so far, beyond the non-significant correlations between amyloid load loss and CDR-SB progression of aducanumab Phase 3 trials and donanemab phase II trial (Liu and Howard, 2021).
Third, there should be a demonstration that the drug has an effect on the potential surrogate marker. This third point is the only one that is not debated regarding aducanumab and the other three other anti-amyloid drugs cited in this article, lecanemab, donanemab, and high-dose gantenerumab.
Finally, amyloid load should be associated with the clinical outcome. In the AD field, the relationship between amyloid and clinical symptoms is highly debated: from the theoretical questioning of the “amyloid cascade” (Karran and De Strooper, 2016), to its implication in the definition of AD (Dubois and Villain et al., 2021).
As a whole, beyond agencies’ definitions, the field should not lightly establish what makes a biomarker “reasonably likely” to be used as a valid surrogate endpoint for future clinical trials. Instead, rigorous methodology should be applied to this key element, as performed in the rest of our work.
References:
Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. 1989 Apr;8(4):431-40. PubMed.
Prasad V, Kim C, Burotto M, Vandross A. The Strength of Association Between Surrogate End Points and Survival in Oncology: A Systematic Review of Trial-Level Meta-analyses. JAMA Intern Med. 2015 Aug;175(8):1389-98. PubMed.
Fleming TR, Powers JH. Biomarkers and surrogate endpoints in clinical trials. Stat Med. 2012 Nov 10;31(25):2973-84. Epub 2012 Jun 18 PubMed.
Ciani O, Buyse M, Drummond M, Rasi G, Saad ED, Taylor RS. Time to Review the Role of Surrogate End Points in Health Policy: State of the Art and the Way Forward. Value Health. 2017 Mar;20(3):487-495. Epub 2016 Dec 22 PubMed.
Planche V, Villain N. US Food and Drug Administration Approval of Aducanumab-Is Amyloid Load a Valid Surrogate End Point for Alzheimer Disease Clinical Trials?. JAMA Neurol. 2021 Nov 1;78(11):1307-1308. PubMed.
Liu KY, Howard R. Can we learn lessons from the FDA's approval of aducanumab?. Nat Rev Neurol. 2021 Nov;17(11):715-722. Epub 2021 Sep 17 PubMed.
Karran E, De Strooper B. The amyloid cascade hypothesis: are we poised for success or failure?. J Neurochem. 2016 Oct;139 Suppl 2:237-252. Epub 2016 Jun 3 PubMed.
Dubois B, Villain N, Frisoni GB, Rabinovici GD, Sabbagh M, Cappa S, Bejanin A, Bombois S, Epelbaum S, Teichmann M, Habert MO, Nordberg A, Blennow K, Galasko D, Stern Y, Rowe CC, Salloway S, Schneider LS, Cummings JL, Feldman HH. Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group. Lancet Neurol. 2021 Jun;20(6):484-496. Epub 2021 Apr 29 PubMed.
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