Abstract
Alzheimer’s disease (AD), the devastating and most prevailing underlying cause for age-associated dementia, has no effective disease-modifying treatment. The last approved drug for the relief of AD symptoms was in 2003. The recent approval of sodium oligomannate (GV-971, 2019) in China and the human antibody aducanumab in the USA (ADUHELM, 2021) therefore represent significant breakthroughs, albeit ones that are fraught with controversy. Here, we explore potential scientific ethics issues associated with GV-971 and aducanumab’s development and approval. While these issues may be belied by socioeconomic and political complexities in the heady business of commercial drug development, they are of fundamental importance to scientific integrity and ultimately, welfare of patients. We posit that the push for approval of both AD drugs based on incomplete research and unconvincing marginal effectiveness is ethically unsound. Regardless of how both these drugs shall perform in the market for the years to come, the scientific ethics issues and potentially questionable research practices should therefore be duly noted and lessons learned.
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Notes
Searches with the term “oligomannate” or “GV-971” conducted at ClinicalTrials.gov (https://clinicaltrials.gov) returned nine projects in various stages of recruitment/completion. Two of these are Phase I trials with healthy participants (NCT02986529 and NCT03715114 (see Table 1) to examine bioavailability and pharmacodynamics. Six of these are Phase I to IV trials on AD and one on post-stroke cognitive impairment. Searches with the term “oligomannate” or “GV-971” made at the Chinese Clinical Trial Registry (CHICTR) (www.chictr.org.cn) returned four projects: ChiCTR2100042680 and ChiCTR2100053873 are on Parkinson’s disease, both 2021), while ChiCTR2000039219 (A multicentre observational study of the efficacy and safety of Sodium Oligomannate Capsules in the treatment of Alzheimer's disease, 2020) and ChiCTR2100047830 (Effects of GV-971 and Donepezil in Alzheimer's Disease, 2021) are on AD.
This requirement is according to that of the US FDA, and may not be one adopted by China’s National Medical Products Administration (NMPA). The “conditional approval” for GV-971 in AD treatment by NMPA would be in accordance with the following that is paraphrased from a slide presented by Xiaoping Cao, Pfizer Senior Director and Head of Global CMC for China at the PharmaLink 2021 conference, and shown in a blogpost by Jerry Chapman (https://redica.com/pharma-an-inside-look-at-chinas-regulatory-and-drug-approval-processes). “During local clinical trial, the clinical data can predict its efficacy and clinical benefits for target indications that are serious and life-threatening with unmet clinical needs, urgent need for drugs to treat rare diseases, drugs urgently needed in public health and vaccines with special approval”. The first two of these would be descriptive of AD.
Geng (and her work on GV-971) is among several other prominent Chinese researchers investigated recently by a committee comprising representatives from several Chinese ministries. According to a “Notice on the Investigation and Handling of Suspected Fraudulent Papers” issued by the Ministry of Science and Technology of China on Jan 2021, no fraud on Geng’s part was found. However, there were instances of misuse of pictures in her papers and remedial education and scientific research integrity reminders shall be implemented.
The dosing used in these trials are complicated by protocol amendments, particularly that to a subset of the test participants who are carriers of the apolipoprotein E (APOE) ε4 allele who are more susceptible to ARIA. Initially by APOE ε4 carriers were only to be tested on the lower doses up to 6 mg/kg, but as of Mar 2017 these were also to be titrated to 10 mg/kg.
PET-SUVR refers to the imaging technique for quantitative evaluation of amyloid load with positron emission tomography (PET) with standardized uptake value ratio (SUVR).
Biogen’s powerpoint presentation file (2019). EMERGE and ENGAGE Topline Results: Two Phase III Studies to Evaluate Aducanumab in Patients With Early Alzheimer’s Disease. (https://investors.biogen.com/static-files/ddd45672-9c7e-4c99-8a06-3b557697c06f).
Initially indicated for all stages of AD, but later revised to include only patients with MCI and mild AD, which is in line with the cohort profile investigated in the phase III trials.
The more technically inclined reader is referred to these papers for further detail analyses.
The Centers for Medicare & Medicaid Services (CMS) has announced a preliminary National Coverage Determination (NCD) restricting Medicare coverage of the aducanumab to patients who are participating in approved placebo-controlled clinical trials.
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Yeo-Teh, N.S.L., Tang, B.L. A Review of Scientific Ethics Issues Associated with the Recently Approved Drugs for Alzheimer’s Disease. Sci Eng Ethics 29, 2 (2023). https://doi.org/10.1007/s11948-022-00422-0
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DOI: https://doi.org/10.1007/s11948-022-00422-0