A month or so ago, the Food and Drug Administration (FDA) kicked-off a bit of a kerfuffle with, depending upon your viewpoint, its innovative, radical, and/or dangerous proposals to overhaul aspects of the regulatory path to approval for new drugs for Alzheimer’s disease. The recently published draft guidance (see pdf here and Webinar here) invited comment and that is exactly what it got. On the one hand, the proposals were welcomed by clinicians and patient groups that are desperate to see new treatments come to market while on the other hand there was a degree of scepticism by those that regarded them being overly favourable towards pharmaceutical companies. But let us first reflect upon why the FDA felt the need to stir the pot in the first place.
It has been noted that of the greater than 100 drugs that entered development for the treatment of Alzheimer’s disease since 1998, only three have achieved Food and Drug Administration (FDA) approval. These drugs were the acetylcholinesterase inhibitors rivastigmine from Novartis (Exelon, approved in 2000) and galantamine from Forest/Janssen (Reminyl, 2001) along with the NMDA receptor antagonist memantine from Merz/Forest/Lundbeck (Namenda, 2003). They joined the acetylcholinesterase inhibitor donepezil (Aricept; Eisai/Pfizer), which was approved in 1996, to comprise the quartet of FDA-approved therapies for the symptomatic treatment of Alzheimer’s disease. More recently, disease-modifying rather than symptomatic-relief approaches have attracted most attention with the amyloid hypothesis predominating, although recent clinical trial failures of amyloid-related drugs have instigated a re-appraisal of this approach (for review see here).
We have previously discussed the state of amyloid-related therapeutics for the treatment of Alzheimer’s Disease, with the focus clearly shifting to the treatment of earlier, mild forms of the disease or the prevention of the disease in susceptible populations (see here). Most notably, the Lilly antibody Solanezumab showed signs of efficacy in early (mild) Alzheimer patients in the failed Expedition 1 and Expedition 2 Phase III studies and these data have encouraged additional Phase III studies specifically targeting such patients, although it should be noted that diagnostic accuracy in such patients could be an issue. Hence, it is not unreasonable to assume that in later stages of the disease, neuronal damage may have become too widespread for effective disease-modifying intervention, particularly as regards amyloid-based therapeutics (see here).
It was the recognition that effective treatment would most likely occur in the early stages of the disease that prompted the FDA’s proposals. At the moment, regulatory requirements for a drug approval require an improvement in cognition to be accompanied by a functional improvement in an activity of daily living, such as making a cup of tea. However, in a recently-published article in New England Journal of Medicine which summarises their proposals, the FDA note that in Alzheimer patients that do not have overt dementia meaningful functional deficits are currently difficult to measure. Accordingly, they propose reducing or dropping the requirement for a functional improvement in early forms of the disease (see Figure below). Moreover, as the chronology of Alzheimer’s disease pathology becomes better defined by biomarker and imaging studies such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI; for example Jack et al, 2013), early cognitive deficits plus appropriate biomarkers may be used to address the issue of accuracy of diagnosis in early Alzheimer’s Disease.
What, therefore, are the implications of these proposals? Well, in a New York Times editorial (18th March, 2013), the FDA’s proposals have been described as lowering the bar for Alzheimer’s disease drug approval. The term “lowering the bar” implies a reduction in scientific rigour but this is not necessarily the case, with the FDA recognising that “innovative approaches to trial design and end-point selection are urgently needed”. Moreover, the phrase implies that the bar could be cleared if only one jumped high enough (i.e. if the drugs were good enough) but as the emphasis moves more towards treating early Alzheimer’s disease, the current requirement for cognitive improvement to be coupled with a functional improvement may be seen more as an insurmountable roadblock than a barrier (especially if there is limited, if any, evidence of a functional deficit in early Alzheimer’s disease). The New York Times Editorial further elaborated on its glass-is-half-empty viewpoint by warning that the FDA might “end up approving drugs that provide little or no clinical benefit yet cause harmful side effects in people who take the medications for extended periods.”
The viewpoint expressed by the NY Times is disputed by those in the field (see here). For example, an opposing glass-is-half-full opinion is offered by Dr. Eric Siemers, senior medical director at Eli Lilly, who commented in the March 14th edition of the New York Times article (the one that triggered the subsequent Editorial) that “This is really a huge advance” and in an era when failures in the drug discovery process can sometimes all too readily be apportioned to the regulatory authorities he added the seldom-heard comment “Kudos to the F.D.A.” There is no doubt that the proposed guidelines map out an innovative path to new treatments that if adopted could circumvent the current potential regulatory road block. Indeed, commenting on a recent article which quantifies the financial costs of dementia in the US (see here), the NY Times itself noted last week “the number of people with dementia will more than double within 30 years, skyrocketing at a rate that rarely occurs with a chronic disease”. So, as the population ages and a tsunami of dementia-related financial and emotional burden looms large, if ever there was a time to reshape the Alzheimer’s disease drug development paradigm it is surely now.