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International Clinical Trials

Scene Change


Running global clinical trials in Alzheimer’s and multiple sclerosis presents numerous operational and clinical challenges, but a range of potential practical solutions are emerging that seek to change the clinical development landscape.

Despite a better understanding of the pathophysiology gained from neuroscience, along with the emergence of novel diagnostic assessments, biomarkers and the improvement and sophistication of research methodology, there continues to be increasing difficulties enrolling patients in clinical research trials involving CNS disorders. Of particular concern is accrual in Alzheimer’s and multiple sclerosis trials.

There are myriad reasons proposed for this escalating difficulty, including the commercialisation of a number of novel treatments; the reluctance of investigators; regulatory authorities and ethics panels to approve placebo-controlled trial designs; concerns reported in the global media around deaths in clinical trials particularly in emerging markets; serious failures of a number of Phase 3 development programmes; the report of a number of novel serious adverse events associated with some investigational products; as well as the challenge of more complex protocols that tax site, investigator, and patient skills and tolerances.

Diseases of Interest

The global medical and economic burdens of multiple sclerosis (MS) and Alzheimer’s disease (AD) are demanding aggressive efforts at clinical treatment development. Drug developers are not just driven by the suffering of those afflicted with these debilitating neurodegenerative diseases, but they are also highly motivated by the promise of rich financial rewards as safe and efficacious treatments will undoubtedly achieve mega-blockbuster status.

Interestingly, the treatment of the relapsing remitting form of MS has enjoyed some recent successes with the approval of two orally delivered, disease-modifying therapies. Regardless of these advances in treatment, further drug development efforts remain strong. These newly authorised products, much like their older established counterparts, continue to leave gaps in efficacy as well as impart their own tolerability burdens. Also of concern in MS treatment has been the very limited effort in treatment development for the more aggressive forms of the disease such as primary and secondary progressive MS.

Unfortunately, despite massive financial, medical and scientific efforts, AD has remained invulnerable to clinical treatment development. The diagnosis and management of AD has only incrementally improved since the introduction of the first treatment, tacrine, more than 20 years ago. Present day AD therapy remains focused on the use of acetylcholinesterase inhibitors along with memantine. These treatments are symptomatic therapies only, offer modest benefit to patients, and fail to change the slope of the disease progression (disease modification). Drug development efforts over the past 10 years for AD have predominately focused on compounds with putative disease-modifying effects; this belief is largely based on the compounds’ impact on various targets within the amyloid cascade, which remains the dominate model for the pathophysiology of AD. While not the only compounds to enter clinical development in recent years, the biologicals, humanised monoclonal antibodies against amyloid beta, as well several small molecules, gamma and beta secretase inhibitors, have been the compounds of greatest interest and hope.

Unlike the symptom treatment trials conducted to bring the acetylcholinesterase inhibitors and memantine to market, disease modification trials have been quite challenging in methodologic terms, requiring enormous sample sizes and treatment durations, as well as requiring frequent CSF sampling and serial MRI and PET assessments. With the addition of lengthy cognitive and behavioural assessments, patient and caregiver time on site for study visits will often exceed four hours. Conducting trials in an elderly, mentally and physically impaired population is desired in order to create a possible treatment which may bend the curve favourably in the diseases progression, meaning that the treatment benefit, if one exists, will not be detectable by the patient or caregiver during the course of the trial. Collectively, the difficult protocols combined with limited patient benefit result in patient retention problems, with many lengthy disease modification trials experiencing tremendous early termination challenges.

Unlike Alzheimer’s disease, MS has enjoyed treatment development success beyond the first disease-modifying therapies – the interferons – which were first marketed in the 1980s. Natalizumab, the first monoclonal antibody marketed for MS, offered a very significant improvement in reducing relapse rates over the interferons. Two oral therapies have now received marketing authorisation including fingolimod (Gilenya) and teriflunomide (Aubagio). These successes, along with the promises of additional safer and more efficacious products in late-stage development such as Biogen Idec’s BG-12, herald a time of optimism in MS treatment. What might explain the differential experiences in the AD development landscape, where failure has been so consistent that it has become an expectation? Quite simply, the fact that neuroscience has given us a much better understanding of the pathophysiology of MS; we are able to identify and assess disease burden more consistently by employing objective assessments, which also allow the centralised assessment of disease progression as a trial endpoint. This methodological advance results in less reliance on highly variable clinical scales. In AD, we have not advanced the science of clinical trials past the identification of ‘probable Alzheimer’s disease’, and the assessment of disease progression is based on very variable and insensitive clinical scales too often inconsistently applied. These differences alone between MS and AD investigations may entirely explain success versus failure.

Alzheimer’s Disease Clinical Development Landscape

Given the exploding global prevalence of AD, coupled with financial analysts reporting that AD will eventually bankrupt many developed countries’ healthcare budgets, the pharmaceutical development efforts in search of a disease modifier is likely to remain robust, despite the reports of late-stage failures in AD. While the ‘holy grail’ of treatment will remain disease modification, important symptom treatments continue to be developed as well. Given the only successful treatments for AD have been symptom treatments, it has been a more encouraging development path. Symptom treatment trials are also far less challenging and costly to conduct, with considerably smaller sample sizes and trial durations.

Despite these advantages, there have been some notable failures here as well, including Dimebon (Pfizer and Medivation). Dimebon is worth further consideration, as this drug performed well, meeting its primary endpoint in a Phase 2 trial conducted in Russia. These data resulted in further aggressive development efforts mainly centred in the US, but all of the trials failed, and development has been largely abandoned. This story is an important lesson to would-be AD treatment developers that positive trial data from one study in one region or country may very well not translate into success globally. There is entirely too much risk for type 1 and 2 errors in early-phase AD research.

What might be a better test for a compound at Phase 2a? Either two Phase 2 trials conducted in different geographic regions or one trial conducted with the inclusion of a mixed geography, preferable including North America as well. An additional challenge for symptom treatment developers is the new difficulty in conducting trials as a monotherapy; otherwise all marketing authorisations for new symptom treatments will only be as adjunctive therapy for patients already stable on acetylcholinesterase inhibitors and or memantine. Therefore interest in recruiting pharmacologically naïve patients with AD into symptom trials remains important; however, it has become increasingly challenging to carry out, particularly in developed countries. While IRBs, regulatory authorities and ethics committees continue to approve the conduct of monotherapy placebo-controlled trials in AD, clinical sites are increasingly reluctant to accept them, and while monotherapy patients can still be recruited in eastern Europe and parts of Asia, the window is closing quickly as the global availability of inexpensive generic acetylcholinesterase inhibitors has exploded.

Theoretically, given the global prevalence of AD, any region of the world could potentially be a good source of patients. Indeed, patients in AD trials have been successfully recruited in all geographic regions; however, the value to include multiple regions and countries versus the risk is complex. There is the challenge of managing the variability imparted with multiple languages and cultural influences, including caregiver differences. Approaches to diagnosis and treatment can vary widely from country to country; the availability of more sophisticated evaluative tools such as PET and cyclotron proximity all must be taken into consideration when planning AD trials. Recent Phase 3 efforts with disease-modifying compounds have had considerable global reach and employed complex protocols and hundreds of investigative sites all working on aggressive patient accrual timelines. All of these trials have failed to achieve their primary endpoints, despite the fact that many experts believe these compounds should be efficacious, largely based on mechanism of action as well as results of animal models.

These disappointments have had a sobering effect upon the AD clinical research landscape. Clinical research in AD will continue; however, future efforts are likely to be more cautious with a focus not just on the quality of the experimental design, but also serious thought as to the operational challenges and management of cumulative trial variability. Expect to see smaller, more focused trials, operationalised in countries where expertise and experience is deep and efforts to control variability can be easily implemented. With this will come a renewed effort to develop promising symptom treatments such as the much heralded nicotinic alpha-7 agonists. Expect to see future trials expand the use of PET to assess amyloid burden, as well as the use of CSF sampling to assess putative biomarkers. Expect future trials to be conducted in very early AD as opposed to the mild to moderate AD population previously selected.

Multiple Sclerosis Clinical Development Landscape

Over recent years, MS, and in particular relapsing/remitting MS (RRMS), has been the busiest single disease target for drug development. Of specific interest was the race to the first commercialised oral disease-modifying therapy. For too many years the interferons dominated the treatment of MS, imparting only a modest efficacy benefit in exchange for a difficult tolerability profile. With the introduction of natalizumab (Tysabri) in 2004, a dramatic improvement in efficacy over interferon therapy was realised; however, the risk of suffering the rare adverse event progressive multifocal leukoencephalopathy (PML) has been linked to the duration of natalizumab therapy, limiting most patients to 18 months of therapy followed by a drug holiday. In September 2010 the FDA approved the first oral disease-modifying therapy for RRMS, fingolimod (Gilenya). The drug reduces relapse rates by 50 per cent, but has been associated with bradyarrythmias. Very recently, the FDA approved a second oral therapy in terifl unomide (Aubagio); this product reduces relapse rates by 30 per cent – certainly disappointing versus natalizumab or fingolimod, but it may turn out to have a better safety profile. Despite these described successes in the treatment of MS, an enormous number of compounds remain in developers’ pipelines.

It is clear that successful products encourage others to follow their lead; however, the availability of new safe and effective treatments greatly reduces the pool of patients willing to participate in clinical trials, particularly in economically developed countries. Interestingly, given the highly differential prevalence rates seen in regions of the world for MS, the majority of the most sought-after patients are in highly developed countries with liberal access to novel therapies. While traditionally clinical trials in MS have focused predominately on sourcing patients in North America and western Europe, now trials are running in global regions with very low MS prevalence rates such as Latin America and Asia. Additionally eastern Europe has arisen as a strong player with the emergence of more sophisticated special medical care.

While experts continue to opine that placebo-controlled trials in MS are ethical and can still be enrolled, experience does not support this assertion. Investigative sites are reluctant to take on these trials, and the MS patient population is one of the most medically and research sophisticated, and hence are generally rejecting of placebo-controlled trials. While regulatory authorities, IRBs and ethics committees may approve placebo-controlled trials, the reality is that they are no longer practical and should be entirely abandoned in favour of alternative designs. Safety and tolerability concerns continue to impact trial design as well as execution and costs. For example, any monoclonal antibody in development will require frequent MRI assessment, and any S1P in development will require significant first dose cardiac monitoring that may include up to a 24-hour hospital stay.

In the future, expect developers working in MS to continue to try to source the majority of their patients out of the traditional regions including North America and western Europe, but also we will see the further inclusion of regions of low prevalence such as Latin America and Asia. Expect trials in MS to be more operationally challenging, largely secondary to more aggressive and frequent safety assessments. Expect more forceful efforts at patient recruitment and retention to include increased utilisation of the internet, particularly social media. With the expansion of personal communication devices, mobile phones, we will see trials reaching out to patients via these devices, email and text messaging; additionally we will begin to see data collected in trials via these devices, which will greatly reduce time on site for patients as well as tremendously reduce costs by eliminating the need for sponsors to purchase eDiaries.

Conclusion

In the near future, we can expect the clinical development landscape of AD and MS to remain crowded. This will be particularly prevalent in developed countries, which offer the most sophisticated level of medical care, as well as access to established research and available patients. It is also important to consider the use of developing countries for both diseases with great caution, and one should expect potential CRO partners to have experience within the suggested regions, as well as specific site experience. We can also expect objective supporting data from medical informatics and site level feasibility studies that support CRO assumptions. Engaging patient recruitment and retention services early on in the trial planning process and developing a multipronged consistent approach that is thoughtful and regionally focused will benefit these clinical trials.

In AD trials, one must try to limit the language and cultural variability within each individual trial as a method to control variability that will impact the signal-to-noise ratio. Making every effort to simplify protocols and minimising both number of study visits as well as time on site will also help. Avoid, if at all possible, the use of placebo-controlled trials and attempt to offer open-label extension options. Particularly in AD trials, we should limit the number of sites to the minimum reasonable to meet timelines, be willing to extend timelines rather than add additional countries and sites, as well as being patient with the process. If these are adhered to, then the outcome will more likely be a positive one.

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Fred Lewis is Vice President, Neurosciences – Scientific Affairs, at PRA International. He is a graduate of Pennsylvania State University, and Southeastern College of Osteopathic Medicine, and is board-certified in general psychiatry. He has more than 20 years’ research and professional experience in psychiatry. He is Associate Professor in the Department of Psychiatry for the college of osteopathic medicine at Nova Southeastern University, and teaches courses at graduate and postgraduate level in psychiatry, psychopharmacology, and substance abuse. Fred has extensive experience in protocol design, development, end point selection, regulatory authority negotiations, organisation of DSMB’s and scientific advisory boards. He has in-depth disease state experience including mood disorders, anxiety disorders, psychotic disorders, Alzheimer’s disease, multiple sclerosis, epilepsy, Parkinson’s disease, pain and sleep disorders.
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