This is quite remarkable - we are on the same wave length.

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paula

Meeting Summary: ISCTM / MJFF Satellite Meeting on Overcoming Barriers to Successful Demonstration of Therapeutic Disease Modification

May 23, 2007
http://www.michaeljfox.org/newsEvent...cle.cfm?ID=192

Introduction: The Need for a Conference Focused on Challenges in Neuroprotective Clinical Trials for Parkinson’s Disease

Development of a Parkinson’s treatment that can halt or slow the underlying disease progression, rather than just mask symptoms, is a major focus for clinicians and drug makers. However, despite several clinical trials of promising ‘neuroprotective’ approaches, no strategy to date has shown definitive evidence of disease modification.

In 2006, as part of its growing focus on accelerating the development of neuroprotective therapies, The Michael J. Fox Foundation (MJFF) considered various strategies to tackle the challenges facing the design and implementation of neuroprotective clinical trials. We interviewed community experts and completed our own internal research, including an audit of past neuroprotective PD trials. When we compiled the results of this work, we saw a clear need to bring together members of the clinical trial community to frankly discuss hurdles facing neuroprotective trials and work toward identifying ways to tackle these challenges.

A number of organizations exist to address clinical trial methodological challenges. One such organization, the International Society for CNS Clinical Trials and Methodology (ISCTM), is devoted to addressing strategic clinical, regulatory, and methodological challenges that arise in the development and clinical use of CNS therapeutic agents. Since its inception in 2005, the ISCTM has held several conferences as open forums for those working in CNS research. Attendees of these meetings include individuals from regulatory agencies, academia, industry, and nonprofits. The consistent goal of the conferences is to question existing methodologies in the hopes of improving clinical testing strategies.

MJFF partnered with ISCTM, leveraging the Society’s infrastructure for hosting large meetings focused on trial challenges. On February 21 and 22, 2007, directly following the third annual ISCTM Congress, MJFF and ISCTM co-hosted a two-day satellite meeting. It attracted more than 130 key clinical trial players including academic institutions, pharmaceutical and biotech companies and regulatory agencies.

Meeting Summary

Meeting speakers and chairs were selected based on their experience with PD neuroprotective clinical trials and knowledge of the various aspects of clinical trial design. Speakers presented short talks that focused on raising consciousness about current issues plaguing neuroprotective clinical trials and generating options for new ways to move forward.

The Satellite was broken into several sessions. Initial talks provided a conceptual framework for neuroprotection, the scope of PD and a discussion of previous neuroprotective clinical trials. This was followed by a deeper discussion of issues related to patient selection, endpoint measurements, biomarkers and statistical issues. Final talks provided perspectives from industry and regulatory agencies (both U.S. and European).
Discussions highlighted many challenges in designing a clinical trial for a disease modifying therapy, including:

• the existence of possible PD subtypes that could affect patient selection,
• the absence of validated outcome measures and clinical definitions of ‘neuroprotection,’
• a lack of useful biomarkers of disease progression and therapeutic action, and
• a general lack of phase II clinical trial designs that impact confidence in moving promising therapies into phase III trials or to provide definitive negative data regarding potential specific targets.

Terminology, Disease Definition and Neuroprotective Treatment Approaches

The presentations opened with a brief definition of ‘neuroprotection’, emphasizing the difficulties inherent in attempts to correlate this mechanistic measure to the clinical outcome of a patient. This would be a common theme for the remainder of the meeting.

Parkinson’s disease extends beyond the dopaminergic nigrostriatal system and includes a host of other clinical features (e.g., REM sleep disorder, cardiac sympathetic denervation, olfactory deficits, constipation), some of which may precede the classic motor features of the disease. Thus, the therapeutic window for delivering protective therapies to affected individuals could be much earlier — assuming patients could be identified at these earlier stages.

There are several underlying pathogenic mechanisms that may cause PD, including genetic and environmental factors. This gives rise to numerous possible models for PD pathogenesis, which would affect how therapeutic strategies would need to be developed: for example, a linear chain of pathological events might only require a single intervention somewhere along the disease pathway, but if multiple independent factors act in combination, then multiple pathways may need to be targeted for adequate disease modification to occur. Ultimately, despite advances in our mechanistic understanding of PD, there is still no clear frontrunner with respect to a pathway or set of pathways the alteration of which would significantly alter PD pathogenesis.

Neuroprotective Clinical Trial Designs

A look at past neuroprotective clinical trial designs, such as those used in large scale trials like DATATOP, PRECEPT and TEMPO, prompted discussion on the problem of distinguishing a neuroprotective effect from symptom-masking effects. Historically, trials have employed several methods for differentiating neuroprotective effects: delay in a disease milestone (e.g., start of dopamine therapy), prolonged effects after drug washout, neuroimaging of nigrostriatal function and, most recently, the delayed/random start design. However, all have caveats and none can entirely rule out symptomatic or other complicating effects. Indeed, at least one meeting participant argued that trial design is not really the issue and that an ideal measure of trial success would focus on whether a treatment provides a clinically meaningful change in a patient-relevant outcome measure over the long term.

Yet another significant hurdle in many trials is the difficulty in transitioning from less-than-ideal preclinical animal models into human studies, where it is difficult to ascertain something as fundamental as optimal dosing for a clinically meaningful effect.

Patient Selection, Clinical Trial Outcome Measures and Biomarkers

The clinical and likely biological (e.g., genetic) heterogeneity of PD could affect clinical trial outcomes, especially when targeting specific disease mechanisms that may not be common to all patients. Homogenous patient populations hold greater potential for delivering consistent trial results, however, recruiting from a relatively rare pool of patient subtypes brings problems of its own. These include the difficulty of achieving a large enough sample and the problems inherent in extrapolating a treatment effect to the larger population.

Furthermore, each disease stage (e.g., early untreated, early treated and advanced) is associated with specific challenges that can affect trial design parameters such as endpoints and duration,. For example, early untreated patients may be the ideal candidates for intervention, but disease progression is often slow at this stage (thus harder to detect) and the accuracy for definitive disease diagnosis may be limited. Later-stage patients may demonstrate clearer clinical endpoints, but studies involving these patients can easily be confounded by concurrent symptomatic medications or other later stage co-morbidities.

In considering the best outcome measures for neuroprotective clinical trials, endpoints should reflect the study’s specific goal and design; no single outcome will ever be ideal for all types of trials. Although a number of traditional measures have been used, such as time to disability, UPDRS, quality of life and clinical global impression scales (among others), none of these has been validated as a measure of neuroprotection. Indeed, no clear ‘gold standard’ definition of clinical neuroprotection exists against which clinicians can compare trial endpoints. Furthermore, current endpoints predominately focus on motor features of the disease and do not adequately reflect other ‘non-motor’ features.

The session concluded with an overview of clinical and non-clinical biomarkers and endpoints that could be useful in neuroprotective clinical trials, in particular as surrogate measures of clinically relevant primary outcomes. An ideal biomarker would be one in which a change in the marker would directly reflect a change in the pathway between underlying disease and clinical outcome in the patient.

Although imaging markers could represent ideal non-invasive measures of potential underlying disease pathology, their usefulness as surrogate endpoints in clinical trials is limited by the lack of any clear and consistent correlation to cell loss and dysfunction, as well as effects of prior pharmacological intervention on these markers.

A variety of non-imaging biomarkers are also being developed and may be useful for helping to improve patient selection by specific disease subtype or prognosis. However, markers that could reflect disease progression or act as surrogate endpoints for clinically relevant outcome measures are likely still far off. Furthermore, there is a critical need for markers of therapeutic activity and pharmacology, which could help with clinical trial dosing and data interpretation.

Statistical Analysis

Although the goal of large phase III trials should be to demonstrate statistically meaningful benefit of a particular treatment, it was argued that earlier clinical phases (phases I and II) should move away from such confirmatory hypothesis testing. Instead, it is important at these initial clinical stages to select for treatments with the greatest potential for exerting a neuroprotective effect. Use of innovative statistical approaches (e.g., ‘futility,’ selection and mixed designs) could help to identify these treatments.

Industry Perspective

While companies possess the resources and expert guidance for developing neuroprotective strategies, they lack the time needed to adequately test for neuroprotection in a clinical trial. When making a development decision, companies both small and large must focus on financial opportunity, risk, feasibility, regulatory viewpoint, costs and demonstrable effect size.

The challenges in defining and measuring neuroprotective effects of PD treatments make it difficult for companies to sink resources into a high-risk PD program. For some treatment strategies, there may be the ability to seek approval for a symptomatic therapy (which is relatively easier to test) and then subsequently look for longer-term neuroprotective effects in post-approval phase IV trials. However, for companies to realistically invest in treatments that may not have an immediate symptomatic effect, research must provide further mechanistic insight into the disease, and clinicians must provide a clearer definition of what neuroprotection means for patients.

Regulatory Perspectives from the United States FDA (Food and Drug Administration)and European EMEA (European Medicines Agency)

Ultimately, for regulatory approval, a treatment must demonstrate clinical efficacy: the benefit derived from being on a treatment must be better than no treatment. However, to be able to claim that a drug works through neuroprotective mechanisms, there must be data to support this. Again, a clear challenge is presented by the distinction between neuroprotection as a mechanistic cell-level effect and the clinical outcome in the patient.

Take-Home Messages

The challenges highlighted throughout the meeting reflect the great complexity of developing a neuroprotective treatment for Parkinson’s disease. In the absence of a direct biomarker of disease pathogenesis, current trials can only measure clinical outcomes. Thus, the focus of trials should be to determine clinical benefit using the most relevant endpoints, patient populations and trial designs/durations. Several key issues were identified:

• Identifying guidelines (e.g., statistical designs, appropriate dosing data, etc.) for appropriately detailed preclinical data and for improving phase II trials could be of great help to the field. Many phase II trials fall short of providing the critical data needed to adequately test treatments in subsequent large-scale phase III trials. Indeed, some drug development programs may be prematurely terminated based on inconclusive phase II trial results.
• There is a critical need for community consensus and standardization of a clinically meaningful endpoint that could indirectly measure neuroprotection . A promising approach is to use delay to a given disability endpoint as a measure of clinical impact. However, for numerous measures of disability, delay could be potentially indicative of a disease-modifying effect.
• A concerted effort — possibly a public-private partnership of nonprofit, government and industry players — could potentially develop resources that would be useful for improving future clinical trials. There continues to be a great need for better understanding of the full spectrum of PD disease risk factors, subtypes, progression and prognostic indicators. Obtaining these data will require collection of data from large patient cohorts followed over years. However, the infrastructure and resources to support such an effort is generally lacking and many opportunities for ongoing data collection (e.g., clinical trial cohorts) are lost as a result.

The ISCTM Satellite Meeting was an important step toward identifying and prioritizing key challenges in neuroprotective clinical trials. The Michael J. Fox Foundation will continue to work vigilantly to determine feasible ways to bring meeting goals to fruition and to improve the field’s ability to carry out trials that can accelerate the development of a neuroprotective therapy for PD.

* International Society for CNS Clinical Trials and Methodology