Update on Planning for Clinical Trials

Planning for Clinical Trials
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The focus of the HSP Research Program is now on clinical trials, which are aimed at determining the extent to which a drug treatment found to be effective with human HSP stem cells in the laboratory is also effective with HSPers themselves.
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Two meetings have been held to plan the way forward for clinical trials. This report is intended to provide an overview of the output from the planning meetings and give the HSP community a sense of the scope and scale of the overall initiative and the issues involved.

Biomarker(s) For HSP
A biomarker is a measurable indicator of the severity of a disease. Currently there is no measure of HSP that is immediately suitable for use in a clinical trial by which to gauge the effectiveness of any treatment. There is no objective clinical measure of sufficient sensitivity to assess HSP severity or how that changes over time. In order to determine the effectiveness of any treatment for HSP in clinical trials, having a sufficiently sensitive and reliable measure is essential. This makes the quest to establish such a biomarker or biomarkers the highest of priorities. Current measures of HSP severity are like observing that the temperature is hot or cold, or getting warmer or cooler. Thermometer measurements bring a level of accuracy and specificity to temperature measurement and how temperature may change over time. We need a similarly accurate and specific way to measure HSP.

Even if an HSP treatment does not lead to improvement, but effectively halts disease progression, that would be a huge step forward. Imagine a younger member of an HSP family who may never experience any appreciable level of HSP symptoms because of a treatment that halts progression. However, measuring the cessation of HSP progression is highly problematic at this point. Given what we know about variability in HSP symptoms and in rates of progression, this is suited to a 10 year experiment. We need to find a reliable treatment outcome measure that can be determined in months or perhaps a year.

Potential measures being considered including electrophysiological studies, neural imaging/radiological measures, metabolic measures, preferably in blood but potentially in cerebrospinal fluid and kinematics/kinetics/clinical gait analysis. Background research needs to be conducted to explore and identify potential opportunities to create an HSP biomarker and some of this work is already underway.

Natural History of HSP
Having a thorough and reliable scientific description of the course of HSP from inception to resolution is of fundamental importance to establishing an effective treatment as it provides the baseline against which measurements are compared. For HSP, with a wide range of genetic causes and huge diversity in the manifestation of symptoms in HSPers, having a good natural history is vital.

Significant work on developing the natural history of HSP has been undertaken over the past 10 – 15 years, but there is still a lot of work to be done on this.

Regulatory, legal and related requirements
The establishment of an Ethics Committee, or possibly committees, is an early step in the whole process. Their function is to examine plans for the clinical trials and their conduct in detail, and assess their compliance or otherwise with specified ethical considerations.

A Steering Committee also needs to be established, to provide advice and guidance across a range of aspects relating to the whole process.

Application seeking approval to conduct a clinical trial must be made to the relevant regulatory body. This is an exacting and demanding task requiring significant documentation to be developed and submitted. Regulatory approval is a prerequisite to being able to hold a clinical trial.

Creating and conducting trials
Trial design
Clinical trials do not come in a ‘one size fits all’ package. Based on the scientific investigation that lies at the heart of a clinical trial, each clinical trial needs to be designed to optimise the potential for a definitive result. The design should reflect and respond to variables such as the numbers of participants available, the nature of treatment being tested, the measures available, statistical considerations, and numerous other considerations including timeframe, logistics, funding and staffing … amongst others.

Choice and procurement of drug
Scientific, logistical and financial issues impact on the choice of drug treatment to investigate in the clinical trials. A thorough collation of the relevant data and due consideration needs to be applied to this most important of decisions. The drug, and an identical placebo, then need to be procured to strict specifications and standards.

Standardised procedures and processes
Examination, assessment, measurement, recording systems and processes require standardisation across all the medical professionals and sites involved. The scope and scale of this undertaking depends on the scope and design of the trials.

Testing
Depending on the choice of drug and biomarker, there will be a need for various forms of testing in the trials. Samples may include blood, urine, cerebrospinal fluid or tissue and may be tested using routine or specialised pathology laboratory services under contract.

Trial implementation
This is the conduct of the clinical trial itself, where participants receive the treatment(s) and various measurements are taken over a period of time. Data is collected, analysed, the results interpreted and conclusions drawn.

Participants
Participant recruitment and the processes undertaken for that are complex, with ethical, medical and logistical considerations requiring care in planning and execution. Selection criteria need to be defined and specified. A registry/database needs to be designed and commissioned. Enrolment and consent processes require strict compliance with various standards and protocols. Participant communications to inform and advise represent a significant undertaking in their own right.

Potential participants will have a clinical assessment/quantification of their HSP status; a physiological assessment e.g. by clinical interview, of general health with relevance to assessing potential side-effects and toxicities; and have samples taken for a serum bank e.g. for baseline measures, and before and after comparisons when biomarkers are developed.

Organisation
Organisational aspects of clinical trials include management, administration, staffing, planning, accounting including costing and budgeting, IT, communications and reporting functions. The clinical trial organisation needs to be created; roles and responsibilities, organisation and reporting structure defined; a database for managing and recording trials designed and commissioned, and so on.

Partnerships and funding
A major challenge for a clinical trial such as this is partnerships and funding. Identification of potential pharmaceutical industry partners will be followed by discussion and negotiation to determine if there is sufficient mutual interest to establish a partnership. Grants for conducting clinical trials are offered by organisations such as the National Health and Medical Research Council. Application for such grants is a rigourous and exacting documentation process requiring significant resources and expertise.

In summary, this is clearly a much more involved, complex and expensive process than giving a bunch of HSPers a pill and seeing what happens. It needs to be approached properly and implemented properly. We all need to remember that, and we should not lose sight of the fact that a successful trial has the potential to improve the lives of hundreds of thousands of HSPers globally. This is being planned and developed as professionally and as expeditiously as possible. We will keep you informed as this progresses.