ALS CLINICAL TRIALS GUIDELINES

1. The diagnosis should conform to the WFN El Escorial/Airlie Criteria (1998).
2. Patients with either sporadic or familial ALS can be entered depending on the nature of the trial.
3. Entry should be limited to patients between the ages of 18 and 85 years.
4. Before entry there should be evidence of progression during a period of six months from onset of symptoms; but not more than 5 years.
5. Patients with significant sensory abnormalities, dementia, other neurologic diseases, uncompensated medical illness, substance abuse and psychiatric illness should be excluded. The patient should not be on concurrent investigational drugs.
6. Primary and secondary end points should be crisply defined. A change in muscle strength (see Appendix 3) or survival and death and/or permanent continuous ventilator dependence are important and, at the present, the most useful primary end points for a therapeutic trials.
7. Quality of life should be used as an outcome measure and therefore should be included in every ALS trial which examines therapeutic efficacy (see Appendix 4). An ALS-specific quality of life assessment should be developed and incorporated into every efficacy trial.
8. Trials should be designed with careful and detailed statistical analysis which should begin in the planning phase (see Appendix 5).
9. "Compassionate release" and treatment INDs should be used such that assessment of therapeutic efficacy of the drug is not compromised. Trials should include the commitment to provide the drug to participants after the period of the trial until the status of the drug is finally determined, subject to safety concerns. In investigator-initiated trials the same guidelines are desirable.
10. The manner in which information is released during and after a trial should be an integral part of the protocol (Appendix 2). It is recommended that no efficacy results be released until peer review publication is imminent, other than at scientific meetings. We recognize that there are legal constraints on release of trial results when a trial is terminated early because of futility, or strong evidence of efficacy. Such release of information should take place only after release of information to trialists and to the patients enrolled in the trial.
11. It is the investigator's and the Companies' responsibility to ensure that commercial concerns do not distort the conduct of a trial
12. As with other clinical trials, ALS trials should be organized in three phases. Phase I trials are conducted to obtain toxicity and pharmacokinetic information. Phase II trials (pilot, exploratory, screening) are performed for dose finding, preliminary efficacy assessment and further safety observations. Phase III studies are performed to definitively determine efficacy and safety.
13. Phase I trials should usually incorporate concurrent placebo control and should be conducted for six months depending on the design.
14. Phase II trials may utilize concurrent placebo controls, historical controls or a cross-over design. This phase is utilized to screen agents with potential therapeutic value. If, in terms of the primary efficacy measure, strength or function are expected to actually improve, the trial should last at least six months. If stabilization or slowing of deterioration is the end point, the trial should last a minimum of 12 months depending on the nature of the drug. Trials lasting more than 9 months are difficult for the patient population to accept. If trials must last longer, an interim analysis should be performed.
15. Phase III trials should be appropriately controlled. These trials should include analysis of muscle strength, pulmonary function and bulbar function as well as time to death (Appendix 1). Survival will usually be the primary endpoint, but need not so.
16. Investigators must always conduct clinical trials in accordance with the statements in the Declaration of Helsinki, and in conformity with good clinical practice. They must fully inform patients about all aspects of their participation in the trial, ensure that patients understand the diagnosis and its implications, minimize the physical and psychological burden of participation, and avoid any discrimination in screening beyond the inclusion/exclusion criteria.
17. ALS/MND trials should be designed to take account of the availability of treatments of proven efficacy and safety. Trials should prove efficacy of a drug either vs. placebo, or vs. drugs of proven efficacy and safety. Combination trials A, A+B, B are ideally done with a placebo arm unless ethical considerations dictate otherwise.
18. An Independent Data and Safety Monitoring Committee (IDSMC) should be established for each trial. This should consist of independent physicians and biostatisticians who periodically review all data during the conduct of the trial and at its conclusion. Other experts, such as an epidemiologist, might be desirable. This Committee issues advice on premature termination. It is also responsible for safeguarding against scientific fraud. It is essential that this committee be free of conflict of interest and act on the patients' behalf.
19. A Steering Committee should be established by mutual agreement between the company and the investigators. It should include representatives selected by the investigators, the Sponsor, and outside experts if and when needed. Patient advocate involvement is desirable. This Committee is responsible for finalizing written agreements between investigators and Sponsor concerning:
    • protocol
    • general agreement guidelines
    • consent form and information sheet
    • full disclosure of all financial relationships between Investigator and Sponsor and other possible sources of conflict of interest
    • patient indemnity
    • open-label trials
    • selection of members of the IDSMC
    • release of information to the public during the study
    • arrangements for "open label" extension of therapy if appropriate at the conclusion of the trial
20. A Publications Committee should be established. It should include representatives selected by the Investigators and the Sponsor, with a majority of the former. It is responsible for writing the manuscript on the primary efficacy analysis, according to the CONSORT guidelines for reporting clinical trials. It must also ensure that journals are informed about sources of financial support for the trial. The Committee should have unrestricted access to the database during preparation of the manuscript. It should negotiate in advance a publication agreement between Investigators and Sponsor which should include:
    • a timetable for peer-reviewed publication of the study results
    • access to the database for all investigators after publication of the primary manuscript upon submission of a specific request to the publication committee.
    • later access to the database, after publication, for investigators outside the study, is desirable. This requires demonstration of the scientific basis for such access and a unanimous decision of the committee.

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