Consensus Guidelines for the Design and
Implementation of Clinical Trials in ALS
2nd Airlie House Workshop 1998
Subcommittee on Motor Neuron Diseases of the World
Federation of Neurology Research Group on
Neuromuscular Diseases
Robert G Miller M.D.
Chairman Clinical Trials Consortium
Theodore L. Munsat M.D.
Conference Organizer
Chairman WFN Research Committees
Michael Swash M.D.
Chairman WFN Committee on Motor Neuron
Diseases
Benjamin Rix Brooks M.D.
Conference Organizer for the Committee on Motor
Neuron Diseases World Federation of Neurology
1. INTRODUCTION ......................................................................................................................... 2
2. ALS CLINICAL TRIALS GUIDELINES ..................................................................................... 3
3. APPENDIX ONE-Measurement Techniques in ALS Clinical Trials ............................................ 5
4. APPENDIX TWO-Disclosure of Information and Publication of Results .................................... 7
5. APPENDIX THREE-Maximum Voluntary Isometric Contraction (MVIC) and Other Strength
Measures ........................................................................................................................................ 8
A. MVIC Strain Gauge Measurement: ....................................................................................... 8
Purpose: ............................................................................................................................... 8
Selection of muscles to test ................................................................................................. 9
Clinical Evaluator (CE): ...................................................................................................... 9
Standardization, Training, Reliability, Variance .................................................................. 9
Costs of MVIC .................................................................................................................... 9
Data Analysis ..................................................................................................................... 10
Surrogate for Survival?...................................................................................................... 10
Future Study: ..................................................................................................................... 10
B. Manual Muscle Testing ....................................................................................................... 10
Background ....................................................................................................................... 10
Standardization .................................................................................................................. 10
Limited Information: ......................................................................................................... 11
Surrogate for Survival?...................................................................................................... 11
Future Research ................................................................................................................. 11
C. Hand Held Dynamometry .................................................................................................... 11
6. APPENDIX FOUR-Quality of Life............................................................................................. 11
Definition: ................................................................................................................................ 11
Recommendations: ................................................................................................................... 12
7. APPENDIX FIVE-Statistical Considerations .............................................................................. 12
Dropouts ................................................................................................................................... 13
Stratification ............................................................................................................................. 13
Adjustment for Prognostic Factors or Other Covariates .......................................................... 14
Analytical Methods .................................................................................................................. 14
Time to Failure Variables......................................................................................................... 14
Lead-ins .................................................................................................................................... 14
Surrogate .................................................................................................................................. 15
8. APPENDIX SIX-Respiratory Issues in Clinical Trials ................................................................ 15
I. Methods and Techniques of Pulmonary Measurement. ........................................................ 15
II. Clinical Factors Which Can Influence Respiratory Status .................................................. 15
III. Respiratory Measures as Outcome Variables ..................................................................... 16
IV. Future Research ................................................................................................................. 16
9. APPENDIX SEVEN-Bulbar Tests .............................................................................................. 16
10.APPENDIX EIGHT-Workshop Chairs, Cochairs, Participants and Attendees .......................... 17
US Food and Drug Administration .......................................................................................... 18
11.APPENDIX NINE-Conference Support and Acknowledgements ............................................. 19
12.REFERENCES .......................................................................................................................... 19
INTRODUCTION
The Consortium on Clinical Trials in ALS, a Subcommittee of the Motor Neuron Diseases
Research Group of the World Federation of Neurology (WFN), met at Airlie House, Warrenton,
Virginia, April 2 to 4, 1998, to refine and expand the consensus Guidelines for Clinical Trials in
ALS/MND that were formulated at the first Airlie House Conference held in 1994. Participants
included clinical investigators, FDA officials, representatives of the Pharmaceutical sector and
patient advocates. The purpose of this meeting was to improve the efficiency and consistency of
trial analysis and design and to facilitate entry to clinical trials of patients earlier in the disease
process.
Several new concepts were discussed, including adoption of the Consort Guidelines for the
conduct and reporting of clinical trials, ethical issues, protection of patient interests, statistical
analytic methods, better definition of surrogate measures of survival, and techniques for
measuring strength and respiratory function. Quality of life measures for patients with ALS/MND
were elaborated for the first time, and progress was made in agreeing upon methods for measuring
bulbar function. Substantial consensus was achieved in elaborating guidelines for investigator and
industry collaboration. The important emerging trend to evidence-based medicine became
apparent in formulating these guidelines. In each major area, issues which deserve further
investigation were identified.
A draft of the document was posted on the website of the World Federation of Neurology
(http://www.wfnals.org) for widespread dissemination. This document represents the consensus
view of the participants and of the Committee on ALS/MND of the WFN, and includes feedback
from experts in the field who commented on the draft.
The process of developing clinical trial guidelines in ALS/MND is a dynamic one, evolving as we
gain experience and promising new therapeutic agents. The design of clinical trials has to take into
account several conflicting needs in the current climate. The importance of selecting patients by
rigorous exclusion and inclusion criteria versus the desire to include patients at the earliest stages
of the disease, the wish to design a trial to detect only a meaningful clinical effect versus the risk
of missing a small effect, the need to conduct trials in the climate of other approved treatments
versus the need for placebo controlled trials, and the lower expense of a short trial using sensitive
sophisticated measurements versus the larger and longer scale required by survival measures.
These guidelines should be regarded as recommendations that should be read in the context of the
Helsinki Guidelines for the conduct of clinical trials, themselves derived from the Nuremberg
declaration. These documents provide the contemporary ethical basis for the conduct of clinical
trials.
These clinical trial guidelines are not meant to be an inflexible, final or complete document.
Rather, they should be viewed as an attempt to gain a degree of consensus. A third meeting to
refine, expand and detail the guidelines is planned in another four years.
The specific guidelines are followed by several appendices which amplify various aspects of the
meeting.
The Committee welcomes further comments.
1. 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.
2. APPENDIX ONE-Measurement Techniques in ALS
Clinical Trials
1.1 Purpose of measurement techniques
Measurement techniques should be sensitive, easily and unambiguously quantifiable,
non-redundant, standardized and validated, with quantified and minimal intra- and inter-rater
variability.
1.2 Properties of measurement techniques.
a.
Measurement techniques should assess change that may represent improvement, arrest
(stabilization) or retardation (slowing) of the disease in pre-symptomatic and
symptomatic patients. Prevention of the onset of the disease or prevention of the spread of
the disease process to unaffected areas from affected areas should also be assessed.
b. Measurement techniques should produce data that provide comparable information at
different times in the course of the disease.
2.0 Recommended measurement techniques in ALS Clinical Trials
2.1 Many measurement techniques are available for ALS Clinical Trials. Particular measurement
techniques may be clinically or statistically robust at different times during the course of ALS, in
different subgroups of ALS patients and in different anatomical regions in the same ALS patient.
2.2 The measurement techniques may be bounded by the clinical questions being tested and
resources available. Multiple measurement techniques are encouraged to maximize the detection
of potential clinical benefits of any intervention.
2.3 The following minimum dataset of measurements is suggested:
a.
Survival and time to failure analysis.
a.1 ALS Clinical Trials should record the time to death, or permanent continuous
ventilator dependence, until the time of study termination of all patients who were
randomized during the course of the trial.
a.2 Time to failure analysis of possible surrogate end points for death or permanent
continuous ventilator dependence include various indices of change in respiratory
function (e.g., FVC in earlier stages, or arterial CO2 or serum chloride in later stages,
need for respiratory support, tracheostomy). These end points require further study for
validation to determine whether practice patterns and geography will influence these
outcomes.
Intermittent noninvasive mechanical ventilation or enteral feeding may improve survival.
These factors must be considered in future clinical trials and require further study for
validation.
a.3 Time to failure for specific clearly defined epochal events may be employed in ALS
Clinical Trials. These events include loss of intelligible speech, swallowing, self?feeding,
use of hands, self?turning in bed and unassisted walking.
b. Reasons for dropouts should be recorded.
2.4 Upper and lower limb strength measurement
a.
Preferred: quantitative myometry (see Appendix 3)
b. Acceptable: manual muscle testing
b.1 The number of muscles tested by manual muscle testing should be increased to permit
proper statistical analysis
2.5 Respiratory function measurement (see Appendix 6)
a. Preferred: forced vital capacity
b. Acceptable: FEVI; chest expansion ratio
2.6 Function tests
a.
Disease-specific functional rating scale
Preferred: ALS Functional Rating Scale, Ashworth Spasticity Scale
Acceptable: Baylor ALS Rating Scale
b. Non-disease specific functional rating scale
Acceptable: Universal functional rating scale, Barthel or Rankin Scale
c. Timed functional tests
Acceptable: Timed walking, Timed standing from sitting, Peg?Board
2.7 Bulbar Tests
Further analysis of bulbar function measurement is required to determine the most efficient and
reproducible means of assessing speech and swallowing functions. This area was identified as one
domain where easily performed, reproducible, valid clinical tests are still lacking (see Appendix
7).
a.
Preferred: Precise measurement of bulbar function to be developed or identified, Bulbar
functional rating scales, Frenchay, Hillel
b. Acceptable: Timed functional tests, Alternate Motion Rates, PaTa,PaTaKa
3. APPENDIX
TWO-Disclosure
of
Information
and
Publication of Results
An ALS Clinical Trial should employ the following Guidelines for Disclosure of Information and
Publication of Results:
Before beginning a trial
The clinical investigators, in cooperation with the sponsor, if industry supported, should establish
a Data and Safety Monitoring Committee, a Steering Committee and a Publications Committee.
This latter committee should establish policy for responsibility, effort, and final authorship as well
as policy regarding issues of release and distribution of information and publication.
Information to patients
Guidelines for post-trial drug opportunities (open-label) should be clearly stated at the outset.
There should be specific delineation of when results will be revealed to the patients and when
safety/efficacy information will be released.
Information disseminated during the trial
Ongoing information should come from the Steering Committee, through each principal
investigator to patients.
No trial should be terminated before completion without the significance being so great and the
trial analysis so valid that it is no longer ethical to ask patients to take placebo.
Publications of the results of a trial
Upon completion of the trial and analysis, publication should be expeditious, whether positive or
negative. The sponsor should not be in a position to prevent publication.
Ownership of the data base
The investigators and sponsor should jointly own the data base subject to proprietary restrictions
previously agreed upon. Individual principal investigators should have access to their own data
and full publication rights after a pre-specified interval.
4. APPENDIX THREE-Maximum Voluntary Isometric
Contraction (MVIC) and Other Strength Measures
A. MVIC Strain Gauge Measurement:
Purpose:
As primary or secondary outcome variable of ALS clinical trial.
Can measure rate of disease progression via impact on muscle strength and may be predictive for
survival (Further study is needed).
Selection of muscles to test
10 muscle groups (5 arm, 5 leg) recommended by Brinkmann et al (J Neurol Sci 1997). As data
accrue, modification may be needed on the basis of future study (see below).
Clinical Evaluator (CE):




Same person for the same patient.
Motivated, intelligent, preferably physical or occupational therapist.
Must meet reliability criteria.
Need backup, similarly trained and tested.
Standardization, Training, Reliability, Variance
Same system in all centers. Agreed upon written protocol for the test. Training video. Brinkmann
et al 1997 can serve as a starting point.
 Bring CE and back-up in for training at a centralized site or sites.
 Return to home site with video and set up locally.
 Test at least 5 subjects and assure competence before testing patients in a trial.
 Do reliability testing (CE and backup, same patient volunteer, two tests each).
 To begin to test patients within a trial, CE test-retest variability must be less than 10%
(intra-rater and inter-rater) or equivalent conservative limit, expressed using other
parameter.
 "Super-CE monitor" visits periodically the individual sites for Quality Assurance.
 Local validation testing (inter and intra-rater ) between visits at fixed intervals.
 Super-CE Quality Assurance Committee to monitor for ongoing problems and remedy
promptly.
See more detailed recommendations in Hoagland et al (Muscle and Nerve 1997; 20:691-695).
Costs of MVIC
Costs (1998 US Dollars):
 Table + frame: $3000; Computer + strain gauge: $3000-5000.
Total may come to $8-12,000
 Training the CE and backup, which involves flying to the session, spending the day
(approx. $3000 for two)
 Super-CE visit for monitoring reliability ($1500)
 Approx. cost of each exam $150 per patient (Medicare allowable for 60 minutes of a
PTs time)
Data Analysis
Standardization by normalization to reference ALS patient population (Andres et al, Neurology
1988; 38:405-408) or according to percent predicted value (National Isometric Muscle Strength
(NIMS) Database consortium, Arch Phys Med Rehabil; 1996;77:1251-1255).
Surrogate for Survival?
Two direct pieces of evidence and one indirect piece of evidence to confirm the clinical impression
that patients who progress faster die sooner, using MVIC measurements:
 Smith et al - (Muscle & Nerve, 1993;16: 624-633) rate of decline by MVIC strongly
related to survival.
 Stambler et al (Neurology 1998;50:66-72) - MVIC decline unrelated, but study could not
show relation.
 Armon et al (IAMNDA 1997 meeting abstract): One point MVIC as part of deriving
linear estimate of rate of decline: highly related to survival.
Future Study:
Optimal muscle groups to use should be the subject of research:
a. Sample cervical region alone or cervical and lumbosacral regions?
b. Standardized panel vs. Select best / most testable / reliable from a group.
c. Those muscles with least variability.
d. Combine muscle groups with myotomal distribution?
Whether reliability testing on patients is better than testing on normals.
MVIC as a surrogate for survival requires further study.
B. Manual Muscle Testing
Background
Hasn't been evaluated as rigorously as MVIC in patients with ALS.
Has been evaluated in polyneuropathy with monoclonal gammopathy.
Was used in an FSH, DMD (steroid) study, and appeared to be comparable to MVIC (when
looking at total scores).
Standardization
The MRC scale was transformed in those studies into a 10 point scale, which may be better than
the original 5-point scale, which has been used in ALS studies.
If used - needs to be approached as a research tool.
Limited Information:
CE
Reliability/Variance
Time of day
Training/Technique
Monitoring
Costs - same as MVIC, minus cost of equipment
Purpose
Surrogate for Survival?
Riluzole 1 study - impact on survival and on MMT; Riluzole II study - impact on survival but not
on MMT; Other studies - no impact on survival or in MMT.
Future Research
All items listed above
C. Hand Held Dynamometry
Electronic hand-held dynamometry supported by Brinkmann et al. 1997. Further reliability data
needed.
5. APPENDIX FOUR-Quality of Life
Definition:
Quality of life is "The extent to which hopes and ambitions are matched by experience". It is an
individual concept. An ideal QoL instrument must be applicable across a range of disability,
relevant to ALS, easy to administer, cost effective and efficient, as well as sensitive to clinically
significant change. Ideally, QoL is measured by direct assessment, from patient-derived data,
rather than through any other person's intervention. It involves domains of health perception,
personal and social achievement and physical and mental well-being. Inter-personal relations are
important determinants of these concepts. It is an independent measure of the effectiveness of a
therapy.
Recommendations:
1. QoL can not be used as a primary or sole outcome measure at this time.
2. More specific and quality related scales are needed that should be valid, reliable,
sensitive to change and relevant to the disease. Any ALS - specific measure should be
used in conjunction with a recognized generic QoL measure to allow comparisons across
disease states.
3. The following generic scales have been used in previous ALS clinical trials:
SIP - Sickness Impact Profile
SF-36 - Short form 36
The SIP has proved difficult to use, and has been reported to cause patient distress. In
addition the SIP is weighted towards functional measures and may partially replicate
functional scales, such as the ALSFRS. There are a variety of other generic QoL measures
that could be used such as the Quality of Life Questionnaire (QLQ-C30), the Nottingham
health index and the Quality of Well Being (QWB) scale. These have not been validated in
ALS. Generic scales are important because they have been used in many different clinical
disorders, both in trials, and in the evaluation of the results of clinical practice. Their
sensitivity, however, varies in these different clinical contexts.
4. The SF-36 is recommended for both screening and for pivotal ALS Clinical Trials. This
generic instrument should be applied in conjunction with an ALS-specific measure, once
this has been developed.
5. There is a risk that if questions are isolated from validated and balanced QoL measures
they may replicate data obtained from functional rating scales. This should be avoided.
6. As part of trial design, consideration should be given to the collection of direct and
indirect cost data for pharmaco-economic analysis. This is important in relation to
marketing, and to decisions made by third party payers in relation to the availability of
the drug once it has been licensed.
7. Consideration should be given to assessment of QoL of caregivers during the trial.
8. The frequency of administration of QoL instruments should be driven by the nature of the
specific instrument. In general, current generic measures should not be administered
more than four times annually, because of the lack of validated alternative forms of these
tests. More frequent administration results in unreliable data due to learning and
familiarity effects.
9. Consideration should be given to the use of a depression scale, e.g. Beck scale, to
recognize treatable factors in altered QoL. Psychological factors have been shown to
influence survival (MacDonald et al 1996).
10. Problems of nonlinearity: QoL measures are ordinal and should be treated accordingly in
statistical analyses.
6. APPENDIX FIVE-Statistical Considerations
The following observations pertain to confirmatory or pivotal trials. A pivotal trial should
demonstrate the effect of a drug when given to a broad spectrum of patients with ALS.
A clinical trial usually requires a collaboration among many different groups of investigators at
different centers. Trialists and /or statisticians can elaborate general principles for trial design but
clinicians must help mould those principles for use in specific diseases such as ALS. Answers to
important questions cannot be assigned to one group or the other but must be reached in
collaboration.
What drives a trial is the question being asked. If a methodology is judged to be an efficient way of
getting to the answer in a particular trial it may be appropriate in that trial even if is not
appropriate in others.
Dropouts
All trials should be structured to keep dropouts to a minimum. All attempts should be made to
obtain at least the primary outcome measure from all subjects entered into the trial. Both of these
issues should be a consideration in the selection of a primary endpoint. Adjustment for dropouts is
always problematic because the relation of dropouts to study medication is unknown. Reasons for
dropout should always be noted in the protocol. Comparisons of baseline variables between
dropouts and completers should be made to see if dropouts have any pattern and to determine if
dropouts were tending in a direction different from those who completed the trial. If dropouts are
truly random then all of the current weighting schemes should give similar results. Since these
schemes all depend upon assumptions about the structure of the data it?s difficult to recommend
one over the other for all situations. If dropouts occur for non-random reasons, it is more
important to discover and adjust for these reasons than to provide a single statistic. Careful
attention should be given to collecting baseline data for comparison of dropout and non-dropout
groups.
As a specific recommendation, last observation carried forward is probably not appropriate for
ALS trials. The analysis should be "intent to treat".
Stratification
Since randomization is not perfect it is often necessary to make sure that key covariates are
balanced between the arms of a trial by stratifying on these variables and then conducting blocked
randomization within strata. Clinical sites are almost always one of the strata. Other possible
strata depend upon the disease and the impact of the covariate on the outcome. Covariates which
should be considered for strata are those which are highly predictive of the outcome measure
being used. The predictiveness of the strata variable should be determined in advance and we
recommend that when the results of any trial have been published, the data (particularly from the
control group) should be made available for analysis of predictive factors. At this time, site of
onset, age, and FVC are all variables in ALS that are worth considering as separate strata in
future trials. The number of stratification factors should be small (at most 3 to 4) and it is more
efficient to have independent variables as strata indicators. Very predictive variables are those
with relative risks of 2 or 3. The strata need to be specified in advance and they are part of the
primary analysis. If the analysis is not adjusted to account for stratification, the power may be
less than what would be expected from simple randomization.
It is important to recognize the distinction between Predictors and effect modifiers. An effect
modifier is a clinical feature that results in different drug effects in different subgroups. When
pre-trial evidence indicates that the effect of the experimental treatment is likely to differ across
subgroups, separate studies in subpopulations should be considered. If this is not the case and
post-hoc explanatory subset analysis is done, these hypothesis-generating results will require
validation with independent data sources.
Adjustment for Prognostic Factors or Other Covariates
The basic reason for planned covariate adjustment is to reduce the risk of confounding, to
increase precision, and to account for structure imposed by stratification at randomization. While
post-hoc adjustment provides useful insights, a significant result that occurs only after adjustment
is less compelling than finding a result using a priori design techniques. Any adjustment
"discovered" during the trial or on the basis of modeling conducted during the trial is still a
discovered result not a pre-planned confirmation. We encourage investigators to engage in
post-hoc analysis for the purpose of learning more about disease and its treatment. Results from
this experience should be considered as hypothesis generating and not hypothesis confirming.
Adjustment with pre-specified variables can be viewed in the same light as stratification, with
similar caveats.
Analytical Methods
The general issue is that an analysis appropriate to the question being asked, the outcome
measures chosen, and the adjustments made, must be specified in advance of the trial. Clinical
difference to be detected, power, and sample size also must be pre-specified and considered in
light of achieving maximum efficiency for the trial. Cox is a perfectly valid analysis procedure and
can be used with covariates, subject to the discussion above, in time to event situations where data
may be censored.
Use of the Cox model assumes proportional hazards. This should need be examined during the
study design phase, not post hoc.
Time to Failure Variables
Almost any clinical variable can be an event, and a time to achieve it can be measured. It should
be a clinically meaningful event or surrogate measure, which can be precisely, unambiguously,
and reliably measured.
Lead-ins
Lead-ins are a method of specifying inclusion, exclusion or stratification criteria for the trial.
They should be judged that way, i.e. do they provide sufficient reduction in variability to overcome
the loss of generalizability they produce and the effort to implement them. Further study of
lead-ins is needed in ALS Clinical Trials.
Surrogate
A better understanding is needed by ALS clinical trialists about what a surrogate measure is, how
it is to be used, and how we can determine whether a given variable is or is not a good surrogate
measure. A similar therapeutic response between a putative surrogate and the outcome measure in
a therapeutic trial is necessary to establish it as a surrogate.
7. APPENDIX SIX-Respiratory Issues in Clinical Trials
I. Methods and Techniques of Pulmonary Measurement.
1. There are no evidence based data as to which pulmonary measurement is most robust.
Vital capacity (FVC or VC) is less variable than measurement of peak pressures, arterial
blood gases or serum chloride.
2. There are no published data supporting VC over FVC, and this is an important issue to
resolve.
3. There are no published data related to use of masks or mouthpieces. However, these
devices can influence pulmonary measurement. Their use should be standardized and
devices should not be changed or introduced during the trial.
4. Pulmonary testing personnel should be well trained and demonstrate adequate test-retest
reliability. Their interaction with the patient should be standardized.
5. There is a learning effect for the patient in the measurement of pulmonary function, and
this must be factored into trial design.
II. Clinical Factors Which Can Influence Respiratory Status
1. There are data that non-invasive ventilation can relieve patient symptoms and prolong
survival. There are no data to determine when to introduce non-invasive ventilation. The
individual investigator should have control over how to manage patients with respect to
non-invasive ventilation. Accordingly, in future trials it is important to obtain data to
develop standards for the timing of instituting non-invasive ventilation.
2. There are also data that enhanced nutrition by gastric feeding may influence respiratory
function and prolong survival. As above, there are no published standards of practice but
investigators should do what is best for the patient, and data for standards are needed.
3. Coexistent pulmonary disease should be treated by best medical care, but should not be
an exclusion criterion.
III. Respiratory Measures as Outcome Variables
1. Non-invasive ventilation and gastric feeding may alter respiratory measurements.
Accordingly, their introduction may represent an endpoint. This must be stipulated before
the trial begins.
2. Non-invasive ventilation and gastric feeding may have significant therapeutic effects,
which must be considered in trial design, especially when survival is the outcome
measure.
IV. Future Research
1. More research is needed to determine the best measure of pulmonary function for clinical
trials.
2. There is a clear need for determining the influence of non-invasive ventilation and gastric
feeding, and their timing, upon functional measurements and survival in ALS/MND.
8. APPENDIX SEVEN-Bulbar Tests
Careful analysis of proper tests for management, clinical studies and treatment trials is
recommended. In addition to precise bulbar measures, special attention should be given to
measurement of early metabolic indicators of dehydration and malnutrition due to dysphagia,
including urine osmolarity, serum pre-albumin, nitrogen balance and body mass index. The
placement of a percutaneous endoscopic gastrostomy [PEG] or gastrostomy tube [GT] may be
employed as a time-to-failure end point in clinical trials. Criteria for the proper timing of PEG or
GT placement require further definition and development.
Advancing the evidence-based foundation of symptomatic treatment of bulbar dysfunction requires
clear definition of clinical trial endpoints and trial design. Measurement tools could include
bulbar and pseudobulbar affect clinimetric scales with attention to confounding effects of
depression.
Use of specific adaptive equipment, such as communication aids, could be evaluated with quality
of life measurement instruments.
Preferred: Precise measurement of bulbar function to be developed
Validated: Bulbar functional rating scales
Frenchay Scale
Hillel Scale
Norris ALS Scale Bulbar Subscale
Timed speech tests
Presently, phonetic feature analysis, videofluoroscopy, and orofacial strength measurement with
bulbar force transducers are acceptable for small, single center studies.
Future Research: Further tailoring of established bulbar functional rating scales to address the
special problems of ALS is identified as a clinical research priority. Timed speech tests should be
further validated. Collaborative efforts with speech therapists and nutritionists are recommended.
In addition to developing valid tests, newer technologies need to be evaluated that may allow for
monitoring the clinical course and effect of treatment.
9. APPENDIX
EIGHT-Workshop
Chairs,
Cochairs,
Participants and Attendees
World Federation of Neurology
Committee on Motor Neuron Disease
Workshop on Therapeutic Trials in ALS
(Members of the Steering Committee are printed in bold)
Robert G. Miller, M.D. , Program Chair; Larry Powe M.D., Co-Chair
# 1 Statistical Issues...... Dr. James Murphy / #2 Design Issues...... Dr. Hiroshi Mitsumoto /
Dr. Gilbert Bensimon
Dr. Michael Brooke
Elizabeth Cronert, M.D.
Ram Ayyar, M.D.
Mamede de Carvalho, M.D.
John Bjerke, M.D.
Mr. George Y. N. Chi
Walter Bradley, M.D.
Thomas Dobbins, M.D.
Jesse Cedarbaum, M.D.
Tom Fleming, M.D.
Andrea Corse, M.D.
Michael Graves, M.D.
Vianney de Jong
David Hoberman, Ph.D.
Yadollah Harati, M.D.
Mr. Kun Jin
Ted Heine
Burk Jubeit, M.D.
Carlayne Jackson, M.D.
Louis Lasagna, M.D.
Jeffrey Rosenfeld, M.D.
Paul Leber, M.D.
Lewis Rowland, M.D.
James A. Russell, D.O.
James W.Russell, M.D.
Robert Sufit, M.D.
Khema Sharma, M.D.
John Turnbull, M.D.
Roberto Sica, M.D.
Audrey Wong
Nancy Stambler, M.D.
Michael Strong, M.D.
# 3 Interaction/Invest/Indust...... Dr. Theodore #4 Survival...... Dr. Vincent Meininger / Dr.
Munsat / Dr. Gian Borasio
Daniel Drachman
Frank Baldino, Ph.D.
David Bristol, M.D.
Tulio Bertorini, M.D.
Wilson Bryan, M.D.
Patrice Douillet, M.D.
David Crump, M.D.
Jonathan Goldstein, M.D.
Merit Cudkowicz, M.D.
Michael Havilcek
Diana Escolar, M.D.
Terry Heiman-Patterson, M.D.
John J. Feeney, M.D.
Dana Hilt, M.D.
Yasuo Iwasaki, M.D.
Ralph Kuncl, M.D.
Edward Kasarkis, M.D.
James Kupiec, M.D.
Nigel Leigh, M.D.
Mary Lyon, M.D.
Susan Mitchell, M.D.
Sabri Markabi, M.D.
Prof. John D. Mitchell
Larry Powe, M.D.
Jeffrey Rothstein, M.D.
Phyllis Salzman, M.D.
Fred Samaha, M.D.
Guenter Ochs, M.D.
Kathryn Peters, R.N.
Stacy Rudnicki, M.D.
Michael Traub, M.D.
Philippe Truffinet, M.D.
# 5 MVIC...... Dr. Hans Neville / Dr. Carmel # 6 Respiratory...... Dr. Mark Bromberg / Dr.
Armon
Roberto Guiloff
Peter Bosch, M.D.
Lora Clawson, M.D.
Claude Des?Nuelle, M.D.
Prof. Richard Dengler
Marianne DeViser M.D.
John Doyle, M.D.
Arthur Dick, M.D.
Marek Gawel, M.D.
Kevin J. Felice, M.D.
Angela Genge, M.D.
Julaine Florence, M.D.
Vern Juel, M.D.
Orla Hardiman, M.D.
Richard Lewis, M.D.
John Kissel, M.D.
Audrey Penn, M.D.
Jesus Mora, M.D.
Prof. Jean Pouget
Daniel S. Newman, M.D.
Michael Rivner, M.D.
Benn Smith, M.D.
George Sachs, M.D.
Rup Tandan, M.D.
Mohammad Sanjak, M.D.
Charles Thornton, M.D.
John H. J. Wokke, M.D.
# 7 Bulbar...... Dr. Benjamin Brooks / Prof. # 8 Quality of Life...... Dr. Michael Swash / Dr.
Ludolph
Steven Ringel
Jerry Belsh, M.D.
Mark Brown, M.D.
Valerie Cwik, M.D.
Linda Boynton DeSapulveda, Ph.D.
John Doyle, M.D.
Alberto Dubrovsky, M.D.
Ole Gredal, M.D.
Dallas Forshew, R.N.
Michael Guillani, M.D.
Laurie Gutmann, M.D.
Paul Ince, M.D.
Ms. Cynthia Joyce
Gabriela Mora, M.D.
Russell Katz, M.D.
Gary Pattee, M.D.
Ruediger Kratz, M.D.
Vincenzo Silani, M.D.
George Levvy, M.D.
Richard Alan Smith, M.D.
Raul Mandler, M.D.
Kunio Tashiro, M.D.
Tippu Siddique, M.D.
US Food and Drug Administration
Division of Neuropharmacological Drug Products
Paul Leber, M.D., Director
Russell Katz, M.D., Deputy Director
John Feeney, M.D., Reviewing Medical Officer
Division of Biometrics
Edward Nevius, Ph.D., Supervisory Mathematical Statistician
David Hoberman, Ph.D., Mathematical Statistician
Center for Biologics Division of Clinical Trial Design & Analysis
Jay P. Siegel, M.D., Director
Karen D. Weiss, M.D., Acting Deputy Director
Marc K. Walton, M.D., Medical Officer
10. APPENDIX
NINE-Conference
Support
and
Acknowledgements
Major contributors
Rhône Poulenc Rorer
Cephalon Inc
Motor Neuron Disease Association (UK)
Sanofi Pharmaceuticals
For participation in Breakout Groups, and in Discussion Groups
Staff of the FDA
Oncology
Pharmacology
AIDS
Cephalon
Rhône Poulenc Rorer
MNDA
Organization
Dr. Theodore Munsat
Ms. Pat Pressman
Ms. Judith Horstman
Staff at Airlie House
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