Amyotrophic Lateral 
Sclerosis: Developing 
Drugs for Treatment 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
September 2019 
Clinical/Medical 
 
   
Amyotrophic Lateral 
Sclerosis: Developing 
Drugs for Treatment 
Guidance for Industry 
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-
guidances 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
September 2019 
Clinical/Medical 
 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DEVELOPMENT PROGRAM ....................................................................................... 2 
A.  General Considerations ................................................................................................................. 2 
1. Early Phase Clinical Development Considerations ......................................................................... 2 
2. Drug Development Population ........................................................................................................ 3 
3. Effectiveness Considerations ........................................................................................................... 3 
4. Safety Considerations ...................................................................................................................... 3 
B.  Specific Effectiveness Trial Considerations ................................................................................. 4 
1. Trial Design ..................................................................................................................................... 4 
2. Effectiveness Endpoints ................................................................................................................... 5 
3. Study Procedures and Timing of Assessments ................................................................................. 6 
4. Statistical Considerations ................................................................................................................ 7 
a.  Prognostic factors ...................................................................................................................... 7 
b.  Integrated assessment of function and survival ........................................................................ 7 
5. Accelerated Approval Considerations ............................................................................................. 7 
6. Benefit-Risk Considerations ............................................................................................................. 7 
C.  Other Considerations ..................................................................................................................... 8 
1. Relevant Nonclinical Safety Considerations .................................................................................... 8 
2. Pharmacokinetic/Pharmacodynamic Considerations ...................................................................... 8 
 
 
  Contains Nonbinding Recommendations 
Amyotrophic Lateral Sclerosis: 
Developing Drugs for Treatment 
Guidance for Industry1 
 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page. 
 
 
 
 
I.  INTRODUCTION 
 
The purpose of this guidance is to assist sponsors in the clinical development of drugs and 
biological products for the treatment of amyotrophic lateral sclerosis (ALS).2  Specifically, this 
guidance addresses the Food and Drug Administrations (FDAs) current thinking regarding the 
clinical development program and clinical trial designs for drugs to support an indication for the 
treatment of ALS.   
 
ALS is a progressive neurodegenerative disease that primarily affects motor neurons in the 
cerebral motor cortex, brainstem, and spinal cord, leading to loss of voluntary movement and the 
development of difficulty in swallowing, speaking, and breathing and shortened life expectancy. 
This guidance addresses the clinical development of drugs intended to treat the main motor 
aspects of ALS (i.e., muscle weakness and its direct consequences, including shortened survival). 
This guidance does not address in detail the development of drugs to treat other symptoms that 
may arise in ALS, such as muscle cramps, spasticity, sialorrhea, pseudobulbar affect, and others.  
 
This guidance focuses on specific clinical drug development and trial design issues that are 
unique to the study of ALS. General issues of concern in drug development, such as the quantity 
of effectiveness evidence needed to support approval for serious and life-threatening diseases or 
approaches to adaptive study design, are discussed in the guidance for industry Providing 
Clinical Evidence of Effectiveness for Human Drug and Biological Products (May 1998)3 and 
                                                 
1 This guidance has been prepared by the Division of Neurology Products in the Center for Drug Evaluation and 
Research in cooperation with the Center for Biologics Evaluation and Research at the Food and Drug 
Administration. 
 
2 For the purposes of this guidance, all references to drugs include both human drugs and biological products unless 
otherwise specified. 
 
3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
1  Contains Nonbinding Recommendations 
the draft guidance for industry Adaptive Designs for Clinical Trials for Drugs and Biologics 
(September 2018),4 respectively. This guidance also does not contain discussion of the general 
issues of statistical analysis or clinical trial design. Those topics are addressed in the ICH 
guidances for industry E9 Statistical Principles for Clinical Trials (September 1998) and E10 
Choice of Control Group and Related Issues in Clinical Trials (May 2001), respectively. 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
 
II.  BACKGROUND 
 
ALS is a motor neuron disease that occurs most often as a sporadic disease with no known cause 
or inheritance pattern. However, in a small minority of patients, the disease has a clear familial 
inheritance pattern that may be associated with an identified gene. In addition, gene mutations 
have been identified in some sporadic ALS patients.  
 
ALS patients can present with weakness and muscle atrophy in different areas of the body, with 
about 75 percent of patients first experiencing weakness in the limbs, and about 25 percent of 
patients presenting with difficulty swallowing and/or speaking (bulbar-onset ALS). ALS is a 
heterogeneous disease, but all forms of the disease share the defining features of degeneration of 
both upper and lower motor neurons. The diagnosis of ALS is based on the identification of its 
characteristic clinical symptoms and signs, along with the exclusion of other diagnostic 
possibilities. ALS is also considered a multisystem neurodegenerative disorder that can include 
cognitive and behavioral changes in addition to muscle weakness.  
 
 
III.  DEVELOPMENT PROGRAM 
 
A.  General Considerations 
 
1.  Early Phase Clinical Development Considerations 
 
Communication between sponsors and those affected by ALS to discuss expectations with 
respect to both effectiveness and safety is important early in drug development. Sponsors should 
understand how affected patients view treatment goals and risk tolerance.   
 
Intrathecal drug delivery may be necessary for some drugs for ALS. Early phase studies can 
often be conducted using single-dose intrathecal injection. However, if long-term intrathecal 
delivery from a device is anticipated, sponsors should consider drug-device codevelopment 
issues early in development.  
 
                                                 
4 When final, this guidance will represent the FDAs current thinking on this topic. 
2  Contains Nonbinding Recommendations 
2.  Drug Development Population 
 
Sponsors should base eligibility for patient enrollment in effectiveness trials in ALS on current 
consensus diagnostic criteria, with a focus on history, physical exam, and objective tests 
appropriate for determining the presence of ALS and for excluding conditions that can mimic 
ALS.  
 
There is a need to understand the safety and effectiveness of investigational drugs for ALS 
across disease stages. Although sponsors may have good reasons to use prognostic enrichment to 
increase the likelihood of demonstrating a drug effect (e.g., to enroll patients who are more likely 
to experience rapid progression) or to use predictive enrichment to direct therapy to patients with 
a particular disease characteristic (e.g., a specific genotype or phenotype), sponsors should not 
unnecessarily exclude patients from trial enrollment based on characteristics such as age or 
disease stage unless scientifically justified.5 Broader inclusion criteria allow more rapid trial 
enrollment, potentially accelerating drug development. An acceptable approach could include 
enrollment of a broad population with the conduct of the primary analysis in a study subset 
defined based on clinical characteristics and/or biomarkers, and analyses of the broader 
population being secondary and supportive. In later stages of development, sponsors can 
consider alternative trial designs, such as decentralized studies, in which mobile technologies or 
other methods are used to collect data in patients homes or by their local providers, to facilitate 
broader and potentially faster enrollment. 
 
3.  Effectiveness Considerations 
 
The statutory standards for effectiveness apply to drugs for ALS just as the standards apply for 
all other drugs. However, FDA has long stressed the appropriateness of exercising regulatory 
flexibility in applying the statutory standards to drugs for serious diseases with unmet medical 
needs, while preserving appropriate assurance of safety and effectiveness.6 
 
Sponsors should consider including prospective plans for interim effectiveness analyses to allow 
for the detection of early benefit in a clinical trial. 
 
4.  Safety Considerations 
 
Phase 1 studies can be conducted in healthy volunteers or in ALS patients, depending on the 
method of administration, safety profile, and potential for detecting pharmacodynamic responses 
in healthy volunteers relative to ALS patients. For cellular and gene therapy products, sponsors 
should discuss the appropriate population for Phase 1 studies with the Center for Biologics 
Evaluation and Researchs (CBERs) Office of Tissues and Advanced Therapies. 
 
In general, Phase 2 and Phase 3 clinical trials in ALS should be conducted under the oversight of 
a data monitoring committee (DMC). The DMC should look at frequent intervals for emerging 
                                                 
5 See the guidance for industry Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness 
of Human Drugs and Biological Products (March 2019). 
 
6 21 CFR 312.80, subpart E, Drugs Intended to Treat Life-Threatening and Severely-Debilitating Illnesses. 
3  Contains Nonbinding Recommendations 
safety signals and, if necessary, take appropriate measures to ensure that patients are not placed 
at unreasonable risk of harm.7 It is important to recognize that a relatively high percentage of 
ALS patients may have serious adverse events or die, especially in trials of relatively long 
duration, and comparison of the rates of those events in treatment and control groups is critical to 
distinguishing effects of the investigational drug from effects of the underlying disease. 
 
To support marketing approval, drug safety must be supported by an adequate number and 
duration of patient exposures to characterize drug risks.8 In general, FDA will consider the 
serious and life-threatening nature of ALS and the treatment benefit when determining the 
minimum number and duration of patient exposures needed.9 During development, sponsors 
should collect safety data, including data from open-label studies or expanded access programs, 
from patients across the spectrum of disease stages and severities, and whenever possible, data 
from patients who may not have been included in effectiveness studies but in whom, based on 
other data, the use of the drug following approval is likely. In general, safety data from a 
reasonable number of patients exposed to the drug for at least 1 year is appropriate to support 
approval of drugs intended for chronic use in treating ALS. The administration of cellular and 
gene therapy products may raise different issues regarding patient exposures; thus, we 
recommend that sponsors of such products discuss patient exposures with CBERs Office of 
Tissues and Advanced Therapies. 
 
B.  Specific Effectiveness Trial Considerations 
 
1.  Trial Design 
 
All patients in ALS trials should receive the best standard of care, and no patient should be 
denied effective therapies in order to be randomized to a placebo-only arm. Various strategies 
can be applied to expedite ALS trials and minimize unnecessary exposure to placebo. For 
example, master protocols (which use a single infrastructure, trial design, and protocol) allow for 
the simultaneous evaluation of multiple drugs, with a common or shared placebo group, and have 
the potential to greatly expedite the development of new drugs. Sponsors should also consider 
adaptive designs10 (including the use of Bayesian features) and enrichment strategies.11   
 
FDA recommends the consideration of add-on designs, in which a treatment previously shown to 
be effective for the treatment of ALS is given to all patients participating in the trial (i.e., no 
patient receives placebo alone), with patients randomized to the added investigational drug or 
                                                 
7 See the guidance for clinical trial sponsors Establishment and Operation of Clinical Trial Data Monitoring 
Committees (March 2006).  
 
8 21 CFR 314.125(b)(2). 
 
9 21 CFR 314.105(c); FDA is required to exercise its scientific judgment to determine the type and quantity of data 
and information a sponsor is required to provide for a particular drug to meet the statutory standards. 
 
10 See the draft guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics. When final, this 
guidance will represent the FDAs current thinking on this topic. 
 
11 See the guidance for industry Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness 
of Human Drugs and Biological Products. 
4  Contains Nonbinding Recommendations 
added placebo. In addition, placebo-controlled trials can be designed as time-to-event trials, with 
attainment of a clinically meaningful worsening in disease as a primary endpoint; patients then 
can be transitioned to open-label investigational treatment.  
 
At present, FDA discourages trials entirely based on a historical control in ALS because the 
course of ALS progression is highly variable among individual patients, and various controlled 
trials have demonstrated differences in rates of progression and survival among placebo cohorts. 
Thus, results from historically controlled trials are likely to be difficult to interpret unless the 
effect size on an objective endpoint is very large. Thus far in ALS development, those effects 
that have been seen, both early and late in development, suggest that such an approach is 
unlikely to succeed. It is possible that historical controls will be of value in future trial designs as 
we develop a more comprehensive and reliable characterization of the disease course. 
 
Trials should include prespecified plans for a long-term, open-label extension that maintains the 
blind to the original treatment assignment after completion of the randomized effectiveness 
portion of the clinical trial. This extension should allow for additional prespecified effectiveness 
assessments. Patients entering the extension will all receive the active investigational drug, but 
the patient, investigator, site personnel, and site monitors should remain blinded to treatment 
group assignment from the randomized treatment period. Only sponsor staff involved in analysis 
of the blinded period results should have access to unblinded data and patient group assignments 
 
2.  Effectiveness Endpoints 
 
Although existing outcome measures that have been developed for ALS may be appropriate, 
FDA supports the development and use of new outcome measures capable of measuring 
clinically meaningful effects in patients. FDA encourages the use of patient input and experience 
in the development of these new measures. Sponsors can also consider novel technologies (e.g., 
wearable biosensors), as appropriate. 
 
In general, effectiveness should be established by the demonstration of a treatment effect (e.g., 
less decline, stabilization, improvement) on function in daily activities as measured, for example, 
by the ALS Functional Rating Scale-Revised or similar scales. In general, in addition to the 
primary endpoint, sponsors should include assessments of various effectiveness outcomes in 
trials, including patient-reported outcomes (PROs). For effective drugs, the results of these 
additional outcomes would be expected to be supportive. 
 
PRO assessments, including those measuring activities of daily living, can be designed to assess 
the abilities and experiences of patients across a spectrum of disease stages and severities. PRO 
assessments can be useful to assess the clinical meaningfulness of an objective finding (e.g., 
muscle strength) even if of relatively small magnitude, and they therefore contribute to 
assessments of benefits and risk. In general, PRO instruments for ALS trials should include a 
limited number of items that assess the most important aspects of the outcome of interest (e.g., 
specific aspects that contribute to health-related quality of life, such as physical functioning). 
PRO instruments that are overly lengthy may increase responder burden and fatigue, increasing 
the potential for missing data. PRO instruments that are overly broad can be difficult to interpret 
and may be insensitive to meaningful change in the outcomes of major interest.  
5  Contains Nonbinding Recommendations 
 
Because loss of strength is a hallmark of disease progression in ALS, a valid measurement of 
muscle strength may be an appropriate endpoint for treatments intended to increase or preserve 
muscle strength. Because changes in muscle strength alone may not necessarily be indicative of 
meaningful effect on function in activities of daily living, the clinical meaningfulness of 
differences in muscle strength should be supported by the magnitude of the effect observed 
(based on the mean change or on a responder analysis of patients who exceed a clinically 
meaningful threshold of change) or by the demonstration of a drug effect on an appropriate 
measure of function in activities of daily living. Sponsors considering a measure of muscle 
strength as a primary endpoint should discuss with FDA their plans to establish the clinical 
meaningfulness of the treatment effect. 
 
Because decline in respiratory function is a direct result of the known pathophysiology of the 
disease, the demonstration of a treatment benefit on respiratory endpoints may also provide 
evidence of effectiveness. Specific clinical respiratory outcomes can include nocturnal 
desaturation, aspiration pneumonia, and progression to mechanically assisted ventilation. 
Measures of respiratory function, such as forced vital capacity, may also be acceptable as 
effectiveness endpoints. As with measures of muscle strength, the clinical meaningfulness of 
differences in respiratory function should be supported by the magnitude of the effect observed 
(based on the mean change or on a responder analysis of patients who exceed a clinically 
meaningful threshold of change) or by the demonstration of a drug effect on an appropriate 
measure of function in activities of daily living. Sponsors considering a measure of respiratory 
function as a primary endpoint should discuss with FDA their plans to establish the clinical 
meaningfulness of the treatment effect. In general, unless the enrolled patient population is only 
capable of manifesting a benefit on respiratory function or the drug is expected to have an effect 
unique to respiratory function, drug effects on pulmonary endpoints would be expected to be 
supported by a treatment benefit on broader measures of function in activities of daily living.  
 
Sponsors should characterize an effect on mortality in all ALS development programs because it 
is important to the consideration of the overall safety and effectiveness profiles. If patient 
function is intended to be assessed by the primary outcome, mortality should be integrated into 
the primary outcome by an analysis method that combines survival and function into a single 
overall measure, such as the joint rank test (see section III.B.4.b., Integrated assessment of 
function and survival). In that situation, the independent assessment of a drug effect on survival 
should be a secondary endpoint. The independent assessment of survival should be combined 
with an evaluation of the need for full-time (or nearly full-time) respiratory support because such 
support can affect survival time. Survival is also acceptable as a primary outcome measure. 
 
3.  Study Procedures and Timing of Assessments 
 
For trials based on functional endpoints, the first on-treatment assessment should be performed at 
the earliest time when a treatment effect is expected and no later than 23 months after 
randomization so that at least one on-drug assessment can be recorded for all or most patients. 
Second and even third measurements should be performed at appropriate, reasonably spaced 
intervals to reduce the effect of random variation and more reliably verify the character of any 
disease progression that has occurred. Use of the mean measurement obtained on two or more 
6  Contains Nonbinding Recommendations 
occasions may decrease the effect of random variation. Variability may also be decreased by 
obtaining baseline assessments on more than one occasion. Sponsors should consider the burden 
to patients in setting the frequency and type of assessments (e.g., in clinic versus remote).  
 
FDA encourages the use of approaches and technologies to minimize the burden of trials on ALS 
patients and limit the need for travel to study sites (e.g., decentralized clinical trials with key 
endpoint measures at baseline and at intervals during the trial conducted in a standardized 
fashion at central testing facilities, remote monitoring for some of the visits). FDA is open to 
exploring the utility of digital biomarkers as clinical endpoints. 
 
4.  Statistical Considerations 
 
a.  Prognostic factors 
 
Survival time in ALS varies greatly. Also, an increasing number of clinical prognostic predictors 
are being identified in ALS. If applicable, FDA recommends that sponsors use randomization 
methods that help ensure that treatment arms are balanced with respect to key prognostic factors. 
Some of these factors may also be prespecified as covariates in the study analysis plan.  
 
b.  Integrated assessment of function and survival 
 
Functional endpoints can be confounded by loss of data because of patient deaths. To address 
this, FDA recommends sponsors use an analysis method that combines survival and function into 
a single overall measure, such as the joint rank test. 
 
5.  Accelerated Approval Considerations 
 
FDA encourages sponsors to incorporate exploratory biomarkers in all phases of development of 
ALS drugs. In the future, greater scientific understanding of ALS may provide opportunities for 
discussion of surrogate endpoints that are reasonably likely to predict clinical benefit and that 
might serve as a basis for accelerated approval. Sponsors considering a development program 
intended to support an accelerated approval in ALS should discuss this approach and the overall 
development program with FDA early in drug development. 
 
Given the typically rapid progression of disease in ALS patients (recognizing considerable 
heterogeneity in the course of individual patients), it is feasible and most efficient to establish a 
clinical benefit based on clinical endpoints capable of supporting full approval, even if the 
benefit is modest. In general, that benefit can be established in trials of practicable size and 
duration (i.e., 6 to 12 months).   
 
6.  Benefit-Risk Considerations 
 
When making regulatory decisions about drugs to treat ALS, FDA will consider patient tolerance 
for risk and the serious and life-threatening nature of the condition in the context of statutory 
requirements for safety and efficacy.  
 
7  Contains Nonbinding Recommendations 
C.  Other Considerations 
 
1.  Relevant Nonclinical Safety Considerations 
 
Nonclinical studies provide important information to help determine whether clinical trials are 
reasonably safe to conduct, and to inform clinical dose selection and safety monitoring. As a 
general matter, for serious and life-threatening diseases for which treatments are not available or 
are inadequate, FDA may permit clinical trials to commence based on less than usual nonclinical 
testing if scientifically justified. In certain cases, the duration of dosing in humans may exceed 
that of the nonclinical studies, if justified based on the available nonclinical and clinical data. 
FDA encourages sponsors to discuss this approach with the Agency early in clinical 
development. In general, carcinogenicity studies can be conducted after approval for drugs 
intended to treat ALS, given the unmet medical need for effective therapies. 
 
2.  Pharmacokinetic/Pharmacodynamic Considerations 
 
During drug development, in general, sponsors should explore the relationship between exposure 
(drug concentration in plasma or other biological fluid) and effectiveness and safety endpoints. 
Exposure-response relationships using biomarkers from early dose-finding studies can help 
identify dose and dosing regimen(s) for controlled effectiveness studies. Importantly, assessment 
of exposure-response can also contribute to interpretation of evidence of effectiveness from 
controlled studies. The response variables used in the exposure-response analyses should include 
prespecified primary and secondary endpoints, as well as results involving biomarkers collected 
in the studies for effectiveness and safety. The exposure-response relationship can help 
determine the need for dose adjustment for various extrinsic and intrinsic factors, such as drug-
drug interactions and organ impairment, among others.   
 
Because pharmacokinetic/pharmacodynamic considerations are different for cellular and gene 
therapy products, sponsors of these products should discuss their development plans with 
CBERs Office of Tissues and Advanced Therapies.   
 
8