DATE: October 16, 2002

TO: Members, Peripheral and Central Nervous Systems Drugs and Nuclear Medicine Drugs Advisory Committees, and Invited Guests

FROM: Staff

Division of Neuropharmacological Drug Products

SUBJECT: Background Document for Joint Advisory Committee Meeting of November 18, 2002: Issues Related to the Role of Brain Imaging as an Outcome Measure in Phase I I I Trials of Putative Drugs for Alzheimer’s Disease

  1. Background
  2. As you know, a joint meeting of the Peripheral and Central Nervous System Drugs and Nuclear Medicine Drugs Advisory Committees of the Food and Drug Administration will be held on November 18 and 19, 2002.

    On November 18, 2002 the Committee will discuss the role of brain imaging as a primary outcome measure in Phase I I I trials of putative drugs for Alzheimer’s Disease. This paper has been prepared in an effort to brief you on the specific issues that we believe need to be addressed by the Agency when considering the use of brain imaging as an outcome measure in such trials. In addition, we are including pertinent publications.

    In this paper we will first describe the objective of the meeting, the FDA’s role in approving new drugs, and the current basis for approving new drugs for the treatment of dementia. Since brain imaging modalities would, from a regulatory standpoint, be considered surrogate markers, we will then outline our current view of surrogate markers which is defined both by current regulations and laws, and by the medical literature. Finally, we will briefly discuss the issues that we hope will be addressed at the meeting to be held on November 18, 2002.

    1. Purpose Of Meeting
    2. The purpose of this Advisory Committee meeting is to achieve a consensus on the role of brain imaging as a primary outcome measure in definitive efficacy trials of drugs intended for Alzheimer’s Disease

    3. Brain Imaging Modalities
    4. A number of specific methods of imaging the brain, including volumetric magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography and other entities, have been proposed as outcome measures in Phase I I I trials of drugs that are under development for the prevention and/or treatment of Alzheimer’s Disease.

      From a regulatory perspective, however, the appropriateness of using any of these modalities as outcome measures has not yet been clearly determined.

      Interest in the use of these modalities as outcome measures in key drug efficacy trials in Alzheimer’s Disease has, so far, been largely focussed on their possible role in demonstrating disease-modifying effects of such drugs. In this context, the term "disease modifying" refers to an effect on the underlying pathology of the disease.

    5. FDA Role In Drug Approval

The FDA approves a drug for marketing based on a determination that such a treatment is both effective and safe, when used to treat one or more specific clinical entities. The entity for which such a treatment is intended, is referred to as the "claim" or "indication" for that drug, and is described in the "Indications and Usage" section of the label. Proposed labeling must accompany the New Drug Application (NDA) submitted by the sponsor.

The Federal Food, Drug, and Cosmetic Act (the Act) requires that the approval of a drug treatment for a specific condition be supported by (among other criteria) "…substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling…". Substantial evidence is further defined as evidence from "adequate and well controlled…clinical investigations…". These definitions make clear that approval of a drug product is linked in part to our ability to adequately describe the drug’s effects in the population for whom its use is intended, in labeling.

In order to do this, the following must generally be true:


The Act also states that the Secretary may refuse to approve an application "if, based on a fair evaluation of all material facts, such labeling is false or misleading." One of several circumstances under which labeling that states that a particular drug is indicated for the treatment of a specific clinical entity could be considered misleading is if the effect of the drug on that condition is not appropriately measured.

Thus if a brain imaging modality is to be used as an outcome measure to support a claim that a drug has a specific beneficial effect in Alzheimer’s Disease, the imaging modality must accurately measure that effect.

    1. Current Basis For Approving Drugs For Dementia
    2. In the last 10 years 4 drugs have been approved by the FDA for the treatment of dementia: tacrine, donepezil, rivastigmine, and galantamine. All 4 drugs have been approved for an identical indication: the treatment of mild to moderate Alzheimer’s Disease. Their approval has been based upon clinical trials, the key elements of which have been as follows

      1. Diagnosis of Alzheimer’s Disease

Patients enrolled in these trials have generally had "probable" Alzheimer’s Disease as defined by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA). Those criteria* are as follows

*The NINCDS-ADRDA criteria for probable Alzheimer’s Disease have been shown to be both valid and moderately reliable. They have a sensitivity of > 90%; their specificity is however lower (50 – 60%) and they are particularly lacking in specificity in distinguishing the frontotemporal dementias from Alzheimer’s Disease, as well as in distinguishing those who have a combination of cerebrovascular neuropathology and Alzheimer’s Disease from those who have pure Alzheimer’s Disease.

      1. Severity Of Dementia
      2. Patients enrolled in these trials have been considered to have dementia of mild to moderate severity at study entry. The severity of their dementia has been assessed based on their Mini-Mental Status Examination scores; the range of such scores that have been considered to fit the "mild to moderate" category has been from 10-26.

      3. Design And Duration Of Clinical Trials
      4. These trials have so far invariably been randomized, double-blind, placebo-controlled, parallel-arm studies. The period of double-blind treatment has ranged from 3-6 months.

        So far, the approval of drugs for the treatment of Alzheimer’s Disease has been based upon demonstrating efficacy in at least 2 such studies, each of at least 3 months’ duration.

      5. Outcome Measures For Assessing Drug Efficacy

Draft guidelines issued by this Agency have recommended that the efficacy of putative drugs for dementia be determined using assessments of the following as pre-specified co-primary outcome measures.

A cognitive rating scale has been recommended as a primary outcome measure, since the core symptoms of dementia are cognitive. However, since the clinical significance of a change on a cognitive rating scale may not be clear, a global scale has been recommended as a second primary outcome measure. For approval to be granted it has been required that superiority of the drug over placebo be demonstrated separately on each of these 2 types of measures.

For most clinical trials completed over the last 12 years, the ADAS-Cog and CIBIC-Plus have been the primary outcome measures.

      1. Symptomatic Effect Versus Disease Modification

The design of clinical trials on which the approval of drugs for Alzheimer’s Disease have been based have thus far been unable to distinguish between a purely symptomatic effect of the drug in question and a disease-modifying effect.

Accordingly, the class labeling for these drugs states: "There is no evidence that -------(name of drug) alters the course of the underlying dementing process."

Two theoretical study designs that have been proposed for making this distinction are further described below. Both designs apply to studies that are randomized, double-blind, placebo-controlled and parallel-arm throughout. Each proposed design has 2 study segments:

Both study designs can still be considered theoretical and have yet to be adequately assessed in a clinical trial setting. The appropriate durations of each segment, the frequency of assessments, and a number of analytical issues need to be resolved.

As an alternative approach, the use of brain imaging measures (especially volumetric magnetic resonance imaging of hippocampal and whole brain atrophy) have been proposed as a means of assessing the effects of putative disease-modifying agents in Alzheimer’s Disease. In protocols for Phase I I I randomized, controlled clinical drug trials that have so far been submitted to this Division, measures of whole brain and hippocampal atrophy have been considered ancillary to more standard clinical outcome measures directed at addressing a now-conventional treatment claim, and have been restricted to a subset of patients participating in these trials.

As has been indicated earlier in this paper, brain imaging modalities would, from a regulatory viewpoint, be considered surrogate markers.

    1. Regulatory View Of Surrogate Markers
    2. A number of critical issues must be examined when considering the propriety of accepting imaging markers as primary measures of drug effect. These issues are cogently discussed in a 1996 article by Fleming and DeMets in the Annals of Internal Medicine, which is included with this mailing. In the following section, some of these considerations are discussed.

      1. Definition
      2. A widely-quoted definition of a surrogate endpoint is that proposed by Temple [Temple,1995].

        "A surrogate endpoint of a clinical trial is a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions, or survives. Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint."

      3. Properties Of An Ideal Surrogate Marker

According to Fleming and DeMets, the properties of an ideal surrogate endpoint should be as outlined below.

The essence of this proposal is that a valid surrogate endpoint should not merely be a correlate of the clinical outcome, but should also capture the full effects of the intervention on the clinical outcome.

However, as Fleming and DeMets point out, even if the surrogate marker captures the full effects of the intervention on the clinical outcome, problems could arise if the surrogate is sensitive out of proportion to a clinically meaningful outcome, or if the surrogate is insensitive on account of "background noise."

      1. Validation Of Surrogate Markers

A few general comments need to be made about the validation of surrogate markers

      1. Examples Of Surrogate Markers
      2. The following table shows a number of examples of proposed surrogate endpoints, not all of which have been validated.

        Surrogate Endpoint

        Clinical Outcome

        Reduction in serum lipid levels

        Reduction in cardiovascular mortality

        Reduction in tumor volume

        Increased survival

        Increased CD4 cell count in AIDS

        Reduced mortality

        Reduction in blood pressure

        Reduction in cardiovascular morbidity


      3. Advantages Of Using Surrogate Endpoints
      4. Potential advantages of using surrogate endpoints include replacing a rare clinical outcome as the primary endpoint, and allowing for shorter study durations and smaller sample size.

      5. Possible Reasons For Failure Of Surrogate Endpoints

Fleming and DeMets have suggested a number of possible mechanisms that may lead to a surrogate endpoint failing as an adequate substitute for a clinical endpoint. These mechanisms are listed below:

      1. Example Of A Failed Surrogate Endpoint

The use of surrogate endpoints that have not been shown to predict the clinical outcome of interest (so-called unvalidated surrogates) as primary measures of drug effect are attractive for the reasons discussed above in Section 1.5.5. Another feature that makes them attractive is that they are often risk factors for specific clinical outcomes, and it appears, "logical", therefore, that a beneficial effect on the surrogate "must" have the desired effect on the clinical outcome. However, there are many examples where a beneficial effect on the surrogate has not resulted in the predicted effect on the clinical outcome

A well-known example of a failed surrogate endpoint is that of ventricular arrhythmias as a surrogate marker for mortality after myocardial infarction in clinical drug trials, as demonstrated by the results of the Cardiac Arrhythmia Suppression Trial (CAST). This example is explained further below:

      1. Regulations And Laws Governing The Use Of Surrogate Markers
      2. While the Agency has long approved drugs on the basis of effects on validated surrogates (e.g., anti-hypertensives, cholesterol lowering agents) it was not until the adoption of the Accelerated Approval Regulations, and subsequently under the Food and Drug Administration Modernization Act, that the Agency gained the explicit authority to approve a drug on the basis of an effect on an unvalidated surrogate.

        1. Accelerated Approval Regulations

The Accelerated Approval regulations are for drugs studied in serious or life-threatening illnesses and which produce meaningful therapeutic benefit to patients over existing treatments. They were instituted in 1992 at a time when there was an urgent need to develop effective drugs for the treatment of AIDS.

Under these regulations, the FDA is permitted to grant marketing approval to drugs based on a surrogate endpoint that appears "reasonably likely" to predict clinical benefit, with actual clinical benefit being confirmed after approval. The regulations are cited below.

        1. Food and Drug Administration Modernization Act

Statements similar to those made under the Accelerated Approval Regulations are in Section 112 of this Act, which was signed into law in 1997.

This section is entitled "Expediting Study and Approval of Fast Track Drugs" and states the following

Limitation.--Approval of a fast track product under this subsection may be subject to the requirement that the sponsor conduct appropriate post-marketing studies to validate the surrogate endpoint

    1. How is a surrogate imaging modality best validated? If one uses an imaging modality to support a disease-modifying effect claim, how does one establish that such an effect occurs?

Based on the outline in Section 1, these interrelated questions may be restated as follows

Thus, if one uses an imaging modality to support a claim for disease-modification, two separate links will need to be established: between the imaging modality and the desired clinical outcome; and between the imaging modality and disease-modification.

Our proposed approach in addressing the above questions, is to first attempt to answer the following

While addressing these questions, we believe that the following should be kept in mind

A practical approach to validating a surrogate marker might consist of

    1. Has any surrogate imaging modality been validated at the present time?

We would be interested in the Committee’s view as to whether any imaging modality in Alzheimer’s Disease could be considered to have already been validated as a surrogate marker, based on the guidelines proposed in Section 1.6, or using other criteria.

Even if no surrogate imaging modality has currently been validated, is it appropriate to use one or more such modalities as primary or ancillary outcome measures of efficacy in Phase I I I clinical trials?

We recognize that validating a surrogate marker, using the guidelines proposed above, imposes a very high standard on the process. We would, therefore, be keen on hearing the Committee address whether there are otherwise sufficient grounds for the use of one or more imaging modalities as primary or supportive outcome measures in clinical trials for Alzheimer’s Disease, even in the absence of formal validation.

We look forward to seeing you in November, and thank you in advance for your efforts.



Buyse M, Molenberghs G. Criteria for the validation of surrogate endpoints in randomized experiments. Biometrics 1998;54(3):1014-29

Code of Federal Regulation, Title 21

Federal Food, Drug, and Cosmetic Act

(As Amended by the FDA Modernization Act of 1997)

Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Annals of Internal Medicine 1996;125(7):605-13

Food and Drug Administration Modernization Act of 1997.

Freedman LS, Graubard BI, Schatzkin A. Statistical validation of intermediate endpoints for chronic diseases. Statistics in Medicine 1992;11(2):167-78

Lin DY, Fleming TR, De Gruttola V. Estimating the proportion of treatment effect explained by a surrogate marker. Statistics in Medicine 1997;16(13):1515-27

Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Statistics in Medicine 1989;8(4):431-40

Temple R. A regulatory authority’s opinion about surrogate endpoints. In: Nimmo WS, Tucker GT, eds. Clinical Measurement in Drug Evaluation. New York, NY: John Wiley & Sons, Ltd; 1995: 3-22

Temple R. Are surrogate markers adequate to assess cardiovascular disease drugs? Journal of the American Medical Association 1999 25;282(8):790-5

The Cardiac Arrhythmia Suppression Trial Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. New England Journal of Medicine 1989;321(6):406-12

The Cardiac Arrhythmia Suppression Trial II Investigators. Effect of the anti-arrhythmic agent moricizine on survival after myocardial infarction. New England Journal of Medicine 1992;327(4):227-33