Guidance for Industry

Providing Clinical Evidence of

Effectiveness for Human Drug and

Biological Products

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)

May 1998

Clinical 6
Guidance for Industry

Providing Clinical Evidence of

Effectiveness for Human Drugs and

Biological Products

Additional copies are available from:

the Drug Information Branch (HFD-210),

Center for Drug Evaluation and Research (CDER),

5600 Fishers Lane, Rockville, MD 20857 (Tel) 301-827-4573

Internet at http://www.fda.gov/cder/guidance/index.htm

or

Office of Communication,

Training, and Manufacturers Assistance (HFM-40)

Center for Biologics Evaluation and Research (CBER)

1401 Rockville Pike, Rockville, MD 20852-1448

http://www.fda.gov/cber/guidelines.htm

(Fax) 888-CBERFAX or 301-827-3844

(Voice Information) 800-835-4709 or 301-827-1800

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)

May 1998

Clinical 6
TABLE OF CONTENTS

I. INTRODUCTION ..................................................... 1

II. QUANTITY OF EVIDENCE NECESSARY TO SUPPORT EFFECTIVENESS ..... 2

A. Legal Standards for Drug and Biological Products ....................... 2

B. Scientific Basis for the Legal Standard ................................ 4

C. The Quantity of Evidence to Support Effectiveness ...................... 6

III. DOCUMENTATION OF THE QUALITY OF EVIDENCE SUPPORTING AN

EFFECTIVENESS CLAIM ............................................. 16

A. Reliance on Less Than Usual Access to Clinical Data 

or Detailed Study Reports ........................................ 17

B. Reliance on Studies with Alternative, Less Intensive 

Quality Control/On-Site Monitoring ................................. 20
This guidance document represents the agency’s current thinking on providing clinical evidence of 1

effectiveness for human drug and biological products. It does not create or confer any rights for or on any person and

does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the

requirements of the applicable statute, regulations, or both. 

 As used in this guidance, the term efficacy refers to the findings in an adequate and well-controlled clinical 2

trial or the intent of conducting such a trial and the term effectiveness refers to the regulatory determination that is made

on the basis of clinical efficacy and other data. 

The Modernization Act requirements in Section 403 also apply to animal drugs and medical devices. These 3

products will be addressed in separate guidances. 

GUIDANCE FOR INDUSTRY1

Providing Clinical Evidence of 

Effectiveness for Human Drug and Biological Products 2

I. INTRODUCTION

This document is intended to provide guidance to applicants planning to file new drug

applications (NDAs), biologics license applications (BLAs), or applications for supplemental

indications on the evidence to be provided to demonstrate effectiveness.

This document is also intended to meet the requirements of subsections 403(b)(1) and (2) of the

Food and Drug Administration Modernization Act (the Modernization Act) of 1997 for human

drug and biological products (P.L. 105-115). Subsection 403(b)(1) directs FDA to provide 3

guidance on the circumstances in which published matter may be the basis for approval of a

supplemental application for a new indication. Section III of this guidance satisfies this

requirement by describing circumstances in which published matter may partially or entirely

support approval of a supplemental application. Subsection 403(b)(2) directs FDA to provide

guidance on data requirements that will avoid duplication of previously submitted data by

recognizing the availability of data previously submitted in support of an original application to

support approval of a supplemental application. Section II of this guidance satisfies this

requirement by describing a range of circumstances in which related existing data, whether from

an original application or other sources, may be used to support approval of a supplemental

application.

In 1962, Congress amended the Federal Food, Drug, and Cosmetic Act to add a requirement that,

to obtain marketing approval, manufacturers demonstrate the effectiveness of their products

through the conduct of adequate and well-controlled studies. Since then, the issue of what

constitutes sufficient evidence of effectiveness has been debated by the Agency, the scientific

community, industry, and others. Sound evidence of effectiveness is a crucial component of the

Agency’s benefit-risk assessment of a new product or use. At the same time, the demonstration

of effectiveness represents a major component of drug development time and cost; the amount
2

and nature of the evidence needed can therefore be an important determinant of when and

whether new therapies become available to the public. The public health is best served by the

development of sound evidence of effectiveness in an efficient manner.

The science and practice of drug development and clinical evaluation have evolved significantly

since the effectiveness requirement for drugs was established, and this evolution has implications

for the amount and type of data needed to support effectiveness in certain cases. As a result of

medical advances in the understanding of pathogenesis and disease staging, it is increasingly likely

that clinical studies of drugs will be more narrowly defined to focus, for example, on a more

specific disease stage or clinically distinct subpopulation. As a consequence, product indications

are often narrower, the universe of possible indications is larger, and data may be available from a

number of studies of a drug in closely related indications that bear on a determination of its

effectiveness for a new use. Similarly, there may be studies of a drug in different populations,

studies of a drug alone or in combination, and studies of different doses and dosage forms, all of

which may support a particular new use of a drug. At the same time, progress in clinical

evaluation and clinical pharmacology have resulted in more rigorously designed and conducted

clinical efficacy trials, which are ordinarily conducted at more than one clinical site. This added

rigor and scope has implications for a study’s reliability, generalizability, and capacity to

substantiate effectiveness.

Given this evolution, the Agency has determined that it would be appropriate to articulate its

current thinking concerning the quantitative and qualitative standards for demonstrating

effectiveness of drugs and biologics. FDA hopes that this guidance will enable sponsors to plan

drug development programs that are sufficient to establish effectiveness without being excessive

in scope. The guidance should also bring greater consistency and predictability to FDA’s

assessment of the clinical trial data needed to support drug effectiveness. 

Another major goal of this guidance is to encourage the submission of supplemental applications

to add new uses to the labeling of approved drugs. By articulating how it currently views the

quantity and quality of evidence necessary to support approval of a new use of a drug, FDA hopes

to illustrate that the submission of supplements for new uses need not be unduly burdensome. 

II. QUANTITY OF EVIDENCE NECESSARY TO SUPPORT EFFECTIVENESS

A. Legal Standards for Drug and Biological Products

Drugs: The effectiveness requirement for drug approval was added to the Federal Food,

Drug, and Cosmetic Act (the Act or the FDC Act) in 1962. Between passage of the Act

in 1938 and the 1962 amendments, drug manufacturers were required to show only that

their drugs were safe. The original impetus for the effectiveness requirement was

Congress's growing concern about the misleading and unsupported claims being made by

pharmaceutical companies about their drug products coupled with high drug prices. After

two years of hearings on these issues, Congress adopted the 1962 Drug Amendments,
 Section 505(d) of the Act uses the plural form in defining “substantial evidence” as “adequate and well- 4

controlled investigations, including clinical investigations.” See also use of “investigations” in section 505(b) of the

Act, which lists the contents of a new drug application.

3

which included a provision requiring manufacturers of drug products to establish a drug’s

effectiveness by "substantial evidence." Substantial evidence was defined in section

505(d) of the Act as “evidence consisting of adequate and well-controlled investigations,

including clinical investigations, by experts qualified by scientific training and experience

to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and

responsibly be concluded by such experts 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 labeling or proposed labeling thereof.”

Since the 1962 Amendments added this provision to the statute, discussions have ensued

regarding the quantity and quality of the evidence needed to establish effectiveness. With

regard to quantity, it has been FDA's position that Congress generally intended to require

at least two adequate and well-controlled studies, each convincing on its own, to establish

effectiveness. (See e.g., Final Decision on Benylin, 44 FR 51512, 518 (August 31, 1979);

Warner-Lambert Co. V. Heckler, 787 F. 2d 147 (3d Cir. 1986)). FDA’s position is based

on the language in the statute and the legislative history of the 1962 amendments. 4

Language in a Senate report suggested that the phrase "adequate and well-controlled

investigations" was designed not only to describe the quality of the required data but the

"quantum" of required evidence. (S. Rep. No. 1744, Part 2, 87th Cong. 2d Sess. 6

(1962))

Nevertheless, FDA has been flexible within the limits imposed by the congressional

scheme, broadly interpreting the statutory requirements to the extent possible where the

data on a particular drug were convincing. In some cases, FDA has relied on pertinent

information from other adequate and well-controlled studies of a drug, such as studies of

other doses and regimens, of other dosage forms, in other stages of disease, in other

populations, and of different endpoints, to support a single adequate and well-controlled

study demonstrating effectiveness of a new use. In these cases, although there is only one

study of the exact new use, there are, in fact, multiple studies supporting the new use, and

expert judgment could conclude that the studies together represent substantial evidence of

effectiveness. In other cases, FDA has relied on only a single adequate and wellcontrolled efficacy study to support approval — generally only in cases in which a single

multicenter study of excellent design provided highly reliable and statistically strong

evidence of an important clinical benefit, such as an effect on survival, and a confirmatory

study would have been difficult to conduct on ethical grounds. 

In section 115(a) of the Modernization Act, Congress amended section 505(d) of the Act

to make it clear that the Agency may consider “data from one adequate and wellcontrolled clinical investigation and confirmatory evidence” to constitute substantial
4

evidence if FDA determines that such data and evidence are sufficient to establish

effectiveness. In making this clarification, Congress confirmed FDA’s interpretation of the

statutory requirements for approval and acknowledged the Agency’s position that there

has been substantial progress in the science of drug development resulting in higher quality

clinical trial data. 

Biologics. Biological products are approved under authority of section 351 of the

Public Health Service Act (PHS Act) (42 U.S.C.§ 262). Under section 351, as in effect

since 1944, licenses for biologics have been issued only upon a showing that the products

meet standards designed to ensure the “continued safety, purity, and potency” of the

products. Potency has long been interpreted to include effectiveness (21 CFR 600.3(s)). 

In 1972, FDA initiated a review of the safety and effectiveness of all previously licensed

biologics. The Agency stated then that proof of effectiveness would consist of controlled

clinical investigations as defined in the provision for “adequate and well-controlled

studies” for new drugs (21 CFR 314.126), unless waived as not applicable to the

biological product or essential to the validity of the study when an alternative method is

adequate to substantiate effectiveness (21 CFR 601.25 (d) (2)). One such adequate

alternative was identified to be serological response data where a previously accepted

correlation with clinical effectiveness exists. As with nonbiological drug products, FDA

has approved biological products based on single, multicenter studies with strong results.

Although section 123(a) of the Modernization Act amended section 351 of the PHS Act

to make it clear that separate licenses are not required for biological products and the

establishments at which the products are made, the evidentiary standard for a biological

product was not changed: the product must be shown to be “safe, pure, and potent”

(section 351 (a)(2) of the PHS Act as amended). In the Modernization Act (section

123(f)) Congress also directed the agency to take measures to “minimize differences in the

review and approval” of products required to have approved BLAs under section 351 of

the PHS Act and products required to have approved NDAs under section 505(b)(1) of

the FDC Act. 

B. Scientific Basis for the Legal Standard

The usual requirement for more than one adequate and well-controlled investigation

reflects the need for independent substantiation of experimental results. A single clinical

experimental finding of efficacy, unsupported by other independent evidence, has not

usually been considered adequate scientific support for a conclusion of effectiveness. The

reasons for this include the following.

! Any clinical trial may be subject to unanticipated, undetected, systematic biases. 

These biases may operate despite the best intentions of sponsors and investigators,

and may lead to flawed conclusions. In addition, some investigators may bring

conscious biases to evaluations.
 p-value = 0.05, two-tailed, which implies an error rate in the efficacy (false positive) tail of 0.025 or one in 5

forty.

5

! The inherent variability in biological systems may produce a positive trial result by

chance alone. This possibility is acknowledged, and quantified to some extent, in

the statistical evaluation of the result of a single efficacy trial. It should be noted,

however, that hundreds of randomized clinical efficacy trials are conducted each

year with the intent of submitting favorable results to FDA. Even if all drugs tested

in such trials were ineffective, one would expect one in forty of those trials to

“demonstrate” efficacy by chance alone at conventional levels of statistical

significance. It is probable, therefore, that false positive findings (i.e., the chance 5

appearance of efficacy with an ineffective drug) will occur and be submitted to

FDA as evidence of effectiveness. Independent substantiation of a favorable result

protects against the possibility that a chance occurrence in a single study will lead

to an erroneous conclusion that a treatment is effective. 

! Results obtained in a single center may be dependent on site or investigator

specific factors (e.g., disease definition, concomitant treatment, diet). In such

cases, the results, although correct, may not be generalizable to the intended 

population. This possibility is the primary basis for emphasizing the need for

independence in substantiating studies. 

! Rarely, favorable efficacy results are the product of scientific fraud. 

Although there are statistical, methodologic, and other safeguards to address the identified

problems, they are often inadequate to address these problems in a single trial. 

Independent substantiation of experimental results addresses such problems by providing

consistency across more than one study, thus greatly reducing the possibility that a biased,

chance, site-specific, or fraudulent result will lead to an erroneous conclusion that a drug

is effective. 

The need for independent substantiation has often been referred to as the need for

replication of the finding. Replication may not be the best term, however, as it may imply

that precise repetition of the same experiment in other patients by other investigators is the

only means to substantiate a conclusion. Precise replication of a trial is only one of a

number of possible means of obtaining independent substantiation of a clinical finding and,

at times, can be less than optimal as it could leave the conclusions vulnerable to any

systematic biases inherent to the particular study design. Results that are obtained from

studies that are of different design and independent in execution, perhaps evaluating

different populations, endpoints, or dosage forms, may provide support for a conclusion of

effectiveness that is as convincing as, or more convincing than, a repetition of the same

study.
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C. The Quantity of Evidence to Support Effectiveness

The following three sections provide guidance on the quantity of evidence needed in

particular circumstances to establish substantial evidence of effectiveness. Section 1

addresses situations in which effectiveness of a new use may be extrapolated entirely from

existing efficacy studies. Section 2 addresses situations in which a single adequate and

well-controlled study of a specific new use can be supported by information from other

related adequate and well-controlled studies, such as studies in other phases of a disease,

in closely related diseases, of other conditions of use (different dose, duration of use,

regimen), of different dosage forms, or of different endpoints. Section 3 addresses

situations in which a single multicenter study, without supporting information from other

adequate and well-controlled studies, may provide evidence that a use is effective.

In each of these situations, it is assumed that any studies relied on to support effectiveness

meet the requirements for adequate and well-controlled studies in 21 CFR 314.126. It

should also be appreciated that reliance on a single study of a given use, whether alone or

with substantiation from related trial data, leaves little room for study imperfections or

contradictory (nonsupportive) information. In all cases, it is presumed that the single

study has been appropriately designed, that the possibility of bias due to baseline

imbalance, unblinding, post-hoc changes in analysis, or other factors is judged to be

minimal, and that the results reflect a clear prior hypothesis documented in the protocol. 

Moreover, a single favorable study among several similar attempts that failed to support a

finding of effectiveness would not constitute persuasive support for a product use unless

there were a strong argument for discounting the outcomes in the studies that failed to

show effectiveness (e.g., study obviously inadequately powered or lack of assay sensitivity

as demonstrated in a three-arm study by failure of the study to show efficacy of a known

active agent).

Whether to rely on a single study to support an effectiveness determination is not often an

issue in contemporary drug development. In most drug development situations, the need

to find an appropriate dose, to study patients of greater and lesser complexity or severity

of disease, to compare the drug to other therapy, to study an adequate number of patients

for safety purposes, and to otherwise know what needs to be known about a drug before it

is marketed will result in more than one adequate and well-controlled study upon which to

base an effectiveness determination. 

This guidance is not intended to provide a complete listing of the circumstances in which

existing efficacy data may provide independent substantiation of related claims; rather, it

provides examples of the reasoning that may be employed. The examples are applicable

whether the claim arises in the original filing of an NDA or BLA, or in a supplemental

application. 
7

1. Extrapolation from Existing Studies

In certain cases, effectiveness of an approved drug product for a new indication, or

effectiveness of a new product, may be adequately demonstrated without

additional adequate and well-controlled clinical efficacy trials. Ordinarily, this will

be because other types of data provide a way to apply the known effectiveness to a

new population or a different dose, regimen or dosage form. The following are

examples of situations in which effectiveness might be extrapolated from efficacy

data for another claim or product. 

a. Pediatric uses

The rule revising the Pediatric Use section of product labeling (21 CFR

201.57(f)(9)(iv)) makes allowance for inclusion of pediatric use

information in labeling without controlled clinical trials of the use in

children. In such cases, a sponsor must provide other information to

support pediatric use, and the Agency must conclude that the course of the

disease and the effects of the drug are sufficiently similar in the pediatric

and adult populations to permit extrapolation from adult efficacy data to

pediatric patients. Evidence that could support a conclusion of similar

disease course and similar drug effect in adult and pediatric populations

includes evidence of common pathophysiology and natural history of the

disease in the adult and pediatric populations, evidence of common drug

metabolism and similar concentration-response relationships in each

population, and experience with the drug, or other drugs in its therapeutic

class, in the disease or condition or related diseases or conditions. 

Examples in which pediatric use labeling information has been extrapolated

from adult efficacy data include ibuprofen for pain and loratidine for

seasonal allergic rhinitis. 

b. Bioequivalence

The effectiveness of alternative formulations and new dosage strengths may

be assessed on the basis of evidence of bioequivalence.

c. Modified-release dosage forms

In some cases, modified release dosage forms may be approved on the

basis of pharmacokinetic data linking the new dosage form to a previously

studied immediate-release dosage form. Because the pharmacokinetic

patterns of modified-release and immediate-release dosage forms are not

identical, it is generally important to have some understanding of the

relationship of blood concentration to response, including an understanding

of the time course of that relationship, to extrapolate the immediate-release
8

data to the modified-release dosage form.

d. Different doses, regimens, or dosage forms

Dose-response relationships are generally continuous such that information

about the effectiveness of one dose, dosage regimen, or dosage form is

relevant to the effectiveness of other doses, regimens, or dosage forms. 

Where blood levels and exposure are not very different, it may be possible

to conclude that a new dose, regimen, or dosage form is effective on the

basis of pharmacokinetic data alone. Even if blood levels are quite

different, if there is a well-understood relationship between blood

concentration and response, including an understanding of the time course

of that relationship, it may be possible to conclude that a new dose,

regimen, or dosage form is effective on the basis of pharmacokinetic data

without an additional clinical efficacy trial. In this situation,

pharmacokinetic data, together with the well-defined

pharmacokinetic/pharmacodynamic (PK/PD) relationship, are used to

translate the controlled trial results from one dose, regimen, or dosage

form to a new dose, regimen, or dosage form (See also section II.C.2.a).

2. Demonstration of Effectiveness by a Single Study of a New Use, with

Independent Substantiation From Related Study Data

The discussion that follows describes specific examples in which a single study of a

new use, with independent substantiation from study data in related uses, could

provide evidence of effectiveness. In these cases, the study in the new use and the

related studies support the conclusion that the drug has the effect it is purported to

have. Whether related studies are capable of substantiating a single 

study of a new use is a matter of judgment and depends on the quality and

outcomes of the studies and the degree of relatedness to the new use.

a. Different doses, regimens, or dosage forms

As discussed in Sections II.C.1.d, it may be possible to conclude that a new

dose, regimen, or dosage form is effective on the basis of pharmacokinetic

data without an additional clinical efficacy trial where blood levels and

exposure are not very different or, even if quite different, there is a wellunderstood relationship between blood concentration and response. Where

the relationship between blood concentration and response is not so well

understood and the pharmacokinetics of the new dose, regimen, or dosage

form differ from the previous one, clinical efficacy data will likely be

necessary to support effectiveness of a new regimen. In this case, a single

additional efficacy study should ordinarily be sufficient. For example, a

single controlled trial was needed to support the recent approval of a once
9

daily dose of risperidone because the once daily and twice daily regimens

had different pharmacokinetics and risperidone’s PK/PD relationship was

not well understood. 

b. Studies in other phases of the disease

In many cases, therapies that are effective in one phase of a disease are

effective in other disease phases, although the magnitude of the benefit and

benefit-to-risk relationship may differ in these other phases. For example,

if a drug is known to be effective in patients with a refractory stage of a

particular cancer, a single adequate and well-controlled study of the drug in

an earlier stage of the same tumor will generally be sufficient evidence of

effectiveness to support the new use.

c. Studies in other populations

Often, responses in subsets of a particular patient population are

qualitatively similar to those in the whole population. In most cases,

separate studies of effectiveness in demographic subsets are not needed

(see also discussion of the pediatric population in section II.C.1.a) 

However, where further studies are needed, a single study would ordinarily

suffice to support effectiveness in age, race, gender, concomitant disease,

or other subsets for a drug already shown to be generally effective in a

condition or to be effective in one population. For example, a single study

was sufficient to support tamoxifen use in breast cancer in males. 

d. Studies in combination or as monotherapy

For a drug known to be effective as monotherapy, a single adequate and

well-controlled study is usually sufficient to support effectiveness of the

drug when combined with other therapy (as part of a multidrug regimen or

in a fixed-dose combination). Similarly, known effectiveness of a drug as

part of a combination (i.e., its contribution to the effect of the combination

is known) would usually permit reliance on a single study of appropriate

design to support its use as monotherapy, or as part of a different

combination, for the same use. For example, a single study of a new

combination vaccine designed to demonstrate adequate immune response

will ordinarily provide sufficient evidence of effectiveness if the new

combination contains products or antigens already proven to be effective

alone or in other combinations. These situations are common for

oncologic and antihypertensive drugs, but occur elsewhere as well. 
See Division of Anti-Infective Drug Products: Points to Consider in the Clinical Development and Labeling 6

of Anti-Infective Drug Products, October 1992.

10

e. Studies in a closely related disease

Studies in etiologically or pathophysiologically related conditions, or

studies of a symptom common to several diseases (e.g., pain) can support

each other, allowing initial approval of several uses or allowing additional

claims based on a single adequate and well-controlled study. For example,

certain anti-coagulant or anti-platelet therapies could be approved for use

in two different settings based on individual studies in unstable

angina/acute coronary syndrome and in the postangioplasty state. Because

the endpoints studied and the theoretical basis for use of an anti-coagulant

or anti-platelet drug are similar, each study supports the other for each

claim. Similarly, single analgesic studies in several painful conditions

would ordinarily be sufficient to support either a general analgesic

indication or multiple specific indications. The recent approval of

lamotrigine for treatment of Lennox-Gastaut Syndrome (a rare, largely

pediatric, generalized seizure disorder) was based on a

single adequate and well-controlled trial, due in part to related data

showing efficacy of the drug in partial-onset seizures in adults.

f. Studies in less closely related diseases, but where the general

purpose of therapy is similar

Certain classes of drug therapy, such as antimicrobials and antineoplastics,

are appropriate interventions across a range of different diseases. For

therapies of this type, evidence of effectiveness in one disease could

provide independent substantiation of effectiveness in a quite different

disease. For example, it is possible to argue that evidence of effectiveness

of an antimicrobial in one infectious disease setting may support reliance on

a single study showing effectiveness in other settings where the causative

pathogens, characteristics of the site of infection that affect the disease

process (e.g., structure and immunology) and patient population are

similar. Similarly, for an oncologic drug, evidence of effectiveness in one 6

or more tumor types may support reliance on a single study showing

effectiveness against a different kind of tumor, especially if the tumor types

have a common biological origin.

g. Studies of different clinical endpoints

Demonstration of a beneficial effect in different studies on two different

clinically meaningful endpoints could cross-substantiate a claim for
11

effectiveness for each outcome. For example, the initial claim for

effectiveness of enalapril for heart failure was supported by one study

showing symptom improvement over several months and a second study

showing improved survival in a more severely ill population. The two

different findings, each from an adequate and well-controlled study, led to

the conclusion that enalapril was effective in both treating symptoms and

improving survival.

h. Pharmacologic/pathophysiologic endpoints

When the pathophysiology of a disease and the mechanism of action of a

therapy are very well understood, it may be possible to link specific

pharmacologic effects to a strong likelihood of clinical effectiveness. A

pharmacologic effect that is accepted as a validated surrogate endpoint can

support ordinary approval (e.g., blood pressure effects, cholesterollowering effects) and a pharmacologic effect that is considered reasonably

likely to predict clinical benefit can support accelerated approval under the

conditions described in 21 CFR 314 Subpart H and 21 CFR 601 Subpart E

(e.g., CD4 count and viral load effects to support effectiveness of anti-viral

drugs for HIV infection). When the pharmacologic effect is not considered

an acceptable effectiveness endpoint, but the linkage between it and the

clinical outcome is strong, not merely on theoretical grounds but based on

prior therapeutic experience or well-understood pathophysiology, a single

adequate and well-controlled study showing clinical efficacy can sometimes

be substantiated by persuasive data from a well-controlled study or studies

showing the related pharmacologic effect. 

For example, a single clearly positive trial can be sufficient to support

approval of a replacement therapy such as a coagulation factor, when it is

combined with clear evidence that the condition being treated is caused by

a deficiency of that factor. Demonstration of physical replacement of the

deficient factor or restoration of the missing physiologic activity provides

strong substantiation of the clinical effect. The corrective treatment of an

inborn error of metabolism could be viewed similarly. In the case of

preventive vaccines, one adequate and well-controlled clinical trial may be

supported by compelling animal challenge/protection models, human

serological data, passive antibody data, or pathogenesis information. The

more evidence there is linking effects on the pharmacologic endpoint to

improvement or prevention of the disease, the more persuasive the

argument for reliance on a single clinical efficacy study.

Note, however, that plausible beneficial pharmacologic effects have often

not correlated with clinical benefit, and, therefore, caution must be

observed in relying on a pharmacologic effect as contributing to evidence
12

of effectiveness. For example, pharmacologic effects such as arrhythmia

suppression by Type 1 antiarrhythmics and increased cardiac output by

phosphodiesterase inhibitors or beta adrenergic inotropes resulted in

increased mortality, rather than, as was expected, decreased sudden death

and improved outcome in heart failure. The reasons for the absence of an

expected correlation between pharmacologic and clinical effects are diverse

and can include an incompletely understood relationship between the

pharmacologic effect and the clinical benefit and the presence of other

pharmacologic effects attributable to a drug in addition to the effect being

measured and thought to be beneficial. Generally, the utility of

pharmacologic outcomes in providing independent substantiation will be

greatest where there is prior experience with the pharmacologic class. 

Even in this case, however, it is difficult to be certain that a pharmacologic

effect that correlates with a clinical benefit accounts for all the clinical

benefit or that other effects are not present and relevant. 

3. Evidence of Effectiveness from a Single Study

When the effectiveness requirement was originally implemented in 1962, the

prevailing efficacy study model was a single institution, single investigator,

relatively small trial with relatively loose blinding procedures, and little attention to

prospective study design and identification of outcomes and analyses. At present,

major clinical efficacy studies are typically multicentered, with clear, prospectively

determined clinical and statistical analytic criteria. These studies are less

vulnerable to certain biases, are often more generalizable, may achieve very

convincing statistical results, and can often be evaluated for internal consistency

across subgroups, centers, and multiple endpoints.

The added rigor and size of contemporary clinical trials have made it possible to

rely, in certain circumstances, on a single adequate and well-controlled study,

without independent substantiation from another controlled trial, as a sufficient

scientific and legal basis for approval. For example, the approval of timolol for

reduction of post-infarction mortality was based on a single, particularly persuasive

(low p-value), internally consistent, multicenter study that demonstrated a major

effect on mortality and reinfarction rate. For ethical reasons, the study was

considered unrepeatable. The Center for Biologics Evaluation and Research has

also approved a number of products based upon a single persuasive study. The

Agency provided a general statement in 1995 describing when a single, multicenter

study may suffice (60 FR 39181; August 1, 1995), but the Agency has not

comprehensively described the situations in which a single adequate and wellcontrolled study might be considered adequate support for an effectiveness claim,

or the characteristics of a single study that could make it adequate support for an

effectiveness claim.
13

Whether to rely on a single adequate and well-controlled study is inevitably a

matter of judgment. A conclusion based on two persuasive studies will always be

more secure than a conclusion based on a single, comparably persuasive study. 

For this reason, reliance on only a single study will generally be limited to

situations in which a trial has demonstrated a clinically meaningful effect on

mortality, irreversible morbidity, or prevention of a disease with potentially serious

outcome and confirmation of the result in a second trial would be practically or

ethically impossible. For example, sequential repetition of strongly positive trials

that demonstrated a decrease in post-infarction mortality, prevention of

osteoporotic fractures, or prevention of pertussis would present significant ethical

concerns. Repetition of positive trials showing only symptomatic benefit would

generally not present the same ethical concerns. 

The discussion that follows identifies the characteristics of a single adequate and

well-controlled study that could make the study adequate support for an

effectiveness claim. Although no one of these characteristics is necessarily

determinative, the presence of one or more in a study can contribute to a

conclusion that the study would be adequate to support an effectiveness claim.

a. Large multicenter study

In a large multicenter study in which (1) no single study site provided an

unusually large fraction of the patients and (2) no single investigator or site

was disproportionately responsible for the favorable effect seen, the study’s

internal consistency lessens concerns about lack of generalizability of the

finding or an inexplicable result attributable only to the practice of a single

investigator. If analysis shows that a single

site is largely responsible for the effect, the credibility of a multicenter

study is diminished.

b. Consistency across study subsets

Frequently, large trials have relatively broad entry criteria and the study

populations may be diverse with regard to important covariates such as

concomitant or prior therapy, disease stage, age, gender or race. Analysis

of the results of such trials for consistency across key patient subsets

addresses concerns about generalizability of findings to various populations

in a manner that may not be possible with smaller trials or trials with more

narrow entry criteria. For example, the timolol postinfarction study

randomized patients separately within three severity strata. The study

showed positive effects on survival in each stratum supporting a conclusion

that the drug’s utility was not limited to a particular disease stage (e.g.,

relatively low or high severity). 
14

c. Multiple studies in a single study

Properly designed factorial studies may be analyzed as a series of pairwise

comparisons, representing, within a single study, separate demonstrations

of activity of a drug as monotherapy and in combination with another drug. 

This model was successfully used in ISIS II, which showed that for patients

with a myocardial infarction both aspirin and streptokinase had favorable

effects on survival when used alone and when combined (aspirin alone and

streptokinase alone were each superior to placebo; aspirin and

streptokinase in combination were superior to aspirin alone and to

streptokinase alone). This represented two separate (but not completely

independent) demonstrations of the effectiveness of aspirin and

streptokinase. 

d. Multiple endpoints involving different events

In some cases, a single study will include several important, prospectively

identified primary or secondary endpoints, each of which represents a

beneficial, but different, effect. Where a study shows statistically

persuasive evidence of an effect on more than one of such endpoints, the

internal weight of evidence of the study is enhanced. For example, the

approval of beta-interferon (Betaseron) for prevention of exacerbations in

multiple sclerosis was based on a single multicenter study, at least partly

because there were both a decreased rate of exacerbations and a decrease

in MRI-demonstrated disease activity — two entirely different, but

logically related, endpoints.

Similarly, favorable effects on both death and nonfatal myocardial

infarctions in a lipid-lowering, postangioplasty, or postinfarction study

would, in effect, represent different, but consistent, demonstrations of

effectiveness, greatly reducing the possibility that a finding of reduced

mortality was a chance occurrence. For example, approval of abciximab as

adjunctive treatment for patients undergoing complicated angioplasty or

atherectomy was supported by a single study with a strong overall result on

the combined endpoint (decreased the combined total of deaths, new

infarctions, and need for urgent interventions) and statistically significant

effects in separate evaluations of two components of the combined

endpoint (decreased new infarctions and decreased need for urgent

interventions). In contrast, a beneficial effect on multiple endpoints that

evaluate essentially the same phenomenon and correlate strongly, such as

mood change on two different depression scales or SGOT and CPK levels

postinfarction, does not significantly enhance the internal weight of the

evidence from a single trial.
15

Although two consistent findings within a single study usually provide

reassurance that a positive treatment effect is not due to chance, they do

not protect against bias in study conduct or biased analyses. For example,

a treatment assignment not well balanced for important prognostic

variables could lead to an apparent effect on both endpoints. Thus, close

scrutiny of study design and conduct are critical to evaluating this type of

study. 

e. Statistically very persuasive finding

In a multicenter study, a very low p-value indicates that the result is highly

inconsistent with the null hypothesis of no treatment effect. In some

studies it is possible to detect nominally statistically significant results in

data from several centers, but, even where that is not possible, an overall

extreme result and significance level means that most study centers had

similar findings. For example, the thrombolysis trials of streptokinase (ISIS

II, GISSI) had very sizable treatment effects and very low p-values, greatly

adding to their persuasiveness. Preventive vaccines for infectious 

disease indications with a high efficacy rate (e.g., point estimate of efficacy

of 80% or higher and a reasonably narrow 95% confidence interval) have

been approved based on a single adequate and well-controlled trial.

4. Reliance on a Single, Multicenter Study — Caveats

While acknowledging the persuasiveness of a single, internally consistent, strong

multicenter study, it must be appreciated that even a strong result can represent an

isolated or biased result, especially if that study is the only study suggesting

efficacy among similar studies. Recently, the apparent highly favorable effect of

vesnarinone, an inotropic agent, in heart failure (60% reduction of mortality in

what appeared to be a well-designed, placebo-controlled, multicenter trial with an

extreme p-value) has proven to be unrepeatable. In an attempt to substantiate the

finding, the same dose of the drug that seemed lifesaving in the earlier study

significantly increased mortality (by 26%), and a lower dose also appeared to have

a detrimental effect on survival. Although the population in the second study was,

on the whole, a sicker population than in the first, the outcomes in similarly sick

patients in each study were inconsistent so this factor does not explain the

contradictory results. 

 

When considering whether to rely on a single multicenter trial, it is critical that the

possibility of an incorrect outcome be considered and that all the available data be

examined for their potential to either support or undercut reliance on a single

multicenter trial. In the case of vesnarinone, there were other data that were not

consistent with the dramatically favorable outcome in the multicenter study. These

data seemed to show an inverse dose-response relationship, showed no suggestion
16

of symptomatic benefit, and showed no effect on hemodynamic endpoints. These

inconsistencies led the Agency, with the advice

of its Cardio-Renal Advisory Committee, to refuse approval — a decision borne

out by the results of the subsequent study.

This example illustrates how inadequacies and inconsistencies in the data, such as

lack of pharmacologic rationale and lack of expected other effects accompanying a

critical outcome, can weaken the persuasiveness of a single trial. Although an

unexplained failure to substantiate the results of a favorable study in a second

controlled trial is not proof that the favorable study was in error — studies of

effective agents can fail to show efficacy for a variety of reasons — it is often

reason not to rely on the single favorable study. 

 

III. DOCUMENTATION OF THE QUALITY OF EVIDENCE SUPPORTING AN

EFFECTIVENESS CLAIM

 

When submitting the requisite quantity of data to support approval of a new product or new use

of an approved product, sponsors must also document that the studies were adequately designed

and conducted. Essential characteristics of adequate and well-controlled trials are described in

21 CFR 314.126. To demonstrate that a trial supporting an effectiveness claim is adequate and

well-controlled, extensive documentation of trial planning, protocols, conduct, and data handling

is usually submitted to the Agency, and detailed patient records are made available at the clinical

sites.

From a scientific standpoint, however, it is recognized that the extent of documentation necessary

depends on the particular study, the types of data involved, and the other evidence available to

support the claim. Therefore, the Agency is able to accept different levels of documentation of

data quality, as long as the adequacy of the scientific evidence can be assured. This section

discusses the factors that influence the extent of documentation needed, with particular emphasis

on studies evaluating new uses of approved drugs.

For the purposes of this section, the phrase documentation of the quality of evidence refers to (1)

the completeness of the documentation and (2) the ability to access the primary study data and the

original study-related records (e.g., subjects’ medical records, drug accountability records) for the

purposes of verifying the data submitted as evidence. These interrelated elements bear on a

determination of whether a study is adequate and well-controlled.

In practice, to achieve a high level of documentation, studies supporting claims are ordinarily

conducted in accordance with good clinical practices (GCPs). Sponsors routinely monitor all

clinical sites, and FDA routinely has access to the original clinical protocols, primary data, clinical

site source documents for on-site audits, and complete study reports.

 
17

However, situations often arise in which studies that evaluate the efficacy of a drug product lack

the full documentation described above (for example, full patient records may not be available) or

in which the study was conducted with less monitoring than is ordinarily seen in commercially

sponsored trials. Such situations are more common for supplemental indications because

postapproval studies are more likely to be conducted by parties other than the drug sponsor and

those parties may employ less extensive monitoring and data-gathering procedures than a sponsor. 

Under certain circumstances, it is possible for sponsors to rely on such studies to support

effectiveness claims, despite less than usual documentation or monitoring. Some of those

circumstances are described below.

A. Reliance on Less Than Usual Access to Clinical Data or Detailed Study

Reports

FDA’s access to primary data has proven to be important in many regulatory decisions.

There are also reasons to be skeptical of the conclusions of published reports of studies. 

Experience has shown that such study reports do not always contain a complete, or

entirely accurate, representation of study plans, conduct and outcomes. Outright fraud

(i.e., deliberate deception) is unusual. However, incompleteness, lack of clarity,

unmentioned deviation from prospectively planned analyses, or an inadequate description

of how critical endpoint judgments or assessments were made are common flaws. 

Typically, journal article peer reviewers only have access to a limited data set and

analyses, do not see the original protocol and amendments, may not know what happened

to study subjects that investigators determined to be non-evaluable, and thus may lack

sufficient information to detect critical omissions and problems. The utility of peer review

can also be affected by variability in the relevant experience and expertise of peer

reviewers. FDA's experiences with the Anturane Reinfarction Trial, as well as literature

reports of the efficacy of tacrine and the anti-sepsis HA-1A antibody, illustrate its

concerns with reliance on the published medical literature. 

Notwithstanding these concerns, the presence of some of the factors discussed below can

make it possible for FDA to rely on studies for which it has less than usual access to data

or detailed study reports to partially or entirely (the so-called paper filing) support an

effectiveness claim. FDA’s reliance on a literature report to support an effectiveness claim

is more likely if FDA can obtain additional critical study details. Section 1 below

describes additional information that, if available, would increase the likelihood that a

study could be relied on to support an effectiveness claim. Section 2 describes factors that

may make efficacy findings sufficiently persuasive to permit reliance on the published

literature alone. Note that the factors outlined in Section 2 are relevant to an assessment

of the reliability of literature reports generally, whether alone, or accompanied by other

important information as discussed in Section 1. 

1. Submission of Published Literature or Other Reports in Conjunction with

Other Important Information that Enhances the Reliability of the Data
18

If a sponsor wishes to rely on a study conducted by another party and cannot

obtain the primary data from the study, for most well-conducted studies it is

possible to obtain other important information, such as a protocol documenting the

prospective plans for the trial, records of trial conduct and procedures, patient data

listings for important variables, and documentation of the statistical analysis. FDA

has considerable experience evaluating large multicenter outcome studies

sponsored by U.S. and European government agencies (NIH, British Medical

Research Council) and private organizations (the ISIS studies, the SAVE study)

for which there was limited access to primary study data, but for which other

critical information was available. Providing as many as possible of the following

important pieces of information about a study, in conjunction with the published

report, can increase the likelihood that the study can be relied on to support an

effectiveness claim: 

a. The protocol used for the study, as well as any important protocol

amendments that were implemented during the study and their relation to

study accrual or randomization.

b. The prospective statistical analysis plan and any changes from the

original plan that occurred during or after the study, with particular note of

which analyses were performed pre- and post-unblinding.

c. Randomization codes and documented study entry dates for the

subjects.

d. Full accounting of all study subjects, including identification of any

subjects with on-treatment data who have been omitted from analysis and

the reasons for omissions, and an analysis of results using all subjects with

on-study data.

e. Electronic or paper record of each subject’s data for critical

variables and pertinent baseline characteristics. Where individual subject

responses are a critical variable (e.g., objective responses in cancer

patients, clinical cures and microbial eradications in infectious disease

patients, death from a particular cause), detailed bases for the assessment,

such as the case report, hospital records, and narratives, should be

provided when possible.

f. Where safety is a major issue, complete information for all deaths

and drop-outs due to toxicity. For postapproval supplemental uses,

however, there is generally less need for the results of lab tests or for

details of adverse event reports and, consequently, much more limited

documentation may be sufficient (e.g., only for unexpected deaths and

previously undescribed serious adverse effects). Exceptions to this
19

approach would include situations in which the population for the

supplemental use is so different that existing safety information has limited

application (e.g., thrombolysis in stroke patients versus myocardial

infarction patients) or where the new population presents serious safety

concerns (e.g., extension of a preventive vaccine indication from young

children to infants). 

2. Submission of Published Literature Reports Alone

The following factors increase the possibility of reliance on published reports alone

to support approval of a new product or new use:

a. Multiple studies conducted by different investigators where each of

the studies clearly has an adequate design and where the findings across

studies are consistent. 

b. A high level of detail in the published reports, including clear and

adequate descriptions of statistical plans, analytic methods (prospectively

determined), and study endpoints, and a full accounting of all enrolled

patients.

c. Clearly appropriate endpoints that can be objectively assessed and

are not dependent on investigator judgment (e.g., overall mortality, blood

pressure, or microbial eradication). Such endpoints are more readily

interpreted than more subjective endpoints such as cause-specific mortality

or relief of symptoms.

d. Robust results achieved by protocol-specified analyses that yield a

consistent conclusion of efficacy and do not require selected post hoc

analyses such as covariate adjustment, subsetting, or reduced data sets

(e.g., analysis of only responders or compliant patients, or of an "eligible"

or “evaluable” subset).

e. Conduct of studies by groups with properly documented operating

procedures and a history of implementing such procedures effectively.

There have been approvals based primarily or exclusively on published reports. 

Examples include the initial approval of secretin for evaluation of pancreatic

function and recent approvals of bleomycin and talc for malignant pleural effusion

and doxycycline for malaria. 
International Conference on Harmonisation Guidance for Industry E6, Good Clinical Practice: Consolidated 7

Guideline, April 1996. 

20

B. Reliance on Studies with Alternative, Less Intensive Quality Control/On-Site

Monitoring

Industry-sponsored studies typically use extensive on-site and central monitoring and

auditing procedures to assure data quality. Studies supported by other sponsors may

employ less stringent procedures and may use no on-site monitoring at all. An

International Conference on Harmonisation guideline on good clinical practices, recently 7

accepted internationally, emphasizes that the extent of monitoring in a trial should be

based on trial-specific factors (e.g., design, complexity, size, and type of study outcome

measures) and that different degrees of on-site monitoring can be appropriate. In recent

years, many credible and valuable studies conducted by government or independent study

groups, often with important mortality outcomes, had very little on-site monitoring. 

These studies have addressed quality control in other ways, such as by close control and

review of documentation and extensive guidance and planning efforts with investigators. 

There is a long history of reliance on such studies for initial approval of drugs as well as

for additional indications. Factors that influence whether studies with limited or no

monitoring may be relied on include the following:

1. The existence of a prospective plan to assure data quality.

2. Studies that have features that make them inherently less susceptible to

bias, such as those with relatively simple procedures, noncritical entry criteria, and

readily assessed outcomes.

3. The ability to sample critical data and make comparisons to supporting

records (e.g., hospital records).

4. Conduct of the study by a group with established operating procedures and

a history of implementing such procedures effectively.