Guidance for Industry
 
Cancer Drug and Biological Products 
 
Clinical Data in Marketing Applications
 
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) 

  October 2001 

Clinical Medical  Guidance for Industry
 
Cancer Drug and Biological Products 
 
Clinical Data in Marketing Applications
 
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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) 

  October  2001 

Clinical Medical 
 Table of Contents
 
I.  INTRODUCTION................................................................................................................ 1
 
II.  BACKGROUND .................................................................................................................. 1
 
A. General Regulations and Guidance................................................................................ 1
 
B. Data Requirements and Guidance.................................................................................. 2
 
C. General Considerations .................................................................................................. 2
 
III. 	 RECOMMENDATIONS FOR DATA COLLECTION .................................................... 3
 
A. Demographic Data........................................................................................................... 3
 
B. Medical History ............................................................................................................... 3
 
C. Cancer Diagnosis and Stage ........................................................................................... 4
 
D. Cancer Treatment History ............................................................................................. 4
 
E. Laboratory Tests............................................................................................................. 4
 
1. Baseline Tests .............................................................................................................. 5
 
2. Follow-Up Tests........................................................................................................... 5
 
3. Tests for Abnormalities............................................................................................... 5
 
F. Physical Examination....................................................................................................... 5
 
G. Efficacy Data and Tumor Measurements..................................................................... 5
 
H. Cancer Drug Dosing ....................................................................................................... 6
 
I.  Toxicity............................................................................................................................ 6
 
J.  Concomitant Medications ............................................................................................... 7
 
K.  Further Anticancer Therapy.......................................................................................... 8
 
IV. 	 DATA COLLECTION DURING THE DEVELOPMENT OF A CANCER DRUG: 

A HYPOTHETICAL EXAMPLE ....................................................................................... 8
  Guidance for Industry1
 
Cancer Drug and Biological Products 
 
Clinical Data in Marketing Applications
 
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.  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 statutes 
and regulations. 
I.   INTRODUCTION 
This document provides recommendations for sponsors on data collection for cancer clinical trials 
submitted to FDA to support marketing claims in new drug applications (NDAs), biologics license 
applications (BLAs), or supplemental applications for new indications. The data collected should 
be sufficient to evaluate the safety and effectiveness of the treatment but need not include other 
data. This guidance is also intended for private investigators, cooperative cancer groups, contract 
research organizations, and others designing and conducting studies that later can be used in a 
marketing application for an anticancer drug or biological product. 
Because of the complexity of clinical trials and different data that should be included in different 
situations, the precise data for each trial cannot be specified in a guidance document. This 
guidance provides general principles for data collection and submission. Sponsors are strongly 
encouraged to begin with these principles, develop specific proposals for data collection, and 
discuss their proposals with the FDA at meetings such as end-of-phase-2 meetings. Specifying 
these data should avoid the collection of unnecessary information, allowing resources to be 
directed toward studying important endpoints, while ensuring that the data collected and reported 
are adequate to support the study. 
II.   BACKGROUND 
A.   General Regulations and Guidance 
This guidance is one in a series of regulations and guidances outlining special 
considerations for evaluation of cancer treatment. In subpart E of the IND drug regulations 
(21 CFR 312 subpart E), special procedures are outlined to expedite the development, 
                                                
1 This guidance has been prepared by the Division of Oncology Drug Products in the Center for Drug Evaluation 
and Research (CDER) and the Oncology Branch of the Division of Clinical Trials Design and Analysis in the 
Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration (FDA). Input was also 
received from the Cancer Treatment Evaluation Program (CTEP) at the National Cancer Institute (NCI). 
1
  evaluation, and marketing of new therapies for life-threatening diseases, such as cancer. 
These procedures reflect the fact that physicians and patients are willing to accept greater 
risks or side effects from products that treat life-threatening illnesses in view of the 
possible benefits of therapy.  Subpart H of the NDA regulations (21 CFR 314 subpart H) 
and subpart E of the BLA regulations (21 CFR 601 subpart E) allow accelerated approval 
of new drugs that provide meaningful therapeutic benefit over existing treatment for serious 
or life-threatening illnesses, such as cancer, based on use of a surrogate endpoint that is 
reasonably likely to predict clinical benefit. Several initiatives were announced in a 1996 
initiative, Reinventing the Regulation of Cancer Drugs (National Performance Review, 
March 1996). In a guidance for industry on FDA Approval of New Cancer Treatment Uses 
for Marketed Drug and Biological Products (December 1998), FDA addressed the 
number and type of studies recommended to support a new oncologic use of a marketed 
drug or biologic product. 
B.   Data Requirements and Guidance 
The regulations at 21 CFR 314.50 require that supporting data be submitted with study 
reports from well-controlled trials but do not describe the amount and type of data that 
should be collected.  The specifics are sometimes determined in meetings with the review 
division prior to submission of the application, but often they reflect established practices. 
Submission of case report forms (CRFs) is required for patients who died or dropped out 
during the study because of an adverse event (22 CFR 314.50(f)(2)), and submission of 
individual patient safety data from all studies and individual efficacy data from controlled 
trials supporting effectiveness is required in case report tabulations (21 CFR 
314.50(f)(1)). These tabulations include the data on each patient from each study, except 
that the applicant can delete those tabulations the Agency agrees in advance are not 
pertinent to a review of the drug's safety or effectiveness. More recently, the Agency stated 
that case report tabulations can be submitted as electronic data sets.2 This is the preferred 
form of data submission for most oncology submissions, because data submitted 
electronically can generally be reviewed more rapidly and thoroughly. 
C.   General Considerations 
The Agency recognizes that the collection, quality control, and entry of data in a database 
is an expensive and time-consuming process. Some sponsors collect large amounts of 
information to be certain they have all the data the Agency can request. Noncommercial 
sponsors, such as cancer cooperative groups, often perform important multicenter studies 
that are later used by commercial sponsors for regulatory submissions. Representatives of 
these noncommercial sponsors have told FDA that commercial sponsors often encourage 
collection of much more data than the investigators would normally collect. In fact, many 
                                                
2
 SAS transport files are the preferred format for electronic data sets. Details on the recommended format of 
electronic data may be found in two guidances:  Providing Regulatory Submission in Electronic Format  NDAs 
(January 1999) and the companion guidance, Regulatory Submissions in Electronic Format  General 
Considerations (January 1999). 
2
  of these data may not be called for in a marketing application for cancer therapy.  It is 
possible that industry representatives are using data submission standards for marketing 
applications for less serious diseases or assuming standards that could be modified in 
many situations. We therefore encourage discussion of specific data requirements at end
of-phase-2 meetings to minimize unnecessary data collection. Ideally, the background 
documents for these meetings should include annotated CRFs indicating the data elements 
that will be collected for the database to facilitate this discussion. When the sponsor and 
FDA agree on the scope of data collection, the agreement should be reduced to writing and 
become part of the administrative record. 
To understand what data should be submitted, it is important to consider the entire drug 
development plan and the role the study will play in providing  data that demonstrate safety 
and effectiveness. Data submitted could vary, depending on factors such as: 
 	  The type of regulatory submission (new marketing application versus efficacy 
supplement using a drug with well-established adverse effects) 
 	  The similarity of the proposed new use of drug to already approved uses of drug 
 	  The population being studied (patients in the surgical adjuvant setting, patients getting 
first-line treatment, or patients with refractory disease) 
 	  The amount of available supplemental information from other sources on the safety of 
the drug, such as data from trials in a similar patient population 
III.   RECOMMENDATIONS FOR DATA COLLECTION 
Experience in reviewing oncology applications in CBER and CDER leads to the following 
recommendations for data collection for trials supporting marketing applications for oncologic 
drug or biologic products.  Data collection plans should be discussed with the Agency prior to 
their implementation. 
 
A.   Demographic Data 
 Demographic data on study participants should include date of birth, race, and sex. Each 
patient should be assigned an identifying number unique to the study. The date of 
randomization should be recorded. 
B.   Medical History 
 
 Information on major diseases that might affect function of critical organs (e.g., renal 
failure, hepatic insufficiency, heart disease) should be collected at baseline in a specified 
number of patients for each new population studied. Such data can be useful for 
determining whether certain diseases predispose patients to particular adverse reactions. 
Collection of additional historical data on diseases affecting specific organ systems can be 
appropriate for some drugs and should be specified in the protocol. 
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  C.   Cancer Diagnosis and Stage 
 
 Data that verify the diagnosis and stage of cancer treated in the study are important. Other 
details vary according to the specific protocol objectives and planned analyses. Important 
prognostic factors for the primary efficacy outcome should be collected. The protocol 
should specify all baseline data that should be included to adequately characterize the 
population, to evaluate the success of randomization in achieving balance of important 
prognostic factors, and to allow for consideration of adjusted analyses. 
D.   Cancer Treatment History 
Collection of data on previous adjuvant therapy is important because this can be prognostic 
for response to treatment. In the metastatic disease setting, it is helpful to note the 
identities of previous chemotherapies received, but other details (e.g., doses of drugs, 
response to treatment) are generally not necessary. Cancer treatment history should be 
recorded for all patients in all trials to the extent warranted to document that patients are 
eligible. For example, for the indication of second-line therapy, details of first-line 
treatment should be documented. Specific data on cancer treatment history should also be 
recorded when there are safety concerns (e.g., the history of anthracycline use will be 
important for a drug suspected of being cardiotoxic). 
Occasionally, approval of a new drug is sought under the accelerated approval regulations 
based on demonstration of tumor responses in patients with tumors refractory to all 
available therapies. Usually these applications involve single-arm studies rather than 
randomized comparative studies. In such cases, when the proposed indication is for 
treatment of refractory disease, the protocol should specifically define the meaning of 
refractory disease, and sufficient treatment history should be collected to document the 
refractory state of the patients entered. Depending on the protocol definition of refractory, 
this can include name of drug, dose of drug, dates of starting and stopping, best response to 
drug, date of progression, and/or reason for stopping drug. 
E.   Laboratory Tests 
Protocols should carefully detail the laboratory tests that should be conducted for full 
evaluation of the drug. All new NDAs or BLAs should contain a sample of patients for 
which a full laboratory evaluation has been carried out that would be a subset of all 
patients studied. (New efficacy supplements may call for less data depending on the 
specific circumstances and what is already known, as discussed in section C.) For the 
intensively monitored group, it is important to collect both scheduled and unscheduled 
laboratory data. The number of patients in this data sample should be determined in 
consultation with the reviewing oncology division at the FDA. This complete collection of 
laboratory data might be warranted, for example, in only one of the trials submitted or in a 
subset of patients from a large trial, assuming that a sufficient number of patients is studied 
and that relevant demographic groups are included. 
4
  1.   Baseline Tests 
Initial applications for marketing a new drug product should contain detailed data 
from a routine battery of laboratory tests collected at baseline in a specified 
number of patients. The number of patients should be determined in discussions 
with FDA during design of the protocol. In these patients, the baseline data are 
important to interpret subsequent abnormal values. Such baseline studies should 
include electrolytes, creatinine, hemoglobin, granulocyte count, platelet count, liver 
enzymes, alkaline phosphatase, bilirubin, and urinalysis. Additional baseline 
laboratory tests and other tests (such as EKG) that are specific to the drug being 
evaluated should be enumerated in the protocol. 
2.   Follow-Up Tests 
Similarly, in a specified number of patients for each drug application, routine 
follow-up tests should include hemoglobin, granulocyte count, platelet count, 
creatinine, liver enzymes, alkaline phosphatase, and bilirubin. If a drug has been 
adequately studied for toxicity in previous applications or other studies, the 
protocol can specify only those laboratory tests the investigator and the sponsor 
agree should be included to allow safe administration of the drug. Again, during 
design of the protocol, the sponsor should discuss with the Agency additional 
follow-up laboratory tests that can be indicated considering the known or suspected 
toxicities of the drug and the specific population to be studied. 
3.   Tests Corresponding to Severe Toxicities 
Scheduled and unscheduled laboratory tests for abnormalities, corresponding to 
grade 4-5 hematologic toxicities and grade 3-5 nonhematologic toxicities, should 
be collected and entered into the database for all regulatory settings. These data 
should also document whether the abnormality resolved and the date of resolution. 
F.   Physical Examination 
Other than body weight and performance status, which should be recorded at baseline, 
most significant findings noted on the prestudy physical exam will be reflected in the 
prestudy medical history, so such data need not be routinely collected. Physical findings 
associated with adverse reactions should be recorded with the toxicity data. 
G.  Efficacy Data and Tumor Measurements 
The schedule for collection of baseline and follow-up data for full evaluation of efficacy 
should be specified in the protocol. In addition to the investigators evaluation of efficacy, 
all raw data collected for evaluating efficacy should be recorded on the CRF and submitted 
to FDA. (Usually, actual tumor images need not be submitted, although tumor images 
should always be available at the investigative site for FDA audit. If there is a need for 
such images, the sponsor and the reviewing division should discuss this at end-of-phase-2 
5
  or presubmission meetings.)  These data allow FDA to examine the basis for efficacy 
assessments. When tumor response or progression are important regulatory endpoints, 
submission of tumor measurement data is critical. On the other hand, when the primary 
endpoint is survival and the sponsor anticipates demonstrating a survival advantage in two 
trials, evaluation of tumor response may not be critical for a determination of efficacy, and 
recording tumor measurements for the database may not always be important. When 
response and progression are evaluated, criteria for these endpoints should be detailed in 
the protocol, and data should be carefully collected at intervals specified in the protocol. 
The following are important considerations for tumor measurement data: 
 	  The protocol and the corresponding CRF should make clear which tumor evaluations 
are intended to be used to evaluate response and progression.  Missing data has been a 
chronic problem for FDA in evaluating these endpoints. 
 
 	  The CRF should document the target lesions identified during the baseline visit, or at 
least prior to treatment. Retrospective identification of such lesions would rarely be 
considered reliable. 
 
 	  Tumor lesions should be assigned a unique identifying letter or number.  This allows 
differentiating among multiple tumors occurring at one anatomic site and matching of 
tumors measured at baseline and tumors measured during follow-up. 
 
 	  It is desirable to have a mechanism that ensures complete collection of data at critical 
times during follow-up.  The CRF should ensure that all target lesions are assessed at 
each follow-up visit, and especially at the visits when response and progression are 
noted. For documenting tumor response, one approach is to add an evaluation form to 
display data from three time points:  the baseline visit, the visit first demonstrating 
tumor response, and the visit verifying that response. 
H.  Cancer Drug Dosing 
 
 Detailed data on dosing of anticancer drugs should be collected on all patients in each 
important study to adequately characterize the dose intensity of therapy in each study arm. 
It is important to demonstrate whether the proposed dose of the study drug is tolerated and 
whether an adequate dose of therapy was given in the control arm. The reasons for 
decreasing the dose should be documented. These data can be collected in the form of 
check boxes corresponding to the expected reasons for dose decrease, with a separate box 
for other, together with a space for comment. 
 
I. 	  Toxicity 
 
D  ata on National Cancer Institute (NCI) grade 4-5 hematologic toxicity and grade 3-5 
nonhematologic toxicity should always be collected. Marketing applications for a new 
regimen should also collect data on grade 1-2 nonhematologic toxicity and grade 1-3 
hematologic toxicity for an adequate number of patients from one or more studies or from a 
subset of patients in these studies. In studies including a large number of patients, it may be 
6
  sufficient to collect detailed data such as laboratory and grade 1-2 toxicity data from only a 
sample of patients studied. Complete data collection might be performed in only one of the 
principal trials or only in a sample of patients from a large trial, assuming that enough 
patients are studied and that relevant demographic groups are included.  FDA and the 
sponsor should determine at an end-of-phase-2 meeting the number of patients with 
complete data that should be included for a marketing application. In supplemental 
efficacy applications that propose a new use for an already marketed drug in a similar 
population, additional data on grade 1-2 nonhematologic toxicity and grade 1-3 
hematologic toxicity may not be important and may not need to be collected.  Data on 
serious adverse events associated with the use of a drug, or adverse events leading to 
discontinuation or dose reduction of treatment should always be collected. 
 
Toxicity duration should be recorded unless the toxicity of the regimen has been well 
characterized in previous applications. Depending on how well toxicity has been 
evaluated in previous studies, duration information may be needed only for a list of 
selected toxicities and/or only in a subset of patients in very large studies.  This should be 
discussed with the Agency during design of the protocol. 
Unless previous applications have fully characterized the toxicity of a regimen, 
documented toxicities should be followed until resolution.  Follow-up visits should record 
whether the toxicity has been reevaluated and/or has resolved. Similarly, unless previous 
applications have fully characterized the toxicity of a regimen, major actions taken should 
be recorded and categorized (e.g., treatment delayed, dose reduced, hospitalized). Data on 
investigator attribution of toxicity is not usually necessary for the marketing submission, 
because there is usually a randomized control arm for comparison. 
In some settings (e.g., for drugs anticipated to provide only marginal clinical benefit) 
quantifying the incidence of certain known toxicities may be important for making a risk-
benefit assessment. In such cases, preplanned data on selected toxicities, including grade 
1-2 toxicities, should be collected.  Such toxicities should be specifically identified in the 
protocol and individually reported in the CRF. 
J.   Concomitant Medications 
If data on concomitant medications are collected, the quality of these data will be 
improved by designing protocols to ask specific questions about specific concomitant 
medications. It is not necessary to record every drug use. For example, antihistamines, 
hypnotics, and analgesics are regularly used by patients and should be recorded only if they 
might reflect responses to drug toxicity or if there is concern about possible interactions. It 
may be sufficient to collect information only on certain classes of medications and record 
whether a particular class of drugs was used, omitting the name and dose of each drug. 
Data should be collected, however, for a list of targeted medications when such 
medications could affect assessment of efficacy (e.g., dexamethasone use in applications 
for treating brain tumors or narcotic use when reduction of pain is an important endpoint). 
7
  If protocol-specific information on targeted concomitant medications is important because 
of special efficacy or safety concerns, the specific medications (or classes of medications) 
should be identified in the protocol. CRFs should be designed to gather data on these 
specific medications or classes of medications to facilitate preplanned analyses. 
K.   Further Anticancer Therapy 
When survival is an important study endpoint, anticancer therapy given after study therapy 
should be recorded. This is especially true when the subsequent therapy represents 
crossover in a randomized study. Only the names of the drugs should generally be 
recorded, not doses or outcomes other than survival. This will allow an evaluation of the 
potential effect of subsequent therapy on survival. It is generally adequate to collect data 
only on the first regimen given after study therapy. Therapy beyond the first regimen is less 
likely to have a survival impact. 
IV.  	 DATA COLLECTION DURING THE DEVELOPMENT OF A CANCER DRUG: A 
HYPOTHETICAL EXAMPLE 
The following illustrates how data collection can vary at different stages of cancer drug 
development. It is a purely hypothetical example of development of Drug A, a new cancer drug. 
During the development of Drug A, comparisons were made to drugs B, C, and D in the treatment 
of cancers E, F, and G. 
Drug A was initially studied in small phase 1 studies. It was then evaluated in three single-arm 
phase 2 studies in patients with refractory E cancer, a cancer of elderly men.  Based on an 
impressive objective tumor response rate from treatment with Drug A, accelerated approval was 
granted under subpart H (21 CFR 314 subpart H) for treatment of refractory E cancer. 
Accelerated approval, with its reliance on a surrogate endpoint (response rate), was possible 
because no other therapies were available for treatment in this refractory setting. For this limited 
indication and for these patients with no other available therapy, the data from only 200 patients 
were sufficient for approval.  Critical to FDAs decision to approve Drug A were (1) the 
companys careful documentation of previous cancer treatments, (2) demonstration that tumors 
were refractory to available therapy, (3) tumor measurements verifying the claimed tumor 
response rate, and (4) collection of detailed safety data on all patients, including toxicity and/or 
adverse drug reactions of all severity. 
As part of its obligations resulting from subpart H approval, the sponsor then planned trials to 
support an indication of first-line therapy for metastatic E cancer. The sponsor performed two 
randomized studies of add-on design comparing Drug B, the standard first-line therapy for this 
cancer, to Drug A in combination with Drug B. Eight hundred patients were randomized in each 
study. The objective of the first study was to demonstrate that survival was improved by treatment 
with Drug A plus Drug B relative to treatment with Drug B alone. In the second study, which was 
a double-blind trial, reduction of symptoms was the primary endpoint, and tumor response was a 
supportive endpoint. FDA noted that most of the detailed data that should be included in the 
application for  first-line treatment of E cancer could be collected in the second study and that the 
8
  first study could be relatively simple, with efforts focused on collecting data on survival and 
serious toxicities.  Data on cancer treatment given after treatment with study drugs were also 
collected in the first study to assess the drugs potential effect on survival. Data on tumor 
response, concomitant medications, and routine laboratory values were not necessary for the first 
study. 
The primary endpoint of the second study was reduction of tumor-associated pain. Relevant 
efficacy data included pain scores, narcotic medications, and tumor measurements. Routine 
laboratory tests included tests described in section III.E.1 of this document. Data were collected 
on dosing of drugs A and B for all patients to allow calculation of relative dose-intensity on the 
two study arms. The CRF for all patients recorded starting dose, dose reductions, and reasons for 
dose reductions. Toxicity duration and all grades of toxicity were collected in this trial to allow a 
full assessment of the added toxicity resulting from Drug A. Analgesic medications were carefully 
documented on the CRF to assist in the evaluation of their potential effect on pain, the primary 
endpoint. Since there was concern about cardiac toxicity from phase 2 studies, cardiac 
medications were recorded for all patients, and serial left ventricular ejection fractions were 
determined in a sample of 100 patients taking Drug A. Survival data were collected for analysis 
as a secondary endpoint. 
The drug was approved for first-line therapy of metastatic E cancer. Later results from phase 2 
studies suggested activity in cancer F, a cancer of elderly men with no approved therapy.  The 
sponsor did two randomized controlled studies comparing Drug A to Drug C, an unapproved 
therapy for cancer F. Because the efficacy of Drug C had not been established, both trials were 
designed to show that treatment with Drug A produced a longer survival than treatment with Drug 
C.  Because Drug A had already been carefully evaluated in an elderly population, data collection 
for these studies focused on survival and serious toxicities.  At a meeting the Agency agreed that 
data on laboratory tests, tumor measurements, mild adverse events, concomitant medications, and 
further anticancer treatment were not necessary for this study. 
Data from phase 3 trials in Europe suggested the effectiveness of Drug A in the treatment of 
metastatic cancer G, a cancer of young and middle-aged women, but these data were unavailable 
for submission to FDA. The sponsor designed large randomized studies to evaluate efficacy of 
Drug A in the adjuvant setting (a setting where chemotherapy is given after surgical removal of all 
known tumor) for cancer G.  The large study was designed to include 4,000 patients to determine 
the disease-free survival and survival rates of Drug A versus Drug D, the standard approved 
adjuvant treatment with a well-characterized survival effect. Because comparative safety data 
were important and because the population was new and potentially tumor-free, detailed toxicity 
data of all grades and routine laboratory data (those specified in section III.E.1 of this document) 
were taken from an adequate sample of patients, the first 400 patients and the last 200 patients 
enrolled, with serious toxicity recorded for all patients. In addition, because the possibility of 
cardiac toxicity was still an issue, serial cardiac ejection fractions were determined in this sample 
of patients. An interim toxicity analysis was performed after evaluation of the first 400 patients. 
Efficacy data on tumor recurrence and survival were collected for all patients. Concomitant 
cardiac medications were collected for all patients, but other concomitant medications were not 
collected.  Specific data on dosing of the study drug and the control drug was recorded in all 
patients to allow calculation of relative dose-intensity on the two study arms and to allow 
9
  exploration for possible dose-related benefits and toxicity. The CRF for all patients recorded 
starting dose, dose reductions, and reasons for dose reductions. Serious toxicities and duration of 
toxicity were recorded in all patients in this trial. 
The above fictitious drug development history shows that data collection recommendations can 
depend on the stage of drug development, the indication sought, and clinical trial design.  Taking 
these factors into consideration can decrease collection of unnecessary data, allow sponsors to 
include more patients in clinical trials, and improve the quality of the data that are collected. 
Sponsors should evaluate their drug development plan, consider the principles outlined in this 
guidance, and develop a data collection proposal. Given the complexity of the drug development 
process for cancer drugs, we encourage sponsors to discuss their plans for data collection with the 
Agency prior to their implementation. 
10