# "ADDITIONAL STUDY-RELATED DOCUMENTS" TO BE SUBMITTED WITH CONSORTIA CHEMOPREVENTION PROTOCOLS

**[INSTRUCTIONS]{.underline}**

1.  A complete initial protocol submission includes the protocol, the
    informed consent and the "Additional Study-Related Documents" that
    are listed below. The "Additional Study-Related Documents" are not
    considered an integral part of the protocol, but rather serve as
    resource documents for important information regarding the conduct
    of the study. As such, these documents should not be referenced in
    the actual protocol.

> The "Additional Study-Related Documents" are:

A.  Recruitment and Retention Plan

B.  Pharmacokinetic and Biomarker Methods Development Report

C.  Case Report Forms (CRFs) and attachments

D.  Data Management Plan (DMP)

E.  Multi-Institutional Monitoring Plan (MIMP)

F.  Data and Safety Monitoring Plan (DSMP)

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2.  Each "Additional Study-Related Document" must be approved by DCP
    before a study can open to accrual. All documents should be
    submitted to the DCP PIO (<nci_dcp_pio@mail.nih.gov>) as directed in
    Items 3 and 4.

3.  The Recruitment and Retention Plan, Pharmacokinetic and Biomarker
    Methods Development Report, and Case Report Forms and attachments
    (documents A-C above) must be submitted with the initial protocol
    submission. Each study-related document should be submitted with
    subsequent protocol revisions until that study-related document is
    approved.

> *Once a study-related document is approved by DCP, it does not need to
> be resubmitted with subsequent protocol submissions.* If a later
> protocol change results in a change to an already approved document
> (e.g., a change to a CRF), then the corresponding study-related
> document must be resubmitted for approval.

4.  Standardized plans applicable to all studies within a given
    Consortium have been developed for the Data Management Plan, the
    Multi-Institutional Monitoring Plan, and the Data and Safety
    Monitoring Plan (documents D-F above). *Once a plan is approved by
    DCP, it does not need to be submitted with any protocol
    submissions.* Instead, the approved plan is referenced in the
    Protocol Submission Worksheet.

> Any attachments documenting protocol-specific additions or
> modifications to the approved plans should be submitted with the
> protocol for review and approval.

5.  Additional instructions for preparing and submitting the plans,
    reports and attachments are provided on the following pages.

DOCUMENT A:

RECRUITMENT, RETENTION AND ADHERENCE PLAN TEMPLATE

## 

Please see Recruitment, Retention and Adherence Plan Template at:

<http://dcp.cancer.gov/files/clinical-trials/rrap.doc>

**DOCUMENT B: PHARMACOKINETIC AND BIOMARKER METHODS DEVELOPMENT REPORT**

**Recommendations for Preparing the Required Summary Report**

**Introduction**

> Method validation studies demonstrate that a particular method is
> appropriate for its intended application. In validating a method, the
> sources of error are evaluated and objective operating values are
> established from the validation studies that control the method
> performance characteristics and minimize variability. The types of
> errors covered by validation are: 1) random errors which give rise to
> a spread of results around the average results. They are defined by
> the repeatability or reproducibility of the procedures, and 2)
> systematic errors which cause a bias in the results obtained, such
> that the average value observed is above or below the true value
> (sources of inaccuracy). The process of validating a method cannot be
> separated from the actual development of the method conditions,
> because the developer will not know whether the method conditions are
> acceptable until validation studies are performed. Therefore,
> development and validation are iterative until a method emerges with
> acceptable efficiency and timeliness.
>
> Not all methods can be validated by conventional means to provide
> standard measures of the method performance characteristics. Some
> newer technologies, particularly biomarker assays, have not yet
> evolved meaningful control parameters, or use samples with very high
> inter- and intra-subject variability. Additionally, analytical
> validation as a term in biomarker literature is often confused with
> measures of the clinical utility of the procedure as a diagnostic test
> (true positive rates/false positive rates, representative sampling for
> adequate disease description). These types of validation are not
> included in this guideline. The recommendations herein are intended
> primarily for quantitative analytical methods used for specific
> analytes in a specific biological matrix (blood, urine, saliva, etc.)
> under certain limitations. A glossary is included as Appendix I for
> clarity.
>
> All pharmacokinetic and biomarker laboratory techniques, assays, and
> procedures should be developed and validated according to this manual,
> and a short draft summary report prepared for NCI, DCP approval.
>
> The degree of validation effort is dependent on the novelty of the
> technology, sophistication of the analyst and phase of clinical
> development. Methods that are modifications of already published,
> validated procedures can be validated by as little as one intra-assay
> accuracy and precision determination at the new laboratory. In the
> early stages of drug development, it is usually not necessary to
> perform all of the various validation studies. Many researchers focus
> on sensitivity, specificity, linearity, accuracy, and precision
> studies for drugs in the preclinical through Phase II (preliminary
> efficacy) stages. The remaining validation studies are performed when
> the drug reaches the Phase III (efficacy) stage of development and the
> study agent has a higher probability of becoming a marketed product.
>
> These Methods Development and Validation Reports should be succinct
> and illustrative, but not exhaustive. Concise summaries and
> tabulations of descriptive statistics should be used whenever
> possible. The function of these reports is to provide enough details
> to facilitate method transfer, prepare a Standard Operating Procedure
> (SOP), and verify the method development and validation work was
> performed as expected. DCP does not intend to delay agent development
> or be burdensome, but has a legitimate and compelling need for the
> development and validation report. The attached Report template
> (Appendix II) should be modified as needed to provide a full or
> partial (modification of published procedure) validation, but should
> contain no more than 3 to 5 pages of information.

**Validation Studies**

> Analytical methods employed for the quantitative determination of
> analytes in biological samples play a pivotal role in the evaluation
> and interpretation of pharmacokinetic data. It is essential to employ
> well-characterized and fully validated analytical methods to yield
> reliable results which can be satisfactorily interpreted. Specific
> validation criteria are needed for methods intended for analysis of
> each analyte. Method validation includes all of the investigations
> undertaken to demonstrate that a particular method is reliable for the
> intended application.
>
> In general, the following items can be evaluated for the validation of
> a quantitative analytical method (see glossary, Appendix I):

-   Reference standards

-   Chemical stability of the analyte in the biological matrix during
    collection, processing, storage and analysis. This includes physical
    freeze/thaw cycling stability of an analyte.

-   Linearity: The range over which the procedure has been demonstrated
    to produce an accurate, reproducible, linear response.

-   Specificity/Selectivity: the degree to which the method can quantify
    the target analyte in the presence of potentially interfering
    materials, other analytes, or matrices

-   Sensitivity: Limit of detection (LOD), limit of quantitation (LOQ),
    and 95% confidence interval of standard curve.

-   Accuracy: The closeness of a determined value to the true value.

-   Precision: The variability of replicate determinations.

-   Ruggedness: Variability between operators, instrument, columns,
    *etc.*

-   System Suitability: start-up parameters and measures of instrument
    function to indicate the procedure may be successfully performed

The Draft Methods Development and Validation Report must contain all the
supporting graphical and computational (with example calculations, if
needed) documentation used in method development. A description of how
the data will be summarized and how missing data or outlier values will
be treated should be provided. Any modification of an analytical method
requires re-validation of the procedure and a new Summary Report to be
provided.

A suggested template for the Report is provided in Appendix II. It is
expected that the analyst has experience with analytical methodology and
familiarity with specific study conditions and terminology contained in
regulatory and analytical guidances \[1-6\] to perform the validation
studies listed above.

> **Recommendations for Pharmacokinetic Analytical Method Development
> and Validation Draft Summary Report**

**Reference standards**

Analysis of drugs and their metabolites in a biological matrix is
usually carried out using samples prepared with known reference
standards (spiked samples, QA samples, concentration standards,
calibration standards, etc.). Clearly, the purity and quality of the
reference standard used to prepare samples will affect the accuracy of
the study. For this reason, an authenticated analytical reference
standard of known identity and purity should be used to prepare
solutions of known concentrations. If possible, the reference standard
should be identical to the analyte. When this is not possible, a
different chemical form of the analyte (free base or acid, salt or
ester) of known purity may be used and a relative reference standard may
be established. A certificate of analysis (COA) for the reference
standards should be submitted in the report appendices.

The standard should be stored correctly and used within the established
use interval. A reference standard that is not obtained from an official
source (i.e., the United States Pharmacopeia) should be of the highest
purity that can be obtained by reasonable effort, and it should be
thoroughly characterized by appropriate methods to ensure its identity,
strength, quality, purity, and potency. The qualitative and quantitative
analytical procedures used to characterize a reference standard are
expected to be different from, and more extensive than, those used to
control the analyte.

**Method Development Summary**

The method report should including a title, report author and
affiliation(s), statement of purpose, scope of the method, a listing of
necessary reagents, test solutions and mixtures, and directions for
preparation, storage, and expiration dating of required materials. It
should also include a listing of the required instruments, instrumental
operating parameters and operating principles. Any health and safety
issues should be clearly stated with appropriate precautions stated for
the safe use of the method.

**Validation Studies**

Each step of the method should be investigated to encompass analyte,
matrix, and procedural variables. Whenever possible, the same biological
material as that of the intended samples should be used for validation.
The usual studies done to examine each of these issues are:

*Linearity*

The concentration range over which the analyte can be accurately
determined, based on evaluation of actual standard samples. A standard
curve should be prepared consisting of a blank sample (matrix sample
without internal standard), a zero sample (matrix sample processed with
internal standard), and samples at concentrations covering the expected
analyte concentration range, including the Limit of Quantitation (LOQ,
see Sensitivity). The regression line generated from this data should
contain the calculated point of intersection with the y axis and the
coefficient of regression (r^2^). The range of linearity (in
concentration terms) should be stated. The method is valid for
quantitation only within the linear concentration range of the standard
curve and for the specific analyte in the specific matrix.

The range of linearity is checked by replicate determinations at 5-6
concentrations of the reference standards (prepared in triplicates)
including samples at least 20 % below and 20% above the expected target
concentration of the specimen samples. A standard curve should be
generated for each analytical run for each analyte and the generated
curve for that run should be used to calculate the concentration of
analyte in unknown samples within that run. At the completion of
linearity studies, the appropriate concentration range for the standards
should be set for all subsequent studies.

*Specificity/selectivity*

> If possible, the specificity of the assay methodology should be
> established using at least 3 different possibly interfering analytes
> in six independent sources of the same type of biological matrix.
> There should be clear separation between the analyte and possible
> interferences.

*Sensitivity*

The limit of detection (LOD) is the lowest concentration of an analyte
that the method can reliably differentiate from background levels. The
lower limit of quantitation (LOQ) is the lowest concentration on the
standard curve that can be measured with acceptable accuracy, precision
and variability. The LOQ is determined by using at least five
independent standards and by determining the coefficient of variation
(CV) or percent Relative Standard Deviation (%RSD). The LOQ serves as
the lowest concentration of the standard curve.

*Accuracy and Precision*

> Determination of accuracy (% recovery) and precision can be
> accomplished by analysis of replicate sets of analyte samples of known
> concentrations from an equivalent biological matrix, using a minimum
> of five determinations per concentration. Specific criteria must be
> set for accuracy and precision over the range of the standard curve.
> At least three concentrations representing the entire range of the
> calibration curve should be studied---one near the lower LOQ, one near
> the center, and one near the upper boundary of the standard curve.

*System Suitability*

> Quality-control (QC) samples are matrix spiked with analyte. QC
> samples in duplicate at three concentrations (one near the LOQ, one in
> midrange, and one approaching the high end of the range) should be
> incorporated into each run. Results of QC samples should be within the
> validated performance values to provide a basis for accepting or
> rejecting the run. Typically, there should be 2 or more suitability
> parameters.

*Stability studies*

> Stability studies should use analyte in the specific matrix of the
> assay method. Variability of the matrix due to its physical state and
> the influence of freeze-thaw cycles on analyte and matrix integrity
> should be examined. The analyte and matrix should be demonstrated to
> be chemically and physically stable for a period of time equal to the
> initial sampling to the final analytical data output.

**Biomarkers Methods Development and Validation**

> For biomarker assays in general, the recommendations above (when
> possible) should be followed. Though many types of assays exist, only
> immunohistochemistry is covered by this Guidance. Immunohistochemistry
> is used to characterize a wide range of biomarkers. This technique is
> not linear; it saturates at higher intensities of staining, and is
> accentuated at the lower intensities of staining. A semi-quantitative
> index has been developed \[7\] incorporating both the staining
> intensity of individual cells and the percent of cells staining at
> each intensity.
>
> The following parameters are essential to ensure the acceptability of
> the results reported from this technique:

-   stability of the antigen in the biological sample (*e.g*., tissue
    biopsy) under study storage conditions,

-   sensitivity of the assay,

-   specificity of the antibody, and

-   intra- and inter-assay reproducibility.

    **Recommendations for Immunohistochemical Methods Validation**

    *Procedure*

> A detailed description and protocol of analytical method and scoring
> methodology (standard operating procedure) should be outlined,
> including a statement of the method operation principles and a listing
> of necessary reagents, test solutions and mixtures with directions for
> their preparation, storage conditions and usable shelf life specified.
> It should also include a listing of the required instruments and
> instrumental parameters, which contains sufficient information to
> allow repetition of the method by a qualified investigator. If a
> detailed method has been published previously, it is sufficient to
> cite the publication and summarize the key operational principles
> (e.g., source and dilution of antibody used, conditions for the assay
> such as overnight binding to primary antibody, use of automatic
> stainer, type of chromogen, etc.).
>
> Stability of the antigen in the biological sample is determined under
> identical study storage conditions (*e.g*., temperature, duration) and
> sample conditions (*e.g*., frozen tissue biopsy, paraffin-embedded
> tissue).
>
> Sensitivity of the assay should be determined using at least three
> sequential antibody dilutions. Specificity of the assay should be
> determined by using at least two different antibodies to the same
> antigen, if feasible. It is also important to perform the assay in the
> absence of antibody in order to determine nonspecific staining.
> Intra-assay reproducibility should be determined by staining different
> serial sections from the same biological sample and/or by showing that
> different antibodies to the same antigen give similar patterns and
> intensities of staining.
>
> Inter-assay reproducibility should be determined by staining the same
> tissue sections for the same antibodies during multiple different
> assay runs on different days. Several parameters can influence
> reproducibility, but variability in antigen expression within the
> tissue can be minimized by using adjacent sections. Day-to-day
> variability due to differences in staining procedure and conditions
> can be minimized by using an automated stainer. Variability introduced
> by the evaluator can be minimized by averaging the scores of two or
> more observers.

**REFERENCES**

1.  Shah, V.P., Midha, K.K., Dighe, S., McGilveray, I.J., Skelly, J.P.,
    Yacobi, A., Layloff, T., Viswanathan, C.T., Cook, C.E., McDowall,
    R.D., Pittman, K.A., and Spector, S. Analytical methods validation:
    Bioavailability, bioequivalence and pharmacokinetic studies. *Pharm.
    Res.* [9]{.underline}: 588--592, 1992.

2.  AOAC International, "Requirements for Single Laboratory Validation
    of Chemical Methods," 2002, http://www.aoac.org

3.  FDA, "Guidance for Industry: Analytical Procedures and Methods
    Validation"Chemistry, Manufacturing, and Controls Documentation,
    8/2000. http://www.fda.gov/cder/guidance

4.  FDA, "Guidance for Industry: Bioanalytical Method Validation".
    http://www.fda.gov/cder/guidance

5.  "A Practical Guide to Analytical Method Validation", Mark Green,
    *Analytical Chemistry* **1996**, (68) 305A-309A

6.  International Conference on Harmonization (ICH), "Q2A and Q2B:
    Validation of Analytical Procedures: Text and Methodology".
    <http://www.ich.org/cache/compo/276-254-1.html>

7.  Myers, R.B., Lampejo, O., Herrera, G.A., Srivastava, S.,
    Oelschlager, D., Brown, D.A., Waterbor, J.W., Grizzle, W.E. TGF
    expression is a relatively late event in the progression of
    prostatic adenocarcinoma. *J. Urol. Pathol.* [3]{.underline}:
    195--203, 1995

    **PHARMACOKINETIC AND BIOMARKER METHODS DEVELOPMENT REPORT:**

    **APPENDIX 1. GLOSSARY**

+-----------------------------------------------------------------------+
| **Accuracy:** The degree of closeness of the determined value to the  |
| nominal or known true value under prescribed conditions. This is      |
| sometimes termed *trueness*.                                          |
+-----------------------------------------------------------------------+
| **Analyte:** A specific chemical moiety being measured, which can be  |
| intact drug, biomolecule or its derivative, metabolite, and/or        |
| degradation product in a biologic matrix.                             |
+-----------------------------------------------------------------------+
| **Analytical run (or batch):** A complete set of analytical and study |
| samples with appropriate number of standards and QCs for their        |
| validation. Several runs (or batches) may be completed in one day, or |
| one run (or batch) may take several days to complete.                 |
+-----------------------------------------------------------------------+
| **Biological marker (biomarker):**  A characteristic that is          |
| objectively measured and evaluated as an indicator of normal biologic |
| processes, pathogenic processes, or pharmacologic responses to a      |
| therapeutic intervention.                                             |
+-----------------------------------------------------------------------+
| **Biological matrix:** A discrete material of biological origin that  |
| can be sampled and processed in a reproducible manner. Examples are   |
| blood, serum, plasma, urine, feces, saliva, sputum, and various       |
| discrete tissues.                                                     |
+-----------------------------------------------------------------------+
| **Blank:** A sample of a biological matrix to which no analytes have  |
| been added that is used to assess the specificity of the              |
| bioanalytical method.                                                 |
+-----------------------------------------------------------------------+
| **Calibration standard:** A biological matrix to which a known amount |
| of analyte has been added or *spiked*. Calibration standards are used |
| to construct calibration curves from which the concentrations of      |
| analytes in QCs and in unknown study samples are determined.          |
+-----------------------------------------------------------------------+
| **Internal standard:** Test compound(s) (e.g. structurally similar    |
| analog, stable labeled compound) added to both calibration standards  |
| and samples at known and constant concentration to facilitate         |
| quantification of the target analyte(s).                              |
+-----------------------------------------------------------------------+
| **Known valid biomarker:**  A biomarker that is measured in an        |
| analytical test system with well-established performance              |
| characteristics and for which there is widespread agreement in the    |
| medical or scientific community about the physiologic, toxicologic,   |
| pharmacologic, or clinical significance of the results                |
+-----------------------------------------------------------------------+
| **Limit of detection (LOD):** The lowest concentration of an analyte  |
| that the bioanalytical procedure can reliably differentiate from      |
| background noise. Typically, the LOD is three times the mean peak     |
| noise level.                                                          |
+-----------------------------------------------------------------------+
| **Limit of quantification (LLOQ):** The lowest amount of an analyte   |
| in a sample that can be quantitatively determined with suitable       |
| precision and accuracy. If not determined experimentally, the         |
| quantitation limit is often calculated as the analyte concentration   |
| that gives a Signal/Noise ratio of ten.                               |
+-----------------------------------------------------------------------+
| **Matrix effect:** The direct or indirect alteration or interference  |
| in response due to the presence of unintended analytes (for analysis) |
| or other interfering substances in the sample.                        |
+-----------------------------------------------------------------------+
| **Method:** A comprehensive description of all procedures used in     |
| sample analysis.                                                      |
+-----------------------------------------------------------------------+
| **Precision:** The closeness of agreement (*degree of scatter*)       |
| between a series of measurements obtained from multiple sampling of   |
| the same homogenous sample under the prescribed conditions.           |
+-----------------------------------------------------------------------+
| **Probable valid biomarker:**  A biomarker that is measured in an     |
| analytical test system with well-established performance              |
| characteristics and for which there is a scientific framework or body |
| of evidence that appears to elucidate the physiologic, toxicologic,   |
| pharmacologic, or clinical significance of the test results.          |
+-----------------------------------------------------------------------+
| **Processed:** The final extract (prior to instrumental analysis) of  |
| a sample that has been subjected to various manipulations (e.g.,      |
| extraction, dilution, concentration).                                 |
+-----------------------------------------------------------------------+
| **Quality control sample (QC):** A spiked sample used to monitor the  |
| performance of a bioanalytical method and to assess the integrity and |
| validity of the results of the unknown samples analyzed in an         |
| individual batch.                                                     |
+-----------------------------------------------------------------------+
| **Quantification range:** The range of concentration, including upper |
| and lower limits and LLOQ, which can be reliably and reproducibly     |
| quantified with accuracy and precision through the use of a           |
| concentration-response relationship.                                  |
+-----------------------------------------------------------------------+
| **Recovery:** The extraction efficiency of an analytical process,     |
| reported as a percentage of the known amount of an analyte carried    |
| through the sample extraction and processing steps of the method.     |
+-----------------------------------------------------------------------+
| **Reproducibility:** The precision between two laboratories. It also  |
| represents precision of the method under the same operating           |
| conditions over a short period of time.                               |
+-----------------------------------------------------------------------+
| **Sample:** A generic term encompassing controls, blanks, unknowns,   |
| and processed samples, as described below:                            |
+-----------------------------------------------------------------------+
| **Selectivity:** The ability of the bioanalytical method to measure   |
| and differentiate the analytes in the presence of components that may |
| be expected to be present. These could include metabolites,           |
| impurities, degradants, or matrix components.                         |
+-----------------------------------------------------------------------+
| **Stability:** The chemical stability of an analyte in a given matrix |
| under specific conditions for given time intervals.                   |
+-----------------------------------------------------------------------+
| **Standard curve:** The relationship between the experimental         |
| response value and the analytical concentration (also called a        |
| calibration curve).                                                   |
+-----------------------------------------------------------------------+
| **System suitability:** Determination of instrument performance       |
| (e.g., sensitivity and chromatographic retention) by analysis of a    |
| reference standard prior to running the analytical batch.             |
+-----------------------------------------------------------------------+
| **Unknown:** A biological sample that is the subject of the analysis. |
+-----------------------------------------------------------------------+
| **Valid biomarker:**  A biomarker that is measured in an analytical   |
| test system with well-established performance characteristics and for |
| which there is an established scientific framework or body of         |
| evidence that elucidates the physiologic, toxicologic, pharmacologic, |
| or clinical significance of the test results.  The classification of  |
| biomarkers is context specific.  Likewise, validation of a biomarker  |
| is context-specific and the criteria for validation will vary with    |
| the intended use of the biomarker.  The clinical utility (e.g.,       |
| predict toxicity, effectiveness or dosing) and use of                 |
| epidemiology/population data (e.g., strength of genotype-phenotype    |
| associations) are examples of approaches that can be used to          |
| determine the specific context and the necessary criteria for         |
| validation.                                                           |
+-----------------------------------------------------------------------+
| **Validation:**                                                       |
|                                                                       |
| -   Full validation: Establishment of all validation parameters to    |
|     apply to sample analysis for the bioanalytical method for each    |
|     analyte.                                                          |
|                                                                       |
| -   Partial validation: Modification of validated bioanalytical       |
|     methods that do not necessarily call for full revalidation.       |
|                                                                       |
| -   Cross-validation: Comparison of validation parameters of two      |
|     bioanalytical methods.                                            |
+-----------------------------------------------------------------------+

**PHARMACOKINETIC AND BIOMARKER METHODS DEVELOPMENT REPORT:**

**APPENDIX II. Suggested Report Template**

1\. Title:

> Ex: "Single Laboratory Validation of the Determination of \[Analyte\]
> in \[Matrix\] by \[Nature of Determination\]" Author, Laboratory
> Affiliation, Other participants

2 . Method Summary, Applicability of Method, Scope and Limitations

3\. Analytes

Common and chemical name

> CAS Registry Number or Merck Index Number
>
> Matrices used
>
> In presence of:
>
> In absence of:
>
> Safety statements and precautions applicable to product

4\. Preparation of sample (following sections as applicable)

> Extraction
>
> Purification
>
> Separation
>
> Measurement
>
> Alternatives
>
> Interferences

5\. Reagents

> Reference standards, identity, source, purity,
>
> Calibration standard solutions,
>
> Preparation, storage, stability
>
> Solvents (special requirements)
>
> Buffers

6\. Apparatus (equipment usually present in a laboratory need not be
listed); provide source, internet address, and catalog numbers of
special items)

> Analytical equipment
>
> Operating conditions
>
> System suitability conditions and acceptance criteria for equipment
>
> Expected suitability parameters
>
> Temperature controlled equipment
>
> Separation equipment (centrifuges, filters)

7\. Calibration Range, number and distribution of standards, replicates.

8\. Procedure

> List all steps of method, including any homogenization of the test
> sample.
>
> Critical points
>
> Stopping points

9\. Calculation Formulae, symbols, significant figures, example
calculations, data treatment, outliers, out of specification results and
their investigation.

10\. Controls

11\. Results of Validation

> Analytes measured and properties utilized
>
> Matrices tested
>
> Reference standard, source, identity, purity
>
> Performance data
>
> Recovery of control material
>
> Repeatability (by replication of entire procedure on same test sample)
>
> Linearity
>
> Limit of detection
>
> Limit of quantitation

12\. Stability data of analyte in biological matrix, analytical
solutions and biological matrix alone. At least 3 freeze/thaw cycles

Appendices (Chromatograms, definitions, glossary, etc.)

**DOCUMENT C:** **CASE REPORT FORMS**

1.  The Case Report Form (CRF) package consists of four parts:

    a.  CRF Attachment #1: Schedule of Forms

> A protocol-specific CRF completion schedule describing which CRFs will
> be completed at each clinical event in a logical order. The CRF
> completion schedule also indicates which CRFs will be completed on
> paper as well as in Oracle Clinical Remote Data Capture (OC-RDC).

b.  CRF Attachment #2: Case Report Forms for the Protocol

> The set of protocol-specific CRFs that are developed from the standard
> set of DCP Chemoprevention CRF Templates using Common Data Elements
> (CDEs). The protocol-specific CRFs designed to collect data outside of
> RDC will also be included in this set. The Consortium will also assess
> any special data collection requirements for pharmaceutical
> collaborators and/or the local institution. CRF and data collection
> issues will be addressed with DCP during protocol development.

c.  CRF Attachment #3: Coding Conventions

> A list of coding conventions that provide information for the
> completion of protocol-specific CRFs and offer guidance to Consortium
> staff for responding to specific data fields. A brief description and
> the intended purpose for CRFs created outside the standard DCP CRF
> template set will also be provided in this attachment.

d.  CRF Attachment #4: Data Management Staff Lists

> [Section 1]{.underline} is a list of key data management staff for a
> specific protocol and their qualifications.
>
> [Section 2]{.underline} is a list of all data management staff and
> their assigned roles in data management for the protocol. RDC accounts
> for the protocol will be generated only for the staff listed in this
> section.

2.  Sample formats and templates for Attachments #1, #3 and #4 are
    included as part of this document.

3.  Further instructions and the CRF templates for use in developing
    Attachment #2 can be found in the Clinical Trials Resource link:

> <http://cancer.gov/prevention/CTR/CONSORTIA/Step1-ProtoDev.html#casereport>

**CRF Attachment #1**

**SCHEDULE OF FORMS**

  ------------------- --------- ---------- ---------- --------- -------- -------
  **Form**            **To be   **Study                                  
                      entered   Events**                                 
                      into                                               
                      RDC**                                              

                                                                         

                                                                         

                                                                         

                                                                         

                                                                         

                                                                         

                                                                         

                                                                         

                                                                         

                                                                         

                                                                         

                                                                         
  ------------------- --------- ---------- ---------- --------- -------- -------

**CRF Attachment #3**

**Coding Conventions**

*List the coding conventions that provide information for the completion
of the protocol-specific CRFs.*

*Include a brief description and the intended purpose for those CRFs
created outside the standard DCP CRF template set as appropriate.*

**CRF Attachment #4**

**SECTION 1: List of Key Data Management Staff and Qualifications**

*Provide a summary of key data management staff and his/her
qualifications in paragraph format.*

*Include name, credentials, organization and qualifications.*

**CRF Attachment #4**

**SECTION 2: List of All Data Management Staff and Assigned Role**

*Complete the table below for all DM Staff involved in the data
management of the protocol.*

*RDC accounts for a protocol will be generated only for the staff
included in this document.*

  ----------------------------------------------------------------------------------------------------------------
  **Organization**   **Last   **First   **Title**   **Role/Task\***   **Phone    **Email Address**  **Comments**
                     Name**   Name**                                  Number**                      
  ------------------ -------- --------- ----------- ----------------- ---------- ------------------ --------------
  []{.mark}                                                                                         

                                                                                                    

                                                                                                    

                                                                                                    

                                                                                                    

                                                                                                    

                                                                                                    
  ----------------------------------------------------------------------------------------------------------------

**DOCUMENT D: DATA MANAGEMENT PLAN (DMP)**

1.  The Data Management Plan (DMP) consists of two parts:

    a.  The Master DMP: This document applies to all studies performed
        within a Consortium. It must be approved by DCP prior to
        subsequent protocol approval. The approved Master DMP is kept on
        file at DCP, the Consortium Lead Organization, and the
        Participating Organizations.

    b.  DMP Attachment #1: Master DMP Addendum

> This attachment describes any additions to the Master DMP that [apply
> only to the specific protocol]{.underline}. This attachment should be
> submitted only when extenuating circumstances require an addendum to
> the Master DMP for the one specific protocol.

2.  When submitting a protocol for review (first or subsequent
    submissions), the following guidelines are to be followed:

    a.  The approved Master DMP does not need to be submitted since it
        is on file at DCP. It should be referenced in the Protocol
        Submission Worksheet only.

    b.  DMP Attachment #1 should only be submitted when extenuating
        circumstances require an addendum to the Master DMP that only
        applies to the particular study.

3.  If changes to the Master DMP that are applicable to all studies
    performed by a Consortium are required, the revised DMP must be
    submitted to DCP for review and approval.

4.  The DMP template can be accessed through this link:\
    <http://dcp.cancer.gov/files/clinical-trials/DMP-Template.doc>

    **DMP Attachment #1**

**Master DMP Addendum**

*This attachment documents those data management processes that apply
only to a specific protocol and are not addressed in the approved Master
DMP. This attachment should only be submitted when extenuating
circumstances require a protocol-specific addition to the Master DMP.*

**DOCUMENT E:** **MULTI-INSTITUTIONAL MONITORING PLAN (MIMP)**

1.  The Multi-Institutional Monitoring Plan (MIMP)) consists of two
    parts:

    a.  The Master MIMP: This document applies to all studies performed
        within a Consortium. It must be approved by DCP prior to
        subsequent protocol approval. The approved Master MIMP is kept
        on file at DCP, the Consortium Lead Organization, and the
        Participating Organizations.

    b.  MIMP Attachment #1: Master MIMP Addendum

> This attachment describes any additions to the Master MIMP that [apply
> only to the specific protocol]{.underline}. This attachment should be
> submitted only when extenuating circumstances require an addendum to
> the Master MIMP for the one specific protocol.

2.  When submitting a protocol for review (first or subsequent
    submissions), the following guidelines are to be followed:

    a.  The approved Master MIMP does not need to be submitted since it
        is on file at DCP. It should be referenced in the Protocol
        Submission Worksheet only.

    b.  MIMP Attachment #1 should only be submitted when extenuating
        circumstances require an addendum to the Master MIMP that only
        applies to the particular study.

3.  If changes to the Master MIMP that are applicable to all studies
    performed by a Consortium are required, the revised MIMP must be
    submitted to DCP for review and approval.

4.  The MIMP template can be accessed through this link:\
    <http://dcp.cancer.gov/files/clinical-trials/mimp.doc>

    **MIMP Attachment #1**

**Master MIMP Addendum**

*This attachment documents those processes that apply only to a specific
protocol and are not addressed in the approved Master MIMP. This
attachment should only be submitted when extenuating circumstances
require a protocol-specific addition to the Master MIMP.*

**DOCUMENT F: DATA AND SAFETY MONITORING PLAN**

1.  The Data and Safety Monitoring Plan (DSMP) consists of two parts:

    a.  The Master DSMP: This document applies to all studies performed
        within a Consortium. It must be approved by DCP prior to
        subsequent protocol approval. The approved Master DSMP is kept
        on file at DCP, the Consortium Lead Organization, and the
        Participating Organizations.

    b.  DSMP Attachment #1: Master DSMP Addendum

> This attachment describes any additions to the Master DSMP that [apply
> only to the specific protocol]{.underline}. This attachment should be
> submitted only when extenuating circumstances require an addendum to
> the Master DSMP for the one specific protocol.

2.  When submitting a protocol for review (first or subsequent
    submissions), the following guidelines are to be followed:

    a.  The approved Master DSMP does not need to be submitted since it
        is on file at DCP. It should be referenced in the Protocol
        Submission Worksheet only.

    b.  DSMP Attachment #1 should only be submitted when extenuating
        circumstances require an addendum to the Master DSMP that only
        applies to the particular study.

3.  If changes to the Master DSMP that are applicable to all studies
    performed by a Consortium are required, the revised DSMP must be
    submitted to DCP for review and approval.

4.  Additional guidelines regarding the development of the Master DSMP
    can be found in the NCI Clinical Trials link at:

> <http://cancer.gov/clinicaltrials/conducting/dsm-guidelines>

**DSMP Attachment #1**

**Master DSMP Addendum**

*This attachment documents those processes that apply only to a specific
protocol and are not addressed in the approved Master DSMP. This
attachment should only be submitted when extenuating circumstances
require a protocol-specific addition to the Master DSMP.*