Submission Procedures


Submission Process

  1. After a protocol has been developed and is ready to begin the formal review process, a Clinical Trial Submission Form must be completed. This must include the total accrual goals for the study as well as the length of time to protocol completion, which will be used by the CSRC to track one aspect of scientific progress.
  2. Each new protocol must be submitted by the Principal Investigator (PI) for the signature of the appropriate Disease Committee Leader. If co-Leaders are listed for a particular disease, either signature can be obtained. The signature must be included on the Submission Form.

    All protocols that are put on the agenda MUST have a Disease Leader signature 
  • No protocol without a Disease Leader signature will be assigned to a reviewer
  • No protocol without a Disease Leader signature will be reviewed at a CSRC meeting o
  • Protocols that are submitted at the deadline for the next meeting WITHOUT a signature (but with a promise of getting it before the review) will NOT be put on the agenda without a signature.

  1. An electronic copy of the Sumbission Form and protocol document, as well as other pertinent documents, may be emailed to csrc@osumc.edu or delivered to:

    Tricia DeFiore, CSRC Coordinator
    A054 Starlling Loving Hall
    320 W. 10th Ave
    Columbus, OH 43210

    The protocol document and submission form must be received by 4:00 pm on the deadline date. In order to provide adequate review, it is imparative that the required documents (with appropriate signatures) are received by the submission deadline.

  2. The Executive Committee of the CSRC or the Committee Chair assigns reviewers to the protocol.
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Review Process

  1. After proper submission, the protocol is then reviewed at the next SCRC meeting. The committee no longer requires that investigators attend CSRC meetings to present their submitted protocols. Any Investigator wishing to present his protocol personally shall notify the committee by completing the appropriate section of the submission form and the request will be accommodated.
  2. The PI will receive a formal letter reporting the action taken at the CSRC meeting within 5 working days. Results from the initial review may be: 1) approved as written; 2) protocol modifications required, stipulations issued; or 3) protocol deferred.
  3. If the protocol is approved as written , the CSRC will grant approval and the project can then proceed for submission to the IRB.
  4. If deemed protocol modifications required and stipulations issued, the PI must send the CSRC a formal letter outlining the responses and a revised protocol highlighting the changes.
  5. The original reviewers review the stipulations and determine if the committee stipulations have been met. If the reviewers determine that the stipulations have been met, the PI will receive a letter stating that all of the committee's stipulations have been met and they may proceed with IRB submission.
  6. If the protocol is deferred, the PI must send the CSRC a formal letter outlining the responses to the reasons for deferral and a revised protocol highlighting the changes. If the reviewers feel the changes to the protocol are adequate, the PI will receive a letter stating that all of the committee's stipulations have been met and they may proceed with IRB submission.
  7. The PI must notify the CSRC coordinator once IRB approval has been obtained, regardless whether the study is or is not managed by the CTO.
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Amendments

It is the responsibility of the PI and/or managing staff to submit all protocol amendments to the CSRC for review by the CSRC Executive Committee.

Submission includes:

  1. Summary of Changes
  2. Protocol/document with highlighted changes
  3. New protocol document including changes

The committee will review the amendments and the PI will receive a formal letter reporting the action at the CSRC meeting.

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Monitoring

All Investigator Initiated and Pharmaceutical Industry protocols are monitored regularly by the CSRC for scientific progress including accrual. Failure to document adequate scientific progress will result in a warning letter. If the protocol performance does not substantially improve, protocol closure will occur.

Definition of Inadequate Accrual and CSRC Actions :

  • During a 6 month period:   less than 50% of annual accrual goal (Action: Warning letter will be sent to the PI).
  • During a 12 month period: less than 50% of annual accrual goal (Action: Permanent closure of protocol).
  • During an 18 month period: less than 100% of annual accrual goal (Action: Permanent closure of protocol).

After a warning letter is issued by the CSRC to the PI, the PI must formally respond to the warning in writing within two weeks. The response must include reasons for low accrual and measures to be taken to improve accrual.

After three months of receipt of said warning letter, the committee will then re-review or, after issuing a warning letter, the committee will continue to closely monitor the protocol for the next six months.

Note : Accrual goals may be modified at any time by the PI during the monitoring process by contacting Tricia DeFiore, the CSRC Coordinator at Tricia.DeFiore@osumc.edu .

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Phase I Trials Guidelines

PURPOSE

This guideline defines the recommended content and format of Clinical Study Protocols for Phase I trials.

DEFINITION

The Study Protocol is the major document governing the performance of the clinical study. It should contain all instructions required for the conduct of the study, including scientific, methodological, administrative and ethical issues.

A Phase I Study is the first trial of a new agent in humans. Some of the objectives of a Phase I study are to determine a safe dose for a Phase II study and to define acute effects on normal tissues. A Phase I study will also examine a drug's pharmacology and may reveal evidence of antitumor activity. Anticancer agents are not tested in patients in Phase I studies unless preclinical activity studies have shows evidence of significant activity in the laboratory.

APPLICABILITY

This guideline is valid for all Phase I trials written and developed at The James Cancer Hospital and Research Institute (CHRI).

RESPONSIBILITY

Responsibility for writing the Study Protocol lies with the department/division who will be sponsoring the study.

CONTENT

The following description of the content of the Study Protocol should be regarded as an outline of a Phase I study. This outline should be followed as closely as possible. Click on each item for a detailed description.

TITLE PAGE

The Study Protocol's title page is the primary source for identifying information. It should include the following information:

    • The local protocol number
    • The NCI protocol number (if applicable)
    • The date the protocol was activated at the CHRI
    • Title of the protocol with investigational drug NSC number (if applicable)
    • A single principal investigator who will be responsible for the study, including his/her name, address, and phone number. Co-investigators may also be listed.
    • Full name and address of department/division at the CHRI submitting the protocol with general contact phone number
    • List of each participating institution/group (if applicable)

TABLE OF CONTENTS

A Table of Contents, including all numbered paragraphs of the document and a list of all appendices, should be given.

OBJECTIVES

The primary and secondary objective(s) of the study should be clearly stated. The objectives should be stated as hypotheses to be tested. The protocol should be designed in order to answer the questions posed by the objectives. The statistical section should clearly state how the data will be analyzed in relation to each of the objectives. The hypotheses to be tested in ancillary studies also must be clearly stated, and the statistical section should address data analyses in relation to these hypotheses.

BACKGROUND AND STUDY RATIONALE

Animal toxicology studies carried out prior to Phase I trials provide the investigator with (a) estimates of a starting dose for clinical trials and (b) prediction of the likely effects of the drug on normal tissues. These data furnish the investigator with clues that help focus clinical observation of the patient. The dose is increased gradually by some defined procedure until a level is found that produces limiting but tolerable toxicity and/or clear representation of therapeutic activity. Phase I trials define acute effects that occur with a relatively high frequency on normal tissues.

Provide sufficient background information to enable the understanding of the relevance of the protocol. Any published data relevant to the rationale should be included in this section. (If this data is extensive, it can be included as an appendix to the protocol.) This section should justify the protocol, not the investigational drug. References to relevant reports and publications should also be provided. Information to support ancillary studies to be performed should be included. The rationale for studying particular correlations between tumor characteristics and outcome measurements should be clearly stated. The choice of the particular techniques to be used should also be justified.

PHARMACEUTICAL INFORMATION

This section should include at least the following:

  • Product Description – Give both the common name and the full chemical name of the compound. Also, include the form in which the drug(s) are supplied, the molecular weight, and the empirical formula. If available, also provide a picture of the structure of the compound(s).
  • Toxicology – Include a description of the drug-associated toxicities that have been seen in the laboratory or in other Phase I studies.
  • Pharmacokinetics – Describe the preclinical and clinical pharmacokinetic research that has been performed.
  • Solution Preparation – Include reconstitution directions and directions for further dilution, if appropriate.
  • Storage Requirements – Include the requirements for the original dosage form, reconstituted solution and final diluted product, as applicable.
  • Stability – Provide the stability of the original dosage form, reconstituted solution and the final diluted product, as applicable.
  • Route of Administration – Include a description of the administration method to be used and the rate of administration, if appropriate.
  • Safe Handling – Describe any precautions required for the safe handling and administration of the drug(s).
  • Supplier - State the drug(s)' supplier. Describe in detail the process to follow to order the drug(s).

PATIENT ELIGIBILITY CRITERIA

List the criteria that the patient must fulfill in order to be included in the study (I.e. histological diagnosis, age, performance status, prior treatment requirements, blood counts, etc.) Be certain to also list all exclusion criteria which may interfere with the evaluation of the study results.

Also in this section, specify any laboratory screening or tests that must be performed in order to confirm the presence of the inclusion criteria and the absence of the exclusion criteria. A time frame within which these pre-study tests must be done should also be given.

Patients eligible for Phase I studies must have confirmed malignant disease that is not satisfactorily treated by conventional forms of therapy or for which there is no standard treatment. Initial patients should have normal organ function so that the investigator may reliably distinguish drug effects from disease effects.

TREATMENT PLAN

The protocol treatment is to be clearly specified so that it can be followed by all medical personnel. The dosage and/or dosing regimen should be stated. Any special procedures used in connection with the administration of the drug(s) (i.e. dosage per kg body weight) should be described. Specify the time schedule for all study and reference products, (i.e. dose level, administration frequency, route of administration, specified times for administration [with allowed ranges], special requirements [fasting, before or after a meal, together with fluid, etc.], dosage sequence, criteria for dose adjustments, where treatment is to be administered and by whom, etc.)

The starting dose of a Phase I trial, as derived from preclinical toxicology, is 1/10 of MELD10 (mouse equivalent of LD10 in mg/m 2 , unless that dose is toxic in any species tested, in which case the trial begins at a lower dose that has been shown to produce no more than minimal and reversible effects in the most sensitive species tested.

In this section, also describe the duration of time the drug(s) will be taken. Explain acceptable deviations from the time schedule and the consequences in the event of treatment interruption, discontinuation or other forms of poor compliance.

Any concomitant therapy that is not allowed during the course of the protocol treatment should be clearly listed.

The number of separate schedules studied in a Phase I protocol is determined by several factors, including evidence of schedule dependence in experimental in vivo systems; pharmacokinetics; mechanism of action, if known; and existing clinical data with similar compounds suggesting superiority of a particular schedule.

Doses are escalated according to a scheme in which the initial increments are large and decrease rapidly as biologic effects become evident. The goal is to arrive at the recommended Phase II dose with the fewest number of escalations consistent with patient safety; this procedure minimizes the number of patients receiving biologically inactive doses. At each dose level, a minimum of three patients not previously treated with the new drug should be entered. Escalation to the next level should not occur until the safety of the current level has been established. This usually means that at least three patients will have been observed for the entire course interval. For some protocols, escalation can proceed with fewer than three patients per level provided no grade 2 toxicity has yet been seen in the study. At least six patients should be treated at the recommended dose should be specified in the protocol. In certain protocols, dose escalations will occur within patients.

Also in this section, describe, if applicable, any procedures used to improve, check and document compliance with the treatment schedule (i.e. calendars, instructions, labels, counts of remaining drug(s), etc.) If there is a quality of life component to the protocol, explain it in detail in this section.

List the criteria used to decide to remove a patient from protocol treatment. The reason for withdrawal should be clearly documented.

Adverse events should be described as well as the procedure to be followed to report such an event. The following information should be included in this description:

All life threatening reaction which may be due to drug administration, all fatal events while on study or within 30 days of treatment, and the first occurrence of any previously unknown toxicity of any grade will be reported as serious adverse events. The Study Coordinator or data manager will report these reactions within 24 hours to the National Cancer Institute Investigational Drug Branch (or Sponsor Pharmaceutical Company if it is a drug company study) at the number listed below. A written report will also be submitted to the NCI (or Sponsor Pharmaceutical Company), if necessary, will decide if a toxicity is most likely drug or disease related.

Investigational Drug Branch Phone: (301) 230-2330
Post Office Box 30012 FAX: (301) 230-0159
Bethesda , Maryland 20824

If the study is sponsored by a Pharmaceutical Company, provide the appropriate information instead of the NCI information.


DATA SAFETY MONITORING PLAN

The data and safety monitoring plan will involve the continuous evaluation of safety, data quality and data timeliness. Investigators will conduct continuous review of data and patient safety at their regular disease group meetings (at least monthly) and the discussion will be documented in the minutes. The PI of the trial will review toxicities and responses of the trial where applicable at these disease group meetings and determine if the risk/benefit ratio of the trial changes. Frequency and severity of adverse events will be reviewed by the PI and compared to what is known about the agent/device from other sources; including published literature, scientific meetings and discussions with the sponsors, to determine if the trial should be terminated before completion. Serious adverse events and responses will also be reviewed by the OSUCCC Data and Safety Monitoring Committee (DSMC). The PI will also submit a progress report (biannually for Phase II and quarterly for Phase I) that will be reviewed by the committee per the DSMC plan. All reportable Serious Adverse Events (SAE) will also be reported to the IRB of record as per the policies of the IRB.

STUDY PARAMETERS

A table or flow-chart outlining the study-specific events that will take place and when they will occur should be provided. This table should include such items as history and physical exam, performance status, toxicity notation, blood and urine sampling, radiology evaluations, pharmacokinetics samples, laboratory correlative samples, and drug(s) administration. It should be specified in detail how patients will be followed for assessment of treatment toxicity and therapeutic effect. The Common Toxicity Criteria specific for the study should be included as an appendix of the study. (This may be the NCI Common Toxicity Criteria table or a cooperative group's toxicity criteria table.)

PHARMACOKINETICS

This section should explain the types of samples (i.e. serum, urine, etc.) and the number of each type that will be collected and how they will be processed in the laboratory. Other information about the storage of the samples and the data analysis may also be included. The name and phone number of the investigator performing these studies should be clearly noted.

The role of pharmacokinetics in Phase I studies is receiving increasing emphasis. The specific focus of pharmacokinetics studies is the possible use of data from these studies to be used to guide dose escalation. Investigators developing Phase I protocols should consider pharmacokinetic determinations an integral part of a Phase I study.

LABORATORY CORRELATIVE STUDIES

Any laboratory correlative studies that will be performed as ancillary components of the protocol should be well described. This section should include how the samples are to be collected, what type of samples (i.e. blood, urine, etc.), sampling intervals, volumes of the samples and how they will be analyzed. Describe how the samples are to be handled, stored, labeled, shipped, etc., from the time of collection to the time at which they are analyzed. The rationale for these studies should also be explained. Also, list the name and phone number of the investigator performing these studies. Be certain to note if there are only certain delivery days which are acceptable (i.e. “Samples may only be shipped Monday through Thursday”) and whether the laboratory must be contacted prior to shipment.

CLINICAL RESPONSE AND ENDPOINT DEFINITIONS

Response criteria should be included. These should be specific for both measurable and evaluable disease. Disease-specific criteria are often required and should clearly indicate acceptable methods of measurement (i.e. CT scans, ultrasounds, etc.)

Clinical response will be recorded in Phase I studies, but the ability to quantitate antitumor effect will not be a criterion for patient evaluability. The following standard definitions can be used.

Measurable Disease: Either 1) bidimensionally measurable lesion with clearly defined margins by medical photograph (skin lesion), or by x-ray or scan, with at least one diameter greater than 1.0 cm or ; 2) palpable lesion with both diameters 2 cm or greater.

Evaluable Disease: Undimensionally measurable lesions, masses with margins not clearly defined, palpable lesions with either diameter less than 2 cm, any lesion with both diameters less than 1.0 cm, bone disease. Markers which have been shown to be highly correlated with extent of disease are also considered evaluable.

Non-Evaluable Disease: Pleural effusions, ascites, disease documented by indirect evidence only (i.e. by lab values).

Complete Response (CR): Disappearance of all evidence of tumor for a period of time of at least one month. The patient must be free of all symptoms of cancer.

Partial Response (PR): Applies only to patients with at least one measurable lesion. 50% or greater decrease under baseline in the sum of the products of the diameters of all bidimensionally measured lesions for a period of time of at least one month. Hepatomegaly must decrease by 50% in the sum of at least two measurements below the costal margin. No lesion may increase in size and no new lesion may appear. No progression of evaluable disease.

Stable Disease (SD): Change in tumor size less than that required for PR or PD.

Progressive Disease (PD): 25% or greater increase in the sum of the products of the diameters of bidimensionally measured lesions, OR appearance of any lesion which had disappeared, OR clear worsening of any evaluable disease, OR the appearance of a new lesion definitely not present at baseline.

Relapse (R): Following a response, the appearance of a new lesion, or a 25% or greater increase in the sum of the products of bidimensionally measured lesions over that observed at the time of maximal regression.

Dose limited toxicity (DLT): is defined as any of the following:

  • Neutropenia (PMN<500/ m l) or thrombocytopenia (<25,000/ m l) persisting for > 5 days.
  • Grade 3 toxicity other than neutropenia or a thrombocytopenia.
  • Irreversible grade 2 toxicity in 2 patients at a dose level.

Maximum tolerated dose (MTD): The highest safety tolerable dosage in man. A minimum of 3 patients will be treated at each dose level. If all 3 patients have been observed for greater than 21 days without experiencing DLT, then the dose will be escalated as described in the treatment plan. If 2 of the 3 patients have DLT, then the previous dose level will be considered the MTD. If 1 of the 3 patients develops DLT, then 3 more patients will be treated at this level. If none develop DLT< the dose will be escalated. If 1 or more develop DLT, the previous level will be considered the MLT.

STATISTICAL CONSIDERATIONS

An adequate statistical section discusses the study design in relation to the objectives of the study and the plan for the evaluation of the data. It specifically discusses the following information.

  1. Method of randomization and stratification
  2. Total sample size justified for adequate testing of primary and secondary hypotheses
  3. Size of the confidence interval to be constructed around the estimated outcome
  4. Estimated accrual rate and/or study duration, with supporting documentation
  5. Stopping rules, including statistical and administrative procedures for monitoring the progress of the trial to implement early termination
  6. Clear specification of primary and secondary hypotheses
  7. Maximum number of patients to be enrolled on the study
  8. Plan for analysis

REGISTRATION GUIDELINES

Procedures for patient entry should be specified. Required information includes the telephone numbers of the protocol registration office and the patient characteristics and stratification factors (if any) to be provided at the time of entry. This section should clearly describe the exact method to be followed to enroll a patient (i.e. what forms to complete, who to call, where to send or fax forms, etc.). Patients must be registered to the protocol prior to the treatment start.

DATA SUBMISSION SCHEDULE

The research forms on which the data from the protocol will be gathered should be detailed in this section. It should also explain where and when the data should be sent. The following information is to be gathered:

  • On-study information, including patient eligibility data and patient history
  • Flow sheets, or other forms, for interim monitoring
  • Specialty forms for pathology, radiation, or surgery, laboratory sample collection when required
  • Off-study summary sheet, including a final assessment by the treating physician

ETHICAL AND REGULATORY CONSIDERATIONS

The following information should be included in this section: Informed Consent: The principles of informed consent are described by Federal Regulatory Guidelines (Code of Federal Regulations 21 CFR 50) and the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal Regulations 21 CFR 56). They must be followed to comply with FDA and HHS regulations for the conduct and monitoring of clinical investigations.

The protocol should discuss the timing and means of obtaining informed consent. Some items that should be discussed are the following: 1) Written informed consent must be obtained before any study specific procedures (screening or treatment) are performed; 2) Acceptable means of consent in minors; 3) Witness signature required on the informed consent; 4) The CHRI offices which should receive and retain a copy of the approved informed consent form along with a copy of each patient's signed informed consent form.

Institutional Review: This study must be approved by an appropriate review committee as defined by Federal Regulatory Guidelines (Code of Federal Regulations 21 CFR 56) and the Office for the Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal Regulations 21 CFR 56).

This protocol should discuss submission of required documents to the IRB, requirement for IRB approval, and retention of IRB documents by the Investigator. It should also explain which offices of the CHRI should receive a copy of IRB approval. Drug Accountability: For each drug supplied for a study, accountability ledger containing current and accurate inventory records covering receipt, dispensing, and the return of study drug supplies must be maintained. Drug supplies must be kept in a secure, limited access storage area under the recommended storage conditions. During the course of this study, the following information must be noted on the accountability ledger: 1) The identification code of the subject to whom the drug is dispensed; 2) The date(s) and quantity of drug dispensed; 3) The date(s) and quantity of drug returned by the subject (subjects should return empty containers to the investigator, with the return noted on the ledger.) These accountability forms must be readily available for inspection and are open to governmental and internal inspection at any time.

REFERENCES

Any publications that are used to write any part of the protocol should be noted in this section.

APPENDICES

The author of the protocol may include any pertinent information that was not already provided in the body of the protocol as an appendix.

Examples of items to be included are the following:

  • Toxicity Criteria
  • Performance Status table
  • Data Forms
  • Model Consent Form
  • Study specific tables
  • Further study-specific background information
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Phase II and III Trials Guidelines

PURPOSE

This Guideline defines the content and format of Clinical Study Protocols for Phase II and III clinical trials.

DEFINITION

The Study Protocol is the major document governing the performance of the clinical study. It should contain all instructions required for the conduct of the study, including scientific, methodological, administrative and ethical issues.

A Phase II study assesses the antitumor efficacy of a new cancer agent, a new combination of agents, or a new modality of therapy. Using the dose and schedule found to be safe in Phase I studies, the new treatment is given to a defined patient population. Usually, between 25 and 50 patients are treated for each tumor type and for each dose and schedule selected from Phase I testing.

A Phase III study is developed when significant activity is observed in any disease during Phase II study. A Phase III clinical trial compares a new drug with the standard (or other experimental) agent or agents. Anywhere from 100 to 1,000 or more patients may be required, and accrual may take 2-5 years or more.

APPLICABILITY

This GUIDELINE is valid for all Phase II and Phase III clinical trials developed at The James Cancer Hospital and Research Institute (CHRI)

RESPONSIBILITY

Responsibility for writing the Study Protocol lies with the department/division who will be sponsoring the study.

CONTENT

The following description of the content of the Study Protocol should be regarded as an outline of a Phase II or Phase III study. This outline should be followed as closely as possible.

TITLE PAGE
The Study Protocol's title page is the primary source for identifying information. It should include the following information:

  • The local protocol number
  • The NCI protocol number (if applicable)
  • The date the protocol was activated at the CHRI
  • Title of the protocol with investigational drug NSC number (if applicable)
  • A single principal investigator who will be responsible for the study, including his/her name, address, and phone number. Co-investigators may also be listed.
  • Full name and address of department/division at the CHRI submitting the protocol with general contact phone number
  • List of each participating institution/group (if applicable)

TABLE OF CONTENTS

A Table of Contents, including all numbered paragraphs of the document and a list of all appendices, should be given.

OBJECTIVES

The primary and secondary objective(s) of the study should be clearly stated and expressed in terms of a specific measurable variable or endpoint. The objectives should be stated as hypotheses to be tested. The protocol should be designed in order to answer the questions posed by the objectives. The statistical section should clearly state how the data will be analyzed in relation to each of the objectives. The hypotheses to be tested in ancillary studies also must be clearly stated, and the statistical section should address data analyses in relation to these hypotheses.

The general objectives of a Phase II study include the following:

(a) Determination of whether a drug has antitumor activity;

(b) Estimating the response rate in a defined patient population and;

(c) A further determination of toxicity (unusual or chronic toxicities, which are often missed entirely in Phase I testing, may appear in Phase II testing).

The general objectives of a Phase III study include the following:

(a) Isolation of the role of a new agent in the treatment of a specific cancer when compared to another treatment (differences in response rates, toxicity, patterns of recurrence);

(b) Determination of the quality of life for patients enrolled on the study and;

(c) Overall and disease-free survival.

BACKGROUND AND STUDY RATIONALE

Sufficient background information should be provided to enable the understanding of the relevance of protocol. The appropriate background information to be provided for a new drug having finishing Phase I evaluation and having the maximum tolerated dose (MTD) defined should provide a description of the drug's derivation, chemistry, mechanism of action as known to date, spectrum of preclinical activity, preclinical pharmacology and toxicity, clinical toxicity, and any evidence of clinical activity. Any unpublished data relevant to the rationale should be included in this section. (If this data is extensive, it can be included as an appendix to the protocol.) This section should justify the protocol, not the investigational drug. References to relevant reports and publications should also be provided. Information to support ancillary studies to be performed should be included. The rationale for studying particular correlations between tumor characteristics and outcome measurements should be clearly stated. The choice of the particular techniques to be used should also be justified.

PHARMACEUTICAL INFORMATION

This section should include at least the following:

  • Product Description – Give both the common name and the full chemical name of the compound. Also, include the form in which the drug(s) are supplied, the molecular weight, and the empirical formula. If available, also provide a picture of the structure of the compound(s).
  • Toxicology – Include a description of the drug-associated toxicities.
  • Pharmacokinetics – Describe the preclinical and clinical pharmacokinetic research that has been performed.
  • Solution Preparation – Include reconstitution directions and directions for further dilution, if appropriate.
  • Storage Requirements – Include the requirements for the original dosage form, reconstituted solution and final diluted product, as applicable.
  • Stability – Provide the stability of the original dosage form, reconstituted solution and the final diluted product, as applicable.
  • Route of Administration – Include a description of the administration method to be used and the rate of administration, if appropriate.
  • Safe Handling – Describe any precautions required for the safe handling and administration of the drug(s).
  • Supplier - State the drug(s)' supplier. Describe in detail the process to follow to order the drug(s).

PATIENT ELIGIBILITY CRITERIA

List the criteria that the patient must fulfill in order to be included in the study (I.e. histological diagnosis, age, performance status, prior treatment requirements, blood counts, etc.) Be certain to also list all exclusion criteria which may interfere with the evaluation of the study results.

Also in this section, specify any laboratory screening or tests that must be performed in order to confirm the presence of the inclusion criteria and the absence of the exclusion criteria. A time frame within which these pre-study tests must be done should also be given.

Patients eligible for Phase II and III studies must have confirmed malignant disease. For each proposed tumor type, there should be separate statements on eligibility. Since it is clear that the extent of prior cytotoxic chemotherapy is an important determinant of probability of response, many Phase II studies restrict the amount of prior therapy to one or two prior regimens, while Phase III studies may exclude patients who have received prior therapy for their cancer, or they may enroll only patients who have had prior therapy. In order to define quantitatively the antitumor activity of a drug, patients in Phase II and III studies must have bidimensionally measurable or evaluable disease parameters. Evidence that the function of major organs is normal is required.

TREATMENT PLAN

The protocol treatment is to be clearly specified so that it can be followed by all medical personnel. The dosage and/or dosing regimen should be stated. Any special procedures used in connection with the administration of the drug(s) (i.e. dosage per kg body weight) should be noted. Specify the time schedule for all study and reference products, (i.e. dose level, administration frequency, route of administration, specified times for administration [with allowed ranges], special requirements [fasting, before or after a meal, together with fluid, etc.], dosage sequence, criteria for dose adjustments, where treatment is to be administered and by whom, etc.). This can be done in a table format as follows:

 

Agent Dose Route Days Re-treatment Interval
         
         

 

In this section, also describe the duration of time the drug(s) will be taken. Explain acceptable deviations from the time schedule and the consequences in the event of treatment interruption, discontinuation or other forms of poor compliance.

Any concomitant therapy that is not allowed during the course of the protocol treatment should be clearly listed.

Also, in this section, describe, if applicable, any procedures used to improve, check and document compliance with the treatment schedule (i.e. calendars, instructions, labels, counts of remaining drug(s), etc.) If there is a quality of life component to the protocol, explain it in detail in this section.

List the criteria used to decide to remove a patient from protocol treatment. The reason for withdrawal should be clearly documented.

Adverse events should be described, and the protocol will define the criteria and reporting for Serious Adverse Events. The following information should be included in this description:

All life threatening reactions, which may be due to drug administration, all fatal events while on study or within 30 days of treatment, and the first occurrence of any previously unknown toxicity of any grade will be reported as serious adverse events. The Study Coordinator or data manager will report these reactions within 24 hours to the National Cancer Institute Investigational Drug Branch (or Sponsor Pharmaceutical Company) and the IRB within ten working days. The principal investigator and the attending physician in collaboration with the NCI (or Sponsor Pharmaceutical Company), if necessary, will decide if a toxicity is most likely drug or disease related.

Investigational Drug Branch Phone: (301) 230-2330
Post Office Box 30012 FAX: (301) 230-0159
Bethesda , Maryland 20824

If the study is sponsored by a Pharmaceutical Company, provide the appropriate information instead of the NCI information.

DOSAGE MODIFICATIONS

In this section, give guidelines regarding when the next cycle of treatment can be initiation. An example of a guideline that may be employed is as follows:

Each cycle of ( drug ) will be initiated if granulocyte count is > 1500/mm 3 and platelet count is > 100,000/ m l

Also, in this section, describe what criteria are used to determine dosage modifications (i.e. nadir counts and interim non-hematologic toxicities of the preceding cycle). Provide a table with Drug Dosage levels.

Outline dose adjustments for both hematologic and non-hematologic toxicities.

DATA SAFETY MONITORING PLAN

The data and safety monitoring plan will involve the continuous evaluation of safety, data quality and data timeliness. Investigators will conduct continuous review of data and patient safety at their regular disease group meetings (at least monthly) and the discussion will be documented in the minutes. The PI of the trial will review toxicities and responses of the trial where applicable at these disease group meetings and determine if the risk/benefit ratio of the trial changes. Frequency and severity of adverse events will be reviewed by the PI and compared to what is known about the agent/device from other sources; including published literature, scientific meetings and discussions with the sponsors, to determine if the trial should be terminated before completion. Serious adverse events and responses will also be reviewed by the OSUCCC Data and Safety Monitoring Committee (DSMC). The PI will also submit a progress report (biannually for Phase II and quarterly for Phase I) that will be reviewed by the committee per the DSMC plan. All reportable Serious Adverse Events (SAE) will also be reported to the IRB of record as per the policies of the IRB.

STUDY PARAMETERS

A table or flow-chart outlining the study-specific events that will take place and when they will occur should be provided. This table should include such items as history and physical exam, performance status, toxicity notation, blood and urine sampling, radiology evaluations, pharmacokinetics samples (if applicable), laboratory correlative samples (if applicable), and drug(s) administration. It should be specified in detail how patients will be followed for assessment of treatment toxicity and therapeutic effect. The Common Toxicity Criteria specific for the study should be included as an appendix of the study. (This may be the NCI Common Toxicity Criteria table or a cooperative group's toxicity criteria table.)

CLINICAL RESPONSE AND ENDPOINT DEFINITIONS

Response criteria should be included. These should be specific for both measurable and evaluable disease. Disease-specific criteria are often required and should clearly indicate acceptable methods of measurement (i.e. CT scans, ultrasounds, etc.)

The following standard definitions can be used:

Measurable Disease: Either 1) bidimensionally measurable lesion with clearly defined margins by medical photograph (skin lesion), or by x-ray or scan, with at least one diameter greater than 1.0 cm or; 2) palpable lesion with both diameters 2 cm or greater.

Evaluable Disease: Undimensionally measurable lesions, masses with margins not clearly defined, palpable lesions with either diameter less than 2 cm, any lesion with both diameters less than 1.0 cm, bone disease. Markers which have been shown to be highly correlated with extent of disease are also considered evaluable.

Non-Evaluable Disease: Pleural effusions, ascites, disease documented by indirect evidence only (i.e. by lab values).

Complete Response (CR): Complete disappearance of all evidence of tumor for a period of time of at least one month. No new lesions. All measurable, evaluable, and non-evaluable lesions and sites must be assessed. The patient must be free of all symptoms of cancer.

Partial Response (PR): Applies only to patients with at least one measurable lesion. 50% or greater decrease under baseline in the sum of the products of the diameters of all bidimensionally measured lesions for a period of time of at least one month. Hepatomegaly must decrease by 50% in the sum of at least two measurements below the costal margin. No lesion may increase in size and no new lesion may appear. No progression of evaluable disease.

Stable Disease (SD): Change in tumor size less than that required for PR or PD. All measurable, evaluable, and non-evaluable lesions and sites must be assessed.

Progressive Disease (PD): 25% or greater increase in the sum of the products of the diameters of bidimensionally measured lesions, OR appearance of any lesion which had disappeared, OR clear worsening of any evaluable disease, OR the appearance of a new lesion definitely not present at baseline.

Relapse (R): Following a response, the appearance of a new lesion, or a 25% or greater increase in the sum of the products of bidimensionally measured lesions over that observed at the time of maximal regression.

Time to Treatment Failure: Time from date of registration to date of progressive disease, or to date off treatment due to toxicity, refusal, or death.

Time to Death: Interval of time from date of registration to date of death.

Duration of Response: Time of designation of CR or PR to first evidence of progressive disease of death.

STATISTICAL CONSIDERATIONS

An adequate statistical section discusses the study design in relation to the objectives of the study and the plan for the evaluation of the data. It specifically discusses the following information.

  • Method of randomization and stratification
  • Total sample size justified for adequate testing of primary and secondary hypotheses
  • Error levels (alpha and beta) in Phase III studies
  • Size of the confidence interval to be constructed around the estimated outcome
  • Estimated accrual rate and/or study duration, with supporting documentation
  • Stopping rules, including statistical and administrative procedures for monitoring the progress of the trial to implement early termination
  • Expected outcome parameters as appropriate (response rate, time to progression, survival times, etc.)
  • Primary endpoint for interim and final analysis
  • Clear specification of primary and secondary hypotheses
  • Maximum number of patients to be enrolled onto the study
  • Plan for analysis

GENDER AND ETHNIC CONSIDERATIONS

Provide statistics in this section regarding the incidence of the particular disease in men versus women and in specific ethnic groups as applicable. Explain what measures will be taken to recruit women and minority patients.

REGISTRATION GUIDELINES

Procedures for patient entry should be specified. Required information includes the telephone numbers of the protocol registration office and the patient characteristics and stratification factors (if any) to be provided at the time of entry. This section should clearly describe the exact method to be followed to enroll a patient (i.e. what forms to complete, who to call, where to send or fax forms, etc.). Patients must be registered to the protocol prior to the treatment start.

DATA SUBMISSION SCHEDULE

The research forms on which the data from the protocol will be gathered should be detailed in this section. It should also explain where and when the data should be sent. The following information is to be gathered:

  • On-study information, including patient eligibility data and patient history
  • Flow sheets, or other forms, for interim monitoring
  • Specialty forms for pathology, radiation, or surgery, laboratory sample collection when required
  • Off-study summary sheet, including a final assessment by the treating physician

SPECIMEN SUBMISSION

Any laboratory correlative studies that will be performed as ancillary components of the protocol should be well described. This section should include how the samples are to be collected, the type of samples to be collected (i.e. blood, urine, etc.), sampling intervals, volumes of the samples and how they will be analyzed. Describe how the samples are to be handled, stored, labeled, shipped, etc., from the time of collection to the time at which they are analyzed. The rationale for these studies should also be explained. Also, list the name and phone number of the investigator performing these studies. Be certain to note if there are only certain delivery days which are acceptable (i.e. “Samples may only be shipped Monday through Thursday”) and whether the laboratory must be contacted prior to shipment.

ETHICAL AND REGULATORY CONSIDERATIONS

The following information should be included in this section:

Informed Consent: The principles of informed consent are described by Federal Regulatory Guidelines (Code of Federal Regulations 21 CFR 50) and the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal Regulations 21 CFR 56). They must be followed to comply with FDA and HHS regulations for the conduct and monitoring of clinical investigations.

The protocol should discuss the timing and means of obtaining informed consent. Some items that should be discussed are the following: 1) Written informed consent must be obtained before any study specific procedures (screening or treatment) are performed; 2) Acceptable means of consent in minors; 3) Witness signature required on the informed consent; 4) The CHRI offices which should receive and retain a copy of the approved informed consent form along with a copy of each patient's signed informed consent form.

Institutional Review: This study must be approved by an appropriate review committee as defined by Federal Regulatory Guidelines (Code of Federal Regulations 21 CFR 56) and the Office for the Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal Regulations 21 CFR 56).

This protocol should discuss submission of required documents to the IRB, requirement for IRB approval, and retention of IRB documents by the Investigator. It should also explain which offices of the CHRI should receive a copy of IRB approval.

Drug Accountability: For each drug supplied for a study, accountability ledger containing current and accurate inventory records covering receipt, dispensing, and the return of study drug supplies must be maintained. Drug supplies must be kept in a secure, limited access storage area under the recommended storage conditions. During the course of this study, the following information must be noted on the accountability ledger:

1) The identification code of the subject to whom the drug is dispensed;

2) The date(s) and quantity of drug dispensed;

3) The date(s) and quantity of drug returned by the subject (subjects should return empty containers to the investigator, with the return noted on the ledger.)

These accountability forms must be readily available for inspection and are open to FDA inspection at any time.

REFERENCES

The following information should be included in this section:

Informed Consent: The principles of informed consent are described by Federal Regulatory Guidelines (Code of Federal Regulations 21 CFR 50) and the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal Regulations 21 CFR 56). They must be followed to comply with FDA and HHS regulations for the conduct and monitoring of clinical investigations.

The protocol should discuss the timing and means of obtaining informed consent. Some items that should be discussed are the following: 1) Written informed consent must be obtained before any study specific procedures (screening or treatment) are performed; 2) Acceptable means of consent in minors; 3) Witness signature required on the informed consent; 4) The CHRI offices which should receive and retain a copy of the approved informed consent form along with a copy of each patient's signed informed consent form.

Institutional Review: This study must be approved by an appropriate review committee as defined by Federal Regulatory Guidelines (Code of Federal Regulations 21 CFR 56) and the Office for the Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal Regulations 21 CFR 56).

This protocol should discuss submission of required documents to the IRB, requirement for IRB approval, and retention of IRB documents by the Investigator. It should also explain which offices of the CHRI should receive a copy of IRB approval.

Drug Accountability: For each drug supplied for a study, accountability ledger containing current and accurate inventory records covering receipt, dispensing, and the return of study drug supplies must be maintained. Drug supplies must be kept in a secure, limited access storage area under the recommended storage conditions. During the course of this study, the following information must be noted on the accountability ledger:

1) The identification code of the subject to whom the drug is dispensed;

2) The date(s) and quantity of drug dispensed;

3) The date(s) and quantity of drug returned by the subject (subjects should return empty containers to the investigator, with the return noted on the ledger.)

These accountability forms must be readily available for inspection and are open to FDA inspection at any time.

APPENDICES

The author of the protocol may include any pertinent information that was not already provided in the body of the protocol as an appendix. Examples of items to be included are the following: 1) Toxicity Criteria; 2) Performance Status table; 3) Data Forms; 4) Model Consent Form; 5) Study specific tables; 6) Further study-specific background information.

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