GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013
COMMITTEE IN CLINICAL TRIALS

1.
PURPOSE
These guidelines...
GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013
COMMITTEE IN CLINICAL TRIALS

2.2.2.
2.2.3.

2.2.4.
2.2.5...
GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013
COMMITTEE IN CLINICAL TRIALS

2.4.6.

2.4.7.
2.4.8.

2.4....
GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013
COMMITTEE IN CLINICAL TRIALS

2.4.17.

3.
3.1.
3.2.
3.3.
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GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013
COMMITTEE IN CLINICAL TRIALS

3.8.

3.9.

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4.1.
4.2.

4...
GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013
COMMITTEE IN CLINICAL TRIALS

5.
REPEALED REGULATIONS
The...
GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013
COMMITTEE IN CLINICAL TRIALS

ANNEX -1: HEADINGS FOR THE ...
GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013
COMMITTEE IN CLINICAL TRIALS

2.11.4.2.4. Controls of Cri...
GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013
COMMITTEE IN CLINICAL TRIALS

ANNEX -2: HEADINGS
TOXICOLO...
GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013
COMMITTEE IN CLINICAL TRIALS

ANNEX -3: HEADINGS FOR THE ...
GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013
COMMITTEE IN CLINICAL TRIALS

ANNEX -4:

EXAMPLES FOR FAC...
GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013
COMMITTEE IN CLINICAL TRIALS

Change in the testing metho...
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Guidelines on the manner of application to the ethics committee in clinical trials, published by Turkish Medicine and Medical Device Agency

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Guidelines on the manner of application to the ethics committee in clinical trials, published by Turkish Medicine and Medical Device Agency

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  1. 1. GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013 COMMITTEE IN CLINICAL TRIALS 1. PURPOSE These guidelines have been prepared to provide guidance on the manner and content of the application to be made to the ethics committee for the conduct of a clinical trial. 2. FORM AND CONTENT OF APPLICATIONS AND NOTIFICATIONS 2.1. Application for the Approval of a Clinical Trial 2.1.1. Application is made by the sponsor or their legal representative in accordance with the respective legislation. 2.1.2. An application is made to the relevant ethics committee to obtain scientific and ethical approval for clinical trials. 2.1.3. Application should be made to the ethics committee by using the applicable application form and cover letter samples published in the web site of the Turkish Medicine and Medical Device Agency according to the type of the clinical trial. 2.1.4. If the trial is an international one, a list of other health authorities to which the same application is submitted should be included in the file. Reasons should be provided for any differences in the trial protocol from the practices in Turkey. 2.1.5. If the applicant is not the trial sponsor, the original document specifying the matters in which their legal representative is authorized to act on behalf of the sponsor should be included in the application file. 2.1.6. In the initial application file and the continuation of the trial, colored files should be used according to the type of trial; red for Phase I clinical studies, yellow for Phase II clinical studies, blue for Phase III clinical studies, black for Phase IV clinical studies, white for observational drug studies and non-drug clinical studies, and orange for bioavailability and bioequivalence studies. 2.1.7. For the initial application and significant change applications, the original and one copy of the bank statement documenting payment of the application fee as published in the web site of the Turkish Medicine and Medical Device Agency should be included in the application file. 2.1.8. The application fee is not required for dissertations or trials with academic purposes. However, the application file should contain a document approved by the department head or responsible education official confirming that the trial in question is for a dissertation or for academic purposes. 2.1.9. If there is no cover letter sample applicable for the subject of the application, the cover letter to be prepared should include the full title of the trial, protocol number (if any) and details of the principal investigator or coordinator. 2.1.10. The cover letter of the application should highlight trial-specific matters such as specific study populations, first-in-man administration of a new active substance; extraordinary investigational products, extraordinary study designs and sub-studies, and specify the location of relevant information and documents in the application file. 2.1.11. Application forms are standardized and published in the web site of the Turkish Medicine and Medical Device Agency. These forms are updated as necessary and applicants must make sure to use the current version of the form in the application. 2.1.12. The trial sponsor or their legal representative undertakes by signing the relevant application form that sufficient information is submitted; the documents attached reflect the available information accurately; it is reasonable, in their opinion, to start the clinical trial for which the application is made, and they agree to start this trial. 2.2. Trial Protocol 2.2.1. The trial protocol is a document that details the trial objective, design, methodology, statistical methods to be used and trial-related arrangements. 1
  2. 2. GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013 COMMITTEE IN CLINICAL TRIALS 2.2.2. 2.2.3. 2.2.4. 2.2.5. 2.2.6. 2.3. 2.3.1. 2.3.2. 2.3.3. 2.3.4. 2.3.5. 2.4. 2.4.1. 2.4.2. 2.4.3. 2.4.4. 2.4.5. The content and format of the trial protocol should comply with applicable legislation and good clinical practices. The protocol attached to the trial file should include the protocol version number, full title of the trial, code numbers of all protocol versions identified by the sponsor, version number and date of the protocol to be updated with changes or the short title or name given to this protocol, and should be signed by the sponsor and coordinator or principal investigator. If any subject cannot provide a written informed consent form, the reason should be provided in the trial protocol. If the trial protocol and protocol amendment have been prepared in languages other than English, Turkish translations of all should be submitted as well. If the trial protocol and protocol amendment are in English, Turkish translations of the original protocol and summary of the protocol and protocol amendment should be submitted. Investigator’s Brochure The content, format and methods of the investigator’s brochure should comply with the applicable legislation. The investigator’s brochure should include clinical and non-clinical data about the investigational product. The investigator’s brochure should include the rationale of the clinical trial in question as well as all available information and evidence supporting the safe use of the investigational product in the trial. If the investigator’s brochure and its amendment have been prepared in languages other than English, Turkish translations of all should be submitted as well. If the investigator’s brochure and its amendment are in English, it is sufficient to submit the originals. Applications regarding the investigator’s brochure and its amendment should be made in accordance with the “Guidelines on Good Clinical Practices” and applicable legislation. Investigational Product Dossier Submission of an investigational product dossier in the applications is not mandatory. However, the ethics committee may request the investigational product dossier or relevant sections of it when it considers them necessary. The investigational product dossier includes information on the quality of an investigational product, including the reference products and placebos to be used in the clinical trial, non-clinical studies and clinical use. The investigational product dossier may include a cross-reference to the investigator’s brochure regarding non-clinical and clinical information. In this case, a summary of non-clinical information and clinical information should preferably be tabulated. The table should provide sufficient information for the assessors to decide on the potential toxicity of the investigational product and its safe use in the trial to be conducted. If clinical or non-clinical data includes a detailed expert statement or any specific conditions warranting discussion other than those normally included in the investigator’s brochure, the sponsor may submit such clinical or non-clinical information as part of the investigational product dossier. A comprehensive investigational product dossier should include documents concerning the quality, production and control of the investigational product, non-clinical data and a summary of clinical data. Main headings are listed in the annex to these guidelines. However, it should be noted that it may not be possible to submit information related with all headings for every investigational product. 2
  3. 3. GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013 COMMITTEE IN CLINICAL TRIALS 2.4.6. 2.4.7. 2.4.8. 2.4.9. 2.4.10. 2.4.11. 2.4.12. 2.4.13. 2.4.14. 2.4.15. 2.4.16. The dossier will depend on many factors including the nature of the investigational product, its development stage, the population to be studied, the nature and seriousness of the disease and the duration of exposure to the investigational product. Relevant scientific reasons should be provided if any data needs to be removed; a new section should be added if no applicable title is available for this procedure. The sponsor should submit summaries of the chemical, pharmaceutical and biological data for any investigational product. Related headings are provided in the annex to these guidelines. The sponsor’s investigational product to be used in the clinical trial should be produced in accordance with the principles of good manufacturing practices (GMP) and GMP Guidelines. The sponsor should submit summaries of the non-clinical pharmacological and toxicological data concerning any investigational product to be used in the clinical drug trial. If such data is not available, the reason should be provided. A list of references and relevant literature references related to the trials conducted should also be submitted. If required, copies of comprehensive data and references concerning the trials should be provided as well. It is preferable that data is tabulated and brief information highlighting the main points accompanies the table. Summaries of the trials conducted should show that the trial is compliant with and is conducted according to an acceptable protocol. The sponsor should submit the non-clinical information under the headings listed in the annex to these guidelines to the extent possible. The headings are not mandatory and not limited to this list. The sponsor should provide a critical analysis of the available data, including any deviations or omissions, and submit a summary of the data about the studies conducted together with an evaluation of the safety of the product within the context of the clinical trial to be conducted. All trials should be conducted according to the most advanced protocols which are currently accepted. In addition, requirements of good laboratory practices (GLP) should be met to the extent possible. The sponsor should provide the reasons for any deviation from these principles and submit a statement regarding the status of all trials in terms of GLP. The test material used in toxicity studies should represent the qualitative and quantitative impurity profiles. Preparation of test materials should be subjected to checks and thereby support the validity of the study. The sponsor should submit a summary of all available information from the past clinical trials and studies on humans conducted with the investigational products. Relevant headings are given in the annex to these guidelines but as much additional information as possible should be provided. The headings are not mandatory and should not be limited to this list. All trials should be conducted in accordance with the principles of good clinical practices (GCP) and the sponsor should affirm in a statement that the trials are conducted in line with GCP rules. If this is not possible, the sponsor should provide an explanation or reason. The sponsor should submit an integrated summary of clinical and non-clinical data, including a critical analysis of the potential risks and benefits of the study to be conducted. The wording should also include the reasons for early discontinuation of any study. These matters should particularly be considered when evaluating trials concerning children and the handicapped. 3
  4. 4. GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013 COMMITTEE IN CLINICAL TRIALS 2.4.17. 3. 3.1. 3.2. 3.3. 3.4. 3.5. 3.6. 3.7. 3.7.1. 3.7.2. The purpose of non-clinical pharmacology and toxicity tests is to demonstrate the main risks of the investigational product. The sponsor should use the relevant pharmacological, toxicological and pharmacokinetic results as the basis of extrapolation to indicate potential risks in humans. The sponsor should integrate all available data, analyze the pharmacological and toxicological effects of the investigational product, and demonstrate possible mechanisms of action. When possible, the safety margin of the investigational product should be discussed based preferably on the AUC and Cmax values instead of the dose administered. The clinical significance of any finding in the clinical and non-clinical trials should be explained as well as its reliability and effect on the clinical trials. If the investigational product is licensed/permitted in Turkey and has a dose regimen with the same form, same indications and same short product characteristics (SPC) or instructions for use (IFU), the sponsor may submit the SPC or IFU version currently approved by the Turkish Medicine and Medical Device Agency. However, additional non-clinical data or clinical data should be submitted to support the safety of the product’s use for a new indication, in a new patient population and at a new dose regimen. NOTIFICATION OF CHANGES AND METHOD OF OBTAINING PERMISSION Changes in the conduct of the clinical trial are allowed to be made after the trial has been initiated. All changes concerning the trial for which permission is required are specified in the applicable legislation. Significant changes in the conduct of the trial may arise from the protocol or new information concerning the scientific documentation supporting the trial. Examples for significant changes are listed in the annex to these guidelines. The sponsor should handle the cases individually, evaluate whether the change is significant, and apply to the ethics committee with the appropriate current form and cover letter sample published in the web site of the Turkish Medicine and Medical Device Agency. In case a significant change affects multiple protocols for a given investigational product, the sponsor or their legal representative should specify this in the cover letter and send a notification to the respective ethics committee for all affected protocols including a list with the full title of the trial, protocol number (if any) and name of the coordinator or principal investigator. Rejection of applications does not eliminate the applicant’s right to resubmit the information. The application for a change should include the following information as a minimum: The appropriate cover letter sample published in the web site of the Turkish Medicine and Medical Device Agency, The current application form which essentially includes the following but is also published in the web site of the Turkish Medicine and Medical Device Agency: 3.7.2.1. The full title of the clinical trial and protocol code number (if any), 3.7.2.2. The sponsor or their legal representative, 3.7.2.3. The version number and date of the updated change, 3.7.2.4. Changes in underlined format; summary of amended documents, if possible, 3.7.2.5. Updated overall risk-benefit assessment, if possible, 4
  5. 5. GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013 COMMITTEE IN CLINICAL TRIALS 3.8. 3.9. 4. 4.1. 4.2. 4.3. 4.4. 4.5. 4.6. 4.7. 4.8. 4.8.1. 4.8.2. 4.8.3. 4.8.4. 3.7.2.6. Possible outcomes for the subjects included in the trial and evaluation of these outcomes. If new developments occurring during the conduct of the study or development of the investigational product have the potential to affect the safety of the subjects, the sponsor or principal investigator may be required to take immediate safety measures to protect the subjects against possible risks. Such safety measures may be implemented without prior approval or permission of the ethics committee or the Turkish Medicine and Medical Device Agency. The sponsor or principal investigator should immediately inform the ethics committee about possible new developments, measures taken against them and plans to take other actions. This notification should first be made via fax and then in the form of a written report. The ethics committee should be notified when the sponsor discontinues the clinical trial (e.g. new subjects are no longer enrolled in the trial or the treatment of subjects already in the trial is discontinued). NOTIFICATION FOR THE DISCONTINUATION OF THE CLINICAL TRIAL The sponsor of the clinical trial or their legal representative should notify the respective ethics committee when the clinical trial is terminated. The sponsor or their legal representative should notify the termination of the clinical trial by using the current form and cover letter sample published in the web site of the Turkish Medicine and Medical Device Agency. The sponsor or their legal representative should inform the respective ethics committee and the Turkish Medicine and Medical Device Agency about the termination of the clinical trial within 90 (ninety) days following such termination. The trial protocol should include a section on the matters concerning termination of the trial, and any changes made in this section should be notified in accordance with the applicable legislation, whatever the reason for such change may be. The date of the last visit of the last subject in the trial can be identified as the termination date of the trial. Any exceptions should be explained in the protocol with reasons. If the sponsor decides not to initiate the trial or not to restart it after the trial is discontinued, the respective ethics committee should be notified; the sponsor should submit a letter that briefly explains the protocol, protocol code number (if any) and the reasons for not initiating or terminating the trial. The sponsor or their legal representative should submit a summary of the clinical trial result report to the respective ethics committee within one year following the termination of the trial at all centers, and comply with the legislation about good clinical practices. Notification about the termination of the clinical trial should be made by using the current form and cover letter sample published in the web site of the Turkish Medicine and Medical Device Agency. In case of early termination of the trial, the following information should be included at the end of the clinical trial report as a minimum: The reason for early termination of the trial, The number of subjects still receiving treatment at the time of trial termination, Patient management recommended for the patients receiving treatment at the time of trial termination, Evaluation of trial results. 5
  6. 6. GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013 COMMITTEE IN CLINICAL TRIALS 5. REPEALED REGULATIONS The “Guidelines on the Manner of Application to the Ethics Committee in Clinical Trials”, which entered into force pursuant to the Authority Approval No. 7668 dated 5 September 2011, have been repealed. 6. ENFORCEMENT These guidelines shall enter into force on their date of approval. 6
  7. 7. GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013 COMMITTEE IN CLINICAL TRIALS ANNEX -1: HEADINGS FOR THE QUALITY DATA OF INVESTIGATIONAL PRODUCT 1. Investigational Product 1.1. General information 1.2. Terminology 1.3. Structure 1.4. General Characteristics 2. Manufacture 2.1. Manufacturer 2.2. Description of the Manufacturing Process and Manufacturing Controls 2.3. Control of Materials 2.4. Control of Critical and Interim Steps 2.5. Process Validation or Assessment 2.6. Development of the Manufacturing Process 2.7. Identification 2.7.1. Description of the Structure and Other Characteristics 2.7.2. Impurities 2.7.3. Control of the Drug Substance 2.7.3.1. Specifications 2.7.3.2. Analytical Procedures 2.7.3.3. Validation of Analytical Procedures 2.7.3.4. Batch Analyses 2.7.3.5. Rationale for the Specifications 2.8. Reference Standards or Materials 2.9. Outer Packaging Closure System 2.10. Stability 2.11. Medicinal Product 2.11.1. Description and Composition of the Medicinal Product 2.11.2. Pharmaceutical Development 2.11.3. Components of the Medicinal Product 2.11.3.1. Drug Substance 2.11.4. Excipients 2.11.4.1. Medicinal Product 2.11.4.1.1. Development of the Formulation 2.11.4.1.1.1. Overages 2.11.4.1.1.2. Physicochemical and Biological Characteristics 2.11.4.1.1.3. Development of the Manufacturing Process 2.11.4.1.1.4. Outer Packaging Closure System 2.11.4.1.1.5. Microbiological Characteristics 2.11.4.1.1.6. Compliance 2.11.4.2. Manufacture 2.11.4.2.1. Manufacturer 2.11.4.2.2. Batch Formula 2.11.4.2.3. Description of the Manufacturing Process and Process Controls 7
  8. 8. GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013 COMMITTEE IN CLINICAL TRIALS 2.11.4.2.4. Controls of Critical and Interim Steps 2.11.4.2.5. Process Validation or Assessment 2.11.4.3. Excipient Control 2.11.4.3.1. Specifications 2.11.4.3.2. Analytical Procedures 2.11.4.3.3. Validation of Analytical Procedures 2.11.4.3.4. Rationale for Specifications 2.11.4.3.5. Excipient of Human or Animal Origin 2.11.4.3.6. New Excipients 2.11.4.4. Control of Medicinal Products 2.11.4.4.1. Specifications 2.11.4.4.2. Analytical Procedures 2.11.4.4.3. Validation of Analytical Procedures 2.11.4.4.4. Batch Analyses 2.11.4.4.5. Identification of Impurities 2.11.4.4.6. Rationale for Specifications 2.11.4.5. Reference Standards or Materials 2.11.4.6. Outer Packaging Closure System 2.11.4.7. Stability 3. Additions 3.1. Facilities and Equipment 3.2. Safety Assessment for Adventitious Agents 3.3. New Excipients 3.4. Rearrangement and Solvents of Diluents 8
  9. 9. GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013 COMMITTEE IN CLINICAL TRIALS ANNEX -2: HEADINGS TOXICOLOGICAL DATA FOR NON-CLINICAL PHARMACOLOGICAL AND 1. Pharmacodynamics 1.1. Brief summary 1.2. Primary pharmacodynamics 1.3. Secondary pharmacodynamics 1.4. Safety pharmacology 1.5. Pharmacodynamic interactions 1.6. Discussion and conclusion 2. Pharmacokinetics 2.1. Brief summary 2.1.1. Analytical methods 2.2. Absorption 2.3. Distribution 2.4. Metabolism 2.5. Excretion 2.6. Pharmacodynamic drug interactions 2.7. Other pharmacokinetic studies 2.8. Discussion and conclusion including an evaluation of toxicokinetics 3. Toxicology 3.1. Brief summary 3.2. Single-dose toxicity 3.3. Repeated dose toxicity* 3.4. Genotoxicity 3.4.1. In vitro 3.4.2. In vivo* 3.5. Carcinogenicity* 3.6. Reproductive and developmental toxicity* 3.7. Local tolerance 3.8. Other toxicity studies 3.9. Discussion and conclusion * These sections should be supported with toxicokinetic evaluations. 9
  10. 10. GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013 COMMITTEE IN CLINICAL TRIALS ANNEX -3: HEADINGS FOR THE DATA FROM CLINICAL STUDIES AND PAST EXPERIENCE IN HUMANS 1. Clinical pharmacology 1.1. Brief summary 1.2. Primary mechanism of action 1.3. Secondary pharmacological effects 1.4. Pharmacodynamic interactions 2. Clinical pharmacokinetics 2.1. Brief summary 2.2. Absorption 2.3. Distribution 2.4. Elimination 2.5. Pharmacokinetics of active metabolites 2.6. Plasma concentration-effect relationship 2.7. Dose and time dependencies 2.8. Specific patient populations 2.9. Interactions 3. Human exposure 3.1. Brief summary 3.2. General description for safety and efficacy 3.3. Study in healthy volunteers 3.4. Patient studies 3.5. Previous experience in humans 3.6. Evaluation of benefits and risks 4. Additions 10
  11. 11. GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013 COMMITTEE IN CLINICAL TRIALS ANNEX -4: EXAMPLES FOR FACTORS WHICH MAY REQUIRE A SIGNIFICANT CHANGE IN CLINICAL TRIALS The following changes are examples only and do not include all possible changes. Examples of Main Significant Changes Physical or mental health of subjects, Scientific value of the trial, The way or method of conducting the trial, The quality or safety of the investigational product used in the trial. Changes Concerning the Trial Protocol Trial objective, Trial design, Informed consent form (ICF), Method of enrolling subjects into the trial, Efficacy measurements, Addition or removal of tests or measurements, Number of subjects, Age range of subjects, Trial inclusion criteria, Trial exclusion criteria, Monitoring of subject safety, Duration of exposure to the investigational product, Change of the investigational product dosage, Change of the comparator, Statistical analysis. Changes Concerning the Administrative Structure Change of the principal investigator, Change of the coordinator, Change of the trial center or addition of new trial sites, Change of the sponsor or their legal representative, Changes Concerning the Investigational Product Change in the quality data of the investigational product, Change of the name or code of the investigational product, Change of the inner packaging material, Change of the active substance manufacturer, Change in the manufacturing process of the active substance, Change in the specifications of the active substance, Changes in the information regarding the manufacture of the medicinal product, Change in the specifications of the medicinal product, Changes in the specifications of excipients in cases where performance of the investigational product is affected, Change in the shelf life of the investigational product, Essential change in formulation, Change in storage conditions, Change in active substance testing methods, Change in medicinal product testing methods, 11
  12. 12. GUIDELINES ON THE MANNER OF APPLICATION TO THE ETHICS 17.04.2013 COMMITTEE IN CLINICAL TRIALS Change in the testing methods of excipients which are not related to pharmacopeia. Changes Concerning the Preclinical Pharmacology and Toxicology Data for Ongoing Trials Results of the newly made pharmacology tests, Novel interpretation of the available pharmacology tests, Results of the newly made toxicity tests, Novel interpretation of the available toxicity tests, Results of new interaction studies. Changes in Data on Usage in Clinical Trial Process and in Humans in Ongoing Trials Change in safety information occurring during the clinical trial process of the investigational product or its usage in humans, Results of the new pharmacology tests, Novel interpretation of the available clinical pharmacology tests, Results of new clinical trials, Novel interpretation of available clinical trial data, New data obtained from the use of the investigational product in humans, Novel interpretation of available data regarding the use of the investigational product in humans. 12

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