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The Difference Between The Difference Between Practice and Research – What Practice and Research – What

the FDA Expects You to the FDA Expects You to UnderstandUnderstand

Harvey M. Arbit, PharmD, MBA, RAC, CCRPHarvey M. Arbit, PharmD, MBA, RAC, CCRPUniversity of MinnesotaUniversity of Minnesota

Director, IND/IDE Assistance Program, Director, IND/IDE Assistance Program, Academic Health CenterAcademic Health Center

Adjunct Associate Professor,Adjunct Associate Professor, College of PharmacyCollege of Pharmacy

Phone 612-625-0930Phone 612-625-0930Fax 612-625-3956Fax 612-625-3956

E-mail E-mail arbit002@umn.eduarbit002@umn.eduwww.ahc.umn.edu/research/ind-ide/www.ahc.umn.edu/research/ind-ide/

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OutlineOutline

Practice vs ResearchPractice vs Research Sponsor and InvestigatorSponsor and Investigator Good Clinical PracticeGood Clinical Practice Clinical Trial MonitoringClinical Trial Monitoring Data & Safety Monitoring BoardData & Safety Monitoring Board Q & AQ & A

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Practice vs ResearchPractice vs Research

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Clinical Practice ≠ Clinical Clinical Practice ≠ Clinical ResearchResearch

Special Special trainingtraining is required. is required. Clinical research Clinical research mustmust be conducted be conducted

according to the written protocol with according to the written protocol with a full understanding of the risk to the a full understanding of the risk to the subjects.subjects.

The laws, regulations and guidelines The laws, regulations and guidelines for clinical research are for clinical research are detaileddetailed and and specificspecific..

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Clinical InvestigationClinical Investigation(Drug Research)(Drug Research)

Clinical investigation - any experiment that involves a test article and one or more Clinical investigation - any experiment that involves a test article and one or more human subjects. human subjects. 21 CFR 50.3(c)21 CFR 50.3(c)

Clinical investigation – any experiment in which a drug is administered or dispensed Clinical investigation – any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course experiment is any use of a drug except for the use of a marketed drug in the course of medical practice. of medical practice. 21 CFR 312.3(b)21 CFR 312.3(b)

Practice - Practice - exercise of an occupation or a professionexercise of an occupation or a profession– No protocolNo protocol– Administer to all patientsAdminister to all patients– Some documentationSome documentation– Not intended to publishNot intended to publish– Billable to insuranceBillable to insurance

ResearchResearch – systematic investigation designed to contribute to generalizable knowledge – systematic investigation designed to contribute to generalizable knowledge– ProtocolProtocol– Administer to some patientsAdminister to some patients– Much documentationMuch documentation– Intend to publishIntend to publish– Not billable to insuranceNot billable to insurance

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Clinical Trials vs Medical Clinical Trials vs Medical PracticePractice

Clinical trails are not to evaluate a Clinical trails are not to evaluate a medicine under actual medical medicine under actual medical practice conditions, but rather under practice conditions, but rather under selected and often artificial conditions selected and often artificial conditions to answer best the trial’s objectives.to answer best the trial’s objectives.

Controlled clinical trials cannot by Controlled clinical trials cannot by definition mimic actual medical definition mimic actual medical practice conditions.practice conditions.

Bert Spilker, Guide to Clinical Trials, 1996, p.554Bert Spilker, Guide to Clinical Trials, 1996, p.554

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Practice of MedicinePractice of Medicine

The practice of medicine combines The practice of medicine combines both both sciencescience as the evidence base as the evidence base and and artart in the application of this in the application of this medical knowledge in combination medical knowledge in combination with with intuitionintuition and clinical and clinical judgmentjudgment to determine the to determine the treatmenttreatment plan for plan for each patient. each patient. (ref. Wikipedia, 2007)(ref. Wikipedia, 2007)

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"Off-Label" Use of Marketed Drugs, "Off-Label" Use of Marketed Drugs, Biologics and Medical DevicesBiologics and Medical Devices

Good medical practice and the best interests of the patient Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment. and devices according to their best knowledge and judgment.

If physicians use a product for an indication not in the If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain rationale and on sound medical evidence, and to maintain records of the product's use and effects. records of the product's use and effects.

Use of a marketed product in this manner Use of a marketed product in this manner when the intent is when the intent is the "practice of medicine"the "practice of medicine" does not require the submission of does not require the submission of an Investigational New Drug Application (IND), Investigational an Investigational New Drug Application (IND), Investigational Device Exemption (IDE) or review by an Institutional Review Device Exemption (IDE) or review by an Institutional Review Board (IRB). Board (IRB).

However, the institution at which the product will be used However, the institution at which the product will be used may, under its own authority, require IRB review or other may, under its own authority, require IRB review or other institutional oversight. institutional oversight. (FDA Information Sheet Guidance for IRB, CI and S. 1998)(FDA Information Sheet Guidance for IRB, CI and S. 1998)

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Clinical TrialClinical Trial A comparison test of a A comparison test of a medicationmedication or other or other

medical treatment, versus a medical treatment, versus a placeboplacebo, other , other medications/devices, or the standard medical medications/devices, or the standard medical treatment for a patient's condition. treatment for a patient's condition.

Researchers test Researchers test hypotheseshypotheses and observe what and observe what happens, clinical trials can be seen as the happens, clinical trials can be seen as the application of the application of the scientific methodscientific method to to understanding human biology.understanding human biology.

Clinical trials are closely supervised by appropriate Clinical trials are closely supervised by appropriate regulatoryregulatory authorities. All studies that involve a authorities. All studies that involve a medical or therapeutic intervention on patients medical or therapeutic intervention on patients must be approved by an must be approved by an ethics committeeethics committee before before permission is granted to run the trial. permission is granted to run the trial. (ref Wikipedia, (ref Wikipedia, 2007)2007)

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Investigational Use of Marketed Drugs, Investigational Use of Marketed Drugs,

Biologics and Medical DevicesBiologics and Medical Devices

The investigational use of approved, marketed The investigational use of approved, marketed products differs from “off-label" use. products differs from “off-label" use.

"Investigational use" suggests the use of an "Investigational use" suggests the use of an approved product in the context of a clinical approved product in the context of a clinical study protocol. When the principal intent of the study protocol. When the principal intent of the investigational use of a test article is to develop investigational use of a test article is to develop information about the product's safety or efficacy, information about the product's safety or efficacy, submission of an IND or IDE may be required. submission of an IND or IDE may be required.

The clinical investigation of a marketed drug or The clinical investigation of a marketed drug or biologic does not require submission of an IND if biologic does not require submission of an IND if all six of the following conditions are met: all six of the following conditions are met:

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Investigational Use of Marketed Drugs, Investigational Use of Marketed Drugs, Biologics and Medical Devices (cont.)Biologics and Medical Devices (cont.)

(i) it is not intended to be reported to FDA in support of a (i) it is not intended to be reported to FDA in support of a new indication for use or to support any other significant new indication for use or to support any other significant change in the labeling for the drug; change in the labeling for the drug;

(ii) it is not intended to support a significant change in the (ii) it is not intended to support a significant change in the advertising for the product; advertising for the product;

(iii) it does not involve a route of administration or dosage (iii) it does not involve a route of administration or dosage level, use in a subject population, or other factor that level, use in a subject population, or other factor that significantly increases the risks (or decreases the significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the acceptability of the risks) associated with the use of the drug productdrug product; ;

(iv) it is conducted in compliance with the requirements for (iv) it is conducted in compliance with the requirements for IRB review and informed consent; IRB review and informed consent;

(v) it is conducted in compliance with the requirements (v) it is conducted in compliance with the requirements concerning the promotion and sale of drugs; and concerning the promotion and sale of drugs; and

(vi) it does not intend to invoke exemption from informed (vi) it does not intend to invoke exemption from informed consent. consent.

(FDA Information Sheet Guidance for IRB, CI and S. 1998)(FDA Information Sheet Guidance for IRB, CI and S. 1998)(IND Exemption Criteria, 21 CFR 312.2(b))(IND Exemption Criteria, 21 CFR 312.2(b))

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IND Assessment ProcessIND Assessment Process

When determining if the risk is When determining if the risk is significantly increased, the parts of significantly increased, the parts of the protocol that are examined are the protocol that are examined are those that concern those that concern – dose, dose, – schedule, schedule, – route of administration, and route of administration, and – patient population.patient population.

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Oncology DrugsOncology Drugs

Guidance for Industry: IND Guidance for Industry: IND Exemptions for Studies of Lawfully Exemptions for Studies of Lawfully Marketed Drugs or Biological Products Marketed Drugs or Biological Products for the Treatment of Cancer for the Treatment of Cancer (Jan. 2004)(Jan. 2004)

Focus is on whether risk is significantly Focus is on whether risk is significantly alteredaltered

Discusses a range of potential Discusses a range of potential scenarios and factors that may alter scenarios and factors that may alter riskrisk

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Sponsor and Sponsor and InvestigatorInvestigator

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http://aapp.org/pdf/HansMayoPresentation.pdf

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SponsorSponsor21 CFR 312.3(b)21 CFR 312.3(b)

An individual or company who takes An individual or company who takes responsibility for and initiates a responsibility for and initiates a clinical investigation. clinical investigation.

The sponsor does not actually The sponsor does not actually conduct the investigation unless the conduct the investigation unless the sponsor is a sponsor-investigator.sponsor is a sponsor-investigator.

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Sponsor-InvestigatorSponsor-Investigator 21 CFR 312.3(b)21 CFR 312.3(b)

An individual who both initiates and An individual who both initiates and conducts an investigation. conducts an investigation.

The term refers only to an individual. The term refers only to an individual. Must comply with the requirements Must comply with the requirements

of both an investigator and a of both an investigator and a sponsor.sponsor.

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Form FDA 1571Form FDA 1571

Investigational New Drug Investigational New Drug ApplicationApplication

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When a sponsor signs the 1571When a sponsor signs the 1571 he/she agrees to the following: he/she agrees to the following:

Wait 30 days before beginning the studyWait 30 days before beginning the study Not begin or continue the study if placed Not begin or continue the study if placed

on clinical holdon clinical hold IRB will be responsible for review and IRB will be responsible for review and

approval of the studyapproval of the study Conduct the study in accordance with all Conduct the study in accordance with all

applicable regulatory requirementsapplicable regulatory requirements ““WARNING: A willfully false statement is a WARNING: A willfully false statement is a

criminal offense.”criminal offense.”

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Responsibilities of Responsibilities of

SponsorsSponsors and Investigators and Investigators 21 CFR 312 Subpart D21 CFR 312 Subpart D

    § 312.50§ 312.50 - General responsibilities of sponsors. - General responsibilities of sponsors.     § 312.52§ 312.52 - Transfer of obligations to a contract - Transfer of obligations to a contract

research organization. research organization.     § 312.53§ 312.53 - Selecting investigators and monitors. - Selecting investigators and monitors.     § 312.54§ 312.54 - Emergency research under - Emergency research under      § 312.55§ 312.55 - Informing investigators. - Informing investigators.     § 312.56§ 312.56 - Review of ongoing investigations. - Review of ongoing investigations.   § 312.57 - Recordkeeping and record retention.   § 312.57 - Recordkeeping and record retention.   § 312.58 - Inspection of sponsor's records and   § 312.58 - Inspection of sponsor's records and reports. reports.   § 312.59 - Disposition of unused supply of   § 312.59 - Disposition of unused supply of

investigational drug. investigational drug.

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InvestigatorInvestigator 21 CFR 312.3(b)21 CFR 312.3(b)

An individual who actually An individual who actually conducts a clinical investigation.conducts a clinical investigation.

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Form FDA 1572Form FDA 1572

Statement of InvestigatorStatement of Investigator

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When an investigator signs the 1572 When an investigator signs the 1572 he/she commits to the following:he/she commits to the following:

To conduct the study according to protocol To conduct the study according to protocol To personally supervise or conduct the To personally supervise or conduct the

investigationinvestigation To inform the subjects of the investigational status To inform the subjects of the investigational status

of the test articleof the test article To report adverse events to the sponsorTo report adverse events to the sponsor To read and understand the Investigator’s BrochureTo read and understand the Investigator’s Brochure To inform all support personnel of the investigation To inform all support personnel of the investigation

requirementsrequirements

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1572 (Cont.)1572 (Cont.) To maintain adequate records and make them To maintain adequate records and make them

available for inspectionavailable for inspection To assure that the IRB is in complianceTo assure that the IRB is in compliance To assume responsibility for initial and continuing To assume responsibility for initial and continuing

review by the IRBreview by the IRB To promptly report study changes and To promptly report study changes and

unanticipated risks to the IRBunanticipated risks to the IRB Not make any changes in the research without Not make any changes in the research without

IRB approvalIRB approval To comply with the requirements regarding the To comply with the requirements regarding the

obligations of clinical investigatorsobligations of clinical investigators ““WARNING: A willfully false statement is a WARNING: A willfully false statement is a

criminal offense.”criminal offense.”

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Responsibilities of Responsibilities of Sponsors and Sponsors and InvestigatorsInvestigators

21 CFR 312 Subpart D21 CFR 312 Subpart D

    § 312.60 - General responsibilities of investigators. § 312.60 - General responsibilities of investigators.     § 312.61 - Control of the investigational drug. § 312.61 - Control of the investigational drug.     § 312.62 - Investigator recordkeeping and record § 312.62 - Investigator recordkeeping and record

retention. retention.     § 312.64 - Investigator reports. § 312.64 - Investigator reports.     § 312.66 - Assurance of IRB review. § 312.66 - Assurance of IRB review.     § 312.68 - Inspection of investigator's records and § 312.68 - Inspection of investigator's records and

reports. reports.     § 312.69 - Handling of controlled substances. § 312.69 - Handling of controlled substances.     § 312.70 - Disqualification of a clinical investigator. § 312.70 - Disqualification of a clinical investigator.

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Good Clinical Practice Good Clinical Practice (GCP)(GCP)

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Protocol elements for INDProtocol elements for IND 21 CFR 312.23(a)(6)(iii)21 CFR 312.23(a)(6)(iii)

Statement of the objectivesStatement of the objectives Names and qualifications of investigatorsNames and qualifications of investigators Inclusion/exclusion criteria and number of Inclusion/exclusion criteria and number of

subjectssubjects Design of the study and methods to Design of the study and methods to

minimize biasminimize bias Dose and duration of exposureDose and duration of exposure Observations/measurements to fulfill Observations/measurements to fulfill

objectivesobjectives Clinical procedures to monitor the effects of Clinical procedures to monitor the effects of

the drug to minimize riskthe drug to minimize risk

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Elements of a Clinical Trial Elements of a Clinical Trial ProtocolProtocol (GCP section 6)(GCP section 6)

Background informationBackground information Trial objectivesTrial objectives Trial designTrial design Selection and withdrawal of subjectsSelection and withdrawal of subjects Assessment of efficacyAssessment of efficacy Assessment of safetyAssessment of safety Statistical planStatistical plan Access to source documentation, QC/QA, Access to source documentation, QC/QA,

ethics, data handling, record keeping, ethics, data handling, record keeping, financial/insurance, publicationfinancial/insurance, publication

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Protocol ComplianceProtocol Compliance

It doesn’t matter who wrote the It doesn’t matter who wrote the protocol – or whether the trial is protocol – or whether the trial is funded by the DHHS or regulated by funded by the DHHS or regulated by FDA – FDA – NO change can be implemented NO change can be implemented without prior IRB approvalwithout prior IRB approval (except to (except to mitigate immediate hazard). The plan mitigate immediate hazard). The plan submitted to (and approved by) the submitted to (and approved by) the IRB cannot be changed without IRB cannot be changed without approval. Some changes must also be approval. Some changes must also be submitted to the FDA.submitted to the FDA.

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Clinical Trial Clinical Trial MonitoringMonitoring

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Proper MonitoringProper Monitoring(FDA Guideline for the Monitoring of Clinical (FDA Guideline for the Monitoring of Clinical

Investigations)Investigations)

To assure – adequate protection of the rights of

human subjects and – the safety of all subjects involved in

clinical investigations and – the quality and integrity of the resulting

data submitted to the FDA.

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Purpose of MonitoringPurpose of Monitoring (GCP section 5.18.1)(GCP section 5.18.1)

Validity and AccuracyValidity and Accuracy To verify that:To verify that:

– Rights and well-being of subjects are Rights and well-being of subjects are protectedprotected

– Reported data are accurate, complete, Reported data are accurate, complete, and verifiable from source documentsand verifiable from source documents

– Conduct of trial is in compliance with Conduct of trial is in compliance with approved protocol, GCP, and regulatory approved protocol, GCP, and regulatory requirementsrequirements

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Site/Clinical MonitoringSite/Clinical Monitoring Staff internal to the sponsor or a group under Staff internal to the sponsor or a group under

contract to the sponsor generally perform contract to the sponsor generally perform site/clinical monitoring. site/clinical monitoring.

They perform “on site” monitoring of They perform “on site” monitoring of individual case histories, assess adherence to individual case histories, assess adherence to the protocol, ensure the ongoing the protocol, ensure the ongoing implementation of appropriate data entry implementation of appropriate data entry and quality control procedures, and in and quality control procedures, and in general assess adherence to good clinical general assess adherence to good clinical practices. practices.

In blinded studies, these monitors remain In blinded studies, these monitors remain blinded to study arm assignment.blinded to study arm assignment.

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Focus of Monitoring VisitsFocus of Monitoring Visits

Informed consent / HIPAA formsInformed consent / HIPAA forms Source documents / CRFsSource documents / CRFs Product accountabilityProduct accountability Protocol adherenceProtocol adherence AE / Safety reportingAE / Safety reporting

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Data & Safety Data & Safety Monitoring Board Monitoring Board

(DSMB)(DSMB)

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DSMBDSMB

All clinical trials require safety monitoring All clinical trials require safety monitoring but not all trials require monitoring by a but not all trials require monitoring by a formal committee external to the trial formal committee external to the trial organizers and investigators.organizers and investigators.

A DSMB is not needed or advised for every A DSMB is not needed or advised for every clinical study.clinical study.

Several factors are relevant to determining Several factors are relevant to determining whether or not to establish a DSMB for a whether or not to establish a DSMB for a particular trial. These relate primarily to particular trial. These relate primarily to safety, practicality, and scientific validity.safety, practicality, and scientific validity.

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DSMB CompositionDSMB Composition

Most DSMBs are composed of Most DSMBs are composed of – clinicians with expertise in relevant clinicians with expertise in relevant

clinical specialtiesclinical specialties– at least one biostatistician at least one biostatistician

knowledgeable about statistical knowledgeable about statistical methods for clinical trials methods for clinical trials

– a medical ethicist knowledgeable about a medical ethicist knowledgeable about the design, conduct, and interpretation the design, conduct, and interpretation of clinical trialsof clinical trials

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Data Safety Monitoring Data Safety Monitoring GCP 5.5.2GCP 5.5.2

The sponsor may consider establishing an The sponsor may consider establishing an independent data monitoring committee to independent data monitoring committee to assess the progress of a clinical trial, assess the progress of a clinical trial, including the safety data and the critical including the safety data and the critical efficacy endpoints at intervals, and to efficacy endpoints at intervals, and to recommend to the sponsor whether to recommend to the sponsor whether to continue, modify, or stop a trial. continue, modify, or stop a trial.

The data monitoring committee should The data monitoring committee should have written operating procedures and have written operating procedures and maintain written records of all its meetings.maintain written records of all its meetings.

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What FDA Looks What FDA Looks ForFor

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What FDA Looks ForWhat FDA Looks For

Does the investigator understand and Does the investigator understand and apply the apply the basic element of quality databasic element of quality data??– Attributable, Legible, Contemporaneous, Attributable, Legible, Contemporaneous,

Original, AccurateOriginal, Accurate Can the investigator produce Can the investigator produce source datasource data

to corroborate the case report form?to corroborate the case report form?– Source data – Generally where data are first Source data – Generally where data are first

recordedrecorded– Must make records available for FDA inspection Must make records available for FDA inspection

(to copy and verify)(to copy and verify)

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What FDA Looks For (cont.)What FDA Looks For (cont.)

Is the drug/device secure and Is the drug/device secure and properly stored?properly stored?

Does the handling preserve Does the handling preserve “blinding” of the study?“blinding” of the study?

Is the drug/device administered/used Is the drug/device administered/used only under the investigator’s only under the investigator’s personal supervision or under personal supervision or under supervision of a sub-investigator supervision of a sub-investigator responsible to the investigator?responsible to the investigator?

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Regulatory ActionsRegulatory Actions

Form FDA 483Form FDA 483 Warning LetterWarning Letter Notice of Initiation of Disqualification Notice of Initiation of Disqualification

Proceeding and Opportunity to Proceeding and Opportunity to ExplainExplain

Disqualified/Restricted/Assurances Disqualified/Restricted/Assurances ListList

Administrative Actions ListAdministrative Actions List

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Summary – Summary – Points of ImportancePoints of Importance

A clinical research career is built on A clinical research career is built on ethics and integrity.ethics and integrity.

Ask a lot of questions before Ask a lot of questions before determining if “off-label” use is practice determining if “off-label” use is practice or research. “It depends …”or research. “It depends …”

Clinical monitoring is not an option.Clinical monitoring is not an option. Signed forms 1571 and 1572 are Signed forms 1571 and 1572 are

contracts with the Federal government.contracts with the Federal government. The FDA is your partner – like it or not.The FDA is your partner – like it or not.

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IND-IDE Assistance Program (IAP)IND-IDE Assistance Program (IAP) IAP DirectorIAP Director

Harvey M. Arbit, PharmD, MBA, RAC, CCRPHarvey M. Arbit, PharmD, MBA, RAC, CCRP arbit002@umn.eduarbit002@umn.edu 612-625-0930612-625-0930

IAP websiteIAP website www.ahc.umn.edu/research/ind-idewww.ahc.umn.edu/research/ind-ide

Are there any Questions ?

Thank you !