Clinical Handbook FINAL

8/3/2019 Clinical Handbook FINAL

http://slidepdf.com/reader/full/clinical-handbook-final 1/30

UNITED STATES HQ

Life Technologies Corporation

5791 Van Allen Way

Carlsbad, CA 92008 USA

Telephone 760.603.7200

Fax 760.602.6500

2009 Life Technologies Corporation. All rights reserved. Trademarks of Life Technologies Corporation include: AIM V ®, AmnioMAX™, DynaChip®, DYNAL®, GIBCO®, LifeTechnologies ™, Life Technologies (logo)™, Molecular Probes®, Prodigy™, SPOT-Light®, StemPro®, Tropix®. TaqMan is a registered trademark of Roche Molecular Systems, Inc.All other trademarks are the sole property of their respective owners. ID C-088255



Contents



03 Life Technologies’ portfolio of in vitro diagnostic(IVD) products is growing rapidly and, as such, manyemployees are now very active in supporting keyprocesses that deliver IVD products to our customers.To that end, the Regulatory Affairs Team hasassembled this handbook in order to help addressthe most common questions associated with IVDproducts and to clarify some of the regulated productterminology.

This handbook prioritized the US and European IVDrequirements. Additional sections addressing IVD

requirements for China, Taiwan, Korea, Canada,Australia, etc. will be prioritized for distribution inearly 2010.

The questions that are discussed in the handbookare real-life questions brought to us by the variouscustomer-facing teams around the world. We canhelp you discuss these matters with customersdirectly to provide even more depth and guidance onthe regulatory environment. The Regulatory Affairsteam is here to enable and drive your business.

Any questions, concerns or suggestions relatingto this handbook or to the Life Technologies IVDproducts should be sent to the Regulatory Affairsglobal email address: !LIFE-Global Regulatory

[email protected].

John D’Angelo

Global Head of Regulatory Affairs and Compliance

[email protected]

For Americas Regulatory Affairs:

Kelli Tanzella

716-774-3122

[email protected]

For EMEA Regulatory Affairs:

Mario Wijker

+31 229 850 283

[email protected]

For AsiaPac Regulatory Affairs:

Hongbo (Julie) Su

+86 10 58 08 58 64

[email protected]



05 CLIA Laboratories

Do understand that it is the customer’s responsibilityto fulll the appropriate regulatory requirements iftheir application does not fall within the intended useof the marketed device.

Do market diagnostic devices to CLIA laboratories butdon’t promote them for use in homebrew diagnosticassays or any other use for which the product is notspecically cleared.

Do speak with Regulatory Affairs or Medical

Marketing if the customer wants to use a LifeTechnologies product to develop a commercialIVD test or collaborate with Life Technologies on adiagnostic application.

Don’t help a customer validate a diagnostic or clinicalprotocol.

Don’t analyze patient data on behalf of the customerin order to provide a diagnostic result.

Clinical DiagnosticsDos and Don’ts





09

09

Life Technologies Is Dedicated to Providing Diagnostic Products Spanning the Value Chain

OEM Components

• Quality Products

• Quality Systems

• Manufacturing Capability

• Reliable Supply

• Breadth of Technologies

• Quality Components

• Global Field Service

• Global Technical Support

• Assay Partner Program

• Variety of Products

• Compliant Quality Systems

• Global Field Service

• Global Technical Support


Lab Developed Test Products

Assay Partner Program

FDA IVD Products



11

11

OEM Components Powered by Life Technologies

Examples:

• Dynal® Beads

• Molecular Probes® uorescence products

• Dye-labeled oligonucleotides

• Tropix® chemiluminescence substrates

Life Technologies Is an OEM Provider

to Many In Vitro Diagnostic Manufacturers

• Wide range of high-quality instrument andreagent components

• Multiple manufacturing sites and planningsystems assure continuity of component supply

• Focus on lean manufacturing and utilization of SixSigma process excellence methodologies

• Quality systems and manufacturinginfrastructure suitable for variety of regulatedproduct requirements

• Custom laboratory services and manufacturingcapabilities



13

13 Life Technologies Develops, Manufactures,

and Commercializes IVD Products

• Variety of IVD instruments and reagenttechnologies

- Real-time PCR

- Transplant diagnostics

- Pathogen detection

- Molecular pathology

• Quality systems and manufacturing infrastructurecompliant with ISO 13485:2003 and QSR

• Global infrastructure of Field Service andTechnical Support personnel


Marketed IVD Products

Examples:

AmnioMAX™-II Complete Medium

AB 7500 Fast Dx Real-Time PCRInstrument

• rtPCR platform

Invitrogen SPOT-Light® HER2 CISH Kit

• Quantitative measure of HER2 gene

expression in breast cancer tumors

Invitrogen DynaChip® System

• Detection and identication ofClass I and II HLA antibodies





1717 4. Where can I obtain copies of our ISO Certicates?

Please contact the Quality Assurance group, whocan provide this information.

5. Where can I obtain a copy of the Certicate ofFree Sales?

You can request a Certicate of Free Salesfrom the Authorized Representative or anothermember of the Regulatory Affairs group.

6. What’s the difference between products that are

labeled RUO, IVD, or have a DMF or 510(k)?• A 510(k) clearance is an authorization by FDA

to market an IVD in accordance with its FDA-cleared intended use. A 510(k) device is subjectto a variety of FDA regulations, including GoodManufacturing Practices (GMPs), adverse eventreporting, recalls, and various enforcementremedies for violation of the regulations. A 510(k)cleared device may be used by CLIA laboratoriesto analyze clinical samples and report the resultsto physicians (assuming that the assay has beenappropriately cleared for use with the instrument).

• An RUO labeled device, in contrast, is not subjectto FDA regulations, so long as it is not used todiagnose clinical samples and report them todoctors or patients. An RUO labeled device, asits name implies, is limited to research use only.Thus, clinical samples may be analyzed but notfor the purpose of diagnosing a patient. Rather,the RUO labeled devices are intended to be usedin preclinical research.

• An IVD is an in vitro diagnostic device. In vitro means that the test occurs outside of the patient’sbody. An IVD can be 510(k) cleared, in which caseit can be used in clinical diagnosis consistent withits clearance or as an RUO directed to preclinicalresearch.

• A DMF is a drug master le. A DMF is a leestablished at FDA that contains condentialinformation about a product. This informationcan be referenced by a drug manufacturer foruse in seeking FDA approval. Life Technologieshas established DMFs on its products so thatinformation can be used by drug companiesseeking New Drug Application (NDA) approval fora drug that will be used in conjunction with a LifeTechnologies IVD.



1919 external body. All other IVDs are considered lowrisk and can be CE marked by the manufacturerin a process known as Self Certication.

11. What do I do if I receive a complaint involving adiagnostic product?

Complaints involving IVD products should beprocessed in the complaint handling system asper normal practice. For more details on thecomplaint handling process, please contact yourlocal Technical Support or Quality Assurancerepresentative. Complaints that involve serious

injury or death must be reported to the authoritieswithin a specic time frame. Please inform theRegulatory Affairs group as soon as you becomeaware of them.

12. What do I do if there is a safety incident involvinga diagnostic product?

Safety incidents involving a Life TechnologiesIVD must be reported to Quality Assurance andRegulatory Affairs immediately. The companyhas a legal obligation to report these incidentsto the authorities within a specic time frame. In

addition, safety incidents involving IVD productsshould be entered into the complaint handlingsystem.

13. In the US, how do I know if the order/complaint/tender I have received concerns an IVD product?How do I identify IVD products?

• All IVD products are labeled with the IVD symboland have the following statement on the label:“For in vitro diagnostic use”.

• This labeling allows the end user to use thenished product in his or her diagnosticapplications after the user has qualied theproduct for its intended use and/or receivedapproval from regulatory authorities for itsintended use.

14. In the EU, how do I know if the order/complaint/tender I have received concerns an IVD product?How do I identify IVD products?

• All IVD products are labeled with the CE and IVD

IVD



2121 SOPs) that I need to be aware of, and if so, wherecan I nd them?

Every department should have procedures forthe activities being performed. Additionally, allcustomer-facing employees should be aware ofthe complaint handling process for customercomplaints, and how to respond to potentialsafety incidents (known as Vigilance or MedicalDevice Reporting cases). Please contact QualityAssurance, who can advise on the availability andlocation of IVD-related internal procedures.

17. How should I apply the intended use statement?Can I promote an IVD product beyond its intendeduse statement?

The intended use statement is dened by themanufacturer and is a statement outlining themanufacturer’s intention on how the IVD shouldbe used and under which purpose the IVD hasbeen registered. You cannot promote an IVD forany use that is not covered by the intended usestatement. For example, the intended use of the3500 Dx instrument, which is currently marketedin the EU, is: “The instrument is intended tobe used by trained operators in the analysis of

human DNA or RNA, for the detection of geneticchanges that may lead to disease presence orsusceptibility.” Therefore, we cannot promote the3500 Dx for specic disease detection.

18. Can we train the customer on how to validatea protocol?

You cannot train the customer on how to validatea clinical protocol. You can refer to particular ISOstandards or guidelines that may apply: ISO 9001(Quality management systems requirements),ISO 13485 (Medical devices quality management

systems), ISO 17025 (General requirements forcalibration and testing laboratories), and ISO15189 (Medical laboratories. Requirements forquality and competence).

19. What is ISO 17025, and how can we help ourcustomers with accreditation?

ISO 17025 is an International Standard thatspecies the general requirements forlaboratory testing and calibrations. Laboratoriesgain accreditation to ISO 17025 as a way ofdemonstrating their competence to provide



2323 of clinical data submitted in a PMA or 510(k)application. Verbal or written complaints frompatients, physicians, or competitors may alsoresult in a directed inspection. Inspections issuedfor PMA data audits also fall into this category.Once an inspection has been completed, anestablishment inspection report (EIR) is preparedand submitted by the district ofce. This reportis then reviewed and classied by the Division ofBioresearch Monitoring. Classications assignedto inspections indicate whether or not theestablishment is operating in compliance with the

regulations. The classication scheme used bythe FDA is as follows:

NAI – No Action Indicated

VAI – Voluntary Action Indicated

OAI – Ofcial Action Indicated

23. What are FDA 483s and Warning Letters?

• When FDA investigators inspect a rm and nddeviations from current GMPs, they are requiredto provide the rm with their observations usingform FDA-483.

• Warning letters are a written communication inletter form from the FDA to advise an individual orcorporation that the FDA considers one or moreproducts, practices, processes, or other activitiesto be in violation of the Federal Food, Drug andCosmetic Act, or other acts. The letter states thatfailure of the responsible party to take appropriateand prompt action to correct and prevent anyfuture violations may result in enforcementaction.



2525 any validation and compliance with any regulatoryrequirements that pertain to the customer’sprocedures and instrument use.

Working with Clinical Diagnostics Customers

1. Can the customer provide a diagnostic result toa patient using an IVD product?

• Life Technologies’ IVD products can providediagnostic results only in accordance with theintended use statement of that product.

• If a customer wants to run an IVD assay on an

IVD instrument, they should conrm whetherthe regulatory requirements have been met forthat system or if they need to conduct furthervalidation.

2. What is the difference between clinical anddiagnostic protocols?

Typically there is no difference; however, somecustomers may dene “clinical” as “clinicalresearch”, and how the end result is used may bedifferent. The “clinical research” segment doesnot fall under the IVD or diagnostic regulations.

3. Can we organize clinical seminars in hospitals?

Yes, you can. Please ensure consistency in thepresentation and avoid interchanging IVD andnon-IVD products. Please also be aware that anymaterials presented or shared at such seminarsmust be reviewed and approved by Legal andRegulatory Affairs prior to being presented.

4. Can we respond to tenders in clinical hospitalson diagnostic targets?

If the intended use of a Life Technologies productmeets the requirements of the tender, then wecan respond. We cannot respond to tenderstowards specic diagnostic disease targets forwhich we do not have an FDA-cleared or EUregulated IVD device with that specic IVD use. Ifthe tender requires particular regulatory labelsand certications we currently do not have, youcannot respond by saying we comply. Pleasecheck with local management and RegulatoryAffairs on how best to respond.



2727 10. My customer is running a 510(k) assay. What LifeTechnologies instrument can they run this assayon?

The customer would have to use whateverinstrument is specied in the 510(k) for that assay,which may or may not be a Life Technologiesinstrument. If a customer uses an assay that hasnot received 510(k) clearance for use with theinstrument, they will be operating in violation ofthe FDA regulations.

11. Can we publish papers with customers on clinical

or diagnostic protocols?

Not at this point, but please forward these toApplication Support and Medical Marketing.

12. Can I help a customer license a new technologyfor clinical diagnostics purposes?

You can support a customer with the technicalprocedure on Life Technologies products as youwould do with any other customers. We cannottake part in clinical validation at this point. If youare asked by a customer to do so, please contactRegulatory Affairs or Medical Marketing, as this

request may turn out to be a future opportunityfor collaboration.

13. Can we help the customer to validate a clinical/diagnostic protocol?

You can support a customer with the technicalprocedure on Life Technologies products as youwould do with any other customers. We cannottake part in clinical validation at this point. If youare asked by a customer to do so, please contactRegulatory Affairs as this request may turn out tobe a future opportunity for collaboration.

14. Can we train the customer on how to validate aprotocol?

You cannot train the customer on how to validatea clinical protocol. Customers in CLIA Labs mustvalidate all assays using standards recognized bythe Clinical Laboratory Standards Institute (CLSI).

15. Can we re-label an RUO labeled product for IVDuse if requested by a customer?

No, we cannot re-label Research Use Onlyproducts. These products have not been



2929 21. If a customer has a homebrew test they wouldlike to license to us to manufacture and sell toother clinical labs as an IVD, what should I do?

Please forward any development requests to theHead of Medical Marketing for appropriate triage.

22. Can we develop custom products for our IVDcustomers?

Life Technologies can develop custom devicesfor IVD customers, but needs to be assured thatdevelopment is consistent with all applicableFDA and European regulations. The customerwill be responsible for interacting with regulatoryauthorities and receiving required marketauthorization. Please direct your inquiry toBusiness Development, Regulatory Affairs, andLegal.

23. My customer has set specications for incomingquality for a Life Technologies product that aredifferent from our product’s specication. Thecustomer wants to return the material. What doI do?

You should log the customer’s request as acomplaint, following the complaint handlingprocess. The Quality Assurance department willadvise on the response to the customer.

24. My customer has received a complaint regardingone of their Laboratory Developed Tests (LDTs)that utilizes a Life Technologies component. Thecustomer wants us to investigate. What do I do/whom do I contact?

• You should log the complaint as per the complainthandling process. If it meets the denition of

a complaint, then the problem with the LifeTechnologies product will be fully investigated.The LDT and other non-Life Technologiescomponents will not be investigated by us and arethe customer’s responsibility. Complaints thatinvolve serious injury or death are high-priorityand should be escalated to Regulatory Affairs assoon as you become aware of them.

• For more details on the complaint handlingprocess, please contact your local QualityAssurance representative.



3131 customer’s responsibility to fulll the appropriateregulatory requirements if they wish to use thissystem for clinical diagnostics.

• A customer can purchase an IVD system includinginstrument and application, which have both beencleared/approved by the regulatory authorities foruse together as a diagnostic system.

2. Can we sell an IVD instrument in the USwithout selling any accompanying diagnosticapplications?

Yes, as long as the instrument has a clearance/approval from the FDA. The instrument willultimately be linked to an appropriate assay by thecustomer (e.g., 7500 Fast Dx and H5N1), but theinstrument has a separate 510(k) enabling LifeTechnologies to sell it individually to customers.

3. Can we sell an IVD instrument in the EUwithout selling any accompanying diagnosticapplications?

Yes, by providing the customer with an IVDinstrument, they have an instrument that hasreceived regulatory clearance, which they can use

to validate diagnostic applications. Having an IVDinstrument removes some of the workload in thecustomer’s validation effort.

4. Can a customer use our IVD instrument fordiagnostic applications? What diagnostic resultscan a customer get with our IVD instrument?

Yes, customers can use our IVD instrument fordiagnostic applications and they can producediagnostic results in accordance with theFDA-cleared or EU regulated intended useof the instrument, so long as the regulatory

requirements for the particular application havebeen met.

5. Can a customer use diagnostic applications fromanother supplier on our IVD instrument?

Diagnostic applications from other suppliersmay be used on our IVD instruments. However,you should not advise the customer on suchuse unless the other supplier’s applicationis cleared for use with the Life Technologiesinstrument. Furthermore, if the customer wishesto provide a diagnostic result using this combined



3333 10. Can we provide the customer with evidencethat service engineers test tools have beencalibrated?

Yes, Service Engineers will carry calibrationcerticates with them for the tools they are usingto validate an IVD instrument. These are availableto customers on request.

IVD Chemistry Frequently AskedQuestions & Answers

1. Do we have evidence of the compatibility withother products?

Yes we do. Please contact Technical Support if yourequire additional information about a specicproduct.

2. Does the customer need to use referencematerials? Where/how can they get thesereference materials?

If reference materials are required thesematerials will either be included with the kit oridentied in the product insert for the customer.

3. Is it possible to give customers results fromstability studies? Have Life Technologiesperformed “open vials” studies?

We do not provide our stability testing resultsto customers but if required we can provide asummary indicating the shelf life of the product.Contact Technical Support if you requireadditional information about product stability.



3535 3. Life Technologies may procure raw materialswhich are non-GMP but may market these samematerials as GMP—what kind of processing andqualication do we undertake on such materialsto ensure they are qualied to a GMP level?

Life Technologies does not procure non-GMPmaterial and then market the same materialas GMP. However, we do procure non-GMP rawmaterials and further process these materialsinto nished products at one of our GMPfacilities registered with the FDA and compliantwith US 21 CFR Part 820. Our facilities have

validated processes and procedures in place toensure that products meet our internal productspecications. The regulations do not require thatall raw materials used in the nished productbe manufactured under the GMPs but they doexpect that the raw materials used meet USP/EP compendia requirements or equivalent whereavailable. If these grade raw materials are notavailable, additional testing may be required toshow that the raw material is safe.

4. What “use” is implied in the following GMPmarketing claims:

KSR XF: “By using KSR XF, researchers willbenet from the regulatory-friendly nature of acGMP formulation containing only human and/or recombinant proteins, dened human-origin,xeno-free serum replacement supplement”

StemPro® MSC SFM: “Batch-to-batchconsistency with each lot—produced under cGMPand qualied using a hMSC performance assay”

The above marketing claims are not clearly

stated.

• KSR XF Medium is manufactured under GMPsand is an animal origin free media formulationthat contains human origin materials. The animalorigin free status is benecial when submittingan application to regulatory authorities as the useof animal origin components can raise additionalquestions from regulatory authorities.

• StemPro® MSC SFM is manufactured underGMPs. Lot-to-lot consistency is obtained viaprocess and product controls in place at each



3737 controls in place to ensure that the raw materialspurchased meet internal specications and thatthe product is produced in a way to ensure batch-to-batch consistency via validation or vericationprocesses. Life Technologies procures non-GMPraw materials and further processes thesematerials into nished products at one of ourGMP facilities.

8. At what point during clinical trials will a customerhave to have all their raw materials producedunder GMPs?

After completion of Phase I clinical trials, theFDA expects that all nished products willbe manufactured following the GMPs. Theregulations do not require that all raw materialsused in the nished product be manufacturedunder the GMPs but they do expect that theraw materials used meet USP/EP compendiarequirements or equivalent where available. Ifthese grade raw materials are not available,additional testing may be required to show thatthe raw material is safe. When a marketingapplication is submitted to FDA, it is easierfor them to approve products that contain

components that are GMP compliant. RUOlabeled products create a challenge for FDA asperformance standards or quality attributes maynot be readily available or understood.

9. If a customer agrees to take on the risk of usingone of Life Technologies materials as part of anal cell therapy formulation to be introducedinto a patient with supportive toxicology data,should we allow it?

Yes, Life Technologies will help to support thecustomer in their regulatory lings (i.e., IND,

IDE) and work very closely with the customerby supplying the necessary documentationto support the integrity of the raw materialsand nished products supplied to them withCerticates of Analysis and raw materialspecications. Currently, we have manycustomers that have used our products in thesetypes of applications and other product lingswith regulatory bodies worldwide.

10. If GMP materials are available through aparticular vendor, do regulatory authorities (FDA)require that our customers use these materials





4141 OIVD is the FDA division within CDRH that hasregulatory responsibilities over IVD devices. TheFDA has recognized three main classes of medicaldevices based on the level of control necessary toassure the safety and effectiveness of the deviceregulated. The FDA regulation of medical devices forcommercialization is based on the categorization intothese three classes.

Class I:

e.g., ASRs, Cell Culture Media, Reagents

• Subject to the least regulatory control

• Subject to general GMP controls, registration,listing, and adverse event reporting

• Most Class I devices are exempt from 510(k)clearance

Class II:

e.g., 7500 Fast Dx Real-Time PCR Instrument, HLATyping Kits, Cell Culture Media for ex vivo application

• Moderate risk device

• Subject to special controls, which could includespecial labeling or performance standards

• Subject to 510(k) Premarket Notication, coveredby 21 CFR 807, Subpart E, and adverse eventreporting

Class III:

e.g., SPOT-Light® HER2 CISH Kit

• High-risk device

• Subject to general controls and special controls

• Subject to Premarket Approval (PMA), covered by21 CFR 814

What is an IVD?IVD products include reagents, instruments, andsystems which are intended to be used in vitro for thediagnosis of disease or other conditions, including adetermination of the state of health, in order to cure,mitigate, treat, or prevent disease or the conditionresulting from a disease. IVD products are intendedfor use in the collection, preparation, and examinationof specimens taken from the human body. An IVDcan be a reagent, reagent product, calibrator, controlmaterial, kit, instrument, apparatus, equipment,interpretation software, or system, which is eitherused alone or in combination.



4343 What is Medical Device Reporting (MDR)?

Medical Device Reporting (MDR), included inregulation 21 CFR, Part 803, is the mechanism for theFood and Drug Administration to receive signicantmedical device adverse events from manufacturers,importers and user facilities, so they can be detectedand corrected quickly.

How does Life Technologies report a problem witha Medical Device?

It is every employee’s responsibility when theybecome aware of an adverse event to report this

immediately to Regulatory Affairs. Device adverseevents or product problems are submitted to theFDA by Regulatory Affairs via the MedWatch programeither online, or by phone, fax, or mail. This processrequires that all adverse events detected by LifeTechnologies staff are reported immediately to theRegulatory Affairs department.

What is a reportable event or device adverse eventthat needs to be reported?

This is classied by the FDA as either a

• Serious injury/(Serious illness) [§803.3(aa)(1)] isan injury or illness that:

- Is life threatening, results in permanentimpairment of a body function or bodystructure; or

- Necessitates medical or surgical intervention

- Examples: Customer receives electrical shock,Customer injures himself using instrument

• A malfunction [§803.3(m)] is a failure of thedevice to meet its performance specications orotherwise perform as intended.

- Example: Instrument fails in delivering correctdiagnostic or monitoring results that may leadto death or injury based on diagnostic decision.





4747 What is the European In Vitro Diagnostic Directive(IVDD)?

The full name of the IVDD is Directive 98/79/EC ofthe European Parliament and of the Council of 27October 1998 on In Vitro Diagnostic Medical Devices. Itis one of a set of Directives that controls how medicaldevices are managed in Europe. The objective of theIVDD is to allow free movement of IVD products withinEurope and to ensure the safety and performance ofIVDs and the health of patients and users.

What is an IVD?

In accordance with the IVDD, an IVD medical device isone which is intended by the manufacturer to be usedin vitro for examining human samples for the purposeof providing information concerning a physiological orpathological state, or a congenital abnormality, or todetermine the safety and compatibility with potentialrecipients, or to monitor therapeutic measures. AnIVD can be a reagent, reagent product, calibrator,control material, kit, instrument, apparatus,equipment, or system, which is used either alone orin combination.

Who is the Manufacturer?

The “Manufacturer” is the natural or legal personwith responsibility for the design, manufacture,packaging and labeling of a device before it is placedon the market under his own name, regardless ofwhether these operations are carried out by thatperson himself or on his behalf by a third party.

What do Manufacturers have to do to comply withthe IVDD?

The manufacturers of IVD products must complywith all the requirements of the IVDD before they

market their IVDs in Europe. EU member states havetransferred the IVDD into their national law, andmanufacturers must check the legal requirementsin the EU country where they wish to market theirIVD to ensure that any additional country regulationshave been met. This can include a range of technical,quality and other requirements and can also meanthat the manufacturer has to translate the IVDlabeling and instructions for use into the primarylanguage of the country where they wish to sell theIVD.



4949 Complaint handling is an important input into theVigilance monitoring system and all complaints mustbe handled as per the internal complaint handlingprocedures. For further information on the complainthandling or vigilance processes, please contact yourlocal Quality representative.

What are the different risk categories for IVDs?

The IVDD has classied certain types of IVDs as high-risk. These IVDs are listed by name in Annex II of theIVDD and include reagents and reagent products fordetermining HIV, HTLV, hepatitis B, C, D, PSA tumor

markers, CMV, etc. The registration process that amanufacturer must follow for high-risk IVDs involvesan assessment by an external third party known asa Notied Body. IVDs that are not listed in Annex IIand are not for self-testing are considered lowerrisk products and these can be registered by themanufacturer without an external assessment in aprocess known as Self Certication.

What is the difference between list A and list B inAnnex II?

Annex II of the IVDD contains two lists of devices.List A includes what are considered the highest risk

devices such as reagents and reagent products fordetermining AOB blood groups, and for the detectionof HIV, HTLV and Hepatitis B etc. The devices inList B are considered a medium risk and include,for example, reagents and reagent products fordetermining rubella, CMV, and PSA tumor markers.The registration route for both lists of devices isslightly different but all products in Annex II require aNotied Body assessment.

What is CE Marking?

The term CE Marking is often used to refer to the

IVD registration process. Afxing the CE Mark to aproduct, however, actually demonstrates that theproduct complies with an EU Directive. CE Marksare used to show compliance to one or more of theDirectives such as the Low Voltage Directive (LVD)and Electromagnetic Compatibility Directive (EMCD).For example, when placing an IVD instrument onthe EU market, the device needs to comply with theIVD, LVD and the EMCD Directives. EU Directives areavailable for many consumer and industrial productslike electronic devices, toys, eyewear, etc. For CEMarking to the IVDD, labeling includes the CE Markplus the label for IVD.





5353 conditions, as ASRs are typically used by CLIA labsand Pharmaceutical companies in their productdevelopment activities.

Certicate to Foreign Government – is a documentprepared by FDA containing information about aproduct’s regulatory or marketing status.

CLIA – Clinical Laboratory ImprovementAmendments of 1988 is Congressional legislation thatpromulgated quality assurance practices in clinicallabs, and required them to measure performance ateach step of the testing process from the beginning to

the end-point of a response to a test result.

CLIA Laboratory – is any laboratory facility whichperforms laboratory testing on specimens derivedfrom humans for the purpose of providing informationfor the diagnosis, prevention, treatment of disease,or impairment or assessment of health and whichhas met the requirements of the Clinical LaboratoryImprovement Amendments (CLIA).

Device Classication – Medical devices are classiedinto Class I, II, and III. Regulatory control increasesfrom Class I to Class III. The device classication

regulation denes the regulatory requirements for ageneral device type. Most Class I devices are exemptfrom Premarket Notication 510(k); most Class IIdevices require Premarket Notication 510(k); andmost Class III devices require Premarket Approval.

Drug Master File (DMF) – a Drug Master File is asubmission to the FDA that may be used to providecondential detailed information about facilities,processes or articles used in the manufacturing,processing, packaging and storing of one or morehuman drugs. Law or FDA regulation does notrequire the submission of a DMF. A DMF is submitted

solely at the discretion of the holder. The informationcontained in the DMF may be used to supportan Investigational New Drug Application (IND), aNew Drug Application (NDA), an Abbreviated NewDrug Application (ANDA), another MAF, an ExportApplication, or amendments and supplements to anyof these.

There are ve types of DMFs.

Type I:

Manufacturing Site, Facilities, Operating Procedures,and Personnel



5555 or otherwise properly approved.

Investigational Device Exemption (IDE) – applicationwhich, when approved, allows the Class III device tobe shipped lawfully for the purpose of conductingclinical studies regarding the safety and effectivenessof the device, without complying with certainrequirements of the Act.

Laboratory Developed Test (LDT) – these are assaysdeveloped by a clinical laboratory, which are forinternal use and are not sold to outside entities.

Master File (MAF) – a Master File is a submissionto the CDRH center of the FDA that may beused to provide condential detailed informationabout facilities, processes or articles used in themanufacturing, processing, packaging and storing ofone or more medical devices.

Premarket Approval (PMA) – is the FDA’s processof scientic and regulatory review to evaluate thesafety and effectiveness of higher risk medicaldevices. (Class III devices are those that support orsustain human life, are of substantial importancein preventing impairment of human health, or

which present a potential, unreasonable risk ofillness or injury, or are new and present unknownsafety or effectiveness issues or risks). PMAis the most stringent type of device marketingapplication required by the FDA. To gain approval,the manufacturer must present adequate scienticevidence to verify that the device is safe and effectivefor its intended use (FDA Approval).

Premarket Notication – also referred to as a 510(k),is a submission to FDA that contains information todemonstrate that a medical device is substantiallyequivalent (SE) to a legally marketed (predicate)

device (FDA Clearance).

Substantially Equivalent (SE) – is a device that has thesame intended use and characteristics as an earlierdevice that has already received FDA clearance.

EU Specic Denitions

Annex II – an annex in the IVD Directive, whichcontains lists of the high-risk IVD devices (list Aand list B). An IVD product associated with thesetests cannot be self certied and must instead beevaluated by a Notied Body.



575721 CFR part 820 .............................................................................34, 35

510(k) ....................................................17, 18, 23, 31, 38, 40–42, 53, 55

Adverse Event ...............................................................17, 41, 43, 54, 56

Analyte Specic Reagent (ASR) ........................................40, 41, 52, 53

Annex II ...............................................................................18, 49, 55, 56

Applications ........................................................6, 19, 20, 28, 30–32, 37

Audit ............................................................................................6, 22, 23

Authorized Representative ..........................................16–18, 46, 48, 56

CE Mark/CE Marking .........................................................18, 19, 49, 55

Center for Biologics Evaluation and Research (CBER) ....................40

Center for Devices and Radiological Health

(CDRH) ..........................................................................18, 40, 41, 54, 55

Center for Drug Evaluation and Research (CDER) ......................40, 54

Certicate of Free Sales ................................................................17, 56

Certicate to Foreign Government ....................................................53

Class I .................................................................................34, 41, 53, 54

Class II ..........................................................................18, 34, 41, 53, 55

Class III .........................................................................18, 34, 41, 53, 55

Classication ............................................................................23, 42, 53

Clinical ....................5, 6, 8, 16, 17, 20–29, 31, 34, 36, 37, 38, 40, 53–55

Clinical Laboratory Improvement

Amendments (CLIA) ..........................................5, 17, 24, 27, 40, 53, 55

Code of Federal Regulations (CFR) ......................22, 34, 35, 40–43, 54

Collaboration ............................................................................24, 26–28

Competent Authority ...............................................................18, 48, 56

Complaint ...........................................................6, 19–21, 23, 29, 48, 49

Custom Products ................................................................................29

Declaration of Conformity .............................................................48, 56

Diagnostic ..................................3, 5, 6, 8, 16–20, 24, 25, 27, 28, 30–32,

36, 38, 40, 42, 43, 46, 47, 52, 54

Directive ............................................................18, 20, 46, 47, 49, 55, 56

Drug Master File (DMF) ...........................................................17, 53, 54

Exempted Devices ...............................................................................54

Food and Drug Administration (FDA) ........6, 16–18, 22, 23, 25–27, 29,

31, 34, 35, 37, 38, 40, 41, 43, 52–55

General Purpose Reagent (GPR) ..................................................40, 54

Good Manufacturing Practices (GMP) ......17, 23, 34–38, 40, 41, 52, 54

Homebrew ............................................................................5, 24, 29, 54

In Vitro Diagnostic (IVD)..............................3, 5, 6, 16–21, 24–33, 36, 38

40–42, 46–49, 52, 55, 56

Inspection .................................................................................22, 23, 56

Index

Documents

Clinical Handbook FINAL