aor_1091 699..702

Japanese Guidance for Ventricular Assist Devices/TotalArtificial Hearts

*†Takashi Yamane, ‡Shunei Kyo, §Hikaru Matsuda, **Yusuke Abe, **Kou Imachi,††Toru Masuzawa, ‡‡Takeshi Nakatani, §§Kazuhiro Sase, ***Koichi Tabayashi,

†††Setsuo Takatani, ‡‡Eisuke Tatsumi, ‡‡‡Mitsuo Umezu,and §§§Toshie Tsuchiya

*National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan; †Pharmaceuticals and Medical DevicesAgency, Tokyo, Japan; ‡University of Tokyo Hospital, Tokyo, Japan; §Hyogo University of Health Sciences, Kobe, Japan;

**Graduate School of Medicine, University of Tokyo, Tokyo, Japan; ††Graduate School of Engineering, Ibaraki University,Hitachi, Japan; ‡‡National Cardiovascular Center, Suita, Osaka, Japan; §§Medical School, Juntendo University, Tokyo,

Japan; ***Graduate School of Medicine, Tohoku University, Sendai, Japan; †††Tokyo Medical and Dental University, Tokyo,Japan; ‡‡‡Department of Advanced Medical Engineering, Waseda University, Tokyo, Japan; and §§§National Institute of

Health Sciences, Tokyo, Japan

Abstract: To facilitate research and development (R&D)and to expedite the review processes of medical devices, theMinistry of Health, Labor and Welfare (MHLW) and theMinistry of Economy, Trade and Industry (METI) foundeda joint committee to establish guidance for newly emergingtechnology. From 2005 to 2007, two working groups helddiscussions on ventricular assist devices and total artificialhearts, including out-of-hospital programs, based on previ-

ous guidance documents and standards. Based on thisdiscussion, the METI published the R&D Guidelinesfor innovative artificial hearts in 2007, and in 2008 theMHLW published a Notification by Director regardingthe evaluation criteria for emerging technology. KeyWords: Guidance—Evaluation criteria—Ventricular assistdevice—Total artificial heart.

Although heart transplantation and artificial heartimplantation are two complementary approaches forsevere heart disease, the number of donor hearts islimited in Japan.The total number of registrations forheart transplantation was 159 over the past 12 years,while only 70 donors were found in Japan, with anaverage of five to six a year. Recent innovations inartificial hearts, on the other hand, particularly inreducing the pump size and in developing noncontactbearings, have enabled devices to be implanted andhave allowed patients to be discharged home. Artifi-

cial hearts are applicable as bridge-to-transplantation(BTT), bridge-to-bridge, bridge-to-recovery (BTR),or destination therapy (DT). Devices for DT, particu-larly those for long-term home care, will be necessaryin the near future. However, in Japan there has beena device lag of several years compared with the USAfrom the application to the approval of medicaldevices. To this end, the necessity has been recog-nized not only for promotion of research and devel-opment (R&D) for these devices among academiaand industry, but also for the establishment of guid-ance for R&D and for clinical evaluation.

There have been several previous guidance docu-ments and standards for ventricular assist devices(VADs) and total artificial hearts (TAHs): the Foodand Drug Administration (FDA) Guidance for VAD/TAH (1), the National Institutes of Health Requestfor Proposal for TAH (2), the American Society forArtificial Internal Organs (ASAIO)--Society of Tho-racic Surgeons (STS) Reliability Recommendation

doi:10.1111/j.1525-1594.2010.01091.x

Received March 2010; revised June 2010.Address correspondence and reprint requests to Dr. Takashi

Yamane, National Intitute of Advanced Industrial Science andTechnology (AIST), Namiki1-2-1, Tsukuba, Ibaraki, 305-8564,Japan. E-mail: yamane.t@aist.go.jp

Presented in part at the 17th Congress of the InternationalSociety for Rotary Blood Pumps held October 1–3, 2009 inSingapore.

Artificial Organs34(9):699–702, Wiley Periodicals, Inc.© 2010, Copyright the AuthorsArtificial Organs © 2010, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

699

for Mechanical Circulatory Support Systems (3), TheAssociation for the Advancement of Medical Instru-mentation Technical Information Report for VAD/TAH (4), the Japanese Society for Artificial OrgansGuidance for Clinical Trials (5), the Reliability Rec-ommendation by the National Clinical Trial InitiativeSubcommittee (6), and International Organizationfor Standardization (ISO) 14708-5 on CirculatorySupport Devices as Active Implants (7).

To facilitate R&D and to expedite the reviewprocesses of medical devices, the Ministry of Health,Labor and Welfare (MHLW) and the Ministry ofEconomy, Trade and Industry (METI) founded ajoint committee to establish guidance for newlyemerging technology. Under the joint committee,two working groups were formed to establish Japa-nese guidance for VAD/TAH. The members of thecommittee represented the Japanese Association forThoracic Surgery and the Japanese Society for Arti-ficial Organs. From 2005 to 2007, the two workinggroups, chaired by Dr. S. Kyo and Dr. H. Matsuda,respectively, held discussions that referred to (i)previous guidance and standards; (ii) the results of aquestionnaire on an out-of-hospital VAD programfor domestic hospitals; and (iii) a survey on out-of-hospital VAD programs through a mission to UShospitals and universities. Based on this discussion,the METI published the R&D Guidelines for inno-vative artificial hearts (8) in 2007 and the MHLWpublished a Notification by Director in 2008 regard-ing the evaluation criteria for emerging technology(9,10).

R&D GUIDANCE

The R&D Guidance, published as METI R&DGuidelines for innovative artificial hearts (8), is com-posed of the following items:

1 Purpose of use: The present guidance covers left/right ventricular assist devices, biventricular assistdevices, and TAHs for bridge and destinationtherapy.

2 Human factors and environments: There shouldbe no adverse events during transportation orexercises. No adverse events in any environmentduring air travel or computed tomography. Noimpingement or necrosis of surrounding tissues.Allowable level of noise/vibration. Usabilityshould be considered for controllers andbatteries. Alarms should satisfy the InternationalElectrotechnical Commission (IEC) 60601-1-8.

3 Fluid dynamic characteristics: Nonpulsatilepumps should satisfy ISO 5198 and pulsatile

pumps ISO 4409. Supplemental information canbe introduced by numerical analyses and/or flowvisualizations.

4 Heating characteristics: There should be noadverse events on surrounding tissues caused byhot spots.The temperature rise should satisfy ISO14708-1.

5 Electronic safety: The device should satisfy IEC60601-1 and ISO 14708-1.

6 Electromagnetic compatibility: The device shouldsatisfy IEC 60601-1-2 and IEC CISPR-11.

7 Control and monitoring: Device should be able tokeep intended flow and flow stability and beimplemented with necessary limiters and withnecessary monitors.

8 Conduits, grafts, artificial heart valves, or heartcuffs: The conduits should be evaluated with ISO7198 and the valves with ISO 5840. The conduits,grafts, or heart cuffs should not induce stenosis orcause air sacks. Junctions should be evaluatedagainst tension, twist, vibration, kink, or leakage.

9 Materials safety: The device materials should beevaluated with ISO 10993-1.

10 Biocompatibility: The device biocompatibilityshould be evaluated with ISO 10993-1, ISO10993-4, and ASTM F1841-97.

11 Animal testing: There should be no severethrombosis caused by the device. The samplesize should be at least six animals and the dura-tion 60 days. Whether a test involving more thaneight animals and 90 days is necessary should beconsidered from the point of international har-monization.

12 Durability (Reliability): The reliability testsshould be conducted with 80% reliability, 60%confidence level (80% is preferable), and a periodof 6 months, to be extended to over 2 years. Testconditions such as flow and pulsatility should bedefined in advance.

Annex A. Supplement for TAH: Common factorsand discrepancies between TAH and VAD.

Annex B. Supplement for durability test: Test con-ditions should reflect the patient’s physiological con-ditions and lifestyle. Handling rules for variousevents should be defined in advance.

Annex C. Supplement for out-of-hospital program:Requests for organizing a medical team for VAD; forestablishing a training system for patients and car-egivers; for establishing discharge criteria; for clarify-ing the emergency system to patients, caregivers, themedical team, and the ambulance system; for arrang-ing a monitoring system; and for arranging a devicemaintenance system.

T. YAMANE ET AL.700

Artif Organs, Vol. 34, No. 9, 2010

CLINICAL EVALUATION GUIDANCE

The clinical evaluation guidance, published asMHLW Notification by Director (9), is composed ofthe following items:

1 Fundamentals: Human factors and environments2 Nonclinical evaluation

In vitro evaluation (including Annex 1)In vivo evaluation (including Annex 2)

3 Clinical evaluation3.1 Compliance with good clinical practice3.2 Clinical trial protocol

3.2.1 Fundamentals: End points, other treat-ments, control, informed consent,patient management/follow-up, out-of-hospital program (Annex 3), trainingprogram for medical and co-medicalstaff, data safety monitoring board, cri-teria for discontinuing the clinical trial,etc.

3.2.2 Applicable diseases: End-stage cardiacdiseases as defined by the Japanese Cir-culation Society.

3.2.3 Objectives: BTT, BTR, or DT.Inclusion criteria: Patients with end-stage heart disease with extremely lowquality of life (QOL).Exclusion criteria: Severe infection, irre-versible multiorgan failure, pregnancy,complications of chronic pulmonarydisease, pulmonary thrombosis, or pul-monary hypertension, etc.

3.2.4 Sample size and duration: Overseasdata allowed. End points suitable for thefeasibility study or the pivotal study(Annex 4).

3.2.5 Facility qualification (Annex 5)3.2.6 Data acquisition rules3.2.7 Adverse events3.2.8 Safety evaluation3.2.9 Final evaluation (Annex 6)

Annex 1. Durability test (Same as R&D guidancesection 12)

Annex 2. Sample size and duration for animaltesting (Same as R&D guidance section 11)

Annex 3. Out-of-hospital program (Same as R&Dguidance Annex C)

Annex 4.Sample size and duration for clinical trials:Recommendations for clinical trials are around fivecases for a feasibility study and around 15 for a pivotalstudy. The recommendations for end points are 3months for the feasibility study, and, in a pivotal study,6 months for BTT and 12 and 24 months for DT.

Annex 5. Facilities for clinical trials: Institutionscertified as VAD facilities that perform more than100 cardiac surgeries a year.VAD implantation expe-riences for more than five cases. They should haveadequate transplantation facilities or be closely affili-ated with these. Staff members must have finisheda training course and there must be a committeeincluding a cardiologist. The procedure should beswitchable to paracorporeal VAD.

Annex 6. Final evaluation: (the Global Harmoni-zation Task Force [GHTF] SG5/N1R8 and SG5/N2R8) For bridge VAD (BTT and BTR), clinicalevaluation should be conducted (i) when patientsremain alive for more than 6 months with satisfactoryQOL, (ii) in the case of heart transplantation within 6months, or (iii) in the case of recovery within 6months. For DT VAD, clinical evaluation should beconducted (i) when patients remain alive for morethan 12 months with satisfactory QOL, (ii) in the caseof heart transplantation within 12 months, or (iii) inthe case of recovery within 12 months. For TAH,clinical evaluation should be conducted whenpatients remain alive for more than 2 months withsatisfactory QOL.

DISCUSSION

Table 1 shows a comparison between historicalguidance and standards. Regarding reliability testing,the FDA guidance (1) requested that X or moredevices are used with less than Y failures over twicethe intended use for short-term use and over Z yearsfor long-term use.The ASAIO-STS (3) required 80%reliability with at least 60% confidence for 1-yearmission life. The National Clinical Trial InitiativeSubcommittee (6) required the same level beforeInvestigative Device Exemption (IDE).The ISO/DISrequires that a reliability of X with at least Y confi-dence for a Z-year mission life is described.The Japa-nese guidance requires 80% reliability with at least60% (80%) confidence for 6 months, similar to theASAIO-STS recommendation.

Regarding animal testing, the FDA (1) required aduration of 5 months. The ASAIO-STS reduced therequest to eight animals for 90 days before IDE. TheISO/DIS requires only that the sample size and dura-tion are described. The Japanese guidance reducedthe request to at least six animals for 60 days withconsideration of eight animals for 90 days if neces-sary, which is a small reduction from the ASAIO-STSrecommendation.

Regarding clinical trials, the Japanese guidancereferred to practical goals for a feasibility studyand for a pivotal study, although most guidance

JAPANESE GUIDANCE FOR VAD/TAH 701

Artif Organs, Vol. 34, No. 9, 2010

documents and standards do not refer to practicalperiods. The present guidance is expected to con-tribute to the clinical application of VAD/TAH inJapan.

CONCLUSIONS

The R&D guidance and the clinical evaluationguidance were established through collaborationbetween academia, industry, and government. Suchcollaboration is very important, not only for artificialhearts but also for all newly emerging medicaldevices. Since the present article is an overview pre-sented by the authors and is not an authorized guid-ance by the MHLW or PMDA, it is recommendedthat readers refer to the original guidance.

Acknowledgments: The introduction of guidanceis funded by the METI Introduction Program ofR&D Guidelines for Medical Devices and theMHLW Introduction Program of Evaluation Criteriafor Newly Emerging Medical Devices.

REFERENCES

1. FDA. Guideline for the preparation and content of applica-tions to the Food and Drug Administration for ventricularassist devices and total artificial hearts. F89-33838; 1987.

2. NIH. Phased readiness testing of implantable total artificialhearts. Request for proposal, NHLBI-HV-92-28; 1992.

3. ASAIO-STS. Long-term mechanical circulatory supportsystem reliability recommendation. Ann Thorac Surg 1998;66:1852–9.

4. AAMI. Ventricular assist and heart replacement systems.TIR26:2000.

5. JSAO. Clinical trial guidance for medical devices for seriousheart diseases. 2003.

6. National Clinical Trial Initiative Subcommittee. Long-termmechanical circulatory support system reliability recommen-dation by the National Clinical Trial Initiative Subcommittee.ASAIO J 2009;55:534–42.

7. ISO. Implants for surgery—Active implantable medicaldevices, Part 5: particular requirements for circulatory supportdevices. ISO 14708-5; 2010.

8. METI. R&D Guidelines for active implants 2007: innovativeartificial heart systems. May 2007. Available at: http://www.meti.go.jp/policy/mono_info_service/service/iryou_fukushi/index.html. Accessed August 1, 2010.

9. MHLW. Notification by Director, OMDE, Yakushokuki-hatsuNo. 0404002: evaluation criteria for emerging technology: clini-cal evaluation criteria for next-generation artificial hearts.April 4, 2008. Available at: http://dmd.nihs.go.jp/jisedai/heart/heart_public.pdf. Accessed August 1, 2010.

10. Tatsumi E, Nakatani T, Imachi K, et al. Domestic and foreigntrends in the prevalence of heart failure and the necessity ofnext-generation artificial hearts: a survey by the working groupon establishment of assessment guidelines for next-generationartificial heart systems. J Artif Organs 2007;10:187–94.

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T. YAMANE ET AL.702

Artif Organs, Vol. 34, No. 9, 2010