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IRB Reponse:

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div class="bodycopy">p>strong>Literature Examples that Underscore the Scientific Merit of Autologous Hamstring Resurfacing Arthroplasty research study.br/>
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/strong>There are three peer reviewed research studies that highlight the need for a autologous hamstring resurfacing arthroplasty research study.br/>
The first study is by Kai Mithoefer et al (JBJS 2005;87:1911-1920).  This was a landmark research case study on knee microfracture thatbr/>
demonstrates that a simple microfracture procedure does infact improve clinical knee scores. br/>
As noted in their report, "at the time of the latest follow-up, knee functionsup> /sup>were rated good to excellent for thirty-two patients (67%), fairsup> /sup>forbr/>
twelve patients (25%), and poor for four (8%). Significantsup> /sup>increases in the activities of daily living scores, International Knee Documentationbr/>
Committee scores, and the physical componentsup> /sup>score of the Short Form-36 were demonstrated after microfracture.sup> /sup>(p < 0.05). "br/>
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As is discussed in the main protocol section of this report, there has been more recent interest in applying a biologic cover over thebr/>
microfracture surface.  I have provided the IRB copies of two recent peer reviewed journal articles which will help demonstrate to the boardbr/>
that this type of "enhanced microfracture" research is becoming commonplace.  Again, my contention is that a strong arguement can be made br/>
that hamstring resurfacing over a microfractured surface could be expected to provide a better biologic response than the inert membranes that br/>
were used in the mentioned research studies.  I have attached a final review article on the biology of tendon metaplasia.br/>
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strong>Equitable Distribution of Patients:br/>
/strong>br/>
The best assurance that I can give the committee of equitable distribution of patients would involve maintenance of the same relative proportion of medicaid, medicare, and commercial insurance that I already have in my clinic.  My clinic spans three counties (Vance, Franklin, and Wake counties) and there is a wide diversity of income levels and education.  We do not keep records of minority percentages nor income levels, but we do have information regarding the number of medicaid, medicare, and commercially insured patients that we serve.  The number of medicaid patients is the best determinant we have of socially disadvantaged patients.  By demonstrating to the committee that the insurance ratios of my clinic patients are similar to the research patients, I can demonstrate equitable distribution.br/>
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 strong>Inclusion Criteriabr/>
/strong>br/>
The inclusion and exclusion criteria in this study have been based on a recent study by Kai Mithoefer et al (JBJS 2005;87:1911-1920)sup>1/sup>.  One way to view the autologous hamstring resurfacing arthroplasty study is that it is really an enhanced microfracture study.  Therefore it makes sense to use similar language and similar inclusion and exclusion criteria that was used in the Mithoefer study.  Based on the recommendations from the IRB committee, I reviewed and identified 12 ongoing clinical research trials that are either studying knee microfracture (or enhanced types of microfracture) or that are comparing knee microfracture to another type of surgical interventions.sup>2-13/sup>  It is striking that the inclusion and exclusion criteria and the language used in each of these studies is similar to the Mithoefer study.  Based on the totality of these studies, I have further revised my inclusion and exclusion criteria to ensure that the language is appropriate for IRB committee approval.  Of note, each of the ongoing clinical trialssup>2-13/sup>, seems to have some commercial objective, where as, the autologous hamstring procedure has none.br/>
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strong>BMI Criteria:/strong>br/>
The IRB committee has questioned the BMI criteria. In the study by Kai Mithoefer et al (JBJS 2005;87:1911-1920) the BMI ranged from 20-40 kg/msup>2 /sup>. (1)  In the other 12 current ongoing clinical trials sup>(2-13), /sup>the maximum BMI cut off criteria ranged from 30-40 kg/msup>2/sup>.  The BMI cut off value of 35 kg/msup>2 /sup>for this study (autologous hamstring resurfacing), is considered to be typical as compared to the other ongoing studies.br/>
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strong>Time Frame:br/>
/strong>The IRB committee wanted more information regarding the appropriate timing for reporting data (time frame).  As with the BMI issue, benchmarks from other research studies were utilized.  In the report by Kai Mithoefer et al (JBJS 2005;87:1911-1920), the follow up period was 2 years.sup>1/sup>  In other 12 current ongoing clinical trials sup>(2-13)/sup>, the follow up period ranged from 6 months to 48 years.  The two year follow up period described in this study (autologous hamstring resurfacing) would be considered typical as compared to other similar studies.br/>
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strong>Patient Selection:br/>
/strong>Finally, one of the other concerns of the committee was a better description of exactly how a patient would be entered into the study (in addition to the inclusion criteria).  All patients in my clinic are given every opportunity for non operative treatment.  This includes aggressive use of anti-inflammatory medications, topical anti-inflammatory medications, physical therapy, steroid injections, hyalauronic acid injections, and in some cases limited prescriptions for narcotic medications. Patients that fail to respond to these measures and who do not have gross evidence of advanced osteoarthritis will have a high incidence of chondral injuries.  The authors of one report noted chondral injuries in 63% of over 31,000 arthroscopic procedures.sup>14/sup>  The high incidence of chondral injuries found at knee arthroscopy has been validated in numerous other studies sup>15-19/sup>.  The patient pool for the autologous hamstring resurfacing arthroplasty will thus be selected fromsup> /sup>group of medical failures that have a high likelihood of having chondral injuries.br/>
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MRI scanning will be strongly encouraged for all potential study candidates.  It is accepted that MRI has low sensitivity but high specificity for chondral injuries of the knee sup>20,21/sup>.  MRI will be useful, however, in helping to minimize the chances that patients are entered into the study only to be excluded at the time of surgery because of objective intraoperative findings.  MRI has been shown to be useful in identifying patients with advanced arthritis (in some cases, radiographs can under-represent degenerative joint disease) sup>22/sup> in which case, these patients would be expected to exceed the 20 cmsup>2/sup> chondral injury limit that is outlined in the exclusion criteria.  Just as import, MRI will assist in ruling out other conditions that would preclude entry into the study (23,24).br/>
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As is discussed below, the preoperative MRI will only be used to help pre-screen potential candidates for entry into the study and will not be used for research purposes.  The only research measurement at the time of the hamstring arthroplasty would be the measurement of the surface area of the chondral injury during the surgical procedure.  This measurement would not only be required as a part of the inclusion/exclusion criteria, but this measurement would also be most useful when compared to the post operative changes in the Oxford knee score. (ie the comparison of the intraoperative size of the chondral injury to relative improvement in Oxford knee scores).br/>
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1 a href="http://www.ejbjs.org/cgi/content/abstract/87/9/1911?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=microfracture&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT">The Microfracture Technique for the Treatment of Articular Cartilage Lesions in the Knee/a> br/>
2 a href="http://clinicaltrials.gov/ct2/show/NCT00729716?term=microfracture&rank=1">Comparison of BioCart™II With span class="hit_org">Microfracture/span> for Treatment of Cartilage Defects of the Femoral Condyle/a>br/>
3 a href="http://clinicaltrials.gov/ct2/show/NCT00719576?term=microfracture&rank=2">A Comparison Between the Performance of Chondrocytes Versus span class="hit_org">Microfracture/span> Technique on Knee Symptoms (SUMMIT)/a>br/>
4 a href="http://clinicaltrials.gov/ct2/show/NCT00945399?term=microfracture&rank=3">Comparison of span class="hit_org">Microfracture/span> Treatment and CARTIPATCH® Chondrocyte Graft Treatment in Femoral Condyle Lesions/a>br/>
5 a href="http://clinicaltrials.gov/ct2/show/NCT00314236?term=microfracture&rank=4">Trial Comparing BST-CarGel and span class="hit_org">Microfracture/span> in Repair of Articular Cartilage Lesions in the Knee/a>br/>
6 a href="http://clinicaltrials.gov/ct2/show/NCT00414700?term=microfracture&rank=5">RCT of ChondroCelect® (in an ACI Procedure) vs span class="hit_org">Microfracture/span> in the Repair of Cartilage Defects of the Knee (TIGACT01)/a>br/>
7 a href="http://clinicaltrials.gov/ct2/show/NCT01041001?term=microfracture&rank=6">Study to Compare the Efficacy and Safety of Cartistem® and span class="hit_org">Microfracture/span> in Patients With Knee Articular Cartilage Injury or Defect/a>br/>
8 a href="http://clinicaltrials.gov/ct2/show/NCT00548119?term=microfracture&rank=7">NeoCart Phase 2 Clinical Trial/a>br/>
9 a href="http://clinicaltrials.gov/ct2/show/NCT01076673?term=microfracture&rank=8">Peripheral Blood-drived Stem Cell Trial on Damaged Knee Cartilage (PBSC)/a>br/>
10 a href="http://clinicaltrials.gov/ct2/show/NCT01066702?term=microfracture&rank=9">Confirmatory Study of NeoCart in Knee Cartilage Repair/a>br/>
11 a href="http://clinicaltrials.gov/ct2/show/NCT00881023?term=microfracture&rank=10">Cartilage Autograft Implantation System (CAIS) for the Repair of Knee Cartilage Through Cartilage Regeneration/a>br/>
12 a href="http://clinicaltrials.gov/ct2/show/NCT01183637?term=microfracture&rank=11">Evaluation of an Acellular Osteochondral Graft for Cartilage LEsions Pilot Trial (EAGLE Pilot)/a>br/>
13 a href="http://clinicaltrials.gov/ct2/show/NCT01110070?term=microfracture&rank=12">ChonDux for Filling Full Thickness Cartilage Defects in the Femoral Condyle of the Knee/a>br/>
14 a href="http://www.ncbi.nlm.nih.gov/pubmed/9276052?dopt=Abstract">Cartilage injuries: a review of 31,516 knee arthroscopies/a>br/>
15 a href="http://www.ncbi.nlm.nih.gov/pubmed/2590323?dopt=Abstract">Articular cartilage lesions of the knee/a>.br/>
16 a href="http://www.ncbi.nlm.nih.gov/pubmed/17428666">Articular cartilage defects: study of 25,124 knee arthroscopies/a>.br/>
17 a href="http://www.ncbi.nlm.nih.gov/pubmed/19026193">Isolated full thickness chondral injuries. Prevalance and outcome of treatment. A retrospective study of 5233 knee arthroscopies/a>.br/>
18a href="http://www.ncbi.nlm.nih.gov/pubmed/12209430">Articular cartilage defects in 1,000 knee arthroscopies/a>.br/>
19 a href="http://www.ncbi.nlm.nih.gov/pubmed/14754746">Articular cartilage lesions in 993 consecutive knee arthroscopies/a>br/>
20) a href="http://www.ncbi.nlm.nih.gov/pubmed/17027399">Sensitivity of routine 1.0-Tesla MRI versus arthroscopy as gold standard in fresh traumatic chondral lesions of the knee in young adults/a>.br/>
21) a href="http://www.ncbi.nlm.nih.gov/pubmed/12904842">Diagnosis of chondral lesions of the knee joint: can MRI replace arthroscopy? A prospective study/a>.br/>
22) a href="http://www.ncbi.nlm.nih.gov/pubmed/19409304">The accuracy of magnetic resonance imaging scanning and its influence on management decisions in knee surgery/a>.br/>
23) a href="http://www.ncbi.nlm.nih.gov/pubmed/12851344">Tumors about the knee misdiagnosed as athletic injuries/a>.br/>
24) a href="http://www.ncbi.nlm.nih.gov/pubmed/3661818">Sports tumors./a> br/>
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strong>Inclusion Criteria:br/>
/strong>br/>
1) Have not responded to nonsteroidal antiflammatory medication, steroid injections, hyaluronic injections or arthroscopic debridementbr/>
2) Have a documented cartilage defect in a weight bearing surface of the knee joint that does not exceed 20 cmsup> 2/sup> in maximum dimension as demonstrated by MRI or prior arthroscopybr/>
3) Patients whose physical examination results show no ligament instability of Grade II or abovebr/>
           (Grade 0: none, Grade I: 0-5 mm, Grade II: 5-10 mm, Grade III: >10 mm)/p>
strong>Exclusion Criteria:/strong>
div> br/>
1) Passive motion deficit of the knee (>5º of extension, >15º of flexion)/div>
div>2) Knee instabilitybr/>
        - patellofemoral instability br/>
        - knee ligament surgery within the past 6 monthsbr/>
        - presence of ligamentous injury which would require reconstruction, br/>
        - patients whose physical examination results show ligament instability of Grade II or abovebr/>
               (Grade 0: none, Grade I: 0-5 mm, Grade II: 5-10 mm, Grade III: >10 mm) br/>
3) Generalized tricompartmental osteoarthritis. br/>
4) Infection:br/>
        - history of knee joint infectionbr/>
        - active osteomyelitisbr/>
        - active infection in either lower limbbr/>
        - patients with infections requiring parenteral administration of antibiotics/div>
p>5) History of substance abuse (alcohol abuse or illicit substance use)br/>
6) Current participation in a study of an investigational product for a similar purposebr/>
7) Active litigation for the knee injury br/>
8) Patients with psychotic diseases, epilepsy, or any history of such diseasesbr/>
9) Patients who had been administered with immunosuppressants such as Cyclosporin A or azathioprine within the past six weeksbr/>
10) Patients with significant cognitive impairment, non-ambulatory status or lower extremities amputation other than toes, serious illness or medication affecting operative risk or wound healing (e.g. steroid intake, anticoagulation), and poorly controlled diabetes mellitus with a baseline HbA1c more than 8br/>
11) Patients with significant peripheral vascular disease as indicated by absent dorsalis pedis or posterior tibial pulses.br/>
12) Subjects with hepatitis, HIV or syphilis br/>
13) Malignancybr/>
14) BMI (Body Mass Index) greater than 35 kg/msup>2/sup>)br/>
br/>
strong> a href="/ortho/12819">Safety of Hamstring Harvest and Determination of Morbidity/a>./strong>/p>
p>br/>
strong>Delineation of Research Procedures: br/>
/strong>In the response letter, the committee wanted more information on " all research procedures that will take place and the timing of such procedures."  The preoperative MRI will only be used to help pre-screen potential candidates for entry into the study and will not be used for research purposes.  For instance, if the patient has advanced joint degeneration (beyond what is suggested on radiographs), there would be an expectation that there would be more than 20 cmsup>2/sup> of chondral injury and therefore the patient would be excluded from participation in the study.  The only research measurement at the time of the hamstring arthroplasty would be the measurement of the surface area of the chondral injury during the surgical procedure.  This measurement would not only be required as a part of the inclusion/exclusion criteria, but this measurement would also be most useful when compared to the post operative changes in the Oxford knee score. (ie the comparison of the intraoperative size of the chondral injury to relative improvement in Oxford knee scores)./p>
p> /p>/div>br/>hr/>br/>br/>br/>Last updated by Clifford R. Wheeless, III, MD on Thursday, November 4, 2010 2:41 pmbr/>

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