text: May 5, 2005 The Honorable Mark McClellanAdministratorCenters for Medicare and Medicaid ServiceAttention: CMS-3818-PRoom 445-GHubert H. Humphrey Building200 Independence Avenue, SWWashington, DC 20201 Re: Comments on Conditions for Coverage for End Stage Renal Disease Facilities; Proposed Rule; CMS-3818-P Dear Administrator McClellan: The American Nephrology Nurses' Association (ANNA) is the professional nursing organization representing over 12,000 registered nurses (RNs) who care for patients with chronic kidney disease. The majority of our members practice in outpatient dialysis settings in a variety of roles including the provision of both direct and indirect care to patients on dialysis, management, staff training and development, and home dialysis training and support. ANNA's members represent those healthcare professionals in the closest and most frequent contact with individuals with ESRD, and as such, are heavily invested in the Proposed Rule revising the Conditions for Coverage for End Stage Renal Disease Facilities and the changes it suggests in how their practice setting will be regulated and how their patients will receive care through the Medicare program. Background ANNA wholeheartedly supports the Agency's fundamental shift in its regulatory approach to create a patient outcome-oriented environment. Suggestions on how it could be improved upon, what might be added or deleted, and which requirements are critical to patient care and safety will form the basis of the following comments. Before addressing the specifics of the Proposed Rule itself, we think it is important to comment that we noted a number of requirements in the Rule that are not consistent with Medicare payment policies. We believe it is incumbent upon the Agency to only establish regulatory requirements that are consistent with program payment rules or to change payment policies to support the rules. This problem was acknowledged with regard to the recommendation for Hepatitis C screening, but not with other provisions. We comment on these areas individually, but also wanted to call attention to them in a global context. Special procedures for approving ESRD facilities §488.60: ANNA is concerned that facilities applying for initial approval may not have the data requested by this rule, other than an attestation of compliance and of having qualified staff. Definitions §494.10: ANNA believes that the definition of "home" should include institutional settings such as a nursing facility (NFs) and skilled nursing facility (SNFs), if that is the patient's permanent residence. ANNA requests the inclusion of definitions of "direct supervision" and "immediate supervision." Direct supervision is cited at 494.140(e)(3). It is important to include a definition of immediate supervision and to be clear about the distinction between the two. We suggest that "immediate supervision" means the supervisor is actually observing the task or activity as it is performed and "direct supervision" means the supervisor is on the premises but not necessarily immediately physically present where the task or activity is being performed. We think this is consistent with the intent of the Proposed Rule but these definitions will make it more clear and must be included in the Final Rule to avoid problems at the facility level in determining compliance with some of the rules. Infection Control ANNA agrees with the proposal to establish Infection Control as a separate condition for coverage. ANNA supports the inclusion of the Healthcare Infection Control Practices Advisory Committee's (HICPAC) guidelines entitled "Hand Hygiene in Healthcare Settings." In its position statement on Vascular Access and in its Standards of Practice, ANNA has recognized the "Guideline for Preventing Intravascular Device-Related Infections" as the appropriate standard of care. We encourage CMS to do likewise in the Final Rule. Regarding Hepatitis C screening, it is unfortunate that the Proposed Rule makes an exception to the CDC recommendations in this regard. We understand that dialysis precautions should be sufficient to prevent the spread of Hepatitis C, but we are also aware that the intra-facility spread of hepatitis C is well documented and that screening patients and staff at baseline and at reasonable intervals, such as semi-annually as CDC recommends, would alert the facilities to significant breaks in the implementation of dialysis precautions. We believe this is an instance where a negative outcome should trigger investigation and stimulate practice correction and are suggesting later in this response that Infection be added to the performance components of the QAPI program. ANNA appreciates the Agency's recognition that Medicare payment policy is not consistent with CDC recommendations in this regard and believes it is unfortunate that payment policies do not consistently support the establishment of good policy for the beneficiaries. ANNA agrees with incorporating the CDC "Recommendations for Preventing Transmission of Infections among Chronic Hemodialysis Patients" and the guidance that staff members caring for HbsAg-positive patients should not care for HBV-susceptible patients at the same time if the definition of "HBV-susceptible" is "an individual who has Hepatitis B antibodies < 10." §494.30(a)(1): This language requires that items that cannot be cleaned and disinfected should be dedicated for use only by a single patient. Blood pressure cuffs are a good example of such items. Disposal of these cloth covered cuffs after patient use is not current practice and, while it may seem highly desirable, there are no cost effective disposable blood pressure cuffs available. Current practice is to surface clean the blood pressure cuff with an approved disinfectant. There are both cost and logistical considerations in requiring a blood pressure cuff for each patient. Storage of these cuffs and the cost of purchasing a cuff per patient make it unrealistic in the dialysis setting. Units with a large patient census would not necessarily have storage space for the cuffs. The challenge of inventing an impermeable, disposable, low cost covering for the BP cuff or inventing another means of blood pressure monitoring is the conceptual alternative to the current practice but is not available at this time. The same section proposes that dialyzers and blood tubing that will be reprocessed have caps placed on ports and lines clamped prior to placing these in a leak proof container for transport to the reprocessing area. We would suggest changing the language to clarify that "if placed into a container, that container must be leak proof." The practice in some facilities is to transport the dialyzer and tubing to the reuse area without the use of separate containers. Requiring a container introduces another piece of equipment that must be purchased and cleaned. §494.30(b)(2): In keeping with the outcome orientation of the Proposed Rule, ANNA does not agree with a requirement for an infection control officer and believes that facilities should determine such a need through their QAPI program and have therefore recommended that Infections be a required performance component of the QAPI program. While we realize that infections are a major concern, we believe that the QAPI focus should provide sufficient attention in this area. With regard to the existing infection control standard at §405.2140(b): ANNA agrees with the proposal to delete the redundant requirement regarding reuse; and with regard to the existing standard at §405.2140(c): ANNA agrees with the deletion of the "written policy" requirement. Water Quality ANNA agrees with the proposal to establish Water Quality as a separate condition for coverage. ANNA agrees with CMS that AAMI is the appropriate authority on water and dialysate quality and believes that the condition should endorse the entire AAMI Dialysate Standard (RD52:2004) as it is the most current standard to guide the user in selecting, maintaining, operating and monitoring water treatment components and the one most relevant to dialysis facilities. References to older AAMI documents related to water treatment would not be needed. Incorporating all of RD52:2004 would require, among other things: (1) a reduction in the allowable dialysate colony counts from 2000 cfu/ml to 200 cfu/ml, which would be a significantstep toward more pure dialysate, which ANNA believes is important, given evidence demonstrating a link between ultrapure dialysate and improved patient outcomes, reduced inflammation and other disease markers; and (2) two carbon tanks in series,with a minimum of 10 minutes Empty Bed Contact Time. We believe that most of the facilities in the US have already implemented this system to prevent the exposure of patients to chloramine. With regard to incorporating such documents by reference, we support a more rapid adoption process to update these regulatory requirements as the AAMI recommendations are updated to reflect changes in understanding and knowledge related to dialysis water and dialysate quality. §494.40(c)(2): ANNA suggests clarifying the language here. The proposed language states, "The water from the exit port of the first component or carbon tank which removes chlorine/chloramine is tested for chlorine/chloramine levels, at a minimum, before each patient shift or every 4 hours, whichever is shorter, during operation of the water treatment system." To provide clarity and maintain consistency with AAMI RD52:2004, the dialysate standard, we suggest the Final Rule read, "The water from the exit port of the first component or carbon tank which removes chlorine/chloramine is tested for chlorine/chloramine levels before each patient shift or at leastevery 4 hours during operation of the water treatment system." §494.40(c)(2)(ii): We suggest the rule should clearly state that using one test of sufficient sensitivity for total chlorine with a result of <0.10 is acceptable, rather than requiring two separate tests. Please note that, with incorporation of the entire AAMI Standard Dialysate for Hemodialysis (RD52:2004), 494.40(c)(2) and (c)(2)(ii) could be omitted, as these issues are addressed in that standard. Physical Environment Consistent with the statement on page 6201 of the Preamble that "patients should be in view of staff at all times during the treatment to ensure safety," we suggest this language be incorporated as a standard at §494.60. §494.60(c)(2)(i) and (ii): ANNA is sympathetic to the problem of maintaining adequate and comfortable temperatures for the majority of the patients and we believe that nurses already strive to keep their patients comfortable, as well as safe, during dialysis, but we do not think it is consistent with an outcome focus that these provisions be included in the final rule. §494.60(d): With the current international concern about bioterrorism, ANNA believes the final rule should address this. CMS could require dialysis facilities to incorporate bioterrorism preparedness procedures in their disaster plan, including such things as a means of communication with the local civil defense organization regarding transportation routes in case of evacuations, requiring patients to have at least 7 days of critical medications on hand, etc. Such things would be necessary in case of limited access to roads or mass transport systems, water supplies, pharmacies, grocery stores, etc. §494.60(d)(3): ANNA agrees with CMS that defibrillators should be required in all dialysis facilities, given the incidence of cardiac disease in the dialysis patient population. We prefer language that mandates automated external defibrillators (AEDs), especially in small, predominantly rural, dialysis facilities that might not have readily available emergency medical systems. The only exception could be facilities located inside hospitals that have ready access to the hospital's emergency response team. We agree that dialysis nursing staff must be trained in the proper use of emergency equipment and emergency drugs, and note that non-automated defibrillators require staff to be certified in Advanced Cardiac Life Support (ACLS). ACLS courses are not readily available to dialysis facilities, are time consuming and costly. If CMS requires non-automated defibrillators, this would also require that there be qualified staff on-duty at all times to operate those defibrillators. This is not practical in the current environment; we support the requirement of AEDs in the final rule. §494.60(e): ANNA suggests that provisions of the Life Safety Code (LSC) apply only to new facilities, those built after the final rule is implemented. Dialysis facilities are often located in buildings that do not have sprinklers. Requiring such a facility to have sprinklers installed would be a prohibitively costly expectation. Enforcement of other provisions of the LSC may require major, costly modifications to a building that currently houses a dialysis facility, or lead to facility closure or relocation. Patients' Rights ANNA suggests a different approach to this entire section. We believe that, as is true for all of us, rights are accompanied by responsibilities. While we recognize that CMS does not regulate patient behavior, we would appreciate a requirement that patients be informed of their responsibilities, to include, at a minimum, coming to scheduled treatments, being on time, following dietary and fluid restrictions, and informing the care team if they are unable to have prescriptions filled or to make physician appointments. §494.70(a)(5): ANNA strongly agrees with the sentiment expressed in the Proposed Rule that patients must be informed about and participate in all aspects of their care, while recognizing that a facility cannot require their patients to participate in the care process. We suggest, however, that the wording "if desired" should be changed to "if capable" to demonstrate an expectation of patient participation in care. We believe that if patients and families are expected to participate they will learn more readily and will be better able to monitor received care as well as assume varying degrees of self-management. This is both a safety and a quality of life issue, and registered nurses are eager to assess for self-management capability, to teach self-management skills to capable patients, and to support patients in self-management. §494.70(a)(6): The options presented should be stated more broadly to allow for new modalities that may emerge; further, the list should include the option for "No Treatment." §494.70(a)(13): ANNA agrees with the strengthened requirements for an internal grievance process. Most facilities already post grievance procedures in the lobby. Patient Assessment ANNA agrees wholeheartedly with CMS that the inclusion of a minimum set of assessment criteria is inconsistent with the agency's stated goal of eliminating unnecessarily prescriptive and process-oriented requirements and we therefore oppose the inclusion in the final rule of a condition on Patient Assessment. CMS seems to agree that there is little need for this in the Preamble, when it states that expanding the existing requirements with regard to patient assessment should not impose any additional burdens on facilities because quality-oriented facilities already routinely perform such assessments upon initiating treatment, and most facilities already have this information in the medical record. It is unclear what evidence of need is driving this requirement, which is in direct opposition to the Agency's new fundamental shift in approach to regulating. As professional nurses we do not need to have spelled out in regulation how to conduct an assessment on a patient with renal failure. In order to develop plans of care, each professional must go through a process that includes data gathering and begins with an assessment of the patient and of objective data related to the patient. Dialysis professionals have been doing this for over thirty years in developing care plans under the existing regulations. Federal oversight is unnecessary to ensure the professional nurse uses the nursing process, which is the foundation for all nursing care. In the Preamble, CMS states it believes the patient assessment and patient care plan are inextricably linked, with which we wholeheartedly agree and which bolsters our suggestion that the assessment should be eliminated as a condition and subsumed under Plan of Care, since an assessment is fundamental to the establishment of any such plan. Therefore, ANNA proposes that the language identifying the interdisciplinary team at §494.80 be moved to the introductory language at §494.90 and that §494.80(a) be deleted. The requirement at §494.80(b) regarding the frequency of assessments for new patients and the language at §494.80(d) regarding patient reassessment should be incorporated into §494.90(b) under the implementation of the plan of care. We believe the language at §494.80(c) related to assessment of treatment prescription is already addressed at §494.90(a)(1). With regard to the language identifying the members of the interdisciplinary team currently at §494.80, ANNA requests clarification of the first sentence with regard to the "inclusion of the patient (if the patient chooses) or the patient's designee." We have two concerns here. First, in the final rule please clarify whether this means either the patient or the patient's designee MUST participate, keeping in mind that some patients are not willing and some of them have no designee. Secondly, we would like to see the wording changed to "if the patient is capable." If the patient is capable but refuses, it is not appropriate to require a designee to take his place. However, if the patient is incapable, a surrogate is appropriate. The use of the word surrogate would make this clear. Understanding that the list of members of the interdisciplinary team is presented as a minimum requirement, ANNA suggests including "non-physician provider" (which can be an advanced practice nurse or a physician's assistant, as recognized in Medicare statute) as an optional part of the team. These professionals are recognized providers, are increasingly used in nephrology settings, and can represent the patient's physician to the extent allowed by law in any state. With regard to proposed §494.80(d)(2)(iv), which we are suggesting be moved to §494.90(b), ANNA has some concerns with this criterion for instability: "Poor nutritional status, with unmanaged anemia and inadequate dialysis." We believe that documented poor nutritional status is appropriate for this category, but do not believe it should be linked with unmanaged anemia and inadequate dialysis. Since there is already a proposed requirement for inadequate dialysis to be assessed on an ongoing basis, we suggest that (iv) should state "Poor nutritional status" and (v) should be added and should state "Unmanaged anemia." Plan of Care ANNA supports combining the elements of the existing long-term program into the patient plan of care. With regard to the proposal that outcomes specified in the patient plan of care must allow the patient to achieve "current evidence-based community-accepted standards," we want to express concern that, while we support requirements for facilities to organize their work in general, and to plan patient care in particular, with the goal of patients meeting at least minimum threshold values of established standards of care, we find this language in the proposed rule too vague. Specifically, "community-accepted" is not appropriate language for the Final Rule. Such language could allow facilities across the country to treat patients differently in terms of the outcomes expected of them. We suggest more specific language that would recognize The National Kidney Foundation's Kidney Disease Outcome Quality Initiative (K/DOQI) or other standards that may be developed by recognized healthcare standard-setting organizations through a rigorous scientific process that has involved experts in the renal field and that have been endorsed and embraced by the renal community. Currently these standards are the K/DOQI guidelines, so we have chosen to reference them in our comments that follow. §494.90(a): ANNA suggests that "bone disease management" should be incorporated into the plan of care and read: "The interdisciplinary team must provide the necessary care and services to achieve a stable skeleton and avoid the consequences of secondary hyperparathyroidism. Calcium, phosphorous and other laboratory tests related to achieving these outcomes should be measured as recommended in clinical performance measures and minimal thresholds should be met." The Final Rule should include additional language that references the specific minimum K/DOQI standard(s) the Agency intends to be met for bone disease management. §494.90(a)(1): The Final Rule should include additional language that references the specific minimum K/DOQI standard(s) the Agency intends to be met for hemo and peritoneal dialysis adequacy. §494.90(a)(2): ANNA believes that albumin is a poor measure of patient nutritional status as it is affected by fluid overload, infection, liver disease, inflammatory conditions etc. A global assessment tool taking into account several markers should be used. We would suggest using Normalized Protein Catabolic Rate (NPCR) as an additional outcome measure. We note the language of the rule requires the interdisciplinary team to "provide the necessary care and services to achieve and sustain an effective nutritional status" and must point out that there is no covered Medicare benefit for any "care and services" that would achieve this end. The team can monitor nutritional status but is handicapped in affecting any outcome measure that would be decided upon. This has been well documented in the Clinical Performance Measure project that has shown no improvement in serum albumin since the initiation of the Core Indicators Project in 1994. This reality should be reflected in the construction of the Final Rule, and the language in the first sentence must be limited to read, "The interdisciplinary team must monitor the patient's nutritional status." §494.90(a)(3): The Final Rule should include additional language that references the specific minimum K/DOQI standard(s) the Agency intends to be met for anemia management. According to the K/DOQI guidelines, patients with hemoglobin and hematocrit in the range specified in the Proposed Rule are evaluated for cause and appropriate treatment for their anemia, including erythropoietin therapy. The language here should be expanded to include these actions. We must also comment here that Medicare payment policy runs contrary to this goal, in that erythropoietin cannot be initiated on a patient who was not treated with erythropoietin prior to beginning dialysis therapy until his/her hemoglobin reaches 10gm/dL. We reiterate that these regulations should be consistent with Medicare payment policies or that payment policies should be changed to support these regulations. §494.90(a)(4): ANNA agrees that the interdisciplinary team must provide the necessary care and services to achieve and sustain vascular access for all patients, but we question how facilities will be reimbursed for the required "monitoring of arteriovenous grafts and fistulae for stenosis" Monitoring by means of frequent physical examination as per the K/DOQI guidelines is certainly a necessary expectation but, if in this context, "monitoring" means mechanical surveillance such as transonic flow measurements, there is no Medicare reimbursement for such services. The only "monitoring" of a vascular access that could have been envisioned when the composite rate payment was developed over three decades ago was done by a professional with eyes, ears (stethoscope), and fingertips. If frequent physical exam is what is meant by monitoring in §494.90(a)(4), ANNA has no problem with it, but that should be made clear. If the intent is more than that, the requirement should be deleted from the Final Rule, unless payment policy can be changed to allow reimbursement for more sophisticated "monitoring." It would be ideal to have a vascular access coordinator (RN) on the interdisciplinary team. We believe that such a role would be very cost effective in a globally-capitated disease management system, but doubt that many facilities could hire a dedicated vascular access coordinator in the current reimbursement environment. §494.90(a)(5): ANNA agrees that the transplant status must be part of the plan of care condition and agrees with CMS that the transplant surgeon need not be involved with the facility interdisciplinary team unless a possible candidate has been identified. ANNA shares CMS' concern that all appropriate potential transplant recipients be referred and followed, but points out that such referral is the responsibility of the patient's attending nephrologist, who is not an employee of the facility. We further agree that in cases when the patient meets the transplantation criteria but declines referral, there must be documentation in the patient plan of care that the patient has made an informed decision to decline renal transplantation. §494.90(a)(6): ANNA applauds the rationale in the preamble for rehabilitation and strongly supports the philosophy of self-management. Unfortunately the current caseloads for all members of the interdisciplinary team plus the acuity level of the patients make this goal unachievable. We believe that the interdisciplinary team must assist the patient in achieving the level of productive activity he/she desires by providing educational materials and referrals to community services. Physical and occupational therapists would be needed to implement, monitor, and evaluate exercise regimens. Except for making appropriate referrals, ANNA believes this requirement goes beyond the scope of the role of a dialysis facility and suggests that it be deleted from the list of minimum elements in the plan of care and that appropriate referrals be addressed under Social Services. In relation to the schooling needs of pediatric patients, again this would be evaluated during the psychosocial assessment but it is beyond the scope of the interdisciplinary team of a dialysis facility to provide for the general education of these patients. However, the team needs to assure that the dialysis schedule and related appointments of patients attending school are tailored to meet their needs. §494.90(b)(2): ANNA believes that the timeframe for implementation of the plan of care for new patients should be measured by the number of treatments rather than the number of days because of the potential for missed treatments. Therefore, if the care planning process is completed in 21 days or 9 treatments, whichever is longer, implementing the plan of care by the conclusion of the 12th treatment provides a more suitable timeframe for the patient starting thrice weekly hemodialysis. We believe 30 days would suffice for the peritoneal dialysis patient. Once established, a plan of care is a dynamic document, changing as the patient's needs and outcomes change, but we agree with CMS that the plan should be formally revisited within three months of initial establishment. §494.90(b)(3): This goes without saying, as it is a normal element of the care planning process. Registered nurses learn this early in their education and it does not belong in federal regulation. §494.90(b)(4): While ANNA agrees that monthly interactions between patients and their physician are desirable, we do not believe the dialysis facility can be expected to ensure that all patients are seen by a physician at least monthly. Furthermore, we believe it is highly inappropriate for CMS to suggest requiring one provider to monitor another provider that Medicare is precluded by statute from regulating. The first sentence of Title XVIII, Section 1801, [42 U.S.C. 1395] states: "Nothing in this title shall be construed to authorize any Federal officer or employee to exercise any supervision or control over the practice of medicine or the manner in which medical services are provided, or over the selection, tenure, or compensation of any officer or employee of any institution, agency, or person providing health services; or to exercise any supervision or control over the administration or operation of any such institution, agency, or person." ANNA strongly suggests that the language at (b)(4) be eliminated from the Final Rule and further suggests that this language is no longer necessary given the recent changes in the physician's MCP payment. §494.90(c): ANNA agrees that the interdisciplinary team or, more specifically, a designated member of the team, will be responsible for tracking the results of each kidney transplant referral until the patient evaluation is complete. We suggest that, since the proposed conditions of participation for transplant centers published in the Federal Register on February 4, 2005, require those centers to notify a patient's usual dialysis facility of the patient's transplant status post referral, and about any changes in their status, that this should be reflected in the final rule. We agree that the dialysis facility should notify the transplant center of changes in the clinical status of patients seeking transplantation. We recognize that when such changes are not communicated in a timely manner, unnecessary delays in the organ placement process may be incurred, potentially negatively impacting the transplant outcome. Recognizing the need for timeliness, we would suggest requiring notification of the transplant center of any change in the patient's status, rather than on any prescribed frequency. We would also like to suggest that secure internet access to the transplant center data base, which could be limited to thedialysis facility provider number and only to that facility's listed patients, would be an efficient way for the dialysis unit to monitor the waiting list as well as to alert the transplant center about changes in a patient's clinical status. §494.90(d): ANNA supports the requirement for a patient education program. Nurses are teachers and we know that the informed patient is more likely to self-monitor and self-manage to the fullest extent possible. To add more substance to other areas in the Conditions, ANNA strongly suggests that (1) education and training on the risks, benefits and outcomes of various access types be included here because patients have the right to know the risks and benefits of each type of vascular access, particularly of the one they are currently using; and (2) "advance care planning" be added here since patients should not only be informed about their right to establish an advance directive at initiation of therapy, but they should also receive ongoing education about the importance of this as part of the plan of care and their participation in it. Care At Home §494.100: ANNA strongly agrees that home dialysis patients receive the comparable quality of care and attention that the in-center patient receives. §494.100(a)(2): ANNA agrees that initial home training of the patient and caregiver should be conducted by a qualified registered nurse and we agree with the qualifications. §494.100(a)(3): ANNA agrees with CMS that specifying the topics for a training program appears to be inconsistent with the goal of reducing the process-oriented requirements and therefore opposes their inclusion. We question what evidence exists that led the agency to prescribe the elements of training, in direct opposition to the expressed new fundamental shift in approach to regulating. Nephrology professionals can be expected to design and carry out home training as they have for the past thirty-five years. §494.100(c): Most of the requirements in this standard are already required of the facility with respect to ALL patients receiving care and services through the facility; therefore, ANNA does not see the need to restate them in this section. The structure seems to distinguish the home dialysis patients from the facility's entire population, when the stated goal is to provide equivalent services to the home dialysis population. We suggest the following: §494.100(c)(1)(i) and (ii) remain as is and the other subsections be deleted as they are not necessary. §494.100(c)(2) is also unnecessary as the facility will maintain a medical record for its home patients and, as stated, §444.330(a)(2) requires Durable Medical Equipment (DME) suppliers to provide the facility with a record of items and services it has provided to home dialysis patients who are being supported by the facility. With regard to dialysis of residents of a NF or SNF or other institutional settings, ANNA agrees with the designation of such institutional settings as a patient's "home" if that is their permanent residence. ANNA is pleased to see the discussion of issues related to dialyzing the frail institutionalized elderly included in the Preamble, but notes there is nothing in the Proposed Rule about this. We take that as an invitation to continue to communicate with the Agency about this important subject since the incidence of ESRD is highest in the age groups that predominate in these types of settings. ANNA also believes the modality of choice for the frail elderly should be peritoneal dialysis, as is the case in many other countries, and encourages the Medicare program to develop payment policies that support that goal. That said, ANNA believes the dialysis facility approved for home training should retain oversight responsibility for the patient and the caregiver as per current home training/home dialysis standards, regardless of whether the caregiver is a paid employee of the training facility, the institution, the patient, or a DME company. We believe that, in recognition of the fact that these patients may have limited skills and abilities, the requirement to train the patient should be waived. Likewise, in recognition of the limited space in such institutional settings, the requirement for one dialysis machine per patient should be waived, and we do not believe that would equate to the creation of a dialysis facility. ANNA does not believe that such institutions should be required to meet these Conditions for Coverage just because they house home dialysis patients. Financial practicalities preclude requiring a nurse to perform all dialysis treatments in these settings, although at times that will be the case. We recommend that a standard be developed based on input from the renal care community that would address the decision-making as to patient-level characteristics that affect the type of caregiver required. ANNA believes that experienced dialysis clinicians (and the experience should be defined) should be able to dialyze multiple patients in the same room, depending on the patients' acuity and stability, as long as personnel from the institution are available to help provide routine medical tasks unrelated to dialysis, like taking vital signs, if and when needed. These are our initial thoughts on this subject and, as mentioned, we look forward to continuing our dialogue with the Agency on this important subject before a Final Rule is promulgated. QAPI §494.110(a)(1): ANNA agrees with the inclusion of a condition requiring a "Quality Assessment and Performance Improvement" program to demonstrate commitment to improved health outcomes and prevent and reduce medical errors. §494.110(a)(2): ANNA agrees with all items listed in the rule for performance components but requests the addition of "bone disease management" as well as "infection." §494.110(a)(2)(vii): With regard to the use of a common instrument for assessing patients' experience of care, ANNA believes this makes a lot of sense and should pose only a minimal time burden for the facilities. However, such paperless technology could initially be expensive and we do not believe it is reasonable to expect that facilities could afford it. Regarding how facilities will "assess the effectiveness of their internal grievance adjudication process, track the outcomes of patient grievances, and identify meaningful criteria for evaluation and tracking purposes," ANNA suggests there should be a standardized tool for patient satisfaction and grievance reporting. It could be brief and concise, and facility specific questions could be added to the standardized tool for internal use. Please note that we believe this patient satisfaction tool should be administered routinely, not just in response to a grievance. Prevention of grievances should be the goal. §494.110(c): ANNA applauds the requirement for prioritizing improvement activities and having a plan for immediate correction of identified problems that jeopardize patients' health and/or safety. Special Purpose Renal Dialysis Facilities §494.120: ANNA believes that if the camp is doing dialysis on site, the facility should also meet the requirements for qualified personnel as in the rule §494.150 (a) Medical Director (b) Nursing Services (e) Patient Care Technicians, and (f) water treatment system technicians. §494.120(d): ANNA agrees that the rule for physician contact is ideal but during natural disasters such as hurricanes, it may be impossible to contact the patient's attending physician. There should be a provision for another physician to provide direction of care in such extenuating circumstances. Personnel Qualifications ANNA agrees with the preamble statements about dialysis technicians, but believes it is more appropriate to say they are the predominant direct patient caregivers in most dialysis facilities. The recognition that they function as extensions of the facility's professional nursing staff is also very helpful. ANNA further agrees with CMS that it is essential that a registered nurse provide the "hands-on" direct supervision to technicians during the clinical component of their training, provided direct supervision is defined as we have suggested in the definitions comments at §494.10. Facilities would not have the staff to permit RNs to provide immediate supervision of these technician trainees. Please refer to our distinction between these definitions at §494.10. ANNA does not believe there is a need for clinical pharmaceutical services beyond continuing staff education on new products for both incenter and home dialysis patients. RNs are the appropriate professionals to monitor patients' medications and do patient teaching. We believe it could be confusing to the patient to further fragment care by introducing another discipline into the patient care scenario. RN workloads could be reduced and patient care improved with regard to medication management by the use of technology for dose conversion, verification, labeling, documentation, and checking for drug-drug interactions. ANNA looks forward to working with CMS, networks or others in the renal community in this regard. ANNA looks forward to reimbursement methodologies that incorporate pay for performance and that promote the use of disease management models. In those scenarios, Advance Practice Nurses will more likely be employed to function as case managers and we believe patient care and outcomes will improve and hospitalizations will decrease. §494.140(b)(3)(i): ANNA strongly opposes the language allowing LPN/LVNs to function as charge nurses. The role of a charge nurse is to supervise and direct the clinical activity while patients are dialyzing at a facility. Most states define the role of licensed practical/vocational nurses along these lines: the provision of care, under the supervision of a physician practicing medicine, or a registered nurse practicing nursing in accordance with applicable provisions of law. In no state in the United States can an LPN/LVN supervise an RN, and these proposed conditions require the presence of an RN when patients are dialyzing. Given this reality, the conditions cannot permit LPN/LVNs to be charge nurses. Medical Records ANNA appreciates the elimination of the requirement for a medical records supervisor. §494.170(d): ANNA believes that requiring all medical records be sent within one working day of a patient's transfer is unrealistic and unnecessary. We believe that only those records that a medical care provider and the facility require to adequately assess and treat the patient safely are necessary upon transfer. Those would include at least the current care plan, one month of treatment records, current physician orders, and medication list. Some patients have received dialysis treatment in a single center for many years, and requiring the entire medical record is unreasonable and burdensome in these circumstances Governance §494.180(b)(1): ANNA wholeheartedly endorses the inclusion of a requirement for an acuity-based staffing plan to ensure that every dialysis facility has "adequate and appropriate staffing" to meet the needs of its patients. The utilization of an acuity based system to determine the adequacy and appropriateness of the numbers and skill mix of staff required to deliver care would provide for improved quality of care. Literature describing acuity-based staffing indicates outcomes of improved quality of care and the reduction of staff burnout, resulting in lower rates of staff absenteeism and turnover. With regard to the concern about "cherry picking" as a result of using minimum standards for accountability purposes, ANNA believes this risk could be minimized by the adoption of a true patient-level acuity-based reimbursement system including an acuity-based staffing model. This would encourage facilities to accept and properly care for patients who are more resource intensive or more difficult to manage and who are less likely to achieve acceptable levels on the performance measures. In the past ANNA developed the basis for a staffing-acuity model; we would welcome the opportunity to collaborate with CMS to update and refine this model to meet the intent of this proposed rule. §494.180(b)(2): ANNA strongly supports this proposed requirement. Dialysis patients are, after all, receiving nursing care for the duration of their stay in the dialysis facility such that a registered nurse must be present. This is a long overdue requirement and we are most pleased to see it. It must remain in the final rule §494.180(b)(5)(i) through (viii): ANNA agrees that the patient care technician training program should incorporate, at a minimum, these content areas, and most already do. ANNA strongly recommends a requirement that all patient care technicians should be certified through a nationally recognized certification program. Successful completion of a standardized certification exam would validate the success of the training program and would provide assurance to the public and to patients that all patient care technicians have a certain minimal level of preparation. While there are currently three national certification exams available for dialysis technicians, only one is designed to test at the competency level. The other two exams are higher levels and may be difficult for the entry-level technician. The competency level exam is the Certified Clinical Hemodialysis Technician (CCHT) offered by the Nephrology Nursing Certification Commission (NNCC) in cooperation with the Center for Nursing Education and Testing (C-NET). More information can be obtained about this examination at the NNCC website, www.nncc-exam.org. We agree that the skills and competencies of patient care technicians are a major patient concern and applaud these steps to mandate a standard minimum program. We urge CMS to take the additional step to require validation of minimal competency by requiring certification of patient care technicians. §494.180(c): ANNA agrees with CMS on the proposal to delete process requirements for medical staff appointments and add a new governing body requirement to inform the facility's medical staff regarding the facility's patient care policies and the facility's QAPI Program. §494.180(f)(4): ANNA supports and appreciates the guidance provided for involuntary discharge of a patient. We further support the statement about facility accountability for personnel adherence to the patient discharge or transfer policies and procedures. §494.180(g)(3): ANNA thinks it is reasonable to remove the requirement for an affiliation agreement with an ESRD certified hospital and the substitution of an agreement with a (any) hospital that can provide inpatient care. §494.180(h): ANNA believes that whatever can be done to reduce the burden of information collection by automated systems, universal data collection tools, and quarterly collections, would certainly reduce the burden for registered nurses to whom such data collection is frequently assigned. ANNA wishes to thank CMS for the opportunity to review and provide comment on these proposed Conditions for Coverage. The order of the content and the references to the existing regulations along with the proposed changes enabled us to understand and reflect on the benefits of the proposed changes. We are impressed with the patient focus of the proposed conditions and believe that the final rule, incorporating our suggested amendments, will lead to greater facility flexibility to focus on improving patient outcomes. Very truly yours, Suzann VanBuskirk, BSN, RN, CNNPresident 2005-06 Lesley Dinwiddie, MSN, RN, FNP, CNNPresident 2004-05 cc: ANNA Board of Directors

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text:
People: William Sprague and Hannah Sprague
SPRAGUE: Circa 1791, Vernon, NJ - Sussex - Family History & Genealogy Message Board - Ancestry.com
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Washington, West of the Cascades: Historical and Descriptive; the Explorers ... - Herbert Hunt, Floyd C. Kaylor - Google Books
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Sprague Family in America (pg. 521) Notes a Catherine as first wife and a Mary as 2nd wife. Daughter Rebecca's birth...
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Sprague Family in America (pg. 521) Rebecca's birthdate is written 1786. The date 1768-69 is not unreasonable and fi...
People: Frazier Taylor, Sr and Rebecca Sprague


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text:
Starting and managing a study conducted under an IND or IDE involves greater risk, complication, and attention from the study team. Clinical Research Support's Regulatory Affairs group is ready to help all Consortium study teams navigate the regulations and processes laid out by the FDA.
In the information below, you'll find answers to some of the most frequently asked questions. Because of the complexity of these studies we encourage you to contact Clinical Research Support for information specific to your study.
Investigational New Drug Application (IND)
Do I need an IND?
It depends on the clinical study. An investigational new drug (IND) application is usually required when the study involves either:
(i) a new or investigational drug (i.e., not approved for marketing in the U.S.), or
(ii) an approved drug where the investigation is intended to support any of the following:
(a) a new indication,
(b) a significant change in labeling or advertisement,
(c) new route of administration,
(d) new dosage level or risks associated with the use of the drug product.
Regulations detailing the need for an IND are found at 21 CFR 312.2.
Certain studies involving a lawfully marketed (approved) drug or biological product, or a combination of approved products, may be IND exempt. This may occur when a study is not intended to support a change in marketing, labeling, or advertising for the product, and the product is not being used in a way that significantly increases the level of risk (or decreases the acceptability of risk) associated with its use. The following FDA Guidances for Industry discuss some scenarios when an IND is NOT needed for the study of an approved product as a treatment for cancer:
IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment of Cancer
Investigational New Drug Applications (INDs)-Determining Whether Human Research Studies Can Be Conducted Without an IND (Draft Guidance)
Whether or not an IND is required, you must comply with all regulations regarding IRB approval and subject informed consent.
You may contact Regulatory Affairs for assistance in determining whether an IND is required, or whether to contact the FDA for additional guidance.
Clinical Research Support Regulatory Affairs can assist you in asking the FDA whether you need an IND for a clinical trial by contacting the appropriate review division and providing information including:
- The name and a brief description of the substance to be administered, the source (e.g., animal, synthetic, etc.), dosage form, sterility (if applicable), and supplier.
- A brief summary of the study including the purpose, hypothesis, number of subjects, patient population, condition or disease (if applicable), dose, route, and duration of substance administration.
- A brief explanation of why you consider the substance safe for administration to human subjects under the conditions of the study (append references, if necessary).
Do I need a pre-IND meeting?
It depends. The primary purpose of a pre-IND meeting is to review and reach agreement on the (i) design of pre-clinical studies, (ii) design of clinical study, (iii) CMC issues in case of an investigational new drug/biologics/gene therapy product, etc. These meetings are not mandatory, but are often useful to obtain valuable feedback from the FDA before a formal IND is submitted.
Pre-IND meetings are usually requested 60 days in advance, and a pre-IND package needs to be submitted to the FDA 30 days prior to the meeting.
Details regarding pre-IND meetings and the pre-IND package can be found at the FDA's website.
A more detailed description of pre-IND meeting and pre-IND package is outlined for anti-viral products, some of which are applicable for drugs and biologics.
Pre-IND consultation contact information can be found online.
Who do I submit my IND to?
If the clinical study involves a biologic (cell or gene therapy products, human tissue products, vaccines etc.), the IND will by reviewed by the Center for Biologics Evaluation and Research (CBER).
For biologics, the application is sent to:
Food and Drug Administration
Center for Biologics Evaluation and Research
HFM-99, Room 200N
1401 Rockville Pike
Rockville, MD 20852-1448
If the study involves a drug, the IND will be reviewed by the Center for Drug Evaluation and Research (CDER). The application is sent to:
Food and Drug Administration
Center for Drug Evaluation and Research
Central Document Room
5901-B Ammendale Rd.
Beltsville, MD 20705-1266
For therapeutic biological products (antibodies, cytokines, peptides etc.) transferred to CDER, the application is sent to:
Food and Drug Administration
Center for Drug Evaluation and Research
Therapeutic Biological Products Document Room
5901-B Ammendale Rd.
Beltsville, MF 20705-1266
What will happen after FDA receives the IND?
Upon receipt of the IND by FDA, an IND number will be assigned and the application will be forwarded to the appropriate reviewing division. The reviewing division will send a letter to the Sponsor-Investigator providing notification of the IND number assigned, date of receipt of the original application, address where future submissions to the IND should be sent, and the name and telephone number of the FDA person to whom questions about the application should be directed.
After I submit an IND, when can I start the clinical trial?
You may begin your clinical trial thirty (30) days after FDA receives your IND application, unless FDA contacts you. If FDA is not satisfied with the information provided in the IND application, they may put the IND on clinical hold until all the issues are resolved or additional information regarding the IND is submitted.
Does a physician, in private practice, conducting research with an FDA regulated product, need to obtain IRB approval?
Yes. The FDA regulations require IRB review and approval of regulated clinical investigations, whether or not the study involves institutionalized subjects. FDA has included non-institutionalized subjects because it is inappropriate to apply a double standard for the protection of research subjects based on whether or not they are institutionalized. An investigator may be able to obtain IRB review by submitting the research proposal to a community hospital, a university/medical school, an independent IRB, a local or state government health agency or other organizations. If IRB review cannot be accomplished by one of these means, investigators may contact the FDA for assistance (Health Assessment Policy Staff, 301-827-1685).
Does a clinical investigation involving a marketed product require IRB review and approval?
Yes, if the investigation is governed by FDA regulations [see 21 CFR 56.101, 56.102(c), 312.2(b)(1), 361.1, 601.2, and 812.2].
Is there a good website to learn more about INDs?
FDA provides a series of video presentations on INDs and other topics. These two sites are good resources for either an overview or more in-depth information:
Expanded Access IND
What is "expanded access" to investigational drugs?
Expanded access, sometimes called "compassionate use," "treatment use," or a "single patient IND," is the use of an investigational drug outside of a clinical trial to treat a patient with a serious or immediately life-threatening disease or condition who has no comparable or satisfactory alternative treatment options. More information about this can be found online.
Criteria for all expanded access uses:
- Patient(s) must have serious or immediately life-threatening disease/condition and no comparable or satisfactory alternative therapy.
- Potential benefit justifies potential risks, and potential risks are not unreasonable in the context of disease/condition.
- Access will not interfere with clinical investigations to support marketing approval of the expanded access use.
For the detailed regulation, please click here. A Draft Guidance for Industry titled "Expanded Access to Investigational Drugs for Treatment Use – Qs & As" was released by the FDA in May 2013.
How do I prepare an expanded access IND submission?
We encourage you to contact Regulatory Affairs/Clinical Research Support for specific information and individualized support if you are considering submitting an Expanded Access IND.
Transferring an IND
What is the procedure to transfer INDs?
An IND sponsor can transfer responsibility for any or all of the IND sponsor obligations to a contract research organization or to another sponsor. Any such transfer shall be described in writing.
To transfer an IND to a new sponsor, the typical procedure is that the "old" sponsor submits an IND amendment to the FDA stating the transfer of the IND sponsorship and outlining the obligations to be transferred. The "new" sponsor also submits an amendment to the FDA accepting the sponsorship and its obligations and informing the FDA about the contact information of the new sponsor.
If not all obligations are transferred, such as the clinical monitoring function, for example, a description of each of the obligations being assumed by the contract research organization or the new sponsor is required in the submission. If all obligations are transferred, a general statement that all obligations have been transferred is acceptable. Any obligation not covered by the written description shall be deemed not to have been transferred.
A sample IND Transfer Letter and information on how to complete the Form 1571 can be obtained from the Regulatory Affairs office.
Contents of an IND Application
What are the contents of an IND submission?
A sponsor must submit information for the IND in the following order:
- Cover sheet (FDA Form-1571)
- Table of Contents
- Introductory Statement and General Investigational Plan
- [(Reserved) — Previously, the FDA separated the Introductory Statement from the General Investigational Plan Since they are combined currently, this section is left "blank".]
- Investigator's Brochure (not needed for investigator-sponsored single-site studies)
- Protocols
- Chemistry, Manufacturing and Control Information (may not be needed for studies utilizing an approved drug)
- Pharmacology and Toxicology Information
- Previous Human Experience
- Additional Information
In addition, the sponsors also need to submit a completed FDA Form-3674 (Certification of Compliance with Requirements of ClinicalTrials.gov Data Bank). FDA Form-3674 can be found online at the FDA forms page.
Electronic or paper copies of the selected publications cited in the IND must be provided to FDA with the IND submission.
The sponsor must submit three copies (one original and two copies) of all submissions to the IND file.
Each submission relating to an IND must be numbered sequentially using a four-digit serial number. The original IND submission is numbered as 0000; subsequent submissions are numbered as 0001, 0002, etc.
Details of an IND submission can be found at 21 CFR 312.23 and also at the FDA website.
Some sample and template documents may be requested from Regulatory Affairs. Another good template for an IND application can be found at: https://www.iths.org/IND
What is FDA Form 1571?
Form 1571 is an FDA form that accompanies the initial IND submission and each subsequent submission to the IND. Similar to all other IND submissions, 1571 must also be submitted in triplicate.
The form and instructions can be found online.
What is FDA Form 1572?
Form 1572 is an FDA form that contains information about the investigator of the study. Investigators may participate in an investigation only after they provide the sponsor with a completed, signed Form 1572. It is your responsibility as a clinical investigator to include all sub-investigators who will be assisting you in the Form 1572.
The form and instructions can be found online.
What is Form 3674?
Form 3674 is a certification of compliance that all applicable requirements of 42 USC § 282(j) have been met. At the time of submission of an Investigational New Drug application, the application must be accompanied by this certification. Where available, such certification must include the appropriate National Clinical Trial (NCT) numbers. The form and instructions can be found online.
Many trials are registered by Clinical Research Support. Additional information on registering your clinical trials is available on the protocol registration website.
What is Form 3500A?
Form 3500A is used for MANDATORY reporting of adverse events under FDA's MedWatch program. Mandatory reporting is required for certain types of safety information under an IND. Note this is not the same as Form 3500, which is used for voluntary reporting of adverse events associated with approved products.
The form and instructions can be found online.
cGMP and Chemistry, Manufacturing and Controls Information
What is cGMP? Is it applicable to my trial?
Current good manufacturing practices (cGMP) are a set of regulations described in 21 CFR Parts 210, 211, 610. These regulations are in place to ensure that the manufacturing of a drug or biologic yields a product that is safe, effective, characterized, consistent, and pure.
FDA has compiled a number of frequently asked questions (FAQs) at the following site describing how to best comply with cGMP for drugs.
I am planning to initiate a Phase I clinical study with an investigational drug/biologic. Is the study subject to all cGMP requirements?
It depends. Some investigational drug/biologics used in a Phase 1 study are exempt from the cGMP requirements as specified in 21CFR 211. These investigational agents need to follow the requirements described in the following guidance document.
What are the regulatory issues regarding the use of antibiotics (penicillin) in the manufacturing of clinical study product?
If antibiotics are used in product manufacturing, there could be two types of problems:
(a) Presence of the antibiotic in the product may interfere with the sterility testing.
You must verify that the antibiotics were removed prior to sterility testing. If the antibiotics cannot be removed, you need to assess the validity of the sterility assay using the bacteriostasis and fungistasis testing as described in USP <71> Sterility Tests. This assay must be performed to ensure that any residual antibiotic present in the product does not interfere with the results of sterility testing.
(b) Certain antibiotics may produce patient reaction.
If beta lactam antibiotics (e.g., penicillins, cephalosporins and related compounds) are used during manufacturing, you need to consider consulting with the IND clinical reviewer at FDA concerning appropriate exclusion criteria for the study and proper informed consent to address potential patient sensitivity. You may also consider whether alternative antibiotics can be used during manufacturing of the investigational product.
IND Sponsor and Investigator Functions/Responsibilities
What is an IND "sponsor" and what are his/her responsibilities?
The "sponsor" is a person who holds the IND, takes responsibility for and initiates a clinical investigation. The sponsor may be an individual, pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator (21 CFR 312.50-59).
Sponsors are primarily responsible for:
- Selecting qualified investigators and providing them with the information they need to conduct an investigation properly;
- ensuring proper monitoring of the investigation(s), ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND;
- maintaining an effective IND with respect to the investigations; and
- ensuring that FDA and all participating investigators are promptly informed of significant new adverse effects, risks, or other safety information with respect to the drug.
What is an "investigator" and what are his/her responsibilities?
The "investigator" is an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a study subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. "Sub-investigator" includes any other individual member of that team (21 CFR 312.60-70).
An investigator is primarily responsible for:
1. ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations;
2. protecting the rights, safety, and welfare of subjects under the investigator's care;
3. for the control of drugs under investigation; and
4. for obtaining the informed consent of each human subject to whom the drug is administered.
FDA has issued an important Guidance for Industry that further describes investigator responsibilities. More detailed information is also listed in the ICH Good Clinical Practice (GCP) guidance document (Section 4).
How long is an investigator required to retain records?
The IND regulations require records be retained for a period of two years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until two years after the investigation is discontinued and FDA is notified.
What are the common "mistakes" made by investigators?
Based on FDA's findings during inspections, the common mistakes made by investigators are
- Revising the protocol without obtaining the sponsor's written concurrence.
- Neglecting to submit the revised protocol to an IRB for approval.
- Not obtaining written informed consent or providing an oral explanation of the study.
- Not updating the consent forms to reflect changes in the protocol.
- Over-delegating responsibilities to non-physicians, such as a diagnosis that determines study eligibility.
- Erasing, using white-out or obliterating original data entry either in the case report forms (CRF) or medical charts.
- Accepting suggested changes to study data without checking the source documents or without justifying such changes.
- "Backdating" the consent forms and signatures.
- Not obtaining IRB approval of consent form revisions.
- Permitting changes to study data without investigator's concurrence, especially after the investigator has "signed-off" the completed CRF.
- Blaming others for inaccuracies in the CRF.
- Creating false records or patients using demographic data or using blood, urine and tissue samples from other subjects.
- Altering patients' diaries to reflect a positive outcome.
- Using staff as subjects in a study not having the condition(s) under investigation.
- Destroying study records.
My study involves both Fred Hutch and UW facilities. Do I need to obtain IRB clearance from both organizations?
If you are a member of the University of Washington/Fred Hutch Cancer Consortium, you receive IRB review and approval from one committee. This committee is organized by Fred Hutch, but maintained for Cancer Consortium members and their studies only.
If you are a Fred Hutch PI only, you receive IRB review and approval from Fred Hutch's IRB.
If you are a UW PI only, you receive IRB review and approval from the UW's Human Subjects Division.
Can I start patient-screening before a prospective patient's participation in a clinical study?
Informed consent must be obtained prior to initiation of any screening procedures that are performed solely for the purpose of determining eligibility for research. Clinical screening procedures for research eligibility are considered part of subject selection and recruitment process, and, therefore, require IRB oversight.
Reference: FDA Information Sheet "Screening Tests Prior to Study Enrollment"
Does the Cancer Consortium have a process for external performance site review for multi-center studies under an IND?
Yes, the External Performance Site Assessment Committee (EPSAC) has been created to aid Cancer Consortium Principal Investigators and/or Cancer Consortium IND sponsors in assuring compliance with CRF 21 Part 312.50.
IND Amendments and Safety Reports
What are the types of IND amendments?
There are three major types of IND amendments: (a) Protocol amendments, (b) Information amendments, and (c) IND Safety reports.
A protocol amendment is filed when there is one of the following:
- New protocol
- Changes to a protocol
- New investigator
An information amendment contains essential information regarding the IND that is not within the scope of a protocol amendment, IND safety report, or annual report. Examples include:
- New toxicology, chemistry, or other technical information
- A report regarding the discontinuation of a clinical study
Safety reports are submitted to FDA when:
- An adverse event occurs that is serious, causally associated with the use of the drug/biologic, and unexpected; or
- There is a finding in laboratory animals or in vitro testing that suggests a significant risk to human subjects; or
- Clinical, epidemiological, or pooled analysis of multiple studies suggest a significant risk to human subjects
What is a serious adverse event (SAE)?
A serious adverse event is any adverse experience that results in:
- Death;
- A life threatening experience;
- Inpatient hospitalization or prolongation of existing hospitalization;
- A persistent or significant disability/incapacity;
- A congenital anomaly; or
- Requires intervention to prevent permanent impairment or damage.
What are the regulations regarding reporting a serious adverse event? How do I know if the SAE is reportable?
FDA has recently revised the reporting criteria of an adverse event. The final rule in the Federal Register can be found online.
The guidance document can be found online as well.
A video presentation on this topic can also be found online.
An adverse event is reportable only if it meets all of these criteria:
- serious (described above),
- unexpected (not described in the Investigator's Brochure or other documented risk information such as the package insert, protocol, or informed consent form), AND
- has a reasonable possibility of being caused by the study drug/biologic ("suspected adverse reaction") or is definitely caused by the study drug/biologic ("adverse reaction").
The final rule expects that the sponsor and investigators will first determine whether an adverse event is causally linked to the investigational drug/biologic. This determination can be made from a single event or from an aggregate analysis of a series of occurrences.
Serious adverse event reports must be made as soon as possible, but no later than 15 calendar days after the sponsor's initial receipt of the information.
In case of an unexpected fatal or life-threatening adverse event that is associated with the use of the drug/biologic, reports must be made by phone or fax as soon as possible but no later than seven calendar days after the sponsor's initial receipt of the information.
The sponsor is also required to submit follow-up information to a safety report as soon as the relevant information is available.
IND Annual Reports
What is an annual report? When is it due?
An annual report is a summary of the progress of the clinical investigation and information obtained during the previous year's clinical and non-clinical investigations. A sponsor shall submit the annual report within 60 days of the anniversary date that the IND went into effect. For example, if an IND was submitted on February 17, 2005, and FDA did not have any comments or questions, then the IND went into effect on March 17, 2005 (after the 30-day waiting period). Thus, the annual report is due on or before May 17, 2006. The annual report is due on or before the same day of each subsequent year.
The format and content of the annual report is described in 21 CFR 312.33.
Medical Devices and Investigational Device Exemptions (IDE)
What is a medical device?
A medical device is defined as "an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:
- recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them,
- intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or
- intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes."
This definition provides a clear distinction between a medical device and other FDA-regulated products such as drugs. If the primary intended use of the product is achieved through chemical action or by being metabolized by the body, the product is usually a drug.
How are medical devices regulated?
The FDA regulates medical devices to assure their safety and effectiveness and develops, and carries out a national program designed to control unnecessary exposures to, and assure safe and efficacious use of, ionizing and non-ionizing radiation-emitting electronic products. The Center for Devices and Radiological Health (CDRH) is the component within the FDA that is responsible for this program. Most of FDA's medical device and radiation-emitting product regulations are in Title 21 CFR Parts 800-1299. These final regulations codified in the CFR cover various aspects of design, clinical evaluation, manufacturing, packaging, labeling and post market surveillance of medical devices. In addition, the regulations address standards and product reports that apply to radiation-emitting products.
If I want to conduct a clinical trial on an experimental medical device, what do I need to do?
Many clinical trials on medical devices are conducted under Investigational Device Exemptions (IDE), which are described under 21 CFR 812. Certain trials may be exempt from these regulations. Clinical trials using a device that is deemed by the reviewing IRB not to represent a "significant risk" are conducted under IND regulations but may not require an IDE submission to FDA ("abbreviated requirements" under 21 CFR 812.2).
Since all medical devices are not regulated equally, the first step is to determine the class of the experimental device, which determines whether clinical trial is needed for the marketing of the device.
The FDA has established classifications for approximately 1,700 different generic types of devices and grouped them into 16 medical specialties referred to as panels. Each of these generic types of devices is assigned to one of three regulatory classes based on the level of control necessary to assure the safety and effectiveness of the device. Device classification depends on the intended use of the device and also upon indications for use. In addition, classification is risk based, that is, the risk the device poses to the patient and/or the user is a major factor in the class it is assigned. Class I includes devices with the lowest risk and Class III includes those with the greatest risk.
Usually clinical studies are conducted for marketing a Class III device. Investigational use also includes clinical evaluation of certain modifications or new intended uses of legally marketed devices.
All clinical evaluations of investigational devices, unless exempt, must have an approved investigational device exemption (IDE) before the study is initiated. An IDE allows the investigational device to be used in a clinical study in order to collect safety and effectiveness data required to support a Premarket Approval (PMA) application (for Class III devices) or a Premarket Notification [510(k)] submission (for Class II devices) to FDA.
What are the procedures to submit an IDE application?
The IDE application is somewhat similar to the IND application (for drugs and biologics) and it is submitted to the Center for Devices and Radiological Health (CDRH). The IDE must contain information in the following order:
- Name and address of the sponsor
- Complete report of prior investigations and summary of the investigational plan
- Manufacturing methods, facilities and controls for the investigational device
- Example of the investigator agreement
- Certification that all participating investigators have signed the investigator agreement.
- List of IRBs, including name and addresses of IRB chairpersons
- Names and addresses of participating institutions not listed in item # 6
- For devices to be sold, a cost recovery justification and an explanation why the sale does not constitute commercialization.
- Claim for categorical exclusion under 21CFR 25.30 or 25.34, or an environmental assessment under 21CFR 25.40
- Copies of all labeling for the device
- Copies of all forms and information materials to be provided to the patients to obtain informed consent
- Any other relevant information
The investigational plan part of the IDE must contain information in the following order:
1. Purpose
2. Protocol
3. Risk analysis
4. Description of device
5. Monitoring procedures
6. Labeling
7. Consent materials
8. IRB information
9. Other institutions
10. Additional records and reports
11. Report of prior investigations
The IDE application is submitted in triplicate and is addressed to:
Food and Drug Administration
Center for Devices and Radiological Health
Document Mail Center - WO66-G609
10903 New Hampshire Avenue
Silver Spring, Maryland 20993-0002
The outside wrapper of each submission should be clearly marked indicating the content of the package (e.g., "IDE application," "Supplemental IDE application," etc).
FDA will notify the sponsor in writing of the date the application is received. FDA may request additional information or may issue an order approving or disapproving the IDE application. If the sponsor does not receive a response from FDA 30 or more days after FDA receives the application, it is technically legal to begin the clinical investigation. However, if a response is not received in 30 days, it may be prudent to contact FDA prior to beginning the study to conform that the investigation may proceed.
A very useful website for medical devices is "Device Advice"
Does the Cancer Consortium have a process for external performance site review for studies under an IDE?
Yes, the External Performance Site Assessment Committee (EPSAC) has been created to aid Cancer Consortium Principal Investigators and/or Cancer Consortium IDE sponsors in assuring compliance with CRF 21 Part 312.50.
Current Good Tissue Practices (cGTP)
What are HCT/Ps?
HCT/Ps are "human cells, tissues, or cellular or tissue-based products". HCT/Ps are defined as articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion or transfer into a human recipient (21CFR 1271.3(d)). Common examples of HCT/Ps are hematopoietic stem/progenitor cells derived from peripheral or cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix, bone, ligament, skin etc.
What are the regulations for using Placental/Umbilical Cord Blood cells?
A guidance document recently published by the FDA states that to use minimally manipulated, unrelated allogeneic placental/umbilical cord blood cells for specific indications, an IND application needs to be submitted. Detailed information can be found online.
What is meant by "donor eligibility determination"?
A "donor eligibility determination" is a conclusion, based on donor screening and testing results, that a donor is either eligible or ineligible to donate cells or tissue to be used in an HCT/P. Under the rule (21CFR 1271.50(b)), a donor is eligible only if:
- Screening shows that the donor is free from risk factors for, and clinical and physical evidence of, infection due to relevant communicable disease agents and diseases, and is free from communicable disease risks associated with xenotransplantation; and
- test results for relevant communicable disease agents and diseases are negative or nonreactive.
General and Miscellaneous Questions
What are guidance documents? Do I need to follow them?
Guidance documents are published by the FDA to provide interpretation of regulations. These documents do not establish any legally enforceable responsibilities. They describe FDA's current thinking on a topic and should be viewed as recommendations, unless specific regulatory or statutory requirements are cited. On a practical note, it is a good idea to follow the recommendations made in the guidance documents. See our "Helpful Links" section for frequently used guidances in conducting clinical trials.
Each guidance document includes the following "disclaimer" by FDA:
"This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the appropriate FDA staff. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance."
What are drug master files?
A Drug Master File (DMF) is a submission to the FDA that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs.
DMFs are generally created to allow a party other than the holder of the DMF to reference material without disclosing to that party the contents of the file, such as a contract manufacturer. There are several categories of DMF depending on the nature of the information it contains.


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Apropos to Alex's post below, the huge news in the last day is a study from Oregon that looked at the effects of expanding Medicaid. As McCardle points out, the study was done under near ideal circumstances. Oregon could not expand Medicaid to everyone who wanted it, so they created a lottery. Sociologists swooped in and recruited. The result was a study of 6000 people with Medicaid and almost 6000 without. One of the authors … Read more
Tag Archive: Health insurance in the United States
College Health
How many times have I said it? When you outlaw cheap insurance, you create more uninsured:
… Read more
Some colleges are dropping student health-insurance plans for the coming academic year and others are telling students to expect sharp premium increases because of a provision in the federal health law requiring plans to beef up coverage.
The demise of low-cost, low-benefit health plans for students is a consequence of the 2010 health-care overhaul. The law is intended


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On-line poker is the name given to a variety of card games. Where gamers bet on the strength of the cards they hold. On-line poker is a sport game that involves a public "pot" made up of the players' wagers, which is granted to the gamer who either holds the highest ranking side when all the cards are proven, or makes a bet which their competitors are reluctant to match.
Poker Celebrities Texas Hold'em poker activities are provided in No Restrict, Pot Restrict and Restrict varieties. For a detailed breakdown of poker side positions, visit our poker side positions page.
Poker Celebrities offers a wide range of poker activities with different rules – Community Cards activities such as Hold'em and Omaha hold'em, where everybody shares part of their poker hand; Man activities where each individual is dealt cards, some of which are invisible and some of which are face up; Draw activities where each individual is worked five credit cards but can exchange some or all of them for new ones; even High/Low Split activities where the pot is separated between the best 'high' and 'low' arms.
All poker activities begin with some pressured bet over which poker gamers contend. In Seven Cards Man, there are two pressured wagers, an bet and a bring-in. In other activities, the pressured wagers are a small sightless and a big sightless (and sometimes also an ante). In any basic poker activity, gamers tactically bet using a variety of activities available to them. The activities are as follows:
If the last bet or raise on the final gambling round is called, a "showdown" happens. This is when it is determined who victories the pot, as gamers display their arms one-by-one. It may be the situation that there is no fight. This happens when a gamer bets or raises and no active gamers select to call the performer's bet (in other words, all gamers fold). In this situation, the gamer doing the gambling or raising victories the full amount of the pot.
At the end of the side, gamers remaining have options regarding the showing of their hand:
• Muck successful hand
If there's only one gamer left in the side before the fight, they can select to either display or not display their cards. If you want to never display your cards in this scenario, examine the 'Don't Show Winning Hand' choice in the 'Options' selection of the primary entrance hall. If this choice is not examined, you will be provided the choice to demonstrate after each successful side.
If the side goes to fight, the successful side is always proven instantly.
• Muck dropping hand
At the fight, gamers whose arms cannot beat the best side proven so far can select to demonstrate or not display their credit cards. If you want to never display your side in this scenario, examine the 'Muck Losing Hand' choice in the 'Options' selection of the primary entrance hall.
All gamers worked into a side have the right to see mucked arms that reach the fight, on request. At On-line poker Celebrities, their offers are proven in the Hand Record and Hand Replayer for each side. Mucked credit cards will only be proven to gamers worked into the side. To see Hand Backgrounds from the current period, go to 'Requests' > 'Display Immediate Hand History' in the entrance hall. To replay any side, just click 'Visualize' from the Immediate Hand Record window, or simply select the red 'replay' symbol at the top of the table. Real cash side histories can also be asked for by email, by going to 'Requests' > 'Hand History' in the primary entrance hall.


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Dáil Éireann - Volume 361 - 23 October, 1985
Written Answers. - Garda Recruitment.
Mr. Kitt Mr. Kitt
23. Mr. Kitt asked the Minister for Justice when it is proposed to recruit extra gardaí.
Minister for Justice (Mr. Noonan, Limerick East) Michael Noonan
Minister for Justice (Mr. Noonan, Limerick East): As indicated in the national plan, recruitment to the Garda Síochána is to continue during the period 1985-87 with a view to maintaining the strength of the force at 11,400. To achieve that and taking account of anticipated wastage, 60 recruits are due to be appointed on 6 November and present plans are to appoint a further 25 before the end of the year. The precise numbers to be appointed will depend on the level of vacancies arising from resignations, retirements and deaths.
Dáil Éireann 361 Written Answers. Garda Recruitment.


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Swartz et al v. DiCarlo
Filing 25
Order Adopting 14 Report and Recommendation denying 8 Motion to remand to State Court . Judge Christopher A. Boyko on 3/8/2013. (R,D)
UNITED STATES DISTRICT COURT NORTHERN DISTRICT OF OHIO EASTERN DIVISION JAMES R. SWARTZ, JR, et al., Plaintiffs, vs. MARK A. DICARLO, Defendant. ) ) ) ) ) ) ) ) ) ) ) ) ) CASE NO. 1:12CV3112 JUDGE CHRISTOPHER A. BOYKO ORDER This Court has reviewed the Report and Recommendation (Doc.# 14) of Magistrate Judge Kenneth S. McHargh regarding the Motion of Plaintiffs James R. Swartz, Jr., et al., for Remand (Doc.#8). The Magistrate Judge recommended that Plaintiffs' Motion for Remand be denied, and that Defendant be granted ten days in which to correct the defects in the Notice of Removal. On February 20, 2013, Defendant filed Mark A. Dicarlo's Compliance with Report and Recommendations. FED. R. CIV.P. 72(b) provides that objections to a Report and Recommendation must be filed within fourteen days after service, but Plaintiffs have failed to timely file any such objections. Therefore, the Court must assume that Plaintiffs are satisfied with the Magistrate Judge's recommendation. Any further review by this Court would be a duplicative and inefficient use of the Court's limited resources. Thomas v. Arn, 728 F.2d 813 (6th Cir. 1984), aff'd, 474 U.S. 140 (1985); Howard v. Secretary of Health and Human Services, 932 F.2d 505 (6th Cir. 1991); United States v. Walters, 638 F.2d 947 (6th Cir.1981). Therefore, the Court adopts in full the Report and Recommendation (Doc.# 14), and denies Plaintiffs' Motion for Remand. IT IS SO ORDERED. Dated: 3/8/2013 S/Christopher A. Boyko CHRISTOPHER A. BOYKO UNITED STATES DISTRICT JUDGE


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seatDivisión en sílabas: seat
Pronunciación: /sēt /
Definición de seat en inglés:
1A thing made or used for sitting on, such as a chair or stool.
Example sentences
- I sat down in the white chair while Dr. Clark took a seat on a stool that sat to my left.
- The stone furniture includes cupboards, beds and seats.
- Benches are more flexible than stools or individual seats because you can squeeze in more people along them.
1.1The roughly horizontal part of a chair, on which one's weight rests directly.
Example sentences
- The package Campbell had brought the night before rested unassumingly on the seat of my chair.
- Artemis sat on top of the back of a chair, his bare feet resting on the seat.
- Invariably they have cushioned seats and foot rests.
1.2A sitting place for a passenger in a vehicle or for a member of an audience: we have a fairly small theater with about 1,300 seats
Más ejemplos en oraciones
- Some audience members took their seats more than 30 minutes ago.
- He has removed reclining seats, so now passengers have to endure the whole flight sitting up straight.
- In that case the seating available for passengers comprised three single seats and a bench seat 7 ft 4 ins in length.
1.3A place in an elected legislative or other body: he lost his seat in the 1998 election
Más ejemplos en oraciones
- Of all state legislative seats nationwide, Republicans had won or were leading in 3,647, Democrats in 3,630.
- In all, there were 153 congressional and state legislative seats in play in California last November.
- Only half of the 60 seats in the Legislative Council, the lawmaking body, are elected directly.
1.4A site or location of something specified: Washington, the seat of the federal government
Más ejemplos en oraciones
- The beck breaks to the surface at the site of the former seat of the city's textile industry.
- He regarded it as the principal seat of the soul and the place in which all our thoughts are formed.
- Strasbourg is a central seat of administration for them, that's right, just as it is for the European Commission.
headquarters, base, center, nerve center, hub, heart;
location, site, whereabouts, place
1.5 short for country seat.
Example sentences
- Her brother and mother have sent her to the Castlewood seat in the country; to be away from the attentions of the Prince.
- Kilkenny castle was built in the 12th century and was the principal seat of the Butlers until 1935.
1.6 short for county seat.
2A person's buttocks.
Example sentences
- They tossed beach balls to one another between the decks and nibbled on cucumber sandwiches as they shook sand from the towels covering their seats.
2.1The part of a garment that covers the buttocks.
Example sentences
- As she was doing this, the instructor worked her tail through a hole in the seat of the garment.
- And for extra room in the seat, try jeans with a low waist, low pockets and a bit of a flare around the ankle.
- The girl sighed at the dark stain that covered the seat of her pants.
2.2A manner of sitting on a horse: he's got the worst seat on a horse of anyone I've ever seen
Más ejemplos en oraciones
- Waging war with such tools required more than courage, common sense, and a firm seat on a horse.
- At the same time she will correct your position on the horse, your seat, your hand and legs.
- If your seat is quiet, the horse is more likely to relax and slow his pace.
verbo[with object] Volver al principio
1Arrange for (someone) to sit somewhere: he seated her next to her husband
Más ejemplos en oraciones
- They seated the audience on a hillside and the action of the play took place in a grassy circle.
- One of McRae's other decisions is to seat the audience on both sides of the long, narrow stage, one section facing the other.
- Where else would he seat his guests for his famous five-course suppers?
informal plonk, park
1.1 (seat oneself or be seated) Sit down: she invited them to be seated (as adjective seated) a dummy in a seated position
Más ejemplos en oraciones
- Start by seating yourself in a comfortable position in a quiet area.
- Rising slightly from his awkward position, he seated himself wearily on the bed, then pulled her down next to him.
- Sighing, she seated herself in her usual position in the Geography class and prepared herself for a long day.
1.2(Of a place such as a theater or restaurant) have seats for (a specified number of people): a large tent that seats 100 to 150 people
Más ejemplos en oraciones
- (By the way, the theatre seats three hundred and fifteen or six hundred and thirty over two nights).
- But estate cars usually seat just five, and this good-looking car seats seven.
- Business needs are well-catered for with seven meeting rooms and four theatres seating a maximum of 1340 people.
have room for, contain, take, sit, hold, accommodate
1.3Fit in position: upper boulders were simply seated in the interstices below
Más ejemplos en oraciones
- It would be unwise to assume that this test proves that you can get better pistol accuracy by simply seating the bullet out further.
- She flipped the second safety off before seating it in the holster and stood up.
- When installed properly, your Toyota hubcaps should be evenly seated around the edge of the wheel.
- 1
by the seat of one's pants
- informal By instinct rather than logic or knowledge.Example sentences
- The steering is utterly lifeless, which means you have to steer by sight rather than by the seat of your pants.
- The rest of the trip will be conducted by the seat of our pants.
- But wars never proceed according to plan; they are always fought by the seat of one's pants, through constant improvisation.
- 2
take one's seat
- Sit down, typically in a seat assigned to one.Example sentences
- National Assembly Speaker Park Kwan Yong was unable to take his seat to call the assembly into session and hold a floor vote because some 40 Uri Party lawmakers held him back.
- Not until 1886 was Bradlaugh, an avowed atheist, allowed to take his seat in Parliament.
- She will take her seat in the assembly from May 1.
- 1
seatless adjetivo
- Example sentences
- The party has three seats out of 47 in greater Dublin, is much reduced in Cork and is seatless in several rural areas.
- This means that, ultimately, the new Verso cannot become a seatless, low-floored delivery van in the way the old one could.
- Each Spartan cell has a seatless toilet, a small sink and metal bed bolted into the wall.
Definición de seat en:
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Pronunciación: ˈɔːθəʊɛpi
the correct or accepted pronunciation of words