# Presentation: 784407

##    GU Advisory Panel Meeting

**Nocturnal Home Hemodialysis**
**Carolyn Y. Neuland, Ph.D.**
**Chief, Gastroenterology and Renal Devices Branch**
**Division of Reproductive, Abdominal and Radiological Devices**
**Office of Device Evaluation**
**Center for Devices and Radiological Health**
**June 8, 2005**

## Overview

- Introduction
- Panel Update
- Regulation of Hemodialysis Devices
- Guidance Documents for Hemodialysis
- Definition of Nocturnal Home Hemodialysis
- Meeting Objectives

## Linda Carr			  Consumer Safety Technician

**Linda Carr**			  **Consumer Safety Technician**
**Jeffrey Cooper, D.V.M.**            	  **Veterinarian / Panel Exec. Sec.**
**Linda Dart, M.S.****	**               **Biochemist**
**Gema Gonzalez, M.S.****	**               **Biomedical Engineer**
**Irada Isayeva, Ph.D.****	****	****  Polymer Chemist**
**Kristina Lauritsen, Ph.D.****	****  Tumor Biologist**
**Barbara McCool, M.S.R.N.**          **Nurse Consultant**
**Joshua Nipper, M.E.****	**               **Biomedical Engineer**
**Kathleen Olvey****	**	  **Biologist**
**Claudia Ruiz-Zacharek, M.D.****	**  **Nephrologist**
**Rebecca Stephenson**		  **Chemical Engineer**
**Kellie Straughn****	****	****  ****Clerk Typist**
**Richard Williams****	****	****  Mechanical Engineer**

## Panel Update

## P020006 - Enteryx Procedure KitBoston Scientific Corporation 

**Description/Indication ****– solution injected into the LES for the treatment of GERD in patients who are responsive to pharmacologic therapy **
**Panel Meeting Date**** – January 17, 2003**
**GU Panel Recommendation**** – Approval with Conditions**
**Modified physician labeling**
**Modified patient labeling**
**Post market study with 36 months follow-up from the last injection**

## 

Current Status  – PMA approved
                                  April 22, 2003

Post-approval Study  

3 year post-implantation follow-up

Medical Device Reporting (MDR) 

**Current Status****  – PMA approved**
**                                  ****April 22, 2003**
**Post-approval Study **** **
**3 year post-implantation follow-up**
**Medical Device Reporting (MDR)**** **

_**P020006**_** - Enteryx Procedure Kit****Boston Scientific Corporation**

## Nocturnal Home Hemodialysis

## Regulation of Hemodialysis Devices

**Class II Medical Devices**
**Risk Based classification**
**Moderate level of risk **
**Requirement for ****General Controls**** and ****Special Controls**** to ensure safety and effectiveness**
**510(k)  - Premarket Notification**
**There are currently no devices cleared by FDA for Nocturnal Home Hemodialysis**

## Regulation of Hemodialysis Devices

**Establishes **_***substantial equivalence***_** ****(SE)**** to a legally marketed predicate device**
***As safe and as effective as predicate device***
**Performance data:**
**Bench studies **
**Clinical studies (especially for Home Systems)**

**Notes:**
The 510(k) process is a Clearance process and not an approval process.  
A medical device is considered cleared when it is determined that the device is substantially equivalent (SE) to a legally marketed predicate device. 
When the device is cleared, it is determined to be “as safe and as effective as the predicate device”. 
If determined to Not to be Substantially equivalent it is automatically classified intyo Class III and usually requires a PMA application. 
The type of performace testing required to demonstrate SE depends on the technology, but usually includes in-vitro bench studies and frequently includes human clinical trials especially when being labeled for home use. 
(A device may be determined to be SE if it has the same intended use and technological characteristics, or the Same intended use and different technological characteristics, but the submission shows that: No new types of questions of safety or effectiveness are raised)

## Dialysis Devices

**Most are regulated as Class II devices**
**Primary classification regulations used:**
**§876.5820 – Hemodialysis systems and ****	****	****	****        accessories**
**Conventional Dialyzers**
**Reuse of Conventional Dialyzers**
**Dialysis Delivery Systems and Tubing Sets**
**Hemodialysates**
**§876.5860 – High permeability hemodialysis ****	****	****	****        systems**
**High Flux Dialyzers**
**Reuse of High Flux Dialyzers**
**Dialysis Systems with Ultrafiltration Controller**

**Notes:**
Turning to the Regulation of Dialysis products specifically – you will note that most of these are classified as Class II devices.  A couple years ago the Hemodialysis Dialysate Delivery systems with Ultrafiltration controllers and High Flux Hemodialyzers were down classified.  It was felt that the safety and effectiveness and the risks to health and the measures which could be taken to minimize those risks were better understood than when they were initially classified, therefore, special controls could be written and they were down-classified to Class II.

## Dialysis Devices

**§876. 5600**** - Sorbent regenerated dialysate    ****	****	****	****                   delivery system for hemodialysis**
**§876. 5665**** - Water purification system for            **
**                         ****hemodialysis**
**§876. 5540**** - Blood access device and accessories**
**Class III for implanted catheters**
**§876.5630**** - Peritoneal dialysis system and ****	****	****	****                  accessories **

## Guidance Documents for Hemodialysis Devices

**Guidance for the Content of Premarket Notifications for Conventional and High Permeability Hemodialyzers – 1998**
**Guidance for the Content of Premarket Notifications for Hemodialysis Delivery Systems – 1998**
**Guidance for Hemodialyzer Reuse Labeling – 1995**
**Guidance for the Content of Premarket Notifications for Water Purification Components and Systems for Hemodialysis – 1997**

## Guidance Document

** “****Guidance documents are documents prepared for FDA staff, applicants/sponsors, and the public that describe the agency’s interpretation of or policy on a regulatory issue” **
**	****21 CFR §10.115 **

## Definition of Nocturnal Home Hemodialysis

**Nocturnal Home Hemodialysis (NHD) is a type of  hemodialysis performed in the home by the patient, while the patient is asleep (*****typically at night*****), over a 6-10 hour period, using slower flow rates for blood and dialysate, and a treatment frequency of 5 to 7 days per week. **

## Nocturnal Home HemodialysisObjectives of Meeting

**To discuss and provide recommendations on the clinical and scientific issues associated with hemodialysis device design, labeling, and training for Nocturnal Home Hemodialysis**
**To discuss and provide recommendations on clinical trial design to study Nocturnal Home Hemodialysis**
**To obtain scientific feedback which can be used to help in device evaluation decisions and may lead to the future development of a guidance document for Nocturnal Home Hemodialysis**

## Nocturnal Home Hemodialysis

**     ****Overview of Conventional **
**Hemodialysis System**
**Joshua Nipper – Biomedical Engineer**
**Gastroenterology and Renal Devices Branch**

## Overview of Conventional Hemodialysis Delivery Devices

**Joshua C. Nipper, M.E.**
**Biomedical Engineer**
**Gastroenterology and Renal Devices Branch**
**Division of Reproductive, Abdominal and Radiological Devices**
**Office of Device Evaluation**
**Center for Devices and Radiological Health**
**June 8, 2005**

## Overview

**Conventional Hemodialysis (HD) Systems**
**A “standard” device**
**Monitored parameters**
**Alarms**
**Accessory Devices**
**Water treatment systems**
**Hemodialysis blood tubing**
**Remote monitoring systems**
**Blood access devices**

## Disclaimer

**Any examples in this presentation are not intended as an endorsement or criticism of any specific technology, device or company**
**No devices are currently cleared for *****nocturnal***** home hemodialysis**

**Notes:**
I will be talking about “conventional” HD devices, e.g., 3x a week for ~4 hours per treatment

## Hemodialysis Delivery Systems

**Classified under two different sections of the Code of Federal Regulations (CFR):**
**21 CFR §876.5820 for a low permeability system**
**21 CFR §876.5860 for a high permeability system (ultrafiltration controller)**
**Suggestions for the content of a 510(k) submission found in the FDA guidance document: “Guidance for the Content of Premarket Notifications for Hemodialysis Delivery System”**

## Blood from Patient

- Air Detector

- Blood Leak Detector

- PT

- PT = Pressure Transducer

- PT

- Venous clamp

- Anticoagulant

- Blood return to Patient

- Dialysate In

- Dialysate / UF Out (green / yellow)

- Informational Display

**A “Standard” HD Delivery System**

- PT

- Mixing System

- Conductivity Meter

- Water, Acid Concentrate, Bicarbonate Concentrate In

- Pre-mixed or sorbent regenerated dialysate

- Saline

- Drip Chamber

## Solute Transfer & Ultrafiltration

**Solute Transfer & Ultrafiltration**

- C blood > C Dialysate
- P blood ≈ P Dialysate

- C blood > C Dialysate
- P blood > P Dialysate

- Blood

- Dialysate

## Monitored HD Parameters

**Blood and dialysate flow rates (pump speed)**
**Pressure**
**Arterial**
**Venous**
**Dialysate**
**Waste / Dialysate Out**
**Transmembrane Pressure (TMP)**
**Patient fluid removed (UF) **
**Temperature**

**Notes:**
TMP is generally calculated from the other monitored pressures

## HD Alarms

**Typically come in two varieties:**

**CAUTION**

**WARNING**

**Notes:**
A caution is a situation that could lead to a warning.  Generally, a patient can troubleshoot a caution and resume treatment.  Not all warnings can be corrected, and Tx may have to be terminated

## Standard HD Alarms

**Temperature**
**Blood leak**
**Flow rates**
**Pressure**
**Arterial**
**Venous**
**Transmembrane Pressure (TMP)**
**Dialysate**
**Waste / Dialysate Out**

**Excessive UF**
**Air embolism**
**Conductivity / pH**
**Water quality**
**System alarms**
**Vascular access disconnection – venous pressure?**

**Notes:**
Pressure and Flow Rate alarms are designed as a “window” around the patient’s normal value and prescription information

## Accessory Devices

**Water Treatment Systems**
**HD Blood Tubing**
**Remote Monitoring Systems**
**Blood Access Devices**

## Water Treatment Systems

**Classified under 21 CFR §876.5665**
**Guidance for The Content of Premarket Notifications for Water Purification Components and Systems for Hemodialysis**
**Converts potable water to purified water meeting the requirements of the Association for the Advancement for Medical Instrumentation (AAMI) RD:62 standard**
**Can be designed for multiple patients, or can be single patient**

## Water Treatment Systems

- Reverse Osmosis

- Deionization

- Carbon Filters
- Worker / Polisher

- Water Out

- Data Out

- Water In

- Ultrafilter

- Pre-treatment

**Notes:**
Pre-treatment can be sediment filters, water softeners, etc.

## Blood Tubing

**Serves as basic conduit for blood**
**Contains a “blood pump” segment**
**Can have multiple connection points**
**Patient access (arterial & venous)**
**Pressure transducers with transducer protectors**
**Air detectors**
**Roller / peristaltic blood pump**

**Notes:**
21 CFR §876.5820 Blood Tubing Set, with or without Anti-regurgitation valve, 78-KOC, 78-FJK, Class II

## Blood Tubing

**Can be “cassette” based, which limits the number of user connections needed**
**Kinked tubing can cause hemolysis, which can lead to death**

## Remote Monitoring Systems

**Can be used for data transmission**
**Connect HD machine to Internet via modem or broadband connection**
**Can transmit real time alarms, and/or completed treatment data**
**FDA labels current systems are contraindicated as the sole method of monitoring a patient during hemodialysis**

**Notes:**
21 CFR §876.5820 Hemodialysis Systems and Accessories, Class II, 78-FKP

## Blood Access Devices

**Long-term, cuffed HD Catheters**
**Single or double lumen**
**Contain luer locks meeting ISO standards for connection to blood tubing**
**Arterio-Venous (AV) Grafts**
**Implanted prosthesis designed to bypass sections of native vessels**
**AV Fistulas**
**Surgical procedure, not a device regulated by FDA**
**Fistula needles are medical devices, and contain the same luer locks as catheters**

**Notes:**
A/V Grafts are 21 CFR 870.3450
Fistula needles are 21 CFR §876.5540 (“Needle, Fistula”) and 21 CRF §880.5200 (“Catheter, Intravascular, Therapeutic, Short-Term Less than 30 Days”). The product codes for this device are 78-FIE and 80-FOZ, and this is a Class II device

## Nocturnal Home Hemodialysis

**Michael Mendelson, D.D.S., M.S.**
**Biomedical Engineer, Director Health Promotion Officer**
**Human Factors Science and Engineering Branch**

## Human Factors and Nocturnal Home Hemodialysis

**Biomedical Engineer, Director Health Promotion Officer**
**Human Factors Science and Engineering Branch**
**Division of Device User Programs**
**Office of Communication, Education, and Radiation Control**
**Center for Devices and Radiological Health**
**June 8, 2005**

**Human Factors and Nocturnal Home Hemodialysis**

## Topics

- Introduction to human factors (HF)
- Magnitude of medical error-caused adverse incidents
- HF methods
- Nocturnal Home Hemodialysis (NHD) challenges and observations
- Human Factors Branch recommendations for premarket submissions

##  General Definition of Human Factors

- Human Factors discovers and applies information about **human behavior**, abilities, **limitations**, and other characteristics to the design of tools, machines, systems, tasks, jobs and environments for productive, safe, comfortable, and effective **human** use. *****
**	****	****	****-- Alphonse Chapanis, 1985**

- *Sanders & McCormick, Human Factors in Engineering
-  and Design., McGraw-Hill, Inc., 1987; p 5

## General Definition of Error

-    Human error is an inappropriate or undesirable human decision or behavior that reduces, or has the potential for reducing, effectiveness, safety, or system performance.*****

*****Sanders & McCormick, Human Factors in Engineering
- and Design., McGraw-Hill, Inc., 1987; p 607

## Magnitude of the Problem of Medical Error

**Magnitude of the Problem of Medical Error**

- Errors during hospital treatment result in 120,000 deaths each year – roughly equivalent to **a jumbo jet’s crashing each day**. (Leape, Harvard School of Public Health)
- At least 44,000 people,and perhaps as many as 98,000 people,die in hospitals each year as a result of medical errors that could have been prevented...(*To Err is Human: Building a Safer Health System*; Institute of Medicine / National Academy of Sciences, 1999)

- Photo courtesy of Boeing

## Design of Hemodialysis Systems Requires Human Factors Engineering Process

- The Quality System Regulation:  HF implied in
- Design Controls Section (21 CFR 820.30)
- Manufacturer
- Must address the intended use
- Must address the needs of the user and patient_ _
- Shall include testing under actual or simulated use conditions
- HF required at *Input phase* (design needs), *Output phase *(compare user needs <===> device design), and *Validation Phase *(realistic “use” study)

## Human Factors Considerations

- Safe &
- effective

- Unsafe or
- ineffective***(Use Error)***

**Use Environment**
-  **Light,  Noise**
** ****Distraction**
** ****Motion/Vibration**

**Device User**
-  **Knowledge**
-  **Abilities**
** ****Expectations**
** ****Limitations**

**Device**
-  **Operational  ****   requirements, procedures**
** ****Device complexity**
** ****Specific user interface characteristics**

_**Use**_

**Device**
**Use**

**Human Factors Considerations**

## Increased Patient Safety through USABILITY of the Use Interface

- Intuitive operation
- Clear displays
- Safe and simple-to-use controls
- Positive and safe connections
- Effective alarms
- Clear and effective labeling
- Safe and simple installation, repair, maintenance, and disposal

##  Two Key Human Factors Messages

- A poorly designed device use interface can needlessly permit and even induce error
- Warnings and instructions in the operating manual (and even on the device) may help but they **can not** OVERCOME a flawed design

##  Important Principles of Good Design*

- Make things visible
- Communicate clearly
- Provide correct and natural mappings
- Don’t be arbitrary, be consistent
- Simplify tasks
- Use appropriate constraints
- Design for error
- *modified from *The Design of Everyday Things*, Donald Norman

## Make Things Visible: This PCA pump fails.

**Make Things Visible: ****This PCA pump fails.**

- Obradovich and Woods (1996)

## Obradovich and Woods (1996)

##  Important Principles of Good Design*

- Make things visible
**Communicate clearly:  e.g., mode / system status**
- Provide correct and natural mappings
- Don’t be arbitrary, be consistent
- Simplify tasks
- Use appropriate constraints
- Design for error
- *modified from *The Design of Everyday Things*, Donald Norman

##  Important Principles of Good Design*

- Make things visible
- Communicate clearly
**Provide correct and natural mappings: “What is this switch for?”**
- Don’t be arbitrary, be consistent
- Simplify tasks
- Use appropriate constraints
- Design for error
- *modified from *The Design of Everyday Things*, Donald Norman

##  Important Principles of Good Design*

- Make things visible
- Communicate clearly
- Provide correct and natural mappings
**Don’t be arbitrary, be consistent: **
**   ****e.g., valve conventions**
- Simplify tasks
- Use appropriate constraints
- Design for error
- *modified from *The Design of Everyday Things*, Donald Norman

##  Important Principles of Good Design*

- Make things visible
- Communicate clearly
- Provide correct and natural mappings
- Don’t be arbitrary, be consistent
**Simplify tasks:  e.g., reduce **
**    ****programming steps**
- Use appropriate constraints
- Design for error
- *modified from *The Design of Everyday Things*, Donald Norman

## Use Appropriate Constraints

**Use Appropriate Constraints**

**FDA, Dec. 28, 1993**

##  Important Principles of Good Design*

- Make things visible
- Communicate clearly
- Provide correct and natural mappings
- Don’t be arbitrary, be consistent
- Simplify tasks
- Use appropriate constraints
**Design for error:  e.g., require confirmation of critical actions**
- *modified from *The Design of Everyday Things*, Donald Norman

## Human Factors: Critical in NHD

**Users**
**Lack of on-site staff and supplies**
**Variable level of education **
**Medically compromised: vision, touch, memory **
**Language and cultural diversity**
**Healthy-patient selection responsible for home safety level***

**Environment**
**Family responsibilities, children, pets**
**Stress**
**Physical (placement, voltage/grounding, temperature, humidity, dust, water quality)**
-     *D’Amico&Bazzi, *Home Hemodialysis*, in Replaplacement of Renal Function by Dialysis, 1989, page 694

## Clinical Incidents: Potential Nocturnal Home Issues? 

**Hazards always exist:**
- For 3 fault codes which indicate need for manual adjustment of transmembrane pressure (TMP) => not actually controllable. Recall. Solution: _labeling_*
- If unit plugged into receptacle without ground fault circuit interrupter (GFCI) – with certain other conditions => overheating. Recall. Solution: _labeling_*

- *ECRI Healthcare Product Comparison System,
- Sept. 2004; p 10 (HDA A5092, A5624)

## NHD User Needs

- Simplify setup: minimize requirements for strict hygiene where possible.
- Minimize burden on training.  Consider periodic retraining.
- Minimize dependence on bulky labeling. Use:
-   On-screen help/voice prompts (“Wizards”)
-   Quick Guides (laminated cards, “cheat
-       sheets”)

## NHD User Needs (continued)

- Monitor supplies and preparation of prescribed dialysate
- Ensure simple set up operation, and adjustment
- Ensure safety of consumables
- Need for priming blood lines, knowing symptoms of air embolism, how to respond

## NHD User Needs (continued)

- Potential interrupted treatment: Ability to detect and respond?
- Allow flexible installation – various viewing angles
- Allow for physical impairment (ESRD co-morbidities)
- Consider touch screen and no cryptic error codes

## NHD User Needs (continued)

- Consider “progressive disclosure” of information– for range of user abilities and wants.
- Facilitate detection of bleeding: enuresis pads, moisture detectors, effective needle dislodgement alarm (single needle?).
- Patient abilities may be lowest at start of session.

## NHD User Needs (continued)

- Consider tricky power-interruption scenarios (error-codes, default settings)
- Design in virtual “guardrails”
- Allow for compromised nocturnal response to alarms

## Human Factors Engineering Process (HFE)

- Start  integrating HFE at concept phase (beginning of design)
- User needs designed in
- Early HF design changes fast , economical, and effective
- Fewer “slapped-on” warnings and bulky manuals
- User acceptance and product life increased
- Usability (HF) study at Validation phase demonstrates: low risk of dangerous use error where and when device is used by typical users (usually a simulation).
- Clinical trials demonstrate: safety and effectiveness where and when used exactly as directed.

## Human Factors Recommendations/Conclusion

- Assume significant patient/user and environmental compromises.
- Minimize burden on training and paper instructions.
- Ensure comprehensive patient/user support from manufacturer or value-added retailer.
- Encourage postmarket feedback from users.
- Design to protect user/patient from error.

## Nocturnal Home Hemodialysis

**Claudia C. Ruiz-Zacharek, M.D.**
**Medical Officer / Nephrologist**
**Gastroenterology and Renal Devices Branch**

**     ****Nocturnal Home Hemodialysis**

**    ****Claudia C. Ruiz-Zacharek, M.D.**
**Medical Officer / Nephrologist**
**Gastroenterology and Renal Devices Branch**
**Division of Reproductive, Abdominal and Radiological Devices**
**Office of Device Evaluation**
**Center for Devices and Radiological Health**
**June 8, 2005**

## Nocturnal Home Hemodialysis Devices

** **
**Optimal device design for actual use conditions**
**Adequate labeling to minimize error**
**Appropriate training for successful treatments **
**Risk analysis to minimize unforeseen problems**
**Clinical study design to demonstrate safety and effectiveness**

**Notes:**
In conclusion, we would like your input  in the following issues on NHHD 

## Overview

**Background Information**
**Nocturnal Home Hemodialysis**
**Clinical Studies**

## Overview

**Background Information**
**Nocturnal Home Hemodialysis**
**Clinical Studies**

## Background Information

**Demographics**
**Review of the literature**
**Definitions and nomenclature**

## Background Information

**Conventional Hemodialysis**
**Typically in-center, 4 hours, 3 X week**
**Medical personnel**
**Patient has a passive role during treatment**
**Nocturnal Home Hemodialysis**
**Performed at home, typically at night, and while the patient sleeps**
**Absence of medical personnel**
**Patient is the performer of the treatment**

**Notes:**
The most common form of renal replacement among the End Stage Renal Disease (ESRD) patient population in the United States is hemodialysis. 
In conventional hemodialysis, all aspects of patient care, from 
obtaining patients’ weight, 
assessment of well being, 
vascular access, and 
dialysis prescription to connection, 
initiation, 
troubleshooting, and 
monitoring of the procedure, are performed by medical personnel.  
The patient is a passive part of the treatment.  

This panel meeting is for the purposes of evaluating a different form of delivering hemodialysis, specifically at night, at home, while the patient is sleeping.  
Nocturnal Hemodialysis (NHD), also referred as Nightly Hemodialysis and Nocturnal Home Hemodialysis, is a type of hemodialysis performed at home, typically at night, and while the patient sleeps.  

## Definitions and Nomenclature

-  **Nocturnal Hemodialysis (NHD)**
**Nightly Hemodialysis **
**Nocturnal Home Hemodialysis **
**Long nocturnal hemodialysis**
**Slow nocturnal hemodialysis**
** ****In-center nocturnal hemodialysis **
** ****Daily hemodialysis**

**Notes:**
Other forms are In-center nocturnal hemodialysis 
 Daily hemodialysis  but we are not considering today

## Definitions and Nomenclature

_**Nocturnal Home Hemodialysis**_
**Performed at home by patient**
**Absence of medical personnel**
**Frequency has reportedly ranged from 5-7 nights a week **
**Length is 6-10 hours per night **

## Definitions and Nomenclature

_**Nocturnal Home Hemodialysis**_
**Blood flows (QB)  200-300 ml/min**
**Dialysate flows (QD)  usually ****~300 ml/min, up to 800 ml/min***
*** ****Pierratos, A. *****Nephrol Dial Transplant***** 1999; 14:2835-2840**

## Data from the United States Renal           Data System (USRDS)

**Prevalence of patients on hemodialysis in the United States, 2002:  281,594**
**0.3% (843) home hemodialysis patients**
**115 NHD patients in 13 centers in North America***
******* ****Lockridge, et al., *****Adv Ren Replace Ther***** 2001; 8(4):250-256.**

**Notes:**
Nocturnal home hemodialysis (NHD) is not a new concept; however, it is uncommon in the United States.  Among the prevalent hemodialysis patients, reported as 281,594 by the United States Renal Data System (USRDS) in 2002, only 0.3% or 843 were home hemodialysis patients, of which an even smaller portion received nocturnal hemodialysis (1).  In 2001, 115 patients in 13 centers in North America were receiving NHD (2).  
The majority of these patients have a high school or college degree, and only 16 patients have DM as etiology for ESRD.
Compared to 45% of ESRD receiving HD have DM as the cause for ESRD in the USA. 
Currently, there are no devices specifically labeled to perform NHD. 

## Population Comparison

_**Lockridge et al.**_
**Diabetic nephropathy*    14%**
**Hypertension                   18%**
**Glomerulonephropathy  11%**
**Polycystic Kidney             9%**
******* ****Lockridge, et al., *****Adv Ren Replace Ther***** 2001**

_**US Demographics (USRDS)**_
**Diabetic nephropathy   45%**
**Hypertension                 28%**
**Glomerulonephropathy   8%**
**Polycystic Kidney         2.3%**

## Background Information – Review of the Literature

| Study | Design |  # Patients |
| --- | --- | --- |
| London Daily/Nocturnal
Dialysis Study, 2003 | Prospective,
observational | 23 (total),
22 matched controls |
| Van Biesen, 2003 | Retrospective | 12 |
| Alloati, 2002 | Prospective | 18 |
| Chan, 2003 | Case control | 9 |
| Agar, 2003 | Prospective | 16 |
| Pierratos, 1999 | Prospective | 37 |

**Notes:**
Some studies done to date; non randomized, some times single arm

## Background Information – Review of the Literature  

| Study | Blood pressure | Calcium -
Phosphorus | Anemia |
| --- | --- | --- | --- |
| London Daily/Nocturnal Dialysis Study, 2003 | Improved  | Improved control | No significant improvement
 |
| Alloati, 2002 | Improved  | Improved control | No significant improvement |
| Chan, 2003 | Improved |  |  |
| Agar, 2003 | Improved | Improved control | Increased epoetin & iron |
| Pierratos,1999 | Improved | Improved control | No significant improvement |

## Background Information – Review of the Literature

| Study | Reported Outcome |
| --- | --- |
| London Daily/Nocturnal Dialysis Study, 2003 | Improved control
reduction of number and severity of  dialysis symptoms |
| Van Biesen, 2003 | Improved serum albumin |
| Agar, 2003 | No fluid or dietary restrictions
Improved sleep patterns |
| Pierratos, 1999 | Reduction of sleep apnea |

## Overview

**Background Information**
**Nocturnal Home Hemodialysis**
**Clinical Studies**

## Nocturnal Home Hemodialysis

**Device Design and Components****	**
**Human Factors Issues****	**
**Water Quality****	**
**Use of a Partner and Remote Monitoring****	**
**Vascular Access and Extracorporeal Circuit Connections****	**
**Labeling****	**
**Lay-User Training****	**

**Notes:**
We will talk about these points we want you to consider

## Nocturnal Home Hemodialysis

**Conventional Hemodialysis**
**Patient is passive recipient**
**Troubleshooting by medical personnel**

**Nocturnal Home Hemodialysis**
**Patient’s active role**
**Presumably asleep**
**Need to troubleshoot**

**Notes:**
Any device malfunction, access problems, or break in the seal of the hemodialysis circuit (e.g., dislodged access needle, blood leaks) would be life threatening, even with the lower blood flows used in nocturnal home hemodialysis.  

## Nocturnal Home Hemodialysis

_**Human Factors Issues**_
**User- friendly**
**Use device successfully while minimizing use error**
**Minimal dependance on labeling and training**

**Notes:**
Tp review what Dr. Mendelson said on HF issues
In the field of medicine, the objective to address human factors is to 
improve human performance, 
reduce the burden on training and labeling, and 
reduce the likelihood of use error and patient injury.
In the application of human factors to medical devices, it is important to ensure that devices are "user friendly" so that users are able to install, calibrate, operate, maintain, and ultimately, dispose of devices safely and effectively with minimal dangerous error and minimal dependence on labeling and training. 
The consideration of human factors in the design, training program and labeling of NHD devices is crucial to their success.

## Nocturnal Home Hemodialysis 

_**Considerations for device design**_**:**
**Redundancy **
**Adequacy of alarms**
** ****Loudness**
** ****Sensitivity**
** ****Ease of understanding and correction**
**Additional safety alarms**

**Notes:**
redundancy into the design so that safety is assured in the event of a component failure during treatment.  
Additional safety alarms at different sites of the hemodialysis circuit may become necessary for a successful hemodialysis session.  Considerations regarding alarms include their loudness, sensitivity, and ease of understanding and correction.  

Other features to be considered as part of the labeling, even though they are not part of the device design, are....Water Quality.

## Nocturnal Home Hemodialysis

_**Water Quality concerns**_
**Conventional Hemodialysis: **
**	****360 L/week**
**Nocturnal Hemodialysis:**
**	****648 L-1080 L/week**
**Standard water quality for hemodialysis vs higher standards**
- Total viable microbial count <200 CFU/mL
- Endotoxin concentration < 2 EU/mL

**Notes:**
This raises the concern as to whether the standard water quality for hemodialysis is sufficient for NHD, or if higher standards should be considered (e.g., lower levels of toxin contaminants).
Water quality is another concern in the consideration of nocturnal home hemodialysis.  In conventional hemodialysis, patients are exposed to about 360 L of dialysate per week; while in nocturnal hemodialysis, assuming dialysate flows of 300 ml/min for 6 hours per treatment, 6 times per week, patients will be exposed to 648 L per week (up to 1080 L if using a dialysate flow rate of 500 ml/min).  

## Nocturnal Home Hemodialysis

_**Water Quality concerns**_
**Types of water treatment systems**
**Reverse osmosis (RO)**
**Deionization (DI)**
**Combination**
**Water source**
** ****Municipal water suppliers**
** ****Well water**

**Notes:**
Water quality has a much higher variability at home than in the clinic...
Another issue to consider is how to handle changes to the water quality or composition by municipal water suppliers.  In such cases, procedures should be in place so that notifications about water changes are communicated appropriately and responses are mounted accordingly.

## Nocturnal Home Hemodialysis

_**Monitoring**_
- Without a partner*
- 59 patients, prospective study
- In-center hemodialysis – constant monitoring
- Home hemodialysis
- * **Raija, et al., Experiences on Home Hemodialysis without an Assistant*****.  Hemodialysis International***** 2003; 7(1):73-104.**

**Notes:**
Some studies have suggested that home hemodialysis can be done by the patient without the need of an assistant or partner (5).  This raises safety concerns, however, that warrant being addressed by the device design, patient training, and/or monitoring performed.
Patients receiving in-center conventional hemodialysis are under constant monitoring by medical personnel.  This is not the case for patients doing home hemodialysis during the day or night.  Further concerns arise from the fact that NHD patients are typically asleep during treatments.  

## Nocturnal Home Hemodialysis

_**Monitoring**_
**“****Monitoring is essential for the initial 3 months of nocturnal HD therapy until the HD team is convinced the patient is stable and compliant.” **
**** *****The London Daily/Nocturnal Hemodialysis Study****. *****AJKD,***** 2003**

**Notes:**
The London Daily/Nocturnal Hemodialysis Study, a prospective, comparative, non-randomized study, suggested that “Monitoring is essential for the initial 3 months of nocturnal HD therapy until the HD team is convinced the patient is stable and compliant” (6).  In cases where a partner is not available and remote monitoring is not used, additional treatment and device safeguards may be necessary to ensure patient safety	

## Nocturnal Home Hemodialysis

**	**_**Vascular access**_
**Long-term cuffed catheter**
**Synthetic graft**
**Arteriovenous fistula**

**Notes:**
Traditionally the vascular access of patients on hemodialysis has not been a part of the device labeling or regulation.  
However, NHD cannot be safely delivered without a properly evaluated and secured vascular access and a discussion is valuable.  Available types of vascular access include arteriovenous fistulae and synthetic grafts, or alternatively, long-term, cuffed hemodialysis catheters.  
The preferred type of vascular access is arteriovenous fistulae, because of the high patency and lower infection rates.  

## Nocturnal Home Hemodialysis

**    **_**Vascular access**_
**Long-term cuffed catheter **
**Synthetic graft **
**Arteriovenous fistula**
- Observational study; 24 patients in daily dialysis; follow up 3.6 years*
*** ****Quintaliani, et al.,  Survival of vascular access during daily and three times a week hemodialysis.  *****Clin Nephrol***** 2000; 53:372-377.**

**Notes:**
Evidence suggests that the increased rate of cannulation of AV fistulas in daily hemodialysis, compared to three times a week, does not increase the rate of complications or infections (7).  
Synthetic grafts are technically more easily placed by the surgeon, and are ready to be used sooner than fistulae; however, the patency rate is inferior to that of fistulae. 
Long-term, cuffed catheters for hemodialysis have the advantages of immediate use after placement, and needle less access for each hemodialysis treatment; however, the disadvantages are the associated higher complication rates, which range from infections to thrombosis.  

## Nocturnal Home Hemodialysis

**Vascular access location**
**Connection to the device**
**Self cannulation**
**Locking devices**
**Fluid detection alarms**
**Moisture sensors**
**Single vs dual needle technique**

**Notes:**
In addition to the vascular access type itself, consider incorporating into the device design or included in the labeling of the device....
The access location should also be considered for NHD.
In addition to the access itself, the connection of the access (patient) to the dialysis device may pose a source of risk.  

Training in self cannulation, use of locking devices, enuresis alarms, and moisture sensors are all issues that should be considered in NHD 

## Nocturnal Home Hemodialysis

_**Labeling**_
**Operator’s Manual**
** ****Warnings**
** ****Precautions**
** ****Device specifications**
** ****Instructions for maintenance**
** ****Cleaning and disinfection**

**Notes:**
Operator’s Manual generally includes:
Such labeling is insufficient for nocturnal home hemodialysis systems, as it does not include information directed to the patient.
What kind of labeling does this device need in addition to what’s regularly expected.

## Labeling

_**Physician’s Instructions for Use**_
**The manual that accompanies a medical device **
**It should also include relevant data from clinical studies and instructions for using and caring for the device**

## Labeling

_**Patient’s Instructions for Use**_
**The manual that accompanies a medical device **
**It should also include relevant data from clinical studies and instructions for using and caring for the device**
**Written for a person with no medical training**

## Nocturnal Home Hemodialysis

_**Training**_
**Teaching provided by the manufacturer**
**Medical expert to train the lay user**
**Lay user to successfully use the device**

**Notes:**
Training is the teaching provided by the manufacturer of the product that allows the medical expert to train the lay user, and the lay user to successfully use the device.

## Nocturnal Home Hemodialysis

_**Lay user training**_
**Conduct safe and effective NHD treatments**
**Length of training reported to be approx 2-8 weeks* ****φ**
******* ****Agar, et al., *****Hemodialysis International***** 2003; 7(4):278-289.**
**Φ****   ****Leitch, et al., *****Am J Kidney Dis***** 2003; 42(1):S56-60****.**

**Notes:**
Let’s now consider training so that the lay user can conduct a safe and effective NHD treatment...
The training of patients and their partners is crucial in being able to conduct safe and effective NHD treatments.  
Since they do not have the background and experience of the professionals that operate these devices in a clinical setting, the training needs to be tailored to their circumstances.  
In published studies, training has been reported to last from 2 to 8 weeks, depending on the complexity of the hemodialysis device and the patient’s familiarity with the hemodialysis process (8, 9). 
In certain circumstances, training has been as short as one day for patients who had previously been on home hemodialysis (3).

## Nocturnal Home Hemodialysis

_**Lay-user training**_
**Appropriate use of the hemodialysis device**
**Interpretation and use of safety features, accessories and hemodialysis treatment itself**
**Test to confirm the adequacy of the training**

**Notes:**

A complete training program should comprise not only the use of the 
hemodialysis device itself,
but the entire array of safety features, 
accessories and 
the hemodialysis treatment itself

## Nocturnal Home Hemodialysis

_**Risk Analysis**_
**Inadvertent disconnections**
**Blood loss from increased frequency of treatments**
**Potential increased rate of vascular access infection **
**Psychological effects**** **

**Notes:**
Additional potential risks the FDA is concerned about:
Increased risk of inadvertent disconnections;
Increased blood loss from increased frequency of treatments;
Potential increased rate of vascular access infection due to increased use of access; and
Psychological effects (e.g., impact of treatments on patients, such as loss of social interaction and the impact of increased responsibility on the patient) requiring need for adjustment or discontinuation of therapy.

## Overview

**Background Information**
**Nocturnal Home Hemodialysis**
**Clinical Studies**

## Clinical Studies

**Purpose**
**Patient selection**
**Study design**

## Clinical Studies

_**Purpose**_
**To demonstrate the safety and  effectiveness  of the NHD devices under actual use conditions**
**Not intended to evaluate the long term morbidity and mortality of NHD as a therapeutic modality compared to conventional hemodialysis**

**Notes:**
FDA believes that clinical studies should be conducted to demonstrate the safety and  effectiveness of the NHD devices under actual use conditions.  

## Clinical Studies

_**FDA concerns**_**:**
**Patient selection for trial**
**Patient selection for marketing**
**Patient performs the entire treatment **
**Patient must wake up to attend the alarms  **

**Notes:**
Would like patients unfamiliar with hemodialysis to test the adequacy of the training

Patients need to be able to learn to perform the entire treatment, from setting up the system to the after-treatment clean up and troubleshooting, either themselves or with the help of a partner.  In addition, patients are expected to wake up to the alarms and be able to respond in a timely manner.  

## Clinical Studies

_**Reported patient selection**_**:**
**Agar, et al., Nocturnal Hemodialysis in Australia.  Hemodialysis International 2003; 7(4):278-289.**
**Alloatti, et al., Long Nocturnal Dialysis.  Blood Purif 2002; 20:525-530.**
**Covic, et al., Long-hours home haemodialysis – the best renal replacement therapy method?  Q J Med 1999; 92:251-260.**

**Notes:**
Regarding patient selection, several studies on NHD have selected highly motivated ESRD patients who have been stable on conventional or home hemodialysis (8, 10).  
This type of selection automatically excludes patients who undergo significant intradialytic hypotension, or patients who suffer from severe congestive heart failure, diabetes or cardiovascular disease (11).

## Clinical Studies

** **_**Reported patient selection**_**:**
**Agar, et al., Nocturnal Hemodialysis in Australia.  Hemodialysis International 2003; 7(4):278-289.**
**16 patients, prospective**
**Clinically stable > 3 mo in HD**
**Psychologically sound**
**Technically adept**
**Stable and supportive home**
**Compliant**

**Notes:**
Regarding patient selection, several studies on NHD have selected highly motivated ESRD patients who have been stable on conventional or home hemodialysis (8, 10).  
This type of selection automatically excludes patients who undergo significant intradialytic hypotension, or patients who suffer from severe congestive heart failure, diabetes or cardiovascular disease (11).

## Clinical Studies

** **_**Reported patient selection**_**:**
**Alloatti, et al., Long Nocturnal Dialysis.  Blood Purif 2002; 20:525-530.**
**18 patients, nonrandomized, prospective**
**Glomerulonephritis (7)**
**Tubulointerstitial (4)**
**Nephroangiosclerosis (3)**
**Diabetic nephropathy (1)**
**Vasculitis (1)**
**Other (2)**

**Notes:**
Regarding patient selection, several studies on NHD have selected highly motivated ESRD patients who have been stable on conventional or home hemodialysis (8, 10).  
This type of selection automatically excludes patients who undergo significant intradialytic hypotension, or patients who suffer from severe congestive heart failure, diabetes or cardiovascular disease (11).

## Clinical Studies

** **_**Reported patient selection**_**:**
**Covic, et al., Long-hours home haemodialysis – the best renal replacement therapy method?  **
**	****Q J Med 1999; 92:251-260.**
**286 UK patients; retrospective, observational study**
**Initially excluded older and frailer patients**
**Excluded patients with diabetes, cardiac failure, and multiple myeloma**
**Currently 33% diabetic patients**

**Notes:**
Regarding patient selection, several studies on NHD have selected highly motivated ESRD patients who have been stable on conventional or home hemodialysis (8, 10).  
This type of selection automatically excludes patients who undergo significant intradialytic hypotension, or patients who suffer from severe congestive heart failure, diabetes or cardiovascular disease (11).

## Clinical Studies

_**Patient selection criteria**_**:**
**Availability of a partner**
**Patient's compliance**
**Psychological well being**
**Home environment (Medicare) **
**Water supply**
**Sewage**
**Electricity**
**Space**
**Social interaction**

**Notes:**
Atypical or unusual for selection criteria are the following,

Besides the patients’ ability to be trained and subsequently perform the hemodialysis process alone, other selection criteria may prove important, such as home environment, patient’s vascular access type and location, availability of a partner, patient’s compliance,  and psychological well being, The impact on patient’s family members living in the house should also be considered. 

## Clinical Studies

_**Study design discussion**_**:**
**Clinical endpoints**
**Effectiveness**
**Safety / Adverse Events**
**Control group**
**Randomized vs patient as own control**
**Length of follow-up**
**Sample size**

**Notes:**
to demonstrate the safety and effectiveness of the NHD devices under actual use conditions.  

Review of Home hemodialysis devices have included about 25 patients, 8 weeks in clinic and 8 weeks at home.

## Clinical Studies

_**Treatment related issues to be considered**_**:**
**Dialysate composition and additives**
**Administration of anticoagulation**
**Choice of dialyzer**
**Type of monitoring**
**Vascular access**
**Dialyzer reuse**

**Notes:**
dialysate composition (including the need for phosphate or other additives), type of anticoagulation (dose, bolus, monitoring), choice of dialyzer (membrane type and permeability), type of monitoring (e.g., partner present, partner awake, no partner but using remote monitoring, no partner or remote monitoring), choice of blood access type and location, and the practice of reuse of dialyzers

## Conclusions

** **_**Nocturnal Home Hemodialysis Devices**_
**Optimal device design for actual use conditions**
**Adequate labeling to minimize error**
**Appropriate training for successful treatments **
**Risk analysis to minimize unforeseen problems**
**Clinical study design to demonstrate safety and effectiveness**

**Notes:**
In conclusion, we would like your input  in the following issues on NHHD 

## References

**United States Renal Data System (USRDS)  **_[www.usrds.org](http://www.usrds.org/)_
**Lockridge RS, Spencer M, Craft V, Pipkin M, Campbell D, McPhatter L, Albert J, Anderson H, Jennings F, and Barger T.  Nocturnal Home Hemodialysis in North America.  Adv Ren Replace Ther 2001; 8(4):250-256.**
**Pierratos, A. Nocturnal home haemodialysis: an update on a 5-year experience.  Nephrol Dial Transplant 1999; 14:2835-2840**
**Mehrabian S, Morgan D, Schlaeper C, Kortas C, and Lindsay RM. Equipment and water treatment considerations for the provision of quotidian home hemodialysis.  Am J Kidney Dis 2003; 42:S66-S70.**
**Raija M, Riitta MK, Meeri K, and Eero H.  Experiences on Home Hemodialysis without an Assistant.  Hemodialysis International 2003; 7(1):73-104.**

## References

**Heidenheim AP, Leitch R, Kortas C and Lindsay RM.  ****Patient Monitoring in the London Daily/Nocturnal Hemodialysis Study.  Am J Kidney Dis 2003; 42:S61-S65.**
**Quintaliani G, Buoncristiani U, Fagugli R, Kuluiranu H, Ciao G, Rondini L, Lowenthal DT, and Reboldi G.  Survival of vascular access during daily and three times a week hemodialysis.  Clin Nephrol 2000; 53:372-377.**
**Agar JWM, Somerville CA, Dwyer KM, Simmonds RE, Boddington JM, and Waldron CM.  Nocturnal Hemodialysis in Australia.  Hemodialysis International 2003; 7(4):278-289.**
**Leitch R, Ouwendyk M, Ferguson E, Clement L, Peters K, Heidenheim AP, and Lindsay RM.  Nursing Issues Related to Patient Selection, Vascular Access, and Education in Quotidian Hemodialysis.  Am J Kidney Dis 2003; 42(1):S56-60.**

## References

**Alloatti S, Molino A, Manes M, Bonfant G, and Pellu V. Long Nocturnal Dialysis.  Blood Purif 2002; 20:525-530.**
**Covic A, Goldsmith DJA, Venning MC, and Ackrill  P.  Long-hours home haemodialysis – the best renal replacement therapy method?  Q J Med 1999; 92:251-260.**
**The following articles have not been cited in the above discussion of NHD, but may provide additional information.  Copies of these may also be found in Appendix F.**
**Chan CT, Hanly P, Gabor J, Picton P, Pierratos A, and Floras JS.  Nocturnal Hemodialysis Lowers Heart Rate during Sleep and Normalizes Its Parasympathetic and Sympathetic Modulation.  Hemodialysis International 2003; 7(1):73-104.**

## References

**Faratro R and Chan CT.  Nocturnal Hemodialysis Improves Productivity of End-Stage Renal Failure Patients.  Hemodialysis International, 2003; 7(1):73-104.**
**Francoeur R and Digiambatista A.  Technical Considerations for Short Daily Home Hemodialysis and Nocturnal Home Hemodialysis.  Adv Ren Replace Ther 2001; 8(4):268-272.**
**Heidenheim AP, Muirhead N, Moist L, and Lindsay RM.  Patient Quality of Life on Quotidian Hemodialysis.  Am J Kidney Dis 2003; 42:S36-S41.**
**Kjellstrand CM and Ing T. Daily Hemodialysis: History and Revival of a Superior Dialysis Method.  ASAIO Journal 1998; 117-122.**
**Kjellstrand CM and Blagg CR. Differences in Dialysis Practice are the Main Reasons for the High Mortality Rate in the United States compared to Japan.  Hemodialysis International 2003; 7(1):67-71.**

## References

**Kroeker A, Clark WF, Heidenheim AP, Kuenzig L, Leitch R, Meyette M, Muirhead N, Ryan H, Welch R, White S, and Lindsay RM.  An Operating Cost Comparison Between Conventional and Home Quotidian Hemodialysis.  Am J Kidney Dis 2003; 42:S49-S55.**
**Lindsay RM,  Leitch R, Heidenheim AP, and Kortas C.  ****The London Daily/Nocturnal Hemodialysis Study – Study Design, Morbidity, and Mortality Results.  Am J Kidney Dis 2003; 42(1):S5-S12.**
**Lindsay RM, Alhejaili F, Nesrallah G, Leitch R, Clement L, Heidenheim AP,  and Kortas C.  Calcium and Phosphate Balance with Quotidian Hemodialysis.  Am J Kidney Dis 2003; 42, S1:S24-29.**
**Nesrallah G, Suri R, Moist L, Kortas C, and Lindsay RM.  Volume Control and Blood Pressure Management in Patients Undergoing Quotidian Hemodialysis.  Am J Kidney Dis 2003; 42:S13-17.**

## References

**Pierratos A.  Daily nocturnal home hemodialysis.  Kidney International 2004; 65:1975-1986.**
**Pierratos A. Quotidian Hemodialysis: Is it the Solution to the Problem?  Seminars in Dialysis 2004; 17(2):77-78.**
**Radford MG, Shultman DS, Pasour AG, Cobb AM, and Chandler JT.  An Incenter Nocturnal Hemodialysis Program – Three Years Experience.  Hemodialysis International 2003; 7(1):73-104.**
**Rao M, Muirhead N, Klarenbach S, Moist L, and Lindsay RM.  Management of Anemia with Quotidian Hemodialysis.  Am J Kidney Dis 2003; 42:S18-S23.**

## References

**Spanner E, Suri R, Heidenheim AP, and Lindsay RM.  The Impact of Quotidian Hemodialysis on Nutrition.  Am J Kidney Dis 2003; 42(1):S30-S35.**
**Suri R, Depner TA, Blake PG, Heidenheim AP, and Lindsay RM.  Adequacy of Quotidian Hemodialysis.  Am J Kidney Dis 2003; 42:S42-S48.**
**Van Biesen W, Veys N, Vanholder R, and Lameire N. Effect of Long Nocturnal Dialysis on Nutritional Status and Blood Pressure Control.  Hemodialysis International, 2003; 7(1):73-104.**
**Weick-Brady M.  Medical Devices: Going Home.  FDLI Update 2003; September/October: 23-24, 29-30.**

## References

**Weinger MB, Foreword to Designing Usability into Medical Products**
**Woods JD, Port FK, Stannard D, Blagg CR, and Held PJ.  Comparison of mortality with home hemodialysis and center hemodialysis: A national study.  Kidney International, 1996; 49:1464-1470.**
**Young BA, Hynes J,  and McComb T.  Home Hemodialysis: Associations with Modality Failure.  Hemodialysis International, 2003; 7:73-104.**