Autologous Serum Eye Drops

Jeffrey S. Jhang, MD

System Director, Blood Bank and Transfusion Services

Mount Sinai Health System

Associate Professor of Pathology

Icahn School of Medicine at Mount Sinai

AABB October 14, 2018

Disclosures

▶ Celularity Inc. (Contractor), Cedar Knolls, NJ

Learning Objectives

▶ Review the current indications for, the efficacy of, and the

complications of of autologous serum eye drops for dry eyes.

▶ Review the methods for manufacturing autologous serum eye drops.

▶ Appreciate the potential clinical impact and future research needed

to develop and utilize this products to best treat our patients.

Dry Eyes – Symptoms and Diagnosis

▶ Multifactorial disease of tears & ocular surface

1. Discomfort

– Stinging, burning, foreign body, or scratching sensation

– Dryness or irritation

– Light sensitivity

– Redness

– Crusting in or around eyes

2. Visual disturbance/blurred vision

– Difficulty with contact lenses or nighttime driving

3. Inflammation and potential damage to the

ocular surface

4. Increased tear osmolarity

K. Tsubota et al. Treatment of dry eye by autologous serum application in Sjögren’s syndrome. Br J Ophthalmol 1999;83:390–395

Tests

▶ Tear osmolarity

▶ Tear production (Schirmer’s test)

▶ Fluorescein clearance

▶ Tear-film break up time

▶ Ocular surface damage

tube.medchrome.com

epomedicine.com

Evaporative

▶ Wind, smoke or dry air

▶ Blinking less often (e.g. reading,

driving or staring at a computer)

▶ Eyelid problems (e.g. ectropion,

entropion)

Lack of Production (Keratoconjunctivitis sicca)

▶ Sjögren syndrome very common (“sicca

complex”)

▶ Diabetes

▶ Rheumatoid arthritis

▶ Systemic lupus erythematosis

▶ Age-related lacrimal dysfunction

▶ Hormonal changes (e.g. birth control,

thyroid disease)

▶ Drug side effects (e.g. antihistamines,

decongestants, diuretics, antidepressants)

▶ Surgical intervention (e.g. LASIK)

▶ Long-term contact lens use

Treatments

▶ Artificial tears is the mainstay of therapy

▶ Made of different electrolyte concentrations and osmolarity as well as the

presence of different preservatives and also viscosity

▶ Hyaluronate may be used as an additive

▶ Steroids

– long-term complications of increased intraocular pressure and cataracts

▶ Cyclosporine A

▶ Punctal plugs

▶ ASEs

Background Autologous serum eyedrops (ASE)

▶ Lacrimal substitute to provide something that

mimics natural tears

▶ Second-line therapy for dry eyes

▶ Natural tears are much more complex

– Water

– Salts

– Proteins

– lipids

– Growth factors

▶ Composition resemble those of tears with similar

concentrations except

▶ More vitamin A, lysozyme, TGF-b, fibronectin, IgA,

EGF and vitamin C than tears

Indications

▶ Sjögren syndrome

▶ Graft-versus-host disease s/p allogeneic bone marrow transplantation

▶ Neurotrophic keratitis

▶ Persistent epithelial defects

▶ Superior limbic keratoconjunctivitis

▶ s/p LASIK with dry eyes

Production

▶ No standards developed

▶ Unregulated in most states

▶ FDA does not regulate this product

▶ Manufacturing methods differ

▶ Different storage and administration standards

Serum Tubes – you can make this at home! (but don’t, please!)

https://www.youtube.com/watch?v=a62v6IQf4XE; Neal Matthews

Office Preparation

https://www.youtube.com/watch?v=_tjYfkOrS0w. Orange County LASIK surgeon

Segments – Prepare plasma

Fill tubing & Make Segments

BiomedDevice Col© System

Efficacy

• 28 eyes of 28 patients

• 2 dropped out

• Group 1:

• 15 (58%) chemical agents

• Group 2

• Chronic eye disease

22 +/- 15 weeks duration

F. Semeraro et al. BioMed Research International 2014

Efficacy in Sjögren’s syndrome

▶ 12 patients with Sjögren’s

syndrome

▶ treated with autologous serum

(diluted to 20% with sterile

saline) for 4 weeks

▶ EGF, vitamin A, and TGF-a were

well preserved for up to 1 month

in the refrigerator at 4°C and up

to 3 months in the freezer at

−20°C.

▶ Rose bengal and fluorescein

scores improved significantly from

the initial scores of 5.3 and 5.6 to

1.7 and 2.5 after 4 weeks,

respectively.

K. Tsubota et al. Treatment of dry eye by autologous serum

application in Sjögren’s syndrome. Br J Ophthalmol 1999;83:390–395

Complications

▶ Usually well-tolerated

▶ Bacterial conjunctivitis

▶ Eyelid eczema

▶ Scleral vasculitis and melting in RA

▶ Immunoglobulin depositius in cornea

▶ Corneal peripheral infiltrates

O. Thanathanee Cornea Volume 32, Number 8, August 2013

Bacterial Contamination

SC Leite et al. Bone Marrow Transplantation (2006) 38, 223–227

Bacterial Contamination

▶ Lysozyme and complement and

IgG may be bacteriostatic

R. Lagnado Br J Ophthalmol 2004;88:464–465

Thank you

▶ Donna Strauss and the New York Blood Center, New York, NY

▶ Faculty and Staff of the New York Eye and Ear Infirmary of Mount Sinai,

New York, NY

Seeking safe stool: Enabling access to

Universal Stool Banks

Pratik Panchal MD MPH

AABB 2018 | October 14th 2018

Disclosures

• Special advisor to OpenBiome

I am large,

I contain multitudes

Walt Whitman

What is stool transplant?

• Fecal microbiota transplantation (FMT) involves the transfer of full spectrum microbiotaTM stool from a healthy screened donor to a recipient with the aim of normalizing the perturbed gut microbiome associated with CDI.

• Bacteria from donors help outcompete C. difficile and patient reestablishes normal composition of flora in their GI tract

Mechanism of Action

Bakken et al., 2011

The Growing Threat of CDI

• 453,000 cases per year

• 20% rate of recurrence

• 29,300 deaths per year

• $4.8 billion per year in hospitalization & treatment

Lessa et al., 2015 Campbell et al., 2013Steiner et al., 2014Ma et al., 2018

History of stool transplant

• A 4th century Chinese researcher , Ge Hong, used ‘yellow soup’ to treat his patients with severe diarrhea.

• Dr. Ben Eisenman published first case series in 1950s

• Van Nood et al published first, landmark RCT of FMT for rCDI in 2013

Change in the regulatory landscape

July 15, 2013

Wellington Sun, MD

Director, Division of Vaccines and Related Product Applications

Office of Vaccines Research and Review

CBER

RM 2302

1451 Rockville Pike

Rockville, MD 20852

Re: Current Consensus Guidance on Donor Screening and Stool Testing for FMT

Dear Dr. Sun:

On behalf of the undersigned medical specialty societies, we thank you for the opportunity to

provide guidance on appropriate screening and stool testing of potential stool donors for Fecal

Microbiota Transplantation (FMT). Our consensus guidance on donor screening and stool

testing is attached as an addendum to this letter.

Our organizations are interested in collaborating with the FDA on establishing a protocol for

FMT that balances appropriate oversight of this effective, yet not fully understood, therapy with

reasonable access for patients with recurrent Clostridium difficile infection (CDI), for whom few

alternatives are available. We thank the FDA for the opportunity to provide our clinical input

and we look forward to further collaboration aimed at allowing appropriate access to FMT

therapy. Please contact Andres Rodriguez with any questions at 703-299-5146 or

arodriguez@idsociety.org.

Sincerely,

David Relman, MD, FIDSA Ronald J. Vender, MD, FACG

President – IDSA President – ACG

Anil K. Rustgi, MD, AGAF Kenneth K. Wang, MD, FASGE

President – AGA President - ASGE

Athos Bousvaros, MD

President - NASPGHAN

Guidelines

Stool donation most closely resembles the

blood donation model

Prior to fecal microbiota transplantation there were predominately two forms of tissue transplantation:

Table: Functional Comparison of Blood and HCT/Ps Donation ProgramsGreen: similar to stool donation; Red: different to stool donation

Blood Donation Human cells, tissues, and cellular and tissue-based products (HCT/Ps)

Supply Continuous On-demand

Indication Discrete Heterogeneous

Recipient Matched or unmatched Matched or unmatched

Collection Minimally invasive Invasive

Donor Alive Alive or cadaveric

Cadence Frequent One-off

Location Decentralized collection centers High-acuity procedure

Head-to-head comparison of regulatory

landscape of human tissue donation

Blood Donation Human cells, tissues, and cellular and tissue-based products (HCT/Ps)

Specifically named protections and services provided to them by clinically trained staff

Donors evaluated by ‘responsible persons’ with no explicit care requirements

Donor health and eligibility is monitored on a dynamic and time dependent scale

Donors health and eligibility is determined at a single point in time

Title 21 CFR 630-640 Requirements for blood and blood components intended for further manufacturing use

Title 21 CFR 1271 Human cells, tissues, and cellular and tissue-based products

Emphasis on donor eligibility and transplant safety, as well as welfare, treatment, and maintenance of donorhealth

Emphasis on donor eligibility and transplant safety, but no specific language about management of donor health

Randomized controlled trials show

FMT is efficacious across delivery modalities

Study Delivery N Clinical Cure Related SAEs

Van Nood et alNEJM 2013

Nasoduodenal 43 81% None

Lee et al JAMA 2016

Enema 232 84% None

Kelly et al Ann Intern Med 2016

Colonoscopy 46 91% None

FMT is more cost-effective than antibiotics

⎼ $1,699 (FMT) vs. $3,788 (vancomycin) according to one study

⎼ Insurance coverage varies, often procedures covered but not

necessarily material

Real-world data from OpenBiome show

FMT is efficacious across modalities

Osman et al., 2016

Allegretti et al., 2016

Barriers to Access

• Of the 330 physicians who did not offer FMT

• 80% reported difficulties with the logistics of preparation and/or delivery

• 45% cited the complexity and cost of donor screening

• A major physician barrier to FMT is preparation and material processing

Bakken et al 2014

Zipursky JS et al 2014

The Universal Stool Bank Model

Donor

Assessment

Stool &

Serological

Testing

• 208-point clinical

assessment

- 45-minute evaluation

by a physician or nurse

overseen by an

internal medicine

specialist

• Stool & serological testing

- 18 stool laboratory investigations

- 14 serological laboratory screens

• 16s microbiome sequencing

• Dual testing & continuous

monitoring

• Safety aliquots

• Process, storage & shipping

controls

• Traceability & quality

assurance program

1 Clinician orders fecal

preparations from a stool bank2 Stool bank provides

rigorously screened,

processed, frozen material

3 The clinician thaws

material and performs FMT

Monitoring &

Re-testing

16

OpenBiome’s Donor Safety Standards

1) Donor Registry

Potential donors answered a pre-

screen survey

Assess for most common reasons for exclusion

- Logistics

- Commitment

- Age

- BMI>30

- Birth country

- Travel history

- Antibiotic use

- Smoking

- Recent vaccination

2) Clinical Assessment

Qualified individuals completed an on-site

clinical assessment

- Transmissible infectious diseases

- Gastrointestinal conditions

- Atopic conditions

- Autoimmune conditions

- Chronic pain syndromes

- Metabolic conditions

- Neurological conditions

- Psychiatric conditions

- Malignancy history

- Medications

- Diet

- Family history

- Vital signs including BMI and waist circumference

3) Laboratory Investigation

Those who passed completed a comprehensive stool and serological

screening panel

Stool: Bacteria

Clostridium difficile, PCR

Salmonella/Campylobacter/

Shigella, Culture-based assay

Vibrio, Culture-based assay

Giardia, EIA

Helicobacter pylori, EIA

VRE, Culture-based assay

CRE, Culture-based assay

ESBL, Culture-based assay

Stool: Parasites

Cryptosporidium, EIA

Cyclospora / Isospora, Acid fast stain

Ova & Parasites, Microscopic exam

Microsporidia, Microscopic exam

Stool: Viruses

Norovirus, PCR

Adenovirus, EIA

Rotavirus, EIA

Nasal: MDRO

MRSA, Culture-based assay

Serological

HIV antibody, type 1 and 2

Hepatitis A (IgM)

Hepatitis B panel (HBsAg, anti-HBc [IgM and Total])

Hepatitis C (HCV antibody)

Treponema palladium, EIA

HTLV I &II

CBC with differential

Hepatic function panel

How is FMT prepared?

• Stool collected on-site in standardized collection kits

• Mixed with an inert cryo-preservative and filtered with microfilter to remove fiber (to ensure it doesn’t damage the scopes

• Homogenized

• Storage –80 deg C

• Transport –20 deg C

2013

0

500

1000

0.00

50.00

100.00

2013 2014 2015 2016 2017

% o

f To

tal U

S Po

pu

lati

on

1 Hour Drive Time

2 Hour Drive Time

4 Hour Drive TIme

No. of Hospital Partners

Drive Time(Hours)

% Population Coverage

1 6.51

2 10.83

4 25.37

Panchal et al. DDW 2018

2014

0

500

1000

0.00

50.00

100.00

2013 2014 2015 2016 2017

% o

f To

tal U

S Po

pu

lati

on

1 Hour Drive Time

2 Hour Drive Time

4 Hour Drive TIme

No. of Hospital Partners

Drive Time(Hours)

% Population Coverage

1 52.95

2 72.16

4 92.36

Panchal et al. DDW 2018

2015

0

500

1000

0.00

50.00

100.00

2013 2014 2015 2016 2017

% o

f To

tal U

S Po

pu

lati

on

1 Hour Drive Time

2 Hour Drive Time

4 Hour Drive TIme

No. of Hospital Partners

Drive Time(Hours)

% Population Coverage

1 77.91

2 92.73

4 98.74

Panchal et al. DDW 2018

2016

0

500

1000

0.00

50.00

100.00

2013 2014 2015 2016 2017

% o

f To

tal U

S Po

pu

lati

on

1 Hour Drive Time

2 Hour Drive Time

4 Hour Drive TIme

No. of Hospital Partners

Drive Time(Hours)

% Population Coverage

1 85.35

2 96.84

4 99.86

Panchal et al. DDW 2018

2017

0

500

1000

0.00

50.00

100.00

2013 2014 2015 2016 2017

% o

f To

tal U

S Po

pu

lati

on

1 Hour Drive Time

2 Hour Drive Time

4 Hour Drive TIme

No. of Hospital Partners

Drive Time(Hours)

% Population Coverage

1 87.54

2 97.74

4 99.89

Panchal et al. DDW 2018

Pediatric access to FMT

Drive Time

(hours)

% Population

Coverage

1 42.96

2 64.54

4 90.06

Panchal et al. IDWeek 2018

• In the US, unlike the adult population,

pediatric access to FMT has not been

universally adopted for rCDI.

• This is partially attributable to lack of a

landmark RCTs and pediatric consensus

guidelines

The disease paradigm has shifted away from infection to immune

mediated diseases

Bach NEJM 2002

Impact of a universal stool bank

• Access

• Safety

• Outcomes

• Research

What does the future look like?

Acknowledgements

• Bharat Ramakrishna

• Carolyn Edelstein

• The Neil & Anna Rasmussen Foundation and the Anna-Maria & Stephen Kellen Foundation.

Novel Banking Modalities: Human Milk

Banking, Fecal Microbiota

Transplantation, and Autologous

Serum Eye Drops

10/14/2018

Faculty Disclosures

The following faculty have no

relevant financial relationships to

disclose:

– Suzanne Arinsburg DO

– Jeffrey Jhang MD

The following faculty have a

relevant financial relationship:

– Pratik Panchal MD, MPH

Finch Therapeutics:

Consultant

www.aabb.org 2

Learning Objectives

• Recognize the current indications for the use of human donor milk, fecal microbiota, and autologous serum eye drops

• Advise clinical departments of the necessary steps needed to be taken to comply with federal, state, and volunteer organization standards

• Appreciate the potential clinical impact and future research needed to develop and utilize these products to best treat our patients

www.aabb.org 3

Volunteer Donor Breast Milk Banking

Suzanne A. Arinsburg, DO

Mount Sinai Hospital

• Financial Disclosures

– None

• Conflicts of Interest

– Medical Advisory Board of the New York Milk Bank –

Volunteer

www.aabb.org 2

Outline

• What is the evidence for donor milk?

• Who can donate milk?

• How is donor milk processed?

• How do I obtain donor milk?

• What are the regulations around donor milk?

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What is the evidence for donor milk?

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Background

• Feeding exclusively human milk consistently demonstrated to improve clinical outcomes in premature infants

• Evidence to support reduced risk of– Late onset sepsis

– Bronchopulmonary dysplasia

– Retinopathy of prematurity

– Improved neurodevelopment

• Decreased risk of necrotizing enterocolitis

www.aabb.org 5Quigley M, Embleton ND, McGuire W. Formula versus breast milk for Feeding Preterm or Low Birth Weight Infants (Review). Cochrane Library; 2018, 6.

Human Milk

• Highly bioavailable macro and micronutrients

• Immunomodulatory molecules (IgG, IgA, interleukins,..)

• Prebiotics

• Probiotics

Superiority of human milk compared to formula has led to

the use of donor human milk when mother’s milk is

unavailable or insufficient

www.aabb.org 6Quigley M, Embleton ND, McGuire W. Formula versus breast milk for Feeding Preterm or Low Birth Weight Infants (Review). Cochrane Library; 2018, 6.

Concerns

• Insufficient amount of protein, calories, and minerals

to support rapid growth

• May require the addition of fortifiers to support

optimal growth

www.aabb.org 7Quigley M, Embleton ND, McGuire W. Formula versus breast milk for Feeding Preterm or Low Birth Weight Infants (Review). Cochrane Library; 2018, 6.

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Endorsed by

• American Academy of Pediatrics

• World Health Organization

• Centers for Disease Control

• The Joint Commission

• Surgeon General Call to Action in 2011

• National Association of Neonatal Nurses

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Who can donate breast milk?

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Milk Donation

• Phone consultation

• Fill out a donor questionnaire

• Medical release forms to obtain information regarding the health of the mother and the baby

• Blood tests

• Education on pumping and milk storage

• Volunteer donors

www.aabb.org 16

Donor Testing

• HIV

• HCV

• HBV

• Syphilis

• HTLV

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Exclusion Criteria

• Smoking or use of tobacco products

• Recreation drug use

• Travel restrictions

• Recent tattoo or piercing unless in a licensed facility

• Blood transfusion within past 6 months

• Certain medications

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Delivery of Milk

• Brought to milk depots

• Coolers provided to ship milk

• Shipped frozen overnight

www.aabb.org 19https://littleheartsbiglove.co.uk/wp-content/uploads/2014/07/express-and-share-02.jpg

Types of Milk

• Colostrum

• Preterm - < 36 weeks gestation

• Term

• Mature > 1 year of age

• Research

• Kosher

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How is breast milk processed?

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Steps in Milk Processing

• Pouring

• Mixing

• Pooling

• Pasteurization

• Culture

• Quarantine

• Delivery

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Holder Pasteurization

• 62.5° C for 30 minutes

• Rapid cooling

• Cultured before distribution

• Quarantined for 48 hours

www.aabb.org 23Lafuente MC et al. A prospective analysis of intake and composition of mother’s own milk In preterm newborns less than 32 weeks’ gestational ge. Journal of Perinatology Medicine. 2018,aop/.

Effects of Pasteurization

Component Maintained >90% Maintained 50-90%

Maintained 10-50%

Abolished

Macronutrients Lactose, Oligosaccharides

ProteinFat

Micronutrients Ca, Cu, Mg, Phos, K, Na, Zn

Fe

Vitamins A Folate, B6, C

CD14, IL-2, Lactoferrin, Lysozyme

IgM, Lymphocytes

Biologically active mediators

IL-8, IL-12, IL13, TGF-⍺, Epidermal Growth Factor, Heparin Binding Growth Factor

Adiponectin, Amylase, Insulin

Erythropoietin, Hepatocyte Growth Factor

Bile salt dependent lipase, Lipoprotein lipase

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Factors Affecting Nutritional Content

• Preprocessing

– Stage of lactation

– Storage

– Containers

– Shipping

– Pooling

• Processing

• Post-processing

• Storage length

• Storage container

• Thawing

• Route of administration

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Processing and Delivery by NY Milk Bank

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Pouring, Mixing and Pooling

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Pasterization

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Testing, Freezing and Storage

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Milk Riders

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Obtaining Donor Milk

• State regulations – California, Texas, Maryland, New York and

New Jersey

• State license if needed

• Contract with either a volunteer donor milk bank or for profit

milk bank

• Develop policy and procedures including logs and consent

• Training and education of staff

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Hospital Receipt and Storage of Donor Milk

• Delivery– Food and nutrition department

– Pharmacy

– NICU

• Inspection

• Designated freezer for frozen milk– Mother’s own milk

– Pasteurized donor milk

• Thawing– Expires at 48 hours post-thaw

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Administration of Donor Milk

• Handled as a blood product

– Parental consent

– Order from a licensed practitioner

– 2 RN verification

– May be aliquoted

• Recorded in distribution log

• Must be tracked

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What are the regulations around donor milk?

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Human Milk Banking Association of North

America (HMBANA)• Accredit nonprofit volunteer donor milk banks in th US

and Canada

• Developed and set international guidelines for pasteurized human milk

• 27 current members:– 24 milk banks in the US

– 3 milk banks in Canada

– 6 developing milk banks

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www.aabb.org 44https://www.hmbana.org/find-a-milk-bank/overview.html

www.aabb.org https://www.hmbana.org/news/blog.html/article/2018/03/14/nonprofit-donor-human-milk-distribution-reaches-record-high-in-2017

European Milk Bank Association

• Promote milk banking and the use of volunteer donor milk

• Cooperation between milk banks throughout Europe and Russia

• Establishment of guidelines

• 233 active milk banks with 14 additional planned banks

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Questions??

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