Beyond Eye DropsOur Translational Journey With an Ocular Coil

Prof. dr. Rudy Nuijts, MD, PhD

on behalf of the OCDC-team

Today’s Topic

Do’s

an

dDon’tsLessons learned

The

of the OCDC project

,

,

Current Practice in Ophthalmology

Eye drops for prevention

and treatment of ocular

diseases:

◆ Multiple drops a day

◆ Multiple bottles each time

Problems with Eye Drops

◆ Non-compliance

◆ Suboptimal drug absorption

◆ Side effects

Overview Ocular Drug Delivery Devices

Intra-ocular devices

Ocusert (removed from the market)

Intra-ocular lens (being developed)

Eye drops

Mydriasert

TODDD (Topical Ophthalmic

Drug Delivery Device)(not yet on the market)

Dextenza (punctum plug)

Bertens CJF, Gijs M, van den Biggelaar FJHM, Nuijts RMMA. Topical drug delivery devices: A review. Exp Eye Res. 2018 Mar;168:149-160

Dextenza (Ocular Therapeutix) – Postoperative inflammation

Overview Ocular Drug Delivery Devices

Ocular coil

The Ocular Coil

The Ocular Coil

Slippery coating to

increase comfort

• Non-invasive

• Easy to insert

• Easy to remove

Capacity to contain

multiple drugsSustained drug delivery up to one month

Does not affect vision

Concept: the OphthaCoil

2000 – 2005

◆ PhD thesis

◆ 6 papers

◆ 3 patents

The Aim of the Project

◆ Aims:

– develop an ocular coil for sustained drug delivery

– perform human safety and comfort trial

– perform preclinical efficacy evaluation in animals

WP#1

Ocular insert

assembly and

manufacturing

WP#2

Microsphere

fabrication and

drug loading

WP#4

Animal efficacy

trial

WP#3

Human safety

and comfort

trial

Project Partners

WP#1

Ocular insert

assembly and

manufacturing

WP#2

Microsphere

fabrication and

drug loading

WP#4

Animal efficacy

trial

WP#3

Human safety

and comfort

trial

WP#1: Ocular insert assembly and manufacturing

WP#1

Ocular insert

assembly and

manufacturing

WP#2

Microsphere

fabrication and

drug loading

WP#4

Animal efficacy

trial

WP#3

Human safety

and comfort

trial

Employees – timing of contracts

1. Oct. 2015 – Postdoc for WP#3 and WP#4

2. Oct. 2015 – PhD student for WP#3 and WP#4

3. Nov. 2015 – Postdoc for WP#2

4. Jan. 2016 – Postdoc for WP#1

5. Apr. 2016 – Technician for WP#1

19

1,2 3 4 5

19

WP#1

Ocular insert

assembly and

manufacturing

WP#2

Microsphere

fabrication and

drug loading

WP#4

Animal efficacy

trial

WP#3

Human safety

and comfort

trial

Initial end date

From design to first-in-human

DESIGN PRODUCTION CLINICAL TRIAL

Quality systems to comply with

◆ Guidelines

◆ EN ISO standards

– ISO13485 Medical devices

– ISO10993 Biocompatibility

– ISO11135 Sterilisation

– ISO14971 Risk management

◆ Medical device directive (MDD) 93/42/EEC

– Instructions for use

– Labelling

FMEA: tool to identify potential risks

FMEA: tool to identify potential risks

◆ Design FMEA– Helped to select one out of 9 different

coil designs

– Resulted in a custom-made blister packaging

– Residual risks were included in instructions for use and patient information letter

◆ Process FMEA– Identified the risks related to each manufacturing step

– Helped to conclude the final manufacturing process

– Defined the quality control criteria for each step

– Set the requirement for all materials from (sub)suppliers

Quality Control of the Ocular Coils

Set detailed specifications for

◆ Good coils

– Length, weight, color, shape,…

◆ Bad coils

– See examples

– To discardDifferent cap morphologies

Distorted winding terminal position

Presence of big microspheresPresence of small

microspheres

< 40 um

Presence of small

microspheres Bent portion

◆ Design FMEA

– Helped to select one out of 9 different coil designs

– Resulted in a custom-made blister packaging

– Residual risks were included in the instructions for use and patient information letter

◆ Process FMEA

– Identified the risks related to each manufacturing step

– Helped to conclude the final manufacturing process

– Defined the quality control criteria for each step

– Set the requirement for all materials from (sub)suppliers

FMEA: tool to identify potential risks

27

Already halfway

the project

But…

Examples:

◆ Removal of the coil from the eye without touching the eye

– Including a magnet as accessory was too complex (regulatory point of view)

– Way forward: use a commercial available CE-marked tweezers for removal

◆ Uniform filling of the coil with microspheres

– Development of an automatic filling process was too time-consuming and expensive

– Way forward: perform manual filling with strict quality control steps

There is a difference between:

NEED to have, and NICE to have!

Manual Cleaning Post Filling

◆ After filling in a cleanroom, some particles were found on the ocular coils.

– What is acceptable?

Before cleaning After cleaningBefore cleaning (SEM)

Do’s and don’ts WP#1

WP#1

Ocular insert

assembly and

manufacturing

◆ FMEA sessions help you to make decisions for the

final design and manufacturing process

◆ Define design and manufacturing process before

preparing documents for (pre)clinical trial

WP#2: Microsphere fabrication and drug loading

WP#1

Ocular insert

assembly and

manufacturing

WP#2

Microsphere

fabrication and

drug loading

WP#4

Animal efficacy

trial

WP#3

Human safety

and comfort

trial

WP#2: Microsphere fabrication and drug loading

WP#3

Human safety

and comfort

trial

◆ Placebo-loaded microspheres

◆ Bought from commercial company

WP#2: Microsphere fabrication and drug loading

WP#4

Animal efficacy

trial

◆ Drug-loaded microspheres

◆ Development within TU/e

However, …

◆ Q4 2016:

– Change of interest from research group TU/e

– Search for new expertise

◆ We looked for alternatives:

– Service from companies (Nanomi)

- But those with experience in the field are likely

to have a conflict of interest

– Collaboration with university of Liège

- But less guarantee to obtain the right product

within time and budget

35

A new collaboration…

◆ Collaboration with university of Liège

– Contract negotiations about IP authorship,

confidentiality, publication policy,

commercialisation,… took > 1 year

– Contract signed Q1 2018

– Drug-loaded microspheres ready by Q3 2018

36

Do’s and don’ts WP#2

◆ Timely change partnerships if goals cannot be

reached

◆ Don’t invent the wheel yourselves

◆ Sometimes you need to hire expertise that is not

available in your team

WP#2

Microsphere

fabrication and

drug loading

WP#3: Human safety and comfort trial

WP#1

Ocular insert

assembly and

manufacturing

WP#2

Microsphere

fabrication and

drug loading

WP#4

Animal efficacy

trial

WP#3

Human safety

and comfort

trial

OCDC team

• Create the documents and submit them

InSciTe(QA/RA)

• Check all documents to be compliant with ISO guidelines

MEC

• Provide ethical check on the documents

Board of directors (MUMC+)

• Provide quality and safety check of the product

IGJ

• Notified body, final checks, can hold the study when needed

From documentation to study approval…

Ethical approval for the Comfort Study

◆ 20-Jul-2016: We received approval for the Human Comfort Study

from the MEC

HOWEVER…

– QA/RA issues were not covered

– We did not have a final design of the ocular coil

– Uncertainty about responsibilities of the manufacturer (eg. liability)

40

The most difficult hurdles that we encountered…

◆ Type of product?

– Coil = drug delivery device but without drugs (placebo)

– Medical device or medicinal product?

– Decision has many consequences (regulatory, commercialization,…)

◆ Sponsor versus manufacturer

– Who takes up which role?

– Each role comes with responsibilities

– Sponsor: when hiring a CRO = EXPEN$IVE

– Manufacturer: needs to get a product liability insurance

Search for help…

◆ Supervision of the quality manager of InSciTe

◆ Creating own “quality system”

◆ > 100 documents

– Design history files

– Work instructions

– Study plans and reports

– Investigational medical device dossier: labelling, packaging, instructions for use, quality management system, sterilization, essential requirements, manufacturing process, …

Search for help…

Medical Devices: CE marking and FDA

regulatory approval pathways course

We consulted Starodub for the documentation

First-in-man study

◆ Study design

– 40 volunteers

– 1 placebo ocular coil

– 1 eye, randomly selected

– 28 days

– Comfort: questionnaires

– Safety: measurements

◆ Started in June 2018

4444

Insertion of the Ocular Coil

First-in-man study

◆ Interim results showed that

– Volunteers tend to loose the coil

during sleeping, eye rubbing,…

– Only 4 of 21 volunteers were able to

keep the coil for the full period (28

days)

◆ Study on hold in Nov. 2018

R e te n tio n t im e

D a y s

Re

ten

tio

n o

f th

e c

oil

(%

)

0 5 1 0 1 5 2 0 2 5

0

2 0

4 0

6 0

8 0

1 0 0

4646

Design improvement

◆ From straight to curved ocular coil

◆ Additional actions:

– Adapt documentation

– Adapt microsphere filling method

– New manufacturing run

– New sterilization run

– Inform MEC & IGJ

– etc..

◆ Took about 3 months

4747

First-in-man study – curved coil

◆ Start April 2019

– 21 volunteers

- 6 were able to keep the coil

for the full period (28 days)

◆ Study ended July 2019

R e te n tio n t im e

D a y s

Re

ten

tio

n o

f th

e c

oil

(%

)

0 5 1 0 1 5 2 0 2 5

0

2 0

4 0

6 0

8 0

1 0 0 S tra ig h t o c u la r c o il

C u rv e d o c u la r c o il

4848

Do’s and don’ts WP#3

◆ Don’t submit too early to the MEC:

– Changes in design or manufacturing will require

amendments to the study dossier (we had 5 in total)

◆ Keep in mind that the METC reviews the protocol

from an ethical point of view ≠ technical review!

◆ Submission to the IGJ is a notification only, not

approval. They don’t review nor provide detailed help

or feedback

WP#3

Human safety

and comfort

trial

WP#4: Animal efficacy trial

WP#1

Ocular insert

assembly and

manufacturing

WP#2

Microsphere

fabrication and

drug loading

WP#4

Animal efficacy

trial

WP#3

Human safety

and comfort

trial

Ethical approval: License

OCDC team

• Create the documents and submit them

IvD (UM)

• Provide ethical and scientific check on the documents

DEC (UM)

• Provide ethical check on the documents

CCD (government)

• Final checks, can hold the study when needed

Ethical approval: License

OCDC team

• Create the documents and submit them

IvD (UM)

• Provide ethical and scientific check on the documents

DEC (UM)

• Provide ethical check on the documents

CCD (government)

• Final checks, can hold the study when needed

52

Jan-2016: First submission intern UM

Mar-2017: License for the experiments by CCD

52

Ethical approval: Working protocol

OCDC team

• Create the documents and submit them

• Performs experiment

IvD (UM)

• Provide ethical and scientific check on the documents

• Checks during experiment

CPV (UM)

• Orders the animals

• Houses the animals

• Provides care to the animals

Average time acceptance Working Protocol: ~4 months

Practical considerations

◆ Keep in mind some practical issues with animal

experiments

– Housing (limited space, males and females separately,

housing occupied by other researchers,…)

– Ordering animals (availability of animals with the

required age and sex, most laboratory animals come

from UK (Brexit),…)

– Availability animal caretakers for assistance

WP#4

Animal efficacy

trial

Another Step to Overcome

◆ Before the final production of the ocular coil:

– Postdoc and technician from WP#1 left

– No one available for the production of drug loaded ocular coils

– Another delay…

◆ In 2 months:

– We trained a new technician:

- to fill the ocular coils

- to cap the ocular coils

Do’s and don’ts WP#4

◆ First discuss your experimental design with the IvD

– In collaboration, create a Project License

– In parallel, develop working protocols and SOPs

◆ Keep in mind some practical issues with animal

experiments

WP#4

Animal efficacy

trial

Lessons learned in the OCDC project

◆ Keep being aligned and hold structure with monthly MT meetings

and weekly TEMs (technical exchange meetings)

◆ QA/RA requires a significant time investment

◆ Realize the challenges of submitting and performing a medical

device study (eg. writing projects, timelines, deadlines)

◆ Be flexible, motivating and decisive in relation to your team

members

Sneak preview of the results from

the first-in-man OCDC study

Please see poster and presentation of

Marlies Gijs and Christian Bertens

Thank you