Iccp Clinical Trials

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What you should know

Experimental treatments

or spinal cord injury:

what you should knowi you are considering participationin a clinical trial.

A guide or people with spinal cord injury, their amilies,riends & caregivers.

Provided by
http://www.campaignforcure.org/


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Experimental treatments for SCI

International Campaign for Cures of spinal cord Injury Paralysis (ICCP) February 2007

Cover image: photo montage shows a research scientist superimposed

over a tri-coloured micrograph of spinal cord tissue.


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AuthorsJohn D Steevesa

James W Fawcettb

Mark H Tuszynskic

Daniel Lammertsed

Armin EP Curta

John F Ditunnoe

Peter H Ellaway

Michael G Fehlingsg

James D Guesth

Naomi Kleitmani

Perry F Bartlettj

Andrew R Blightk

Volker Dietzl

Bruce H Dobkinm

Lei A Havtonm

Robert Grossmann

Deborah J Shorto

Masaya NakamurapHiroyuki Katohp

William P Colemanq

Manuel Gaviriar

Alain Privatr

Michael W Kalichmans

Cynthia Raskt

a. ICORD, University o British Columbia & Vancouver Coastal Health Research Inst., 2469-6270 University Blvd. Vancouver, BC, V6T1Z4, Canada

b. Cambridge University Centre or Brain Repair, Robinson Way, Cambridge CB2 2PY, UK

c. Center or Neural Repair, University o Caliornia at San Diego, La Jolla, CA 92093, USA

d. Craig Hospital, 3425 South Clarkson Street, Englewood, CO 80113-2811, USAe. Jeerson Medical College, Thomas Jeerson University, 132 South 10th Street, Philadelphia, PA 19107 USA

. Department o Movement & Balance, Div. o Neuroscience & Mental Health, Imperial College London, Charing Cross Campus, St Dunstans

Road, London W6 8RP, UK

g. University o Toronto, Krembil Neuroscience Center, Head Spine and Spinal Cord Injury Program, Toronto Western Hospital, 399 Bathurst

St. Toronto Ontario M5T 2S8, Canada

h. Department o Neurological Surgery and the Miami Project to Cure Paralysis, Lois Pope LIFE Center, 1095 NW 14th, Miami, FL, 33136, USA

i. National Institute o Neurological Disorders and Stroke, NIH, 6001 Executive Blvd, Bethesda MD 20892-9525, USA.

j. Queensland Brain Institute, Ritchie Bldg 64A, Univ o Queensland, St Lucia QLD 4072, Australia

k. Acorda Therapeutics, 15 Skyline Drive, Hawthorne, NY 10532, USA

l. Spinal Cord Injury Center, Balgrist University Hospital, Forchstrasse 340, CH-8008 Zurich, Switzerland

m. Department o Neurology, University o Caliornia Los Angeles, Geen School o Medicine, Neurologic Rehabilitation and Research

Program, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA

n. Baylor College o Medicine, Department o Neurosurgery, One Baylor Plaza , Houston TX 77030, USA

o. Midlands Centre or Spinal Injuries, Robert Jones & Agnes Hunt Orthopaedic and District Hospital NHS Trust, Oswestry, ShropshireSY10 7AG, UK

p. Keio University, School o Medicine, Dept Orthopaedic Surgery, 35 Shinanomachi Shinjuku-Ku, Tokyo 160-8582, Japan

q. WPCMath 703 West Ferry St., C-20, Bualo, NY, 14222, USA

r. Institut des Neurosciences - CHU St Eloi, INSERM U-583, 80 rue Augustin Fliche, 4295 Montpellier cedex 05, France

s. Research Ethics Program and Dept. o Pathology, University o Caliornia - San Diego, La Jolla, Caliornia, USA

t. Institute or OneWorld Health, San Francisco, Caliornia, USA

Address or correspondence:

Dr. John Steeves, ICORD at UBC and VCH, 2469-6270 University Boulevard, Vancouver, BC, V6T 1Z4, Canada


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Experimental treatments or SCI

The ICCP is comprised o the ollowing memberorganizations:

Christopher Reeve Foundation (USA) Institut pour la Recherche sur la Molle pinire et lEncphale

(France) International Spinal Research Trust (UK) Fondation internationale pour la recherche en

paraplgie (Switzerland) Japan Spinal Cord Foundation Miami Project to Cure Paralysis (USA) Neil

Sacshe Foundation (Australia) Paralyzed Veterans o America (USA) Rick Hansen Foundation (Canada)

Neil Sachse Foundation (Australia) Wings or Lie (Austria)
http://www.wingsforlife.com/http://www.spinalcure.org.au/http://www.nsf.org.au/http://www.rickhansen.com/http://www.pva.org/http://www.themiamiproject.org/http://www.jscf.org/http://www.irp.ch/http://www.spinal-research.org/http://www.irme.org/http://www.christopherreeve.org/


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Section i Summmary Page 7

Section 1 Introduction: Why have we written this booklet? 10

Section 2 What are the chances that you will see some unctional improvement ater spinal cord injury(SCI) without a drug treatment or transplantation o cells?

11

The ASIA scale 11

Section 3 What are the risks o undergoing a treatment that has not completed a valid clinical trialsprogram or been approved by an appropriate regulatory agency?

13

Section 4 What is a clinical trial and what is the pre-clinical process or developing a therapeutictreatment or SCI

13

Clinical trial phases 13

Trial design 15

Preclinical process 16

Section 5 What is ethical and unethical in the conduct o a clinical trial and what is inormed consent? 18

Inormed consent 19

Risks 19

Section 6 What can jeopardize the accurate interpretation o the outcomes or a clinical trial and whatcan be done to prevent this rom happening?

20

Bias 20

Control subjects 20

Blinded assessements 20

Section 7 How are unctional benets o an experimental treatment measured or SCI? 22

Use o the ASIA Scale to measure changes in unction 22 Other tools or measuring changes in neurological unction 23

Functional tests 24

Section 8 I you participate in a clinical trial, how does it eect your participation in uture SCI clinicaltrials?

25

Section 9 What are some o the current experimental treatments proposed or the treatment o SCI andat what stage are they in terms o their validation as benecial?

25

Selected experimental approaches or the treatment o SCI 27

Section 10 What should you ask beore agreeing to take part in a clinical trial? Your participationchecklist.

31

What should the answers be? 33

Section 11 Glossary o terms 34

Section 12 Reerences 38

Contents


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Note: This guide is based on published scientic papers and the

proessional opinion o the authors as o 00. The inormation

will be periodically reviewed. The recommendations are subject to

change as new knowledge becomes available. The contents o this

document are intended to be an additional resource or you, and are

not intended to substitute or replace current clinical treatments.

Users o this guide should periodically review the material to ensurethat the advice herein is consistent with: . the current reasonable

clinical care they are receiving, and . the protocols o any

experimental treatment being oered to improve their unctional

outcomes ater spinal cord injury.


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iSummaryExperimental treatment or spinal cord injury: whatyou should know i you are considering participation ina clinical trial.

Ater a spinal cord injury, patients are oten

told that there are no treatments available that

will repair the damage. This is still true, and

the advice is given to persuade people to ocus

on their rehabilitation rather than hoping or

a miracle cure. However, great advances have

been made in the science o spinal cord repair,

and treatments that will improve the unction

o people with spinal injury are now emerging,although a complete cure is still not easible

(a list o potential approaches currently being

examined is provided in the ull booklet).

As these new treatments move rom the

laboratory to the clinic, they will need to

undergo clinical trials. This booklet oers

advice to you should you consider participating

in a trial.

Why are clinical trials necessary?It can be surprisingly dicult to nd out i a treatment

is sae and i it really works. Patients oten believe they

have got better as a result o a new treatment, but the

improvement may not really have been caused by the

treatment. There are two main problems.

Spontaneous recovery. Immediately ater a spinal injury

patients are oten completely paralyzed. Most people will

recover to some extent without treatment, and or a ew

ortunate people the recovery can be dramatic, almost

back to normal. The rate o recovery is greatest in the rst

three months, but recovery continues or a year or even

more. It is very dicult to work out whether recovery in

an individual is due to this spontaneous recovery, or due

to the eects o a treatment, particularly i the treatment

is given soon ater the injury. [see section 2]

The placebo eect. People with spinal injury are

desperate to get better. Ater being given a treatment

their belie and hope usually leads them to report

an apparent improvement. In clinical trials, patients

receiving a sham or placebo treatment usually report

a considerable improvement in their condition,

and this may be just as large an improvement as is

reported by the patients receiving the experimental

(sometimes called active) treatment. [see section 5, 6]

There is a real danger that treatments that

do not really work or might even do

harm might become standard

medical care because they

were not subjected to a proper

clinical trial. [see section 6]


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Why should you think carefully before enlisting in aclinical trial?People with spinal injuries are understandably desperateto get better. Scientists have been working extremelyhard to develop new treatments, and want very much tosee their treatments help people with spinal injuries as

soon as possible. The urge or both groups to cut cornersis considerable. The majority o clinical trials will be wellplanned and careully conducted. However there maybe a ew that should be avoided. This brochure, and thelarger accompanying ICCP document should help youidentiy good clinical trials. [see section 5]

A good clinical trial will be testing a treatment that hasundergone extensive investigation in animals and willhave shown a strong and repeatable eect. The clinicaltrial will be careully designed to compare a group opatients receiving the experimental treatment withothers receiving no treatment or a placebo.

Experimental treatments offered without havingcompleted a trial. Some possible treatments

may be oered to patients, usually by doctorswho believe strongly that they will work. In the

absence o a clinical trial in which the eectso the treatment are compared with a control

group o patients receiving a placebo treatment, it isalmost impossible to determine whether the treatment isreally eective.

Treatments offered for material gain. Unortunately,where patients are desperate or a cure, there is theopportunity or less scrupulous organizations to oerunproven treatments to those who can pay. You shouldnot have to pay or any procedure specifcally relatedto a clinical trial program, but you, or your health careinsurance system, may have to pay or the currentstandard o medical care.

Creating new treatments or those with spinal injury isprobably the most difcult thing that medicine has everattempted. There is a very small chance that a treatmentoered prematurely without completing a properlydesigned clinical trial will work, but it is more likely that

it will be ineective or even do harm. We advise verystrongly that you should only participate in properlydesigned and conducted clinical trials o treatmentsor which there is compelling evidence o efcacy romanimal experiments.

How are clinical trials structured?It takes three clinical trial steps, orphases, to qualiy atreatment or human patients. [see section 4]Phase 1 is to fnd out i the treatment is sae. A airly

small number o patients, usually between 20 and80, are given the treatment, usually initially at a lowdose, to see i there are side eects.

Phase 2 is designed to look or positive treatmenteects, comparing patients receiving the treatmentswith a control group.

I a useul eect is seen in Phase 2, the trial proceedsto Phase 3. Here a larger number o patients, usuallyin several clinics, are given the active treatment ora control treatment. I the treatment shows a clearuseul eect and no serious side-eects, usually intwo separate Phase 3 trials, then it will be approvedby the national regulatory agencies or clinical use.

Design of clinical trials: The key eature o mostclinical trials is the comparison o a group o patientsreceiving the active (experimental) treatment with acontrol group, that either does not receive the treatmentor receives an inactive placebo treatment. The only typeo trial in which this is not the case is on e in whichpatients whose condition is very stable (this would meanpatients 1 year or more ater spinal injury) who act astheir own control group, and are given a treatment tosee whether their condition improves compared withtheir previous abilities. When the eect o a treatment

on the experimental group is being compared with theoutcomes rom a control group, steps should be takento make sure that the people doing the assessmentsare unaware o whether patients have received active ordummy treatments (this is known as blinding). In manytrials the patients are also blinded to the group theyhave been assigned, although this type o blinding issometimes hard to achieve with spinal injury treatmentsrequiring surgery. [see section 4]

How would participation in a clinical trial affectyou? Beore anyone can be enrolled in a trial they mustgive inormed consent. I a treatment has to be given verysoon ater spinal injury, some patients may not be ullyconscious, and then their amily can give consent on theirbehal. Not all patients will qualiy or a trial, becausemost trials will select particular groups o patients withparticular types o injury. All trials have criteria becausei the patients are too dierent rom one another it maybe impossible to fnd out i a treatment has worked. Aterenrollment, patients are randomly assigned to the activetreatment or control group. Ater or during the treatment,there will be requent ollow up examinations, or which itwill be necessary to attend the clinic. These examinationsmay include a ull physical exam, blood tests, and testso the ability to perorm daily living tasks to assess spinalcord unction. You should not have to pay or these visits.


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What if you get assigned to the control group?

Most patients would obviously preer to receive theactive treatment. However, as we described above,it is impossible to decide i a treatment really worksunless there are control patients with whom to makecomparisons. I by mischance the treatment has anundesirable side eect, then being in the control group

is an advantage. Patients participating in a trial shouldall beneft by receiving the current best care. The trialinvestigators will have a policy on what to oer memberso the control group at the end o the trial. Rapidenrollment in a second trial is sometimes a possibility,as is receiving some orm o approved treatment. I this isnot clear, you may need to enquire. [see section 4]

What should you expect after aclinical trial? At the end o thetrial you are unlikely to be completelycured. Could you then obtain anothertreatment in a dierent trial? Theenrollment criteria or some trials mayexclude patients that have already received

some types o experimental treatment.Those running the trial will have a policy onwhat to oer patients at the end. There is moreinormation on this issue in the ull document, andyou can discuss it with the investigators running the clinicaltrial. [see section 8]

You have been invited to participate in a clinical trial.How can you decide?

Beore entering any trial you or your relatives will have to

give inormed consent. [see section 5] Here are some othe things about which you should satisy yoursel.

Experimental evidence that the treatment works. Anytreatment reaching clinical trials should have beentested in animals with spinal injuries, and shouldhave produced a clear improvement without toxic sideeects. It is important that this positive result hasbeen published and reviewed by other scientists, andhas been repeated several times, in dierent types oexperimental spinal cord injury, and in more than onelaboratory. I you ask you should receive a detailedaccount o this work. [see section 4]

Evidence that the treatment is safe. Beore being appliedto human patients any treatment should have gone

through a series o saety tests. It may have already been

tested in Phase 1 or 2.Design of the trial. You should know whether youbeing enrolled in Phase 1, 2 or 3. The trial should beregistered with an appropriate government regulatorybody. In a well conducted Phase 2 or 3 trial there willbe a treatment and control group, and patients will berandomly assigned to one or the other. Steps should betaken to blind the assessors as to whether you are in thetreatment or control group. There will be a number oollow-up examinations over a period, oten as long asa year ater the treatment, conducted in the appropriateclinic. You should not have to pay or these. At the endo the trial there should be a clear policy on what canbe oered to patients in both the active treatment andcontrol groups.

Where can you get advice?You have a number o options:

There are good websites run by the various spinalinjury organizations that are members o the ICCP (seepage 39). You can contact the oundations directlyand ask or advice. Many o them are staed bypeople who themselves have spinal cord injuries.Some government research agencies also have

useul inormation on their websites (or instance theNational Institutes or Health in the USA).

Spinal injury researchers are generally pleased to oeradvice i you ask them; it is best to do this by email. Youcan get names o researchers rom the oundations.

Most patients will have a regular physician, who willbe prepared to oer advice or direct you to the mostappropriate person.

Keep reading: the rest o this document contains manymore details about the inormation touched on in this

summary. We start with an overview o the ASIA scaleand spontaneous recovery, and then look at the riskso unapproved treatments. We examine in-depth theanatomy o a clinical trial, rom Phase 1 to Phase 4,as well as the basics o trial design and pre-clinicalstudies. We discuss the ethics o clinical trials, bias,

controls, and the importance o inormed consent.We review some scales that are used to measureunctional benefts, and outline some concerns thatmight arise regarding the possibility o taking part ina uture trial ater already participating in a trial. Weintroduce you to some experimental approaches to SCIcurrently being studied. Finally, we provide you witha list o questions that you can pose to a researcherinviting you to participate in a human study. Thischecklist might assist you in your decision whether ornot to participate in the trial.


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0

This booklet is primarily directed to people living with aspinal cord injury (SCI), their amilies and riends. It mayalso be o value to health care proessionals and scientistswhen discussing experimental treatments or SCI.

We aim to answer some o your concerns aboutexperimental treatments and SCI clinical trial* procedures,but most importantly, we wish to provide you with a seto questions that should be answered to your satisactionbeore you agree to accept an experimental treatment orparticipate in a clinical trial program (see section 10).

This document is based onpublished, peer-reviewedliterature in reputable scienticand medical journals, as well asthe opinions o a panel o expertsdrawn rom across the globe. Thispanel consisted o proessors anddoctors with extensive scienticand clinical experience in SCI,many o whom have conducted SCIclinical trials, as well as peoplewho are amiliar with ethics andclinical regulatory practices. ThisSCI Clinical Guidelines Paneldrated an initial set o guidelinesor the valid conduct o a clinicaltrial or SCI. These guidelines havebeen peer-reviewed and published

in the journal, Spinal Cord.1 2 3 4

Around the world, the annualincidence o SCI (paraplegia and tetraplegia) variesby region rom less than 20 per million people to morethan 50 per million people.5 However, with continuingimprovement in medical care, as well as an increasingliespan or people living with SCI, the worldwide numbero survivors is now over two million people.

Scientists and doctors around the world are searchingor innovative ways to treat SCI and improve unctionaloutcomes, as well as quality o lie ater SCI. The list oexperimental interventions, therapies, and assistivedevices that have been developed in pre-clinical animalmodels is extensive. More importantly, i these potentialtherapies are to be accepted as valid treatments orpeople with SCI, then they will need to undergo clinicaltrials in the near uture. Some early stage SCI clinicaltrials have recently been started and several more are ata late stage o pre-clinical animal testing.

Why have we written this booklet?

Each day we deal with patientsand amilies desperately

searching or answers to spinalcord injury. Until now, we havehad woeully little to sharewith them to help answer theirquestions about clinical trials,human studies, and promisingor questionable therapies.This booklet will provide an

invaluable roadmap or all.

- Susan HowleyExecutive Vice President and Director or Research

Christopher Reeve Foundation

However, one troubling act is that some experimentaltherapies, such as cellular transplants into the injuredspinal cord, have been introduced into clinical practicewithout a valid clinical trial program being completed.

One o the aims o this document is to explain thedierences between such practices and sound clinicaltrials using valid study designs.

The International Campaign or Cures o spinal cordinjury Paralysis (ICCP) is an aliation o not or protorganizations, which aims to acilitate the translation

o valid treatments or SCI romexperimental studies in animalmodels through clinical trials toestablish best clinical practices.

You will nd a list o memberinstitutions on page 4 o this

booklet.

The ICCP SCI Clinical GuidelinesPanel elected to direct the initialset o guidelines towards thedesign o clinical trials or theincreasing number o experimentalcell-based and pharmaceuticaldrug treatments to protect orrepair the injured spinal cord,whether at the acute or chronicstage o SCI. The reasons or thisocus are the substantial risks

and potential benets or thesetypes o treatments, and the act

that some o these treatments have either been oeredwithout completing a clinical trial or will soon enterclinical trials. The members o the panel, whose namesappear in the list o authors, volunteered their timeand eort towards this project or two years (2004-06).The panels travel and accommodation expenses weresupported by the ICCP, with Vancouver-based ICORDproviding all logistical coordination.

This booklet contains a discussion o the many actorsthat must be considered when designing clinical trials

in SCI, and whether an individual should agree toparticipate in a trial or accept a treatment that has notbeen validated through a regulated clinical trial program.By adhering to logical clinical trial guidelines, we believea legitimate path can be established or the validation oeective therapies that can improve both unction andquality o lie or people living with SCI.

* terms dened in the glossary are underlined in red the rst time they appear in the text


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What are the chances that you will see someunctional improvement ater SCI withouta drugtreatment or transplantation o cells?

The degree o unctional recovery expected to occur

naturally or spontaneously ater SCI depends primarilyon the severity or extent o the spinal injury. The mostcommon clinical evaluation tool used by doctors toclassiy the extent o SCI is the ASIA impairment scale(Fig. 1), initially developed by the American Spinal InjuryAssociation (ASIA). Components o the ASIA scale havealso been used to assess the results or outcomes othe ew clinical trials completed to date.

The ASIA scale was developed as a method or classiyingthe neurological level and severity o a spinal injury6and is based on a careul assessment which maps anypreserved sensory and muscle or motor unctions

(Fig. 2). It is continually reviewed and rened by an

international panel. One strength o the ASIA scale isthat it requires little or no equipment to be completed.

Figure . The key muscle groups and sensations examined along the spinal cord. Each representative muscle is graded on the strength ocontraction rom 05, whereas perception o light touch or pin prick sensation is graded on a more limited scale o 02. Note: there is no reliabletesting o motor unction or the upper cervical spinal cord (in the neck) or or the thoracic spinal cord (in the chest).

Figure . The most common classication o SCI (ASIA Grades A E)

ASIA IMPAIRMENT SCALEA=Complete: no motor or sensory function is preserved in the sacral segments S4-S5B=Incomplete: sensory but not motor function is preserved below the neurological

level and includes the sacral segments S4-S5C=Incomplete:motor function is preserved below the neurological level, and more than

half of key muscles below the neurological level have a muscle grade less than 3D=Incomplete: motor function is preserved below the neurological level, and at least

half of key muscles below the neurological level have a muscel grade of 3 or moreE=Normal: motor and sensory function are normal

CLINICAL SYNDROMESCentral CordBrown-SequardAnterior CordConus MedullarisCauda Equena


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However, the scoring o the ASIA scale, and its subsidiarysensory and motor scores can still be relatively subjective.It requires rigorous training or a correct assessment to be

made and or an accurate interpretation o the outcomes.Due to its relative simplicity and widespread adoptionacross the world, the ASIA scores have been used as anoutcome tool to ollow changes in neurological unctionater SCI, whether these occur spontaneously or as aresult o a therapeutic intervention. Figures 1 and 2 showsome o the unctional dierences between the dierentASIA classication grades, which range rom ASIA Athrough to ASIA E.

Individuals initially classied as having completeSCI, losso sensory and motor unction below the level o injury, areclassied as ASIA A (Fig. 1 & 2) and have the most limitedprognosis or regaining any additional unction ater SCI.Several studies suggest that approximately 80% o theseindividuals will remain as an ASIA A classication (Fig. 3).Individuals who initially have some sensory unction aslow as the anal sphincter but show no evidence o motorunction below the level o SCI are classied as ASIA B.As many as 40% o those individuals initially classiedas ASIA B may convert to an ASIA C classication, eventhough the majority o the recovered motor unction maynot be completely unctional (Fig 3). On a more positivenote, up to 40% o those initially classied as ASIA B may

Figure . The percentage o peoplewith a spinal injury converting romeach initial AIS (or ASIA ImpairmentScale) classication, sometimescalled the ASIA grade. The initialclassication is usually establishedwithin the rst three days to ourweeks ater injury. In this gure,the classication o the ASIA gradehas been re-assessed at the oneyear anniversary date ater SCI andthe percentage change rom theinitial classication is charted. Forexample, approximately 80% oindividuals initially classied asASIA A will remain as an ASIA A atthe one year anniversary ater SCI.

This inormation is drawn rom theU.S. Model Systems database, theSygen clinical trial database andthe EMSCI (European MulticenterSpinal Cord Injury) databases. Eventhough there is more than twentyyears between the time when someo the data was collected or the

U.S. Model Systems versus theEMSCI databases, there is stillsome consistency in terms o thedegree o spontaneous recoveryater SCI that was observed inthese two groups. With continuallyimproving emergency services,acute care and rehabilitation, thesedata are likely to show an increasein recovery rates.

convert to an ASIA D classication where the majority omuscles do show unctionally useul movement. Finally,the majority (60% to 80%) o those individuals who

initially present as an ASIA C classication will recover toan ASIA D status (Fig 1 & 3). Many people with an ASIA Dclassication are able to walk independently.

Thus, even when the only signs o initial spared(preserved) unction are or sensation (ASIA Bclassication), there is substantial evidence or unctionalimprovement. On average, the unctional outcomesimprove dramatically or those individuals where thereis initial evidence or the preservation o minimal motorunction (ASIA C). Recent evidence indicates that thosepeople with incomplete SCI (ASIA B-D) can continue toimprove their unctional abilities with vigorous and activephysical rehabilitation ater SCI.7

This leaves an individual with incomplete SCI the dicultdecision o weighing the benets versus the risks oan invasive experimental treatment, such as the directtransplantation o cells into the spinal cord or the inusiono a drug into their body. Will they regain more unctionor risk losing what they have already recovered? Dicultdecisions like this require a dispassionate and objectiveassessment o all the risks and benets, based on theavailable preclinical and clinical evidence.


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What are the risks o undergoing a treatment that hasnot been approved by an appropriate regulatory agency?There are potential risks or undergoing a treatment thathas not been validated and approved by an appropriatenational regulatory agency, such as the Food and DrugAdministration (FDA) in the United States. The role o healthregulatory agencies is to make sure that both the risksand the benets o a particular treatment are quantied tocertain minimum standards beore they can be approvedas sae and ecacious within the limits established by avalid clinical trial program. An individual who receives anunapproved treatment is unlikely to achieve a unctionalbenet that can be clearly attributed to that treatment,while risking unknown and potential harm.

General clinical trial guidelines have been accepted andratied by most nations. They are in place to protectthe public rom the harm that could result rom an

unsubstantiated and unapproved treatment. For SCI,these could include:

1. increased and long-lasting pain,2. urther loss o unction,

3. increased disability,4. other medical dysunction, and/or5. deathFurthermore, should there be medical complicationsarising rom an unapproved treatment, subsequenthealth care coverage and/or disability support paymentsmay be lost. Depending on the treatment received, yourparticipation in a uture SCI clinical trial may also belimited or disallowed (see section 8).

Many people living with SCI, as well as their amilies,believe that health care providers in the developed worldare slow to adopt new therapies that are sometimesmade available in an emerging nation. In act, SCIscientists, clinicians, and institutions (in developednations) are very eager to provide any new treatment,

but only when it has been validated in an objective andunbiased manner as sae and benecial, using careullydeveloped standards.

Phase I clinical trials test a new biomedicalintervention in a small group o people (20-80) orthe rst time to evaluate saety (determine a saedosage range, identiy side eects, etc.).

Phase II clinical trials study the biomedical orbehavioral intervention in a larger group o people(several hundred) to determine ecacy and tourther evaluate its saety.

Phase III studies investigate the ecacy o thetherapy in large groups o human subjects (romseveral hundred to several thousand), comparingthe intervention to other standard or experimentalinterventions as well as to monitor adverse eects

Phase IVstudies are conducted ater theintervention has been marketed. These studies aredesigned to monitor eectiveness o the approvedintervention in the general population and tocollect inormation about any adverse eectsassociated with widespread use.

What is a clinical trial, and what is the pre-clinicalprocess or developing a therapeutic treatment or SCI?A clinical trial is a research study in human subjects todetermine the ecacy o a new therapy or drug. Thereare our phases (or levels) o

clinical trials. All the phases o aclinical trial program are usuallynecessary or the appropriateregulatory body to grant theapproval o the therapeutic orclinical use and each phase mayinvolve a number o successive orparallel trials.

Phase - Saety Pilot : Phase 1 (orpilot) trials begin with the rstadministration o the therapeuticintervention to a human subject

(e.g. experimental drug, cellulartransplant, rehabilitationstrategy, or assistive device) andexamines a number o aspectso the saety and interactionbetween the treatment and thesubject, oten in a small numbero subjects. A Phase 1 study (seepage 15) is usually based on extensive preclinical saetyevaluations and designed with a built-in margin o saety

between the highest doses and durations o treatmentexplored in animal studies and/or earlier human

treatment protocols. Evaluation o

saety is an important aspect o allphases o clinical development,but it is the primary outcome inPhase 1 trials, which can exposethe most common adverse events(side eects or complications) oany intervention.

Another important aspect o Phase1 drug studies is measuremento the pharmacokinetics, andpotentially the pharmacodynamicso the therapeutic.

Pharmacokinetics is the study o owhat the body does to a drug, withemphasis on the time requiredor absorption, distribution withinbody tissues, the mode and extento metabolism, or breakdownand the method o excretion.Pharmacodynamics is the study

o what a drug does to the body, with emphasis on itsbiochemical and physiological eects o drugs, as well


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as the mechanisms o drug action and the relationshipbetween drug concentration and eect. In the case ocellular treatments, equivalent studies o the ate oimplanted cells or tissues will be important to pursue,but may be much more dicult to implement.

Phase 1 trials may, but more oten do not, include controlsubjects and are usually carried out in an unblinded,

or open label ashion, with both the participants andinvestigators knowing what drug is being tested andwhat dosages are being used. Phase 1 studies onon-invasive or minimally-invasive treatments (i.e.not requiring surgery) are oten undertaken in healthyvolunteer subjects. In contrast, many o the potentialSCI therapies are likely to be invasive; thus most Phase1 trials would be expected to only involve subjects withSCI. As a result, there is an opportunity to undertakea preliminary evaluation o the possible therapeuticbenet o the experimental treatment when it is rsttested in humans. When this occurs the study is otenre-labeled as a Phase 1/2a trial. Note that any ecacy(clinical benet) data derived in a Phase 1/2a trialwould not be a validation or that treatment, primarilybecause o the small sample size and the lack o blindedassessments.

Phase - Therapeutic Exploratory: In Phase 2 trials, theprimary objective shits to the exploration o potentialtherapeutic eect when compared to an untreated orplacebo control group. This is also the clinical phasewhere the most appropriate outcome measures todetect a potential therapeutic benet are examined.Thus, a Phase 2 trial is designed to demonstrate theactivity o an intervention: that is, to demonstrate that

the intervention is associated with a positive change inrelevant outcome variables, with less stringent statisticalcriteria than Phase 3 trials. There are a number oprotocol designs or Phase 2 trials, but all trials at thisstage should include control subjects and some orm oblinded assessment where the person undertaking theoutcome measurement and/or evaluating the outcomedata does not know the treatment or control group towhich the subject was assigned. The preerred Phase 2design would be a Randomized Control Trial (RCT) whereeach participant is recruited prospectively (i.e. in a go-orward manner) and randomly assigned to either the

experimental or control group o the study and where theinvestigators and i at all possible the participants, areblinded to which study group they have been assigned.

Another common characteristic o Phase 2 trials is theuse o relatively restrictive inclusion criteria to ensurea more uniorm study and thereby reduce randomvariations and outcomes. For example, it may not beoptimal in a Phase 2 trial to simultaneously comparedata rom motor complete (ASIA A and B) with motorincomplete (ASIA C and D) subjects. To avoid comparing

apples with oranges, many Phase 2 trials have dierentstudy groups o subjects (sometimes called trial armsor study cohorts), which are distinct rom other groupsand may be evaluated separately.

Even though most Phase 2 trials declare a primaryclinical endpoint and outcome threshold, they shouldalso evaluate a number o dierent clinical endpoints

(secondary outcomes) to guide the selection o the mostdenitive primary outcome to be used later in a Phase3 trial. It is not uncommon to undertake more than onePhase 2 trial to explore other target populations thatmight receive benet rom the therapeutic agent.

Phase Therapeutic Ecacy: Phase 3 clinical trials aregenerally the denitive or pivotal clinical trial phaseand are typically undertaken as a randomized controltrial. The objective is to conrm the preliminary evidenceobtained at the Phase 2 stage with a statisticallysignicant clinical benet o the experimental treatmentin a large group o subjects, usually across multiple

study centers. These trials also provide the mostinormative saety data because they usually address atleast a ew hundred subjects and provide inormation onpeople who are treated, as well as people who are parto the placebo control group. A air comparison can bemade o the rate o occurrence o adverse events o alltypes, and a wide range o other clinical measures whichare monitored in great detail, looking or the possibilityo unexpected and undesirable changes.

Given that the Phase 2 trial may have been conductedon a well-dened subset o patients with SCI, it is alsopossible to consider including a broader spectrum o

subjects in a Phase 3 study. Nevertheless, it is generallyadvisable to keep the design o Phase 3 studies closeto that o the preceding Phase 2 trials so that theoutcome is more predictable. Likewise, it is only possibleto accurately estimate how many subjects would berequired or a statistically signicant Phase 3 trial i thereis pre-existing data rom a similar study using similarsubjects.

I the Phase 3 investigation concludes with the validdemonstration o a statistically signicant clinical benetrom the therapeutic and an acceptable saety prole, anapplication is usually made to the appropriate regulatory

body or approval to market the treatment. Somejurisdictions, or example the United States, preer thata second conrmatory Phase 3 trial be completed priorto approval o the treatment being granted, but thereare many actors that can infuence this requirement,including the relative benets o current treatments.The submission or regulatory approval entails anenormous amount o documentation, regarding everypreclinical and clinical study perormed and the medicaldocumentation o every subject, so that the regulatory


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agency can perorm its own independent analysis o thecomplete set o data regarding the saety and ecacy othe new intervention.

Phase - Therapeutic Use: Phase 4 begins withmarketing approval, labeling and introduction o thetherapeutic intervention or clinical use or a specictype o disorder. It includes ongoing surveillance

related to therapeutic saety, including possibledrug interactions and contraindications, continuedoptimization o dose and therapeutic delivery regimens,as well as studies to delineate additional inormation onthe interventions risks, benets, and optimal use.

Clinical trial protocol congurations and study designs:There are numerous ways to design trials and eachhas its particular strengths andlimitations. An important concernor all clinical trials is the potentialor bias, however unintentional,to infuence the interpretation o

clinical outcomes. There are varyingdegrees o blinding to control andlimit who knows what treatment, iany, the subject has received. Therst clinical trial is oten an openlabel wherein the identity o the treatment received isknown to both the investigators and participants. Thisshould normally be reserved or Phase 1 studies thataddress saety. Open Label protocols have been used inthe study o both drug and surgical SCI interventions inPhase 1 trials.8 9 10 11 12

The next level is a single blind study where either the

clinical investigator or the subject, but not both, areblinded. For SCI trials where a surgical intervention ispart o the experimental protocol, it may be necessaryor the surgeon to know what is being undertaken inthat subject. While it is preerred that the patients inboth experimental and control groups remain blindedto the treatment received, this is not always possible.It is important, however, that the examiners assessingthe outcomes remain blinded to the treatment provided.This may require monitoring to assure a subject does notdisclose to the assessor to which treatment group theyhave been assigned.

Ethical or legal diculties may interere with the useo blinding when it entails sham operative procedures.Nonetheless, sham surgical trials have beenimplemented in neurological disorders in recent years,and proven critical to understanding and interpretingthe results,13,14 so they should be considered in SCI trialsas well. Once again, outcome assessments should beblinded using such techniques as identical bandaging othe overlying skin during assessments by independentexaminers. Single blinding o a primary outcome

measurement has been utilized in recent Phase 2randomized controlled trials using a patients own whiteblood cells (known as autologous macrophages) in thetreatment o SCI.12

Finally, a double blind design is optimal, where neitherthe participating trial subject nor the investigators,institutional sta or sponsoring company are aware o

the treatment each subject has received during the trial.Ideal blinding would ensure that the treatments cannotbe distinguished by subjective experience, appearance,timing, or delivery method by any o the subjects,investigators, research sta, or clinical sta. This shouldbe maintained throughout the conduct o the entire trialrom determination o eligibility through evaluation oall outcomes. Double blind design has been used in a

number o pharmacological trialsin SCI including investigationso methylprednisolone and GM-1ganglioside in acute SCI,15 16 17 18 194-aminopyridine in chronic SCI20 21and in surgical trials or Parkinsonsdisease.10

Parallel Group Design is the mostcommon clinical trial design or

pivotal Phase 3 trials. Subjects are randomly assigned(oten in equal numbers) to one or more treatmentarms, each testing a dierent treatment or combinationo treatments. The treatments might include theinvestigational product at one or more doses, and one ormore control conditions such as an inactive placebo,16 22or a comparative drug.15 23 A current treatment may haveto be present in both active and control arms o the study,

such as methylprednisolone in the multi-center GM-1trial.19 Assumptions underlying the parallel group designare less complex and more robust than those o otherdesigns.

Crossover Designs randomly assign the order in whichsubjects are exposed to a sequence o two or moretreatments (e.g. placebo control and experimentaltherapeutic). Hence, subjects receive the treatment andplacebo at dierent times, and act as their own controlsor treatment comparisons. This approach has beenused in the evaluation o 4-aminopyridine in chronicinjury.20 When subjects act as their own controls, the

unctional capacity o the subject should be stable(unchanging) prior to application o the experimentaltreatment. Because the unctional capacities o a personwith acute or sub-acute SCI can vary dramatically over ashort period o time, this type o design will normally berestricted to studies o chronic SCI, where the unctionalcapacity to be assessed is expected to be relatively stable.

The relevant eects o treatment should develop ullywithin the treatment period and reverse ollowingremoval o treatment. One important concern o a

There are many ways todesign a clinical trial. Trials

can be designed as openlabel, single blind ordouble blind


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crossover design is the possibility o residual eects(carryover infuence) o the experimental or placebocontrol treatment, which can infuence the outcome aterthe subject has crossed over to the opposite treatmentarm. The washout time period between treatmentarms should be suciently long to allow the completereversibility o any treatment eect. An advantage o thecrossover design is that it may allow a reduction in thenumber o subjects or assessments needed to achieve aspecic statistical power.

Pre-clinical process or developing a therapeutictreatment or SCI: Most people living with SCI want tounderstand how a scientic discovery becomes a validtherapy. Listed below are some o the undamental stepsin this process. Please note that there are no governmentregulations restricting the claims made by the authors

o pre-clinicalstudies usinganimal models.Instead, scientistsare constrained bythe healthy andoten demandingskepticism o thepeer-review processthat is used by anylegitimate scienticor medical journal.For many reasons,scientists otendo not completeall the elements

o experimentsthat the majorityo the scienticworld would like tosee accomplishedbeore a therapeuticdiscovery isintroduced ortranslation tohuman treatment.Fortunately inmost developedcountries, there

are several saetybarriers that mustbe passed, to thesatisaction othe appropriateregulatory agency,

beore an investigational treatment is given to humansubjects.

Here is a desired validation pathway or any pre-clinicaldiscovery. The essential element is that the initial ndings

should be conrmed through independent studies by oneor more groups o scientists. This validation o the originalresults may involve a complete replication o the initiallyreported experiment, but may also:

1. use slightly dierent types or variations on theexperimental treatment or SCI, which woulddemonstrate the robustness o the nding. In

short, ater the therapeutic target has beeninitially identied, a number o dierent scientictechniques can be utilized to address it. Some or allo these complementary, but dierent approachesshould provide similar results.

2. use dierent species, which would demonstratethe fundamental nature o the therapeutic targetand/or intervention. There is divided opinion onwhether primate (e.g. monkey) animal models mustbe completed prior to a clinical trial. However, mostscientists would support the notion that more thanone animal model o SCI (i.e. dierent animal species)should be completed prior to a clinical trial. Usually

studies in two species are required or evaluation othe saety o a new treatment.

3. use the most clinically appropriate type o spinalinjury to mimic the human condition, which woulddemonstrate the relevance o the discovery topossible human application. Increasingly, researchersare convinced that the pre-clinical ecacy shouldbe established in a clinically relevant model o thehuman condition. In humans, the most common SCIis a contusion or compression type o injury. Thus,i the initial ndings utilized a lacerating type ospinal injury (i.e. a cut spinal cord or use o an animalmodel with a minimal lesion o the cord), then a

series o experiments examining the ecacy o theexperimental treatment in a contusion type o spinalinjury would also be desired.

Another important aspect o preclinical studies shouldbe the inclusion o a unctional outcome measurethat is similar to one which could be used in a humanclinical trial. In other words, anatomical evidence oneuronal repair is enticing, but insucient. I a clinicaltrial ails to demonstrate a clinical benet, it is importantto know whether this is because the clinical assessmentused an outcome measure which was not able to detecta subtle unctional change or whether the treatment

simply did not work in humans. Having comparable andvalidated outcome measures at both the pre-clinical andclinical level o study would make a stronger case that theexperimental treatment had been tested airly, but was noteective in humans, as it may have been in an animal.

O course, you may logically ask, Why are preclinicalresults not always independently replicated andvalidated beore going to a clinical trial? There are manyexplanations, including:

1. There is little incentive to replicate another persons

The preclinicalprocess:

A researcher has anidea or a new therapy

Studies are conductedon animal models,

including unctionaloutcome measures

which could also beused in human clinial

trials

The research ispeer reviewed and

independentlyvalidated

Regulatory bodies arenotied

A clinical trial isdesigned, including

establishment opharmacodynamics,

pharmacokinetics andpreclinical saety


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ndings, because: little credit goes to an investigator or being

second ailure to replicate the initial nding is oten

claimed to be due to dierences in methodologyby the original authors.

2. There is no appetite by any government regulatoryagencies to validate or regulate discoveries at thepreclinical stage (e.g. FDA mandate is to protectpeople, not validate science). Thus, there is noenorcement o preclinical ndings and it is unlikelyto ever be coordinated on a worldwide basis.

3. In the case o commercially-sponsored research, thetherapeutic compound under investigation may notbe reely available to other scientists. Because o thehigh costs o ailed clinical development programs,commercial enterprises are usually most careulabout replicating their results beore proceeding.However, they are oten reluctant to allow researchto be done out o their control, particularly because

o the potential loss o related intellectual property(i.e. patents).4. Without patent protection, many potential therapies

have little chance o being taken orward to clinicaldevelopment. The development and validation o adrug or clinical use can exceed $500 million dollars!

5. Other approaches--particularly surgicalinterventions--that are not highly regulatedmay proceed to clinical studies in the hands oenthusiasts who may be too impatient to carry outmore animal studies.

For the sake o discussion, lets say the pre-clinicalscientic nding has been independently replicated.What should happen now? Well, there are a numbero important details that need to be established. Forexample, some o the more prominent issues are:

1. The appropriate regulatory agency (such as the FDAin the United States) should be contacted so thereis an understanding o the requirements or movingtowards a human trial.

2. The route or delivering the treatment to the patient(the eective clinical method or administering thedrug or cells) needs to be established. For example,will it involve transplantation o cells directly intothe spinal tissue, on top o the cord, or into the

bloodstream? Does the experimental drug need tobe inused into the spinal cord, on top o the cord,intravenously, or provided as an oral medication?The more invasive the route o administration, thegreater the risks to the patient (e.g. risk o inection).

3. The timing o the experimental treatment (theeective window o opportunity) needs to beidentied. Can the treatment be provided at any timeor does it need to be administered within a denedtime window ater SCI?

4. A acility needs to be established or the sae andconsistent production o the precise ormulation othe experimental drug, device or cell. There are verydetailed regulations that apply to such a acility,known as Good Manuacturing Practices (GMP)which are issued by the regulatory agencies. Theundamental characteristic o these regulationsis that every ingredient, process, procedure andpiece o equipment used in the trial procedures isrigorously evaluated, documented and not allowed

to change without equivalent levels o testing,evaluation and documentation.5. Based on continuing animal studies, the

pharmacodynamics and the pharmacokinetics o thedrug or cell must be established, including dose-response relationships and the necessary scaling upo the presumed eective dose or human use.

6. The preclinical saety (with hopeully someadditional ecacy) o the treatment in non-rodentanimal species must be independently established,oten by a contract research organization (CRO),which operates under another set o strict guidelinesor validation and documentation o methods,

known as Good Laboratory Practices (GLP). Thesestudies would include a series o screens toestablish that the experimental treatment does notcause adverse side-eects at the intended dosesand durations o treatment, usually by testing muchhigher doses and longer treatments to explore thelimits o tolerability.

By now, you might be thinking this is a very involvedand demanding development process. It should be.The treatments we are considering could have direconsequences or people i they are not completed in astringent manner.


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What is ethical and unethical in the conduct o aclinical trial and what is inormed consent?potential conusion rom a wide variety o actors thatcould make the outcomes o the treatment unclear. A

clinical trial must be conducted in a manner that is likelyto produce interpretable and useul inormation aboutwhether a new treatment is or is not sae and eective.Trials that yield no useul conclusions are costly to the SCI

community and society, as a whole.

It is important that subjects consideringenrolling in a clinical trial understandthat they are consenting to a purelyexperimental procedure that is ounknown benet, and which could evencause serious adverse events includingworsening o neurological unction or

death.

Potential benets o a clinical trialshould not be exaggerated. Allparticipants in a clinical trial willreceive the current standard ocare, but in later stage trials, onlysome o the subjects will receivethe experimental treatment that isbeing tested. To be sure that evena small improvement is detected,most clinical trials must comparethe eects o a current treatment to

the eects o the current treatmentplus the experimental treatment. Thealternative to the experimental treatment is oten calleda placebo treatment. The group o subjects receivingthe placebo treatment is known as the control group,and while they will not directly benet rom any possibleimprovements, they will also not have the risks oany unexpected problems that might occur with theexperimental approach.

It must also be remembered that it is relatively easyto get positive responses rom subjects in a trial whenthey know they have been treated with an experimental

therapy and when they expect or hope or a benet. Thisis an example o a placebo eect.

Even research investigators are not immune rom the risko bias, because o their hope to nd something that iseective. To reduce the possibility o bias in the outcomeo a trial, ethical and valid clinical trials usually assignsubjects to either the experimental or control group o thestudy in a random manner. Ideally, neither the investigatornor subject should know which group the subject hasbeen assigned until ater the study has been completed

It is essential thatclinical trials beconducted ethically:

researchers should notreceive payment or

testing treatments,and subjects shouldnot be asked to pay toparticipate in trials;

trials should bedesigned to yield useulconclusions;

potential benets shouldnot be exaggerated.

Ethical obligations: The value o any research, includingSCI research, depends in part on the ethical design and

conduct o the research studies. A study involving riskto human subjects cannot be ethically deensible i itis not scientically deensible. We all have an interestin the ethics o research investigations, including theobligation to protect the individualsrights and to minimize harm, aswell as maximize benet. It is alsoin everyones interest to avoid anycompromise o the ethical conduct oa clinical trial that would result in thenecessity to question any ndings.Unethical and poorly designed trialscan lead to tremendous costs in terms

o time, money, and most importantlythe potential or injury or lostopportunities among those who are thestudy subjects. For these reasons, mostresearchers in the world adhere to wellestablished principles or the ethicalconduct o human research.

Any human clinical trial must, at aminimum, adhere to the internationalguidelines o the Declaration oHelsinki24 and the standards o thehost country, such as the Belmont

report in USA.25 Where standards comeinto confict, it is the responsibility othe investigators to work with review committees andregulatory agencies to determine how best, i at all, thestudy can proceed.

One ethical point, sometimes overlooked, is thatprincipal investigators leading a clinical trial arenot allowed to accept payment or the treatmentbeing tested, nor are subjects to be charged or theirparticipation. This rule is in place to limit an investigatorrom biasing the outcomes o a clinical trial to nda benet or a therapy where none actually exists.

I a clinician or surgeon charged a patient to receivetreatment with an experimental therapy that had yetto be validated or approved or clinical use, this wouldbe viewed by the scientic community as not an ethicalclinical trial. By denition, a clinical trial is conductedbecause we do not know whether the experimentaltreatment will be eective or sae. It would be unethicalto charge someone or their willingness to assume thepossible risks o participating in such a human study.

Good clinical trials are designed to avoid or minimize


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and analyzed. In short, everyone is blinded with regardsto which treatment was provided to which subject.

Assessments or any changes in a subjects capabilitiesare also done in a blinded ashion, usually by a highlytrained clinical evaluator (usually not the principalinvestigator) who is unaware and does not ask whetherthe subject has received the experimental or placebo

control treatment. These are key rules or a credibleclinical trial and are necessary standards to remove bothsubject and investigator bias. Such a trial is known asan RCT (randomized control trial) and is the late stage(e.g. Phase 2 or 3) trial design mostoten used to determine whetheran experimental treatment has aunctional benet

When a clinical trial is conductedto test an experimental treatmentthat involves a surgical procedure,it is oten desired that the results be

compared with subjects who receiveda placebo or sham surgery. This isto rule out the possible benet othe surgery alone. Should there bemedical, ethical or legal reasonsor not undertaking a sham surgicalprocedure, then appropriate controlsubjects should be presented orassessment in such a ashion that the evaluator cannotdistinguish a subject rom the experimental group roma participant within the control group, perhaps usingsuch techniques as identical bandaging o the overlyingskin. O course, the control subjects would know they

are not part o the experimental treatment group, butthey must not divulge this to the evaluators or it couldbias the accurate interpretation o the eects or theexperimental treatment.

Research studies should proceed only i they areadequately designed to yield interpretable inormationregarding the objective benet or lack o benet o anexperimental treatment. Thereore, the trial shouldinclude appropriate control groups, accurate andsensitive outcome measures, objective data collectionand analysis, blinded analysis (whenever possible),and extended ollow-up assessments over a time period

sucient to draw clear conclusions.

Numerous guidelines or the general conduct o anyand all clinical trials have been developed and readersare encouraged to make themselves amiliar with theseteachings, especially those developed by the InternationalConerence on Harmonization (ICH) o TechnicalRequirements or Registration o Pharmaceuticals orHuman Use.26 The United States FDA website also providesits guidelines and those o the ICH at its website.27

Inormed consent: some individuals aced with thedisability caused by SCI may choose to receive anexperimental treatment or enter a clinical trial, notbecause they have weighed the potential risks against asmall chance o benet, but because their desperationleads them to disregard anything other than thepossibility o a benecial outcome. This situation places ahigh ethical obligation on clinical investigators to explainall possible outcomes to potential research subjects.

You need to have sucient inormation in order todecide whether or not to participate in a clinical trial.

This includes an understanding that youmay be assigned to the control group (inother words, you would not receive thenew treatment) or you may be assignedto the experimental treatment group, orwhich the researchers remain uncertainabout its saety and/or potentialbenets. This is a minimal expectationor any research study, but thestandards or inormed consent mustbe higher than normal or a project thatrequires sham surgery on the centralnervous system (CNS).

There are many points that should bemade clear to a person consideringparticipation in a clinical trial. These

include, but are not limited to, making clear to everypotential subject that:

1. an experimental intervention is research, not therapy,and the reason or conducting the study is to

determine whether or not it is sae and/or benecial;2. the current standard o treatment or SCI will beprovided regardless o the subjects decision toparticipate in the research study; and

3. participation is always voluntary, and the subjectcan withdraw at any time or any reason.

An important part o that process is to clearly convey theprobable and possible harm to someone who agreesto be a research subject. The ollowing are exampleso risks that should be explained in inormed consentdocuments or SCI clinical trials.

Risk o pain: therapies that aim to improve the

growth o injured connections in the spinal cordcould possibly also stimulate the growth o damagedpain bers or sprouting rom undamaged pathways,resulting in heightened pain that may be permanentor poorly responsive to therapy.

Risk o spasticity, dysrefexia: therapies that aimto improve the growth o injured connections inthe spinal cord could possibly also stimulate thegrowth o any ber type in the spinal cord, resultingin an unknown spectrum o side eects includingworsened spasticity or increased autonomic

Beore you agreeto participate in aclinical trial, you mustunderstand all thepotential risks involved

in the experimentaltreatment. This isknown as inormedconsent.


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0

dysrefexia, which is a syndrome o elevatedblood pressure that can be dangerous or atal (iuntreated).

Risk o loss o unction:there is a possibility that theexperimental therapy will improve unction, cause nochange in unction, or cause a minor or a major losso unction, possibly including segments o the spinalcord that are currently unaected by your injury.

Uncertainty o adverse eects: because this is anexperimental procedure, there may be risks that arecurrently unoreseeable. You will be inormed o anysignicant new ndings regarding the potential oadverse events in this trial.

Risk o inection: any invasive procedure carries thepotential risk o inection, particularly implantationo cells that are not ully sterilized prior toimplantation. Cellular therapies may also requirethe administration o immunosuppressive agents,rendering subjects less resistant to inections suchas pneumonia or urinary tract inections.

Burden on participating subjects: while not usuallya direct risk to your health, you should consider thevarious demands o the trial, such as the amounto time you may have to commit or the necessaryassessments over the duration o the trial. You willthen be able to decide i the burden is such that youdo not want or will not be able to ully participateuntil the end o the trial.

What can jeopardize the accurate interpretation othe outcomes or a clinical trial and what can be

done to prevent this rom happening?

The short answer is there is an almost innite numbero ways bias can conound a clinical trial. The longeranswer is there is an almost innite number o waysbias can conound a clinical trial, including the ollowingpossibilities:

1. An investigator who knows the type o treatment

the subject has received could knowingly orunknowingly bias the measured outcome in avoro a desired result, especially when there are noappropriate control subjects in the study. Clinicalinvestigators are human and we all have a bias whenit comes to our lies work!

2. Likewise, i a person living with SCI has paid ora treatment either with money or their physicaland emotional involvement, it is likely they willwish to see and report a benet, even i there isno objective, measurable data to support such aclaim (the placebo eect). In the more extremesituations, when an experimental treatment coststens o thousands o dollars or the entire communityhas helped pay or the procedure, there is a naturaltendency to report a benet so everyone can eeltheir support was worthwhile.

3. The very act o looking or a therapeutic benet canlead to the perception o something positive, eveni it is not due to the presumed treatment, otentermed a alse positive outcome.

All o these situations are a orm o bias, and are some othe reasons that clinical trials are designed to avoid suchconounding infuences (see Section 4).

Because some people living with SCI will improve ordeteriorate without any treatment (g.3), we will never

be able to accurately conclude whether the experimentaltreatment under study is benecial or detrimental to thepatient without including appropriate control subjectsin a clinical trial. It is not sucient to rely on historicalcontrol data, because conditions change with time andthe control subjects rom a previous trial may have beendiagnosed, treated, or assessed dierently than patientsat the present time. Without appropriate controls,we learn little and without controls, we do not have adenitive trial o ecacy, nor is the treatment likely tobe approved as a valid clinical therapy by a governmentregulatory body.

Control subjects should closely match the experimentalsubjects in as many ways as possible. Here are justa ew more examples o conounding actors thatshould be randomly and equally distributed betweenthe experimental and control groups: age, sex, othermedications or damage to other organs, severity oSCI, level o spinal damage, surgical history, andrehabilitation history.


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Thus, it is generally agreed that the clearest and mostreliable inormation regarding the actual value o apotential therapy requires the analysis o some typeo control group, the blinding o the subject to theidentity o their treatment group, and assessments bya blinded evaluator over a suciently long recoveryperiod (or acute SCI treatments this oten means overat least a year) to ensure that any alteration in outcomeis an enduring change. For example, it is possible thata simple surgical procedure itsel, independent o anyinjected test substance or transplantedcell, may improve outcomes ater SCI.This could be a consequence o surgeryrelieving pressure or tension on thespinal cord, improving the circulationo blood or cerebrospinal fuid, orother actors, including the potentiallypowerul eects o subject andinvestigator expectation about desiredoutcomes and benets.

The choice o an appropriately matchedcontrol group and the ability to perormdouble-blinded analyses is not alwaysa straightorward issue in SCI. Forexample, it is not dicult to include acontrol group when the substance underinvestigation is an orally administereddrug with a relatively sae adverse eventprole. In this case, a placebo-controlarm is straightorward to include inthe study, and double blinding can beimplemented.

When the study requires open surgicalmanipulation, then the use o a shamsurgery control group may subjecta patient to risk o adverse eventscaused by the sham procedure itsel. SCI patients maybe medically unstable, concurrently inected, or at highrisk o suering post-operative complications such aspneumonia or other inection. Sham surgical procedurescould also lead to autonomic dysrefexia. These risks arenot trivial, and are particularly notable ater acute SCI.

However, these risks may be made more acceptableby the value to be gained or science and medicine ina clinical trial that will yield a clear and statisticallyinterpretable outcome.19 Under these circumstances,an experimental SCI trial could be o benet to society,

even i the subjects do not directly benet. It shouldbe remembered that the subjects who receive theexperimental treatment are exposed to even greaterrisks with the possibility that they will gain no unctionalbenet. Discussions in the medical literature generallysupport the inclusion o control groups in clinical trials,even when these control procedures could representsome risk to the subjects health.29

Indeed, the consequences to humanity o allowinginvasive surgical procedures without the adequate

study o control groups has, in othermedical conditions, led to countlessunnecessary surgeries and theirassociated risks. 2 Examples oineective surgical procedures includemammillary artery bypass or ischemicheart disease and extracranial-to-intracranial artery bypass proceduresor cerebral ischemia.31 32 There is a realrisk that a surgical intervention without

real benet or SCI could gain wideacceptance and implementation dueto the lack o perormance o a clearlyinterpretable clinical trial. In such a case,hundreds o thousands o SCI patientscould subsequently be exposed tounnecessary surgical procedures that insome proportion o patients would leadto medical complications, potentiallyworsening their disability or evenleading to death.

Even though the research investigators

and ethics review committees mightconclude that such research isacceptable, it ultimately must be up toindividual research subjects to decide

whether they perceive their personal risks to be justiedby the possible benets to society. The burden is oninvestigators to ensure that potential subjects will beenrolled only ater they clearly understand and acceptthe uncertainty o any possible benet, the nature opossible risks or participating in the research study, andthe possibility o being assigned to the control group.This is a minimal expectation or any research study, butthe standards or inormed consent must be higher than

normal or a project that involves a direct interventioninto the central nervous system (see Section 5).

To reduce thepotential or biasin a clinical trial,the trial shouldinclude a controlgroup, subjects

should not knowto which treatmentgroup theyvebeen assigned,and results shouldbe assessed by ablinded evaluatorover an appropriatetime period.


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How are unctional benets o an experimentaltreatment measured or SCI?

The efcacy oexperimentaltreatments can bemeasured accordingto improvementsin neurologicalunction, unctionalcapacity, andquality o lie.

Sensitive and accurate outcome measures are criticalin designing useul SCI therapeutic clinical trialsand objectively validating or invalidating a potential

benecial treatment. Dierent clinical targets suchas tactile sensation, movement, autonomic unction,personal capacity, perormance, or communityparticipation, normally require distinct and appropriateways to measure an outcome (oten called assessmenttools). Dierent Phases o clinical trials also havedierent objectives and thereore require dierentoutcome measurement tools. In brie, Phase 1 ocuseson saety, Phase 2 on unctional activity, and Phase 3 isthe denitive or pivotal trial where clinically unctionalbenet must be demonstrated.2Assessment methodologies (i.e. tools)or evaluating a clinical endpoint o anSCI trial all into three main categories:

1. Assessments aimed at describingthe neurological connectionsto and within the spinal cord,regardless o the ability o thepatient to unctionally use thoseconnections in an everyday activity.The ASIA scale is an example osuch an assessment. This wouldalso include assessments oneurological capacity that measurethe activity or anatomy o the

central nervous system, such aselectrophysiological recordings orimaging assessments. When these outcome toolscan be shown to accurately predict the long termunctional benets (or, clinical endpoints) resultingrom a therapeutic intervention, they can also bethought o as surrogate endpoints. Once validated,surrogate endpoints can then be used in Phase 2trials to evaluate early indications or the activity oan experimental treatment.

2. Assessments o the abilities o a patient with SCIto perorm activities associated with everyday lie.Examples are the Functional Independence Measure

(FIM) and the Spinal Cord Independence Measure(SCIM). Such evaluations more directly measureclinically meaningul changes in the unctionalcapacity o a study subject, but the changes inunctional outcomes may not always be the resulto a demonstrated change in spinal neurologicalactivity or connectivity. Instead, any change in apersons unctional capacity ater SCI may be dueto adaptive or compensatory changes within and/orwithout the central nervous system (CNS), including

environmental accommodations and/or alternativestrategies.

3. Assessments o an individuals level o participation

in societal activities, or Quality o Lie (QoL). QoLcan be dened as a persons perception o theirsituation or position in lie, within the context oboth their personal and their societys values andculture, and relates to their personal concerns,standards and goals. The Short Form 12 or 36 Itemmedical outcomes health survey (SF-12 and SF-36)are examples o a health and QoL survey. This is ageneric measure, as opposed to one that targets aspecic age, disease, or treatment group.

Considerations or the use o the

ASIA scale to measure a change inneurological unction

There has been debate abouthow soon ater acute SCI the ASIAexamination can provide useulpredictions about the eventual degreeo impairment. It has been suggestedthat an ASIA assessment within therst 24 hours may not provide anaccurate prognosis and that a laterexamination at 72 hours is a morereliable indicator, as the patient ismedically more stable.31 32 At later time

points (greater than 12 months aterSCI), the ASIA assessment may not capture the mostimportant aspects o any unctional change, since it wasnot meant to assess activities o daily living. Functionaltests (see below) are perhaps more useul primaryoutcome tools or chronic studies.

Regardless o these concerns, it is essential thatsteps should be taken to standardize and optimizethe accuracy o the ASIA assessment. For all patientsbeing considered or entry into a trial, the clinical trialcenter(s) must conduct an independent and blind ASIAassessment just prior to the participant being randomly

assigned to the therapeutic intervention or relevantcontrol group. Subsequent ollow-up ASIA assessmentsshould also be undertaken at relevant time points overthe course o recovery, as dened or that trial (e.g.rst ew weeks, rst couple o months, and then atxed intervals throughout the duration o the study)in the same blinded ashion, and preerably by thesame examiner. In the absence o a more sensitive andaccurate outcome tool, at least these ASIA assessmentsenable us to ollow any initial detriments or benets o acandidate therapy.


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As valuable as the current ASIA Impairment Scale hasbeen to the diagnosis o the severity and level o SCI,every measure has its limits in terms o sensitivity andaccuracy. Since the ASIA scale only has 5 grades (A-E), itmay not be sensitive enough to detect a small or subtletherapeutic eect. Only an experimental treatment with avery large eect could be validated with such an outcomemeasure or clinical endpoint. However, an interventionwith a potentially smaller result might require a moresensitive outcome measure, such as a statisticallysignicant change in the ASIA motor score (an ASIAsub-score, see g.2)2, which is a hundred point scale.Ten dierent muscle groups are assessed on each sideo the body, each representing the unctional motor stateor a dierent level o the spinal cord. The strength oeach muscles contraction is scored on a 5 point scale asthe individual attempts to initiate a voluntary movementwhich involves that particular muscle group.

In general, establishing a unctionallymeaningul ASIA motor score threshold

to document the benet o a therapeuticintervention depends on both the leveland severity o the SCI, as well as thedegree o spontaneous change in themotor score (throughout the period othe trial). For example, previous studieshave indicated that a low-cervical,ASIA A injured patient is likely to showa spontaneous improvement o about10 ASIA motor points during the rstyear ater SCI. Thereore, to demonstrate the ecacy oa therapeutic intervention, a response to the treatmento an additional 10 point improvement in the ASIA motor

score (ecacy threshold now being 20 points) might beconsidered a statistically valid primary outcome threshold,when compared to an appropriate control population.1

Dierent thresholds need to be specied or a responseat each level and severity o SCI. For example, thespontaneous recovery o ASIA B cervical patients oneyear ater a cervical SCI has been reported to be about30 (out o the 100) motor points. Thus, demonstrationo a therapeutic benet might require an additional20 point improvement to indicate a unctional benet.It should be noted that the absolute dierence in thenumber o ASIA motor points between an experimental

and appropriately matched control group is not asimportant as a statistically valid dierence betweenthe experimental and control groups and whether thatdierence coners an improved unctional outcome to theperson with SCI.

Finally, several studies have reported a substantial(25-50) motor point improvement during the rst yearater SCI or people with ASIA C and D classications,which is on top o their initially high ASIA motor score.This creates a ceiling eect that may make it dicult

to discriminate a statistical dierence between the ASIAmotor scores o SCI participants in the experimentaland control arms o a study. In short, a treatment eectwould not be detectable. Thereore, a unctional test (seebelow) may be a more appropriate primary outcome toolor ASIA C and ASIA D trial participants.

Statistically speaking, the use o ASIA motor scores as

a primary outcome endpoint is perhaps most useulor SCI subjects initially enrolled in a clinical trial aseither ASIA A or ASIA B. The obvious drawback with thissuggestion is ASIA A and ASIA B subjects initially havemotor-complete spinal injuries and it may be dicult toproduce or discern a clinically meaningul improvementin their subsequent ASIA motor score. I the ASIA scalemeasurements are somewhat limited in their sensitivityand accuracy or discerning whether a treatmenthas a signicant benet, then what other outcomemeasurement tools might be used?

Other tools or measuring a changein neurological unction ater

experimental treatment o SCI

Electrical recording techniques suchas somatosensory evoked potential(SSEP), electromyographic (EMG)and motor evoked potential (MEP)recordings can provide objective datasuch as the speed and strength oneural signals to assess preservedor recovering spinal connections.

These quantitative signals can be analyzed by ablinded investigator. Furthermore, electrophysiologicalrecordings have the advantage that they can be

perormed on comatose or otherwise unresponsivesubjects. EMG recordings are useul in the assessmento unction, both in response to voluntary eort andwhen combined with electrical or magnetic stimulationo peripheral nerves (refexes) or motor cortex (i.e. MEP).These technologies complement the ASIA neurologicalassessment, and a combination o SSEP, MEP and/orEMG measurements provides inormation about spinalcord unction that is not retrievable by other clinicalmeans and may have additional value in predictingunctional outcomes.33 34

Non-invasive imaging, such as magnetic resonanceimaging (MRI) has become a cornerstone or detectingthe location (and to some degree the severity) o anacute SCI, as well as detecting possible complicationsarising during chronic SCI. MRI, along with Computerizedaxial Tomography (CT) and x-ray images, are useuldiagnostic tools and potentially helpul or screeningparticipants to be included or excluded rom a clinicaltrial. MRI has been useul in determining the extent ocord compression, outlining hemorrhages and edemaater human spinal injury and in the near uture, mightbe useul in monitoring regressive or progressive

Efcacy can bemeasured using theASIA scale, electrialrecording techniquesand unctionaltesting.


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changes in spinal cord tracts.35 36 37 38 With urtherdevelopment, MR technologies may provide a useulearly measure that would accurately predict the longerterm unctional benets o an experimental interventionater SCI.38

Functional tests

A measurable improvement in the perormance o

a meaningul unction, behavior, or activity o dailyliving (ADL) is absolutely necessary or any therapeuticintervention to be universally accepted as benecial.Accurate and sensitive unctional outcome measures arethereore critical to SCI clinical trialsand this will be especially true or anyPhase 3 studies.

It has been suggested that theFunctional Independence Measure(FIM) scale is a general disabilityscale, which is not specic or SCI andthereore may not be the most suitable

scale or assessing unctional changesater SCI. The recently developedSpinal Cord Independence Measure(SCIM) assessment may be a morespecic and accurate outcome tool ordetecting clinical endpoints in SCI.3940 41 The continued development andvalidation o tests that quantiy highlyrelevant behaviors such as walking orhand unction are most important; suchtools may have greater utility or documenting the subtlebenet o an experimental treatment than a more globalscale o disability.

For clinical trials involving people with motor-incompleteSCI (ASIA C and ASIA D), several validated tests obalance and ambulatory perormance have beendeveloped, including the Walking Index or Spinal CordInjury (WISCI) and a number o timed walking tests.42 43WISCI is a 21-level hierarchical scale o walking based onphysical assistance and the need or braces and devices,with a range rom 0 (unable to walk) to 20 (walkingwithout assistance or at least 10m). It is an example oa sensitive scale or rating a specic unctional activityin people with incomplete SCI. WISCI is currently a valid

outcome measure or strategies directed to improveambulation by subjects with incomplete SCI.42 A moreaccurate assessment may be provided by a combinationo WISCI plus some o the more quantitative timedwalking tests.

The number o people surviving with a cervical level spinalinjury has risen dramatically over the past ew decades

and cervical SCI now accounts or approximately 50%o all people living with a SCI. Validating a unctionaloutcome tool to assess arm and hand capacity ater acervical spinal injury has thereore been identied as a

top priority. There is currently a lack oagreement on what might be the mostuseul test o arm and hand unctionater SCI. Many o the scales developedhave been deemed too insensitive totrack small but potentially meaningulunctional gains. The majority otests have been developed within thedomains o stroke or hand surgery, but

less oten to describe the impairmentand course o hand unction recoveryater SCI. An initiative is now underwayacross Canada, the United States, andEurope to develop an integrated handunction test as a valid assessment toolor SCI clinical trials.

Improvement o unctional abilities,refected in activities o daily living

will be the most meaningul and valued outcomes.However, the early phase clinical trials or drug therapies(Phase 1 and 2) completed to date have ocused on

assessment o neurological connectivity to provideproo o principle measures. It is likely that theseneurological assessments will continue to be usedas outcome measures. However, no experimentalintervention will be considered eective or thetreatment o people living with SCI unless it improvestheir ability to unction and engage in everyday liewithin their society. Outcome assessment tools thataccurately and sensitively demonstrate such benetswill need to be incorporated into the more denitive andconrmatory Phase 3 clinical trials.

A measurableimprovement in theperormance o ameaningul unction,behavior, or activity

o daily living isabsolutely necessaryor any therapeuticintervention to beuniversally acceptedas benefcial.


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I you participate in a clinical trial, how does it aectyour participation in uture SCI clinical trials?The answer to this important question depends on theoverlap in the mechanism o action or the experimentaltreatments used in each o the successive trials and

the time span between the trials. Simply speaking,i the two dierent trials involve aninvestigation o similar experimentaldrugs or drugs with similar cellularmechanisms, it is pos

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