A Prospective Multicenter Study to Assess The Clinical Outcomes of Low Energy Lens Fragmentation Cataract Extraction in Patients Undergoing Cataract Surgery
Phase: NA
Conditions: Cataract
Sponsor: Carl Zeiss Meditec, Inc.

PROTOCOL MICOR-304-101 
PROTOCOL MICOR-304-101 
VERSION A.6 
05-4-2021
A PROSPECTIVE MULTICENTER STUDY TO ASSESS THE CLINICAL OUTCOMES OF 
LOW ENERGY LENS FRAGMENTATION CATARACT EXTRACTION IN PATIENTS 
UNDERGOING CATARACT SURGERY 
CARL ZEISS MEDITEC CATARACT TECHNOLOGY, INC. 
748 TECHNOLOGY WAY 
RENO, NV 89521 

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TABLE OF CONTENTS  
1 PERSONNEL AND FACILITIES .......................................................................................... 3 
2 STUDY SYNOPSIS .............................................................................................................. 4 
3 INTRODUCTION AND RATIONALE .................................................................................... 6 
4 STUDY OBJECTIVES ......................................................................................................... 8 
5 STUDY DESIGN .................................................................................................................. 8 
6 STUDY POPULATION ......................................................................................................... 9 
7 STUDY PROCEDURES ..................................................................................................... 11 
8 STATISTICAL METHODS ................................................................................................. 15 
9 Adverse Events ................................................................................................................ 16 
10 Ethical and Regulatory Considerations ........................................................................ 18 
Appendix 1:Schedule of Events and Procedures ........................................................... 200 
Appendix 2: Examination Procedures, Tests, Equipment & Techniques ...................... 221 
Appendix 3: Declaration of Helsinki................................................................................... 25 
Investigators Signature Page ............................................................................................. 32 
 
 
 
 
 
 
 
 
 

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PROTOCOL MICOR 304-101 
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1 PERSONNEL AND FACILITIES 
 
 
PRIMARY INVESTIGATOR: 
Farrell Tyson, MD 
4120 Del Prado Blvd 
Cape Coral FL 33904 
Mobile. 239-281-2020 
 
 
MEDICAL MONITOR: 
 
 
 
Farrell Tyson, MD 
 
 
4120 Del Prado Blvd 
 
 
Cape Coral FL 33904 
 
 
Mobile. 239-281-2020 
 
 

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2 STUDY SYNOPSIS 
Study Objective    
The purpose of this research study is to evaluate the clinical outcomes of the use of low-
energy segment removal with a micro-interventional irrigation/aspiration port (MICOR-304) to 
evacuate the lens prior to intraocular lens insertion in subjects undergoing routine cataract 
surgery.  
 
Study Population 
Only 1 eye per subject will be enrolled into the study. Up to 100 subjects (100 eyes) will be 
enrolled into the first phase of the study and an additional 200 subjects (200 eyes) will be 
enrolled in the second phase of the study, for a total of 300 subjects (300 eyes). Subjects will 
be enrolled in one of the two cohorts of this clinical investigation. For the first 100 eyes 
enrolled – up to 75 eyes may be enrolled in Cohort 1 and up to 75 eyes in Cohort 2. For the 
additional second phase of 200 eyes – up 150 eyes may be enrolled in Cohort 1 and up to 
150 eyes in Cohort 2. Overall, for the 300-study eye investigation, there should be no more 
than 225 eyes in either Cohort 1 or 2.   
 
Study Design   
This is multicenter, multi-cohort, prospective clinical study designed to provide longitudinal, 
observational, non-comparative clinical outcome data for mechanical non-phacoemulsification 
lens extraction using low-energy segment removal with a micro-interventional 
irrigation/aspiration port (MICOR-304) to evacuate the lens prior to intraocular lens insertion.  
 
Subjects will be stratified into two Cohorts.  Cohort 1 is comprised of eyes  with mild-to- 
moderate cataracts only (Grade 1 to 2).   Cohort 2 is comprised of eyes with moderate to 
more dense cataracts only (Grade 2+ to 3+).  
 
Inclusion Criteria  
1. Able to understand study requirements, willing to follow study instructions and willing 
to return for required study follow-up visits. 
2. Willing and able to understand and complete the informed consent document 
3. Subjects with a cataract grade of 1 to 3+ and are scheduled to undergo cataract 
surgery 
4. Subjects > 18 years of age 

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5. Clear intraocular media, other than cataract 
Exclusion Criteria for both Cohorts  
1. Polar cataracts 
2. Zonular instability 
3. Subjects who have been diagnosed with dry eye which has been untreated and or 
would affect postoperative visual acuity outcomes (i.e., if the subject has had dry eye 
treatments / devices and has, or is undergoing treatment and deemed to be stable, 
they would be an eligible study candidate). 
4. Concurrent participation or participation in any clinical trial up to 30 days prior to 
preoperative visit. 
5. Subjects that are pregnant, lactating or planning to become pregnant during the course 
of the study 
 
Primary Endpoint 
Efficacy: Total lens removal time and amount of irrigation solution fluid volume used during the 
surgical procedure.   
• 
Total lens removal time is defined in two phases:  
o The beginning time starts when the surgeon enters into the eye with the 
MICOR-304 to start the lens removal process and completing when the 
surgeon finishes the nucleus lens removal with the MICOR-304 before 
changing over to irrigation and aspiration. 
o The second phase of lens removal time is the irrigation and aspiration stage for 
cortex removal which starts when the irrigation and aspiration tip enters the eye 
and completion time is when the cortex is removed. 
• 
Total irrigation solution volume will be recorded using the indicators on the waste bag 
which will have labels that have pre-defined markers to indicate milliliters (ml) of 
volume of irrigation solution used for the surgical procedure.    
Safety: Rate of occurrence of intraoperative and postoperative adverse events (AEs) 
Secondary Endpoints 
• 
UCVA on day 1 
• 
BCVA on days 7, 30 
• 
Change in corneal thickness from baseline through Day 30 
• 
Rate of occurrence of intraoperative and postoperative adverse events (AE) 
• 
Results of slit lamp and fundus examinations, which are not considered to be AEs 

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• 
Total procedure time: defined as the beginning time when the surgeon makes the first 
incision in the eye and completion time is when the eye speculum is removed at the end of 
the procedure.   
Schedule of Visits 
Screening visit, intraoperative visit, post-operative day 1, day 7, day 30. 

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3 INTRODUCTION AND RATIONALE   
 
Background 
Global estimates suggest that 94 million people are visually impaired due to cataract and, of 
these, 20 million are blind.1 Because the incidence of cataracts increases with age, an 
increase in the elderly population will lead to a significant increase in cataract prevalence.  
Approximately 25% of people aged 65-69 years have cataracts, a proportion increasing to 
over 68% of those aged 80+ years.3 
 
In 2014, nearly 23 million cataract surgeries were performed worldwide; of these, over 3.6 
million procedures were performed each in the US and EU.4 Cataract extraction with 
intraocular lens (IOL) implantation is the most commonly performed surgical procedure in the 
world. The safety and effectiveness outcomes of modern-day cataract surgery are well 
described in the literature.6 Technological advances have transformed cataract surgery so that 
now over 99% are performed on an outpatient basis with excellent surgical outcomes.8  
 
As cataract surgery has become minimally invasive and more procedural in nature, it has 
been performed much earlier in the course of disease and patients’ lives. It is not uncommon 
to perform cataract surgery in the patient’s 5th decade rather than their 70’s even at very low 
levels of visual impairment. This early intervention has placed additional emphasis on safety 
and reduced ocular trauma during cataract surgery. 
 
Current phacoemulsification approach to cataract extraction involves high-frequency 
thermogenic ultrasonic needle to fragment the lens and remove it from the anterior segment of 
the eye. This can be associated with significant ocular morbidity particularly in advanced 
cataracts because the phacoemulsification needle produces significant amount of energy and 
generates heat which is detrimental to the cornea and the endothelium. 
 
Mechanical approaches to lens fragmentation and aspiration such as the MICOR-304 
fragmentation and lens removal provide an alternative to phacoemulsification with no 
cavitation, no thermogenic energy in the eye which can eliminate the generation of heat inside 
the eye while at the same time maintaining the same minimally invasive surgical approach 
through a small clear-cornea 2.5 mm incision. 
 

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4 STUDY OBJECTIVES 
 
The purpose of this research study is to characterize the clinical outcomes of mechanical and 
ultrasound-assisted lens fragmentation techniques in routine cataract surgery. The study will 
provide longitudinal, observational, non-comparative clinical outcomes data for mechanical 
lens fragmentation techniques.  
 
5. STUDY DESIGN 
 
This study protocol is a dual cohort, prospective, multi-center, interventional study whose goal 
is to evaluate the clinical and surgical outcomes of mechanical lens fragmentation techniques.  
The study is planned for up to 10 investigational sites.  Only 1 eye per study subject will be 
enrolled into the study.  
 
 
 
 
  
 
  
 
 
  
 
  
 
 
6. STUDY POPULATION   
 
Individuals will be assessed for study eligibility based on the criteria presented below: 
Inclusion Criteria  

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1. 
Able to understand study requirements, willing to follow study instructions and willing 
to return for required study follow-up visits 
2. 
Willing and able to understand and complete the informed consent document 
3. 
Subjects with a cataract grade of 1 to 3+ and are scheduled to undergo cataract 
surgery 
4. 
Subjects ≥ 18 years of age 
5. 
Clear intraocular media, other than cataract 
 
Exclusion Criteria for both Cohorts  
1. 
Polar cataracts 
2. 
Zonular instability 
3. 
Subjects who have been diagnosed with dry eye which has been untreated and or 
would affect postoperative visual acuity outcomes (i.e., if the subject has had dry eye 
treatments / devices and has, or is undergoing treatment and deemed to be stable, 
they would be an eligible study). 
4. 
Concurrent participation or participation in any clinical trial up to 30 days prior to 
preoperative visit 
5. 
Subjects that are pregnant, lactating or planning to become pregnant during the 
course of the study 
 
Primary Endpoints 
Efficacy: Total lens removal time and amount of irrigation solution fluid volume used during the 
surgical procedure.   
• 
Total lens removal time is defined in two phases:  
o The beginning time starts when the surgeon enters the eye with the MICOR-
304 to start the lens removal process and completing when the surgeon 
finishes the nucleus lens removal with the MICOR-304 before changing over to 
irrigation and aspiration. 
o The second phase of lens removal time is the irrigation and aspiration stage for 
cortex removal which starts when the irrigation and aspiration tip enters the eye 
and completion time is when the cortex is removed. 
• 
Total irrigation solution volume will be recorded using the indicators on the waste bag 
which will have labels that have pre-defined markers to indicate milliliters (ml) of 
volume of irrigation solution used for the surgical procedure.    
 

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Safety: Rate of occurrence of intraoperative and postoperative adverse events (AE) 
 
Secondary Endpoints 
• 
UCVA on day 1,7,30 
• 
Change in corneal thickness from baseline through Day 30 
• 
Rate of occurrence of intraoperative and postoperative adverse events (AE) 
• 
Results of slit lamp and fundus examinations, which are not considered to be AEs 
• 
Total procedure time is defined as the beginning time when the surgeon makes the first 
incision in the eye and completion time is when the eye speculum is removed at the end of 
the procedure   
 
Schedule of Visits 
Screening visit, intraoperative visit, post-operative day 1, day 7, day 30 
 
7 STUDY PROCEDURES 
 
Subject Entry 
Participants who meet the inclusion and exclusion will be asked to enroll in the study.  The 
investigator or designee will explain the study purpose, procedures and responsibilities to the 
potential participant and provide sufficient opportunity to ask questions, while allowing 
adequate time for consideration of the information provided.  Upon participant confirmation of 
interest, written informed consent will be obtained and the subject will be enrolled in the study.  
One copy of the informed consent document (ICD) will be retained with the subject’s medical 
records and one copy will be provided to the subject.   
 
Subject Cohort Selection: 
Subjects with mild to moderate cataracts (Grade 1-2) who meet the inclusion criteria, will be 
assigned to Cohort 1. Subjects with severe cataracts (Grade 2+ - 3+) meeting the inclusion 
criteria will be assigned to cohort 2. Subjects with intermediate cataracts, which may qualify 
for either Cohort, will be assigned based on investigator discretion and clinical judgement 
since exact lens density judgment is impossible to determine prior to surgery. 
 
Only 1 eye per subject will be enrolled into the study.  Up to 100 subjects (100 eyes) will be 
enrolled into the first phase of the study and an additional 200 subjects (200 eyes) will be 
enrolled in the second phase of the study, for a total of 300 subjects (300 eyes).   Subjects will 

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be enrolled in one of the two cohorts of this clinical investigation.  For the first 100 eyes 
enrolled – up to 75 eyes in Cohort 1 and up to 75 eyes in Cohort 2.  For the additional second 
phase of 200 eyes – up 150 eyes per subject in Cohort 1 and up to 150 eyes in Cohort 2.  
Overall, for the 300 study eye investigation, there should be no more than 225 eyes in either 
Cohort 1 or 2.    
Surgical Procedure 
All subjects will undergo routine cataract surgical intervention with IOL implantation. All 
subjects will receive the standard of care preoperative and peri-operative medications and 
assessments. The procedure can be performed under either topical or peri/retrobulbar 
anesthesia per investigator discretion. Clear cornea cataract surgery will be performed with 
the following steps: 
 
  
Study Eye
For each subject, one or both eyes may be treated; however, if both eyes are scheduled for 
treatment, then one eye will be designated as the “study eye” based on investigator 
discretion prior to any surgical intervention. 
Study Visits  
All subjects enrolled will return for defined follow-up visits pre- and post-operatively.  Data 
collected from each scheduled and unscheduled (or interim) exam will be recorded on a Case 
Report Form (CRF).   
Subjects who become ineligible for study participation after enrollment will be exited from the 
study and the reason for exit will be documented on the Subject Screening Log and noted as 
a screen failure. 

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Pre-Operative/Screening Visit 
This visit can occur 0 to 60 days prior to surgery.  The following information will be captured 
for the study eye at this visit: 
•
Demographic data (gender, age, race / ethnicity)
•
Ocular history / ocular medications
•
Cohort selection 1 or 2
•
Identification of study eye (OS or OD)
•
Cataract type and grade
•
Manifest refraction and best-corrected visual acuity (BCVA)
•
Slit lamp biomicroscopy
•
Dilated pupil size measurement
•
Goldmann tonometry
•
Dilated fundus examination and C:D ratio assessment
•
Central corneal pachymetry
•
Macular OCT (optional)
Intraoperative 
The following information will be captured for the study eye during surgery: 
•
Total lens removal time
•
Total volume of irrigation fluid used
•
Anesthesia type
•
Other surgical procedures performed
•
Device failure / malfunction
•
Method / device used for cataract pre-segmentation
•
MICOR-304 model used
•
Type of viscoelastic used
•
Total procedure time
•
Any intraoperative AEs (capsule tear, corneal haze, other)
1 DAY Postoperative 
This visit must occur at postoperative days 1-2. The following information will be captured for 
the study eye at this visit: 
•
Ocular medications

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• 
UCVA (pinhole) 
• 
Slit lamp biomicroscopy  
• 
Goldmann tonometry  
• 
Central corneal pachymetry 
• 
AE assessment  
• 
Macular OCT (optional) 
 
1 WEEK Postoperative 
This visit must occur at postoperative days 5-10. The following information will be captured for 
the study eye at this visit: 
• 
Ocular medications 
• 
Manifest BCVA 
• 
Slit lamp biomicroscopy  
• 
Goldmann tonometry  
• 
Central corneal pachymetry 
• 
AE assessment  
• 
Macular OCT (optional) 
 
1 MONTH Postoperative 
This visit must occur at postoperative days 21-35. The following information will be captured 
for the study eye at this visit: 
• 
Ocular medications 
• 
Manifest BCVA 
• 
Slit lamp biomicroscopy  
• 
Goldmann tonometry  
• 
Central corneal pachymetry 
• 
Dilated fundus examination and C:D ratio assessment 
• 
AE assessment  
• 
Macular OCT (optional) 
 
The examinations associated with each study visit are outlined and summarized in Appendix 
1 (Schedule of Events and Procedures) and a description of methodology for these 
examinations is provided in Appendix 2 (Examination Procedures, Tests, Equipment and 
Techniques).  

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Unscheduled Visits 
Unscheduled visits are those which are not required by the study protocol, but which occur 
due to a surgical procedure performed on the study eye, or a subject complaint regarding this 
eye.  No specific testing is required at unscheduled visits; rather, the Investigator and/or 
qualified investigational staff will perform the procedures necessary to evaluate the subject at 
these visits.  Clinical data from these visits will be recorded on the relevant CRF.     
Subject Identification 
The subjects will be identified by a five digit number comprised of a two-digit site number 
followed by a three-digit subject # (e.g., 01-001, 01-002, 01-003 etc.).  The subject 
identification number will be assigned when informed consent is obtained.   
Source Documents and Case Report Forms  
Adequate original records will be maintained for the study.  All original source documents will 
be retained at the site.  The study sponsor, sponsor’s representative, and appropriate 
regulatory authorities shall have access to the source documents as needed.    
8 STATISTICAL METHODS 
Analysis Plan 
Primary and secondary endpoints will be analyzed with descriptive statistics. Point estimates 
and confidence intervals will be calculated for each outcome. 95% confidence intervals for 
lens removal time and irrigation fluid volume will be calculated based on a t distribution. 
Frequency tabulations of safety outcomes will be made at the 1 week and 1-month follow-up 
evaluations. 
Sample Size 
The sample size for this study is based on the following: 
For safety, the pooled  sample of 100 eyes will have a greater than 90% chance of detecting 
one or more rare adverse events, i.e., those with an expected rate of occurrence of 2.5%. 
We anticipate that for Cohort 1 (grades 1 – 2) the mean lens removal time will be 
approximately 5 minutes, with standard deviation of 1 minute, and for Cohort 2 (grades 2+) the 
mean lens removal time will be about 10 minutes, with standard deviation 2 minutes.  Under 

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these assumptions a sample of 50 eyes will produce a confidence interval width of 
approximately 0.56 minutes for Cohort 1 and 1.14 minutes for Cohort 2. 
For Irrigation Fluid Volume we anticipate a mean of 30ml with a standard deviation of 
approximately 5ml for both Cohorts.  Under these assumptions, a sample of 50 eyes will 
produce a confidence interval width of approximately 2.8ml for each Cohort. 
Adverse Events 
The number of subjects reporting at least 1 AE of a given type will be summarized.  AEs not 
listed that occur during the study will be added to the summary of AEs. Summaries will also be 
provided for AEs considered to be related to the device.   Each AE will be summarized by 
incidence and percentage. 
Central Corneal Pachymetry 
Central corneal pachymetry data will be summarized with N, mean, standard deviation, 
minima, median, and maxima.  A 95% confidence interval will be provided for the change and 
percentage change from baseline.  Change between two consecutive visits will also be 
summarized. 
Slit Lamp and Fundus Exam Findings 
Slit lamp, and fundus examination findings at scheduled follow-up visits will be tabulated such 
that the number and percentage of subjects in each category will be summarized. 
9 ADVERSE EVENTS 
All ocular AEs in the study eye must be reported on the relevant CRF.  AEs will be 
categorized by degree of harm to the subject (mild, moderate, or severe). 
Ocular conditions or diseases present at the time of study enrollment will be considered as 
“baseline”.  Changes in a chronic condition or disease that are consistent with natural disease 
progression are not considered AEs. 
AEs that might reasonably be expected to occur include, but are not limited to, the following: 
•
Anterior chamber cell and flare requiring initiation of steroid treatment

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• 
Capsular tear and rupture 
• 
Vitreous loss 
• 
Endophthalmitis 
• 
Corneal edema  
• 
Retinal tear / detachment  
• 
Dialysis, flap tears or proliferative vitreoretinopathy 
• 
Cystoid Macular Edema 
• 
Hypopyon  
• 
Hyphema 
• 
Lens dislocation 
• 
Pupillary block 
• 
Acute corneal decompensation 
• 
Raised IOP requiring treatment 
• 
Severe inflammation 
• 
Secondary Surgical Intervention 
Grading of Adverse Events 
AEs will be graded on a 3-point scale (mild, moderate, severe) using the following definitions: 
• 
Mild:  Discomfort noticed, but there is no disruption of normal daily activity 
• 
Moderate:  Discomfort is sufficient to reduce or affect normal daily activity 
• 
Severe:  Subject is incapacitated as evidenced by the inability to work or perform 
normal daily activity 
Follow-up of Adverse Events 
AEs will be followed until resolution or stabilization of the event. 
 
Expedited Reporting of Adverse Events 
 
An AE should be classified as SERIOUS if it: 
• 
Caused or led to death. 
• 
Was life threatening (i.e., the AE placed the subject at immediate risk of death). 
• 
Required or prolonged inpatient hospitalization (i.e., the AE required at least a 24-hour 
inpatient hospitalization or prolonged a hospitalization beyond the expected length of stay). 
• 
Was sight threatening.   

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•
Was disabling (i.e., the AE resulted in a substantial disruption of the subject's ability to carry out
normal life functions).
•
Resulted in a congenital anomaly/birth defect (i.e., an adverse outcome in a child or fetus of
a subject due to participation in this study).
•
Does not meet any of the above serious criteria but jeopardized the subject by requiring
medical or surgical intervention to prevent one of the outcomes listed above.
Serious events or serious device related adverse events should be reported in accordance with 
the following requirements: 
Event Type 
Reporting Timeframe 
Serious device 
related  adverse 
event 
Within 24 hours of becoming aware of the event 
SAE 
Within 1 week of becoming aware of the event 
Any ocular-related serious adverse event (SAE) should be reported to the study sponsor 
WITHIN ONE WORKING DAY of learning of the event.  Non-ocular-related SAEs should be 
reported to the study sponsor within TWO WORKING DAYS of learning of the event.  Email 
the Adverse Event CRF to gary@gsmservicesus.com 
Any serious device related adverse events must be reported to the following three entities: 
1.
The study sponsor – Within ONE WORKING DAY of the investigator first learning of
the event, email the AE CRF to gary@gsmservicesus.com; and
2.
The reviewing Institutional Review Board(IRB) Committee – As soon as possible, but
no later than 7 working days after the investigator first learns of the event, report per
the IRB instructions.
3.
FDA under the reporting requirements for 21 CFR Part 803 Medical Device Reporting
10 ETHICAL AND REGULATORY CONSIDERATIONS 
This protocol was designed and will be conducted in accordance with the recommendations 
guiding physicians in biomedical research involving human subjects adopted by the 18th World 
Medical Assembly, Helsinki, Finland, 1964 and later amendments.  Basic responsibilities of 
the study Investigators and overseeing Institutional Review Board(s) (IRB) are as noted 
below: 
Investigator Responsibilities 
The Investigator is responsible for maintaining clinical study records and reports as noted 
below for at least 2 years following the latter of: the date which the study is terminated or 

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completed, or the date that the records are no longer required for purposes of supporting a 
marketing application.  The Investigator will make these records available for audit and review 
by FDA as requested by the Agency. 
Clinical Study Records: 
•
AEs
•
Signed Investigator Agreements and Investigator Curriculum Vitae (CV)
•
Financial disclosure information under 21 CFR Part 54
•
Study Electronic Case Report Forms
•
Study-related correspondence
Clinical Study Reporting: 
•
Results of evaluation of any serious device related adverse event to all Investigators,
IRBs and FDA in accordance with reporting requirements under 21 CFR Part 803
Medical Device Reporting  after receiving notice of the event
•
Withdrawal of IRB approval to all Investigators, IRBs and FDA within 5 working days
•
Progress reports to all IRBs annually or as required by the IRB
•
Final report to all IRBs within 6 months of study termination or completion
Institutional Review Board 
This protocol and the subject ICD must be reviewed and approved by an IRB operating in 
accordance with local procedures and 21 CFR Parts 50, 56, and 812 before enrollment of 
subjects.   
The Investigator is responsible for maintaining IRB approval for the study protocol and ICD 
and for keeping the IRB informed of protocol amendments and AEs in accordance with IRB 
requirements.  

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AE Assessment 
X 
X 
X 
X 
1 All procedures/examinations will be performed on the study eye only 

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APPENDIX 2 EXAMINATION PROCEDURES, TESTS, EQUIPMENT AND TECHNIQUES 

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APPENDIX 3 WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by 
the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 
added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
 
 
A.  INTRODUCTION 
1.  The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. The Declaration is intended to be read 
as a whole and each of its constituent paragraphs should not be applied without 
consideration of all other relevant paragraphs. 
 
2.  Although the Declaration is addressed primarily to physicians, the WMA encourages other 
participants in medical research involving human subjects to adopt these principles. 
 
3.  It is the duty of the physician to promote and safeguard the health of patients, including 
those who are involved in medical research. The physician's knowledge and conscience 
are dedicated to the fulfillment of this duty. 
 
4.  The Declaration of Geneva of the WMA binds the physician with the words, “The health of 
my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical 
care.” 

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5.  Medical progress is based on research that ultimately must include studies involving 
human subjects. Populations that are underrepresented in medical research should be 
provided appropriate access to participation in research. 
 
6.  In medical research involving human subjects, the well-being of the individual research 
subject must take precedence over all other interests. 
 
7.  The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best current 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
 
8.  In medical practice and in medical research, most interventions involve risks and 
 
burdens. 
 
9.  Medical research is subject to ethical standards that promote respect for all human 
subjects and protect their health and rights. Some research populations are particularly 
vulnerable and need special protection. These include those who cannot give or refuse 
consent for themselves and those who may be vulnerable to coercion or undue influence. 
 
10. Physicians should consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration. 
 
B. PRINCIPLES FOR ALL MEDICAL RESEARCH 
 
11. It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. 
 

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12. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
 
13.  
Appropriate caution must be exercised in the conduct of medical research that may 
harm the environment. 
 
14. The design and performance of each research study involving human subjects must be 
clearly described in a research protocol. The protocol should contain a statement of the 
ethical considerations involved and should indicate how the principles in this Declaration 
have been addressed. The protocol should include information regarding funding, 
institutional affiliations, other potential conflicts of interest, incentives for subjects and 
provisions for treating and/or compensating subjects who are harmed as a consequence 
of participation in the research study. The protocol should describe arrangements for post-
study access by study subjects to interventions identified as beneficial in the study or 
access to other appropriate care or benefits. 
 
15. The research protocol must be submitted for consideration, comment, guidance and 
approval to a research ethics committee before the study begins. This committee must be 
independent of the researcher, the sponsor and any other undue influence. It must take 
into consideration the laws and regulations of the country or countries in which the 
research is to be performed as well as applicable international norms and standards but 
these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. The committee must have the right to monitor 
ongoing studies. The researcher must provide monitoring information to the committee, 
especially information about any serious AEs. No change to the protocol may be made 
without consideration and approval by the committee. 
 
16. Medical research involving human subjects must be conducted only by individuals with the 
appropriate scientific training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional. The responsibility for the protection of research subjects 

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must always rest with the physician or other health care professional and never the 
research subjects, even though they have given consent. 
 
17. Medical research involving a disadvantaged or vulnerable population or community is only 
justified if the research is responsive to the health needs and priorities of this population or 
community and if there is a reasonable likelihood that this population or community stands 
to benefit from the results of the research. 
 
18. Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved 
in the research in comparison with foreseeable benefits to them and to other individuals or 
communities affected by the condition under investigation. 
 
19.  
Every clinical trial must be registered in a publicly accessible database before 
recruitment of the first subject. 
 
20. Physicians may not participate in a research study involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed. Physicians must immediately stop a study when the risks are 
found to outweigh the potential benefits or when there is conclusive proof of positive and 
beneficial results. 
 
21. Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the research subjects. 
 
22. Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees. 
 
23. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on their 
physical, mental and social integrity. 
 

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24. In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential 
risks of the study and the discomfort it may entail, and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in the 
study or to withdraw consent to participate at any time without reprisal. Special attention 
should be given to the specific information needs of individual potential subjects as well as 
to the methods used to deliver the information. After ensuring that the potential subject has 
understood the information, the physician or another appropriately qualified individual must 
then seek the potential subject’s freely given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be formally 
documented and witnessed. 
 
25. For medical research using identifiable human material or data, physicians must normally 
seek consent for the collection, analysis, storage and/or reuse. There may be situations 
where consent would be impossible or impractical to obtain for such research or would 
pose a threat to the validity of the research. In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
 
26. When seeking informed consent for participation in a research study the physician should 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent should be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
 
27. For a potential research subject who is incompetent, the physician must seek informed 
consent from the legally authorized representative. These individuals must not be included 
in a research study that has no likelihood of benefit for them unless it is intended to 
promote the health of the population represented by the potential subject, the research 
cannot instead be performed with competent persons, and the research entails only 
minimal risk and minimal burden. 
 
28. When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition 

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to the consent of the legally authorized representative. The potential subject’s dissent 
should be respected. 
 
29. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research 
population. In such circumstances the physician should seek informed consent from the 
legally authorized representative. If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give 
informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be 
obtained as soon as possible from the subject or a legally authorized representative. 
 
30. Authors, editors and publishers all have ethical obligations with regard to the publication of 
the results of research. Authors have a duty to make publicly available the results of their 
research on human subjects and are accountable for the completeness and accuracy of 
their reports. They should adhere to accepted guidelines for ethical reporting. Negative 
and inconclusive as well as positive results should be published or otherwise made 
publicly available. Sources of funding, institutional affiliations and conflicts of interest 
should be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
 
31. The physician may combine medical research with medical care only to the extent that the 
research is justified by its potential preventive, diagnostic or therapeutic value and if the 
physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
 
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best current proven intervention, except in the following 
circumstances: 

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• 
The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or 
• 
Where for compelling and scientifically sound methodological reasons the use of 
placebo is necessary to determine the efficacy or safety of an intervention and the 
patients who receive placebo, or no treatment will not be subject to any risk of serious 
or irreversible harm. Extreme care must be taken to avoid abuse of this option. 
 
33. At the conclusion of the study, patients entered into the study are entitled to be informed 
about the outcome of the study and to share any benefits that result from it, for example, 
access to interventions identified as beneficial in the study or to other appropriate care or 
benefits. 
 
34. The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never interfere with the patient-physician relationship. 
 
35. In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the 
patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgment it offers hope of saving life, re-establishing health or alleviating 
suffering. Where possible, this intervention should be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information should be 
recorded and, where appropriate, made publicly available.