assessing scientific literature...2018/12/05 · journal of ophthalmic and vision research (list...
TRANSCRIPT
![Page 1: Assessing Scientific Literature...2018/12/05 · JOURNAL OF OPHTHALMIC AND VISION RESEARCH (list date 5/31/18) JOURNAL OF OPHTHALMIC DISEASES (list date 1/20/16) JOURNAL OF OPHTHALMIC](https://reader031.vdocuments.net/reader031/viewer/2022011914/5fb7e0610e2a8c131275b7f2/html5/thumbnails/1.jpg)
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Assessing Scientific Literature
Mark Hillen, PhD, ELZA Institute, Zürich
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Disclosure
ELZA AG – employmentBackground
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PRESS
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Background
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The challenge of clinical trials(as a medical writer)
GPP
ICMJE
I/II/III
10 Xa
Background
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ADVANCES IN OPHTHALMOLOGY & VISUAL SYSTEM (list date 6/19/17)AL-BASAR INTERNATIONAL JOURNAL OF OPHTHALMOLOGY (list date 5/29/18)AMERICAN JOURNAL OF OPHTHALMOLOGY-GLAUCOMA (list date 2/15/18)APERITO JOURNAL OF OPHTHALMOLOGY (list date 10/25/18)ASIAN JOURNAL OF OPHTHALMOLOGYAUSTRALIAN AND NEW ZEALAND JOURNAL OF OPHTHALMOLOGYAUSTRALIAN JOURNAL OF OPHTHALMOLOGYBRITISH JOURNAL OF OPHTHALMOLOGYCANADIAN JOURNAL OF OPHTHALMOLOGYCASE REPORTS IN OPHTHALMOLOGY (list date 3/6/17)CHINESE JOURNAL OF OPHTHALMOLOGYCLINICAL AND EXPERIMENTAL VISION AND EYE RESEARCH (list date 1/9/18)CLINICAL OPHTHALMOLOGY (list date 9/4/14)DELHI JOURNAL OF OPHTHALMOLOGY (list date 7/14/15)DELTA JOURNAL OF OPHTHALMOLOGY (list date 5/29/18)DIGITAL JOURNAL OF OPHTHALMOLOGYEC OPHTHALMOLOGY (list date 2/18/16)EGYPTIAN RETINA JOURNAL (list date 5/29/18)EUROPEAN MEDICAL JOURNAL - OPHTHALMOLOGY (list date 7/30/14)EXPERT REVIEW OF OPHTHALMOLOGY (list date 12/13/11)EYE AND BRAIN (list date 9/4/14)EYE REPORTS (list date 10/30/14)HONG KONG JOURNAL OF OPHTHALMOLOGYINDIAN JOURNAL OF CLINICAL AND EXPERIMENTAL OPHTHALMOLOGYINDIAN JOURNAL OF OPHTHALMOLOGYINTERNATIONAL JOURNAL OF GLAUCOMA (list date 7/16/18)INTERNATIONAL JOURNAL OF OPEN ACCESS OPHTHALMOLOGY INTERNATIONAL JOURNAL OF OPHTHALMOLOGY & EYE SCIENCE (IJOES)INTERNATIONAL JOURNAL OF OPHTHALMOLOGY & VISION RESEARCHINTERNATIONAL JOURNAL OF OPHTHALMOLOGY AND CLINICAL RESEARCHINVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE JOURNAL KLINISCHE MONATSBLÄTTER FÜR AUGENHEILKUNDEJOURNAL OF CLINICAL & ACADEMIC OPHTHALMOLOGY (list date 10/21/15)JOURNAL OF CLINICAL OPHTHALMOLOGY AND RESEARCH (list date 5/31/18)JOURNAL OF CLINICAL RESEARCH AND OPHTHALMOLOGY (list date 6/5/18)JOURNAL OF GLAUCOMA (list date 6/24/14)JOURNAL OF OPHTHALMIC AND VISION RESEARCH (list date 5/31/18)JOURNAL OF OPHTHALMIC DISEASES (list date 1/20/16)JOURNAL OF OPHTHALMIC SCIENCE (list date 3/8/16)JOURNAL OF OPHTHALMOLOGY & EYE CARE (list date 9/14/18)JOURNAL OF PEDIATRIC OPHTHALMOLOGY & STRABISMUS (list date 3/30/10)JOURNAL OF REFRACTIVE SURGERY (list date 3/30/10)JOURNAL OF THE EGYPTIAN OPHTHALMOLOGICAL SOCIETY (list date 10/16/13)JOURNAL OF VISION (list date 7/12/10)KARGER KOMPASS OPHTHALMOLOGIE (list date 3/6/17)KERALA JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)KLINISCHE MONATSBLATTER FUR AUGENHEILKUNDEMIDDLE EAST AFRICAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)NEPALESE JOURNAL OF OPHTHALMOLOGY (list date 4/5/10)NEW FRONTIERS IN OPHTHALMOLOGY (NFO) (list date 3/31/17)NEW ZEALAND JOURNAL OF OPHTHALMOLOGYNIGERIAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)OMAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)OPEN ACCESS JOURNAL OF OPHTHALMOLOGY (OAJO) (list date 10/9/18)OPHTHALMIC RESEARCH (list date 3/6/17)OPHTHALMIC SURGERY, LASERS AND IMAGING (list date 3/30/10)OPHTHALMOLOGICA (list date 3/6/17)
INTERNATIONAL JOURNAL OF OPHTHALMOLOGY AND CLINICAL RESEARCH (list date 11/21/17)INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE (list date 7/12/10)JOURNAL KLINISCHE MONATSBLÄTTER FÜR AUGENHEILKUNDEJOURNAL OF CLINICAL & ACADEMIC OPHTHALMOLOGY (list date 10/21/15)JOURNAL OF CLINICAL OPHTHALMOLOGY AND RESEARCH (list date 5/31/18)JOURNAL OF CLINICAL RESEARCH AND OPHTHALMOLOGY (list date 6/5/18)JOURNAL OF GLAUCOMA (list date 6/24/14)JOURNAL OF OPHTHALMIC AND VISION RESEARCH (list date 5/31/18)JOURNAL OF OPHTHALMIC DISEASES (list date 1/20/16)JOURNAL OF OPHTHALMIC SCIENCE (list date 3/8/16)JOURNAL OF OPHTHALMOLOGY & EYE CARE (list date 9/14/18)JOURNAL OF PEDIATRIC OPHTHALMOLOGY & STRABISMUS (list date 3/30/10)JOURNAL OF REFRACTIVE SURGERY (list date 3/30/10)JOURNAL OF THE EGYPTIAN OPHTHALMOLOGICAL SOCIETY (list date 10/16/13)JOURNAL OF VISION (list date 7/12/10)KARGER KOMPASS OPHTHALMOLOGIE (list date 3/6/17)KERALA JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)KLINISCHE MONATSBLATTER FUR AUGENHEILKUNDEMIDDLE EAST AFRICAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)NEPALESE JOURNAL OF OPHTHALMOLOGY (list date 4/5/10)NEW FRONTIERS IN OPHTHALMOLOGY (NFO) (list date 3/31/17)NEW ZEALAND JOURNAL OF OPHTHALMOLOGYNIGERIAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)OMAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)OPEN ACCESS JOURNAL OF OPHTHALMOLOGY (OAJO) (list date 10/9/18)OPHTHALMIC RESEARCH (list date 3/6/17)OPHTHALMIC SURGERY, LASERS AND IMAGING (list date 3/30/10)OPHTHALMOLOGICA (list date 3/6/17)OPHTHALMOLOGY (list date 9/26/17)OPHTHALMOLOGY AND ALLIED SCIENCES (list date 7/26/16)OPHTHALMOLOGY AND EYE DISEASES (list date 2/1/12)OPHTHALMOLOGY AND VISION SCIENCE (list date 2/12/18)OPHTHALMOLOGY RETINA (list date 9/26/17)RMJ CLINICAL OPHTHALMOLOGY (list date 6/9/15)RUSSIAN OPHTHALMOLOGICAL JOURNAL (list date 11/28/17)SAUDI JOURNAL OF OPHTHALMOLOGY (list date 1/25/10)SUDANESE JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)TAIWAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)THE EGYPTIAN JOURNAL OF CATARACT AND REFRACTIVE SURGERY (list date 5/31/18)THE OPHTHALMOLOGY - OPEN JOURNAL (list date 10/16/17)TNOA JOURNAL OF OPHTHALMIC SCIENCE AND RESEARCH (list date 5/31/18)TURKISH JOURNAL OF OPHTHALMOLOGY (list date 5/3/16)US OPHTHALMIC REVIEW (list date 1/9/18)WORLD JOURNAL OF OPHTHALMOLOGY (list date 5/20/14)
ADVANCES IN OPHTHALMOLOGY & VISUAL SYSTEM (list date 6/19/17)AL-BASAR INTERNATIONAL JOURNAL OF OPHTHALMOLOGY (list date 5/29/18)AMERICAN JOURNAL OF OPHTHALMOLOGY-GLAUCOMA (list date 2/15/18)APERITO JOURNAL OF OPHTHALMOLOGY (list date 10/25/18)ASIAN JOURNAL OF OPHTHALMOLOGYAUSTRALIAN AND NEW ZEALAND JOURNAL OF OPHTHALMOLOGYAUSTRALIAN JOURNAL OF OPHTHALMOLOGYBRITISH JOURNAL OF OPHTHALMOLOGYCANADIAN JOURNAL OF OPHTHALMOLOGYCASE REPORTS IN OPHTHALMOLOGY (list date 3/6/17)CHINESE JOURNAL OF OPHTHALMOLOGYCLINICAL AND EXPERIMENTAL VISION AND EYE RESEARCH (list date 1/9/18)CLINICAL OPHTHALMOLOGY (list date 9/4/14)DELHI JOURNAL OF OPHTHALMOLOGY (list date 7/14/15)DELTA JOURNAL OF OPHTHALMOLOGY (list date 5/29/18)DIGITAL JOURNAL OF OPHTHALMOLOGYEC OPHTHALMOLOGY (list date 2/18/16)EGYPTIAN RETINA JOURNAL (list date 5/29/18)EUROPEAN MEDICAL JOURNAL - OPHTHALMOLOGY (list date 7/30/14)EXPERT REVIEW OF OPHTHALMOLOGY (list date 12/13/11)EYE AND BRAIN (list date 9/4/14)EYE REPORTS (list date 10/30/14)HONG KONG JOURNAL OF OPHTHALMOLOGYINDIAN JOURNAL OF CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY INDIAN JOURNAL OF OPHTHALMOLOGYINTERNATIONAL JOURNAL OF GLAUCOMA (list date 7/16/18)INTERNATIONAL JOURNAL OF OPEN ACCESS OPHTHALMOLOGY INTERNATIONAL JOURNAL OF OPHTHALMOLOGY & EYE SCIENCE (IJOES)INTERNATIONAL JOURNAL OF OPHTHALMOLOGY & VISION RESEARCH
INTERNATIONAL JOURNAL OF OPHTHALMOLOGY AND CLINICAL RESEARCH INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE (list date 7/12/10)JOURNAL KLINISCHE MONATSBLÄTTER FÜR AUGENHEILKUNDEJOURNAL OF CLINICAL & ACADEMIC OPHTHALMOLOGY (list date 10/21/15)JOURNAL OF CLINICAL OPHTHALMOLOGY AND RESEARCH (list date 5/31/18)JOURNAL OF CLINICAL RESEARCH AND OPHTHALMOLOGY (list date 6/5/18)JOURNAL OF GLAUCOMA (list date 6/24/14)
ADVANCES IN OPHTHALMOLOGY & VISUAL SYSTEM (list date 6/19/17)AL-BASAR INTERNATIONAL JOURNAL OF OPHTHALMOLOGY (list date 5/29/18)AMERICAN JOURNAL OF OPHTHALMOLOGY-GLAUCOMA (list date 2/15/18)APERITO JOURNAL OF OPHTHALMOLOGY (list date 10/25/18)ASIAN JOURNAL OF OPHTHALMOLOGYAUSTRALIAN AND NEW ZEALAND JOURNAL OF OPHTHALMOLOGYAUSTRALIAN JOURNAL OF OPHTHALMOLOGYBRITISH JOURNAL OF OPHTHALMOLOGYCANADIAN JOURNAL OF OPHTHALMOLOGYCASE REPORTS IN OPHTHALMOLOGY (list date 3/6/17)CHINESE JOURNAL OF OPHTHALMOLOGYCLINICAL AND EXPERIMENTAL VISION AND EYE RESEARCH (list date 1/9/18)CLINICAL OPHTHALMOLOGY (list date 9/4/14)DELHI JOURNAL OF OPHTHALMOLOGY (list date 7/14/15)DELTA JOURNAL OF OPHTHALMOLOGY (list date 5/29/18)DIGITAL JOURNAL OF OPHTHALMOLOGYEC OPHTHALMOLOGY (list date 2/18/16)EGYPTIAN RETINA JOURNAL (list date 5/29/18)EUROPEAN MEDICAL JOURNAL - OPHTHALMOLOGY (list date 7/30/14)EXPERT REVIEW OF OPHTHALMOLOGY (list date 12/13/11)EYE AND BRAIN (list date 9/4/14)EYE REPORTS (list date 10/30/14)HONG KONG JOURNAL OF OPHTHALMOLOGYINDIAN JOURNAL OF CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY (list date 3/20/15)INDIAN JOURNAL OF OPHTHALMOLOGYINTERNATIONAL JOURNAL OF GLAUCOMA (list date 7/16/18)
ADVANCES IN OPHTHALMOLOGY & VISUAL SYSTEM (list date 6/19/17)AL-BASAR INTERNATIONAL JOURNAL OF OPHTHALMOLOGY (list date 5/29/18)AMERICAN JOURNAL OF OPHTHALMOLOGY-GLAUCOMA (list date 2/15/18)APERITO JOURNAL OF OPHTHALMOLOGY (list date 10/25/18)ASIAN JOURNAL OF OPHTHALMOLOGYAUSTRALIAN AND NEW ZEALAND JOURNAL OF OPHTHALMOLOGYAUSTRALIAN JOURNAL OF OPHTHALMOLOGYBRITISH JOURNAL OF OPHTHALMOLOGYCANADIAN JOURNAL OF OPHTHALMOLOGYCASE REPORTS IN OPHTHALMOLOGY (list date 3/6/17)CHINESE JOURNAL OF OPHTHALMOLOGYCLINICAL AND EXPERIMENTAL VISION AND EYE RESEARCH (list date 1/9/18)CLINICAL OPHTHALMOLOGY (list date 9/4/14)DELHI JOURNAL OF OPHTHALMOLOGY (list date 7/14/15)DELTA JOURNAL OF OPHTHALMOLOGY (list date 5/29/18)DIGITAL JOURNAL OF OPHTHALMOLOGYEC OPHTHALMOLOGY (list date 2/18/16)EGYPTIAN RETINA JOURNAL (list date 5/29/18)EUROPEAN MEDICAL JOURNAL - OPHTHALMOLOGY (list date 7/30/14)EXPERT REVIEW OF OPHTHALMOLOGY (list date 12/13/11)EYE AND BRAIN (list date 9/4/14)EYE REPORTS (list date 10/30/14)HONG KONG JOURNAL OF OPHTHALMOLOGYINDIAN JOURNAL OF CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY (list date 3/20/15)INDIAN JOURNAL OF OPHTHALMOLOGYINTERNATIONAL JOURNAL OF GLAUCOMA (list date 7/16/18)INTERNATIONAL JOURNAL OF OPEN ACCESS OPHTHALMOLOGY (list date 11/22/17)INTERNATIONAL JOURNAL OF OPHTHALMOLOGY & EYE SCIENCE (IJOES) (list date 10/1/15)INTERNATIONAL JOURNAL OF OPHTHALMOLOGY & VISION RESEARCH (list date 1/30/18)
INTERNATIONAL JOURNAL OF OPHTHALMOLOGY AND CLINICAL RESEARCH (list date 11/21/17)INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE (list date 7/12/10)JOURNAL KLINISCHE MONATSBLÄTTER FÜR AUGENHEILKUNDEJOURNAL OF CLINICAL & ACADEMIC OPHTHALMOLOGY (list date 10/21/15)JOURNAL OF CLINICAL OPHTHALMOLOGY AND RESEARCH (list date 5/31/18)JOURNAL OF CLINICAL RESEARCH AND OPHTHALMOLOGY (list date 6/5/18)JOURNAL OF GLAUCOMA (list date 6/24/14)JOURNAL OF OPHTHALMIC AND VISION RESEARCH (list date 5/31/18)JOURNAL OF OPHTHALMIC DISEASES (list date 1/20/16)JOURNAL OF OPHTHALMIC SCIENCE (list date 3/8/16)JOURNAL OF OPHTHALMOLOGY & EYE CARE (list date 9/14/18)JOURNAL OF PEDIATRIC OPHTHALMOLOGY & STRABISMUS (list date 3/30/10)JOURNAL OF REFRACTIVE SURGERY (list date 3/30/10)JOURNAL OF THE EGYPTIAN OPHTHALMOLOGICAL SOCIETY (list date 10/16/13)JOURNAL OF VISION (list date 7/12/10)KARGER KOMPASS OPHTHALMOLOGIE (list date 3/6/17)KERALA JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)
EXPERT REVIEW OF OPHTHALMOLOGY (list date 12/13/11)EYE AND BRAIN (list date 9/4/14)EYE REPORTS (list date 10/30/14)HONG KONG JOURNAL OF OPHTHALMOLOGYINDIAN JOURNAL OF CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY (list date 3/20/15)INDIAN JOURNAL OF OPHTHALMOLOGYINTERNATIONAL JOURNAL OF GLAUCOMA (list date 7/16/18)INTERNATIONAL JOURNAL OF OPEN ACCESS OPHTHALMOLOGY (list date 11/22/17)INTERNATIONAL JOURNAL OF OPHTHALMOLOGY & EYE SCIENCE (IJOES) (list date 10/1/15)INTERNATIONAL JOURNAL OF OPHTHALMOLOGY & VISION RESEARCH (list date 1/30/18)
INTERNATIONAL JOURNAL OF OPHTHALMOLOGY AND CLINICAL RESEARCH (list date 11/21/17)INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE (list date 7/12/10)JOURNAL KLINISCHE MONATSBLÄTTER FÜR AUGENHEILKUNDEJOURNAL OF CLINICAL & ACADEMIC OPHTHALMOLOGY (list date 10/21/15)JOURNAL OF CLINICAL OPHTHALMOLOGY AND RESEARCH (list date 5/31/18)JOURNAL OF CLINICAL RESEARCH AND OPHTHALMOLOGY (list date 6/5/18)JOURNAL OF GLAUCOMA (list date 6/24/14)JOURNAL OF OPHTHALMIC AND VISION RESEARCH (list date 5/31/18)JOURNAL OF OPHTHALMIC DISEASES (list date 1/20/16)JOURNAL OF OPHTHALMIC SCIENCE (list date 3/8/16)JOURNAL OF OPHTHALMOLOGY & EYE CARE (list date 9/14/18)JOURNAL OF PEDIATRIC OPHTHALMOLOGY & STRABISMUS (list date 3/30/10)JOURNAL OF REFRACTIVE SURGERY (list date 3/30/10)JOURNAL OF THE EGYPTIAN OPHTHALMOLOGICAL SOCIETY (list date 10/16/13)JOURNAL OF VISION (list date 7/12/10)KARGER KOMPASS OPHTHALMOLOGIE (list date 3/6/17)KERALA JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)KLINISCHE MONATSBLATTER FUR AUGENHEILKUNDEMIDDLE EAST AFRICAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)NEPALESE JOURNAL OF OPHTHALMOLOGY (list date 4/5/10)NEW FRONTIERS IN OPHTHALMOLOGY (NFO) (list date 3/31/17)NEW ZEALAND JOURNAL OF OPHTHALMOLOGYNIGERIAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)OMAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)OPEN ACCESS JOURNAL OF OPHTHALMOLOGY (OAJO) (list date 10/9/18)OPHTHALMIC RESEARCH (list date 3/6/17)OPHTHALMIC SURGERY, LASERS AND IMAGING (list date 3/30/10)OPHTHALMOLOGICA (list date 3/6/17)OPHTHALMOLOGY (list date 9/26/17)OPHTHALMOLOGY AND ALLIED SCIENCES (list date 7/26/16)OPHTHALMOLOGY AND EYE DISEASES (list date 2/1/12)OPHTHALMOLOGY AND VISION SCIENCE (list date 2/12/18)OPHTHALMOLOGY RETINA (list date 9/26/17)RMJ CLINICAL OPHTHALMOLOGY (list date 6/9/15)RUSSIAN OPHTHALMOLOGICAL JOURNAL (list date 11/28/17)SAUDI JOURNAL OF OPHTHALMOLOGY (list date 1/25/10)SUDANESE JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)TAIWAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)THE EGYPTIAN JOURNAL OF CATARACT AND REFRACTIVE SURGERY (list date 5/31/18)THE OPHTHALMOLOGY - OPEN JOURNAL (list date 10/16/17)TNOA JOURNAL OF OPHTHALMIC SCIENCE AND RESEARCH (list date 5/31/18)TURKISH JOURNAL OF OPHTHALMOLOGY (list date 5/3/16)US OPHTHALMIC REVIEW (list date 1/9/18)WORLD JOURNAL OF OPHTHALMOLOGY (list date 5/20/14)
ADVANCES IN OPHTHALMOLOGY & VISUAL SYSTEM (list date 6/19/17)AL-BASAR INTERNATIONAL JOURNAL OF OPHTHALMOLOGY (list date 5/29/18)AMERICAN JOURNAL OF OPHTHALMOLOGY-GLAUCOMA (list date 2/15/18)APERITO JOURNAL OF OPHTHALMOLOGY (list date 10/25/18)ASIAN JOURNAL OF OPHTHALMOLOGYAUSTRALIAN AND NEW ZEALAND JOURNAL OF OPHTHALMOLOGYAUSTRALIAN JOURNAL OF OPHTHALMOLOGYBRITISH JOURNAL OF OPHTHALMOLOGYCANADIAN JOURNAL OF OPHTHALMOLOGYCASE REPORTS IN OPHTHALMOLOGY (list date 3/6/17)CHINESE JOURNAL OF OPHTHALMOLOGYCLINICAL AND EXPERIMENTAL VISION AND EYE RESEARCH (list date 1/9/18)CLINICAL OPHTHALMOLOGY (list date 9/4/14)DELHI JOURNAL OF OPHTHALMOLOGY (list date 7/14/15)DELTA JOURNAL OF OPHTHALMOLOGY (list date 5/29/18)DIGITAL JOURNAL OF OPHTHALMOLOGYEC OPHTHALMOLOGY (list date 2/18/16)EGYPTIAN RETINA JOURNAL (list date 5/29/18)EUROPEAN MEDICAL JOURNAL - OPHTHALMOLOGY (list date 7/30/14)EXPERT REVIEW OF OPHTHALMOLOGY (list date 12/13/11)EYE AND BRAIN (list date 9/4/14)EYE REPORTS (list date 10/30/14)HONG KONG JOURNAL OF OPHTHALMOLOGYINDIAN JOURNAL OF CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY INDIAN JOURNAL OF OPHTHALMOLOGYINTERNATIONAL JOURNAL OF GLAUCOMA (list date 7/16/18)INTERNATIONAL JOURNAL OF OPEN ACCESS OPHTHALMOLOGYINTERNATIONAL JOURNAL OF OPHTHALMOLOGY & EYE SCIENCE (IJOES) INTERNATIONAL JOURNAL OF OPHTHALMOLOGY & VISION RESEARCH
INTERNATIONAL JOURNAL OF OPHTHALMOLOGY AND CLINICAL RESEARCHINVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE (list date 7/12/10)JOURNAL KLINISCHE MONATSBLÄTTER FÜR AUGENHEILKUNDEJOURNAL OF CLINICAL & ACADEMIC OPHTHALMOLOGY (list date 10/21/15)JOURNAL OF CLINICAL OPHTHALMOLOGY AND RESEARCH (list date 5/31/18)JOURNAL OF CLINICAL RESEARCH AND OPHTHALMOLOGY (list date 6/5/18)JOURNAL OF GLAUCOMA (list date 6/24/14)JOURNAL OF OPHTHALMIC AND VISION RESEARCH (list date 5/31/18)JOURNAL OF OPHTHALMIC DISEASES (list date 1/20/16)JOURNAL OF OPHTHALMIC SCIENCE (list date 3/8/16)JOURNAL OF OPHTHALMOLOGY & EYE CARE (list date 9/14/18)JOURNAL OF PEDIATRIC OPHTHALMOLOGY & STRABISMUS (list date 3/30/10)JOURNAL OF REFRACTIVE SURGERY (list date 3/30/10)JOURNAL OF THE EGYPTIAN OPHTHALMOLOGICAL SOCIETY (list date 10/16/13)JOURNAL OF VISION (list date 7/12/10)KARGER KOMPASS OPHTHALMOLOGIE (list date 3/6/17)KERALA JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)KLINISCHE MONATSBLATTER FUR AUGENHEILKUNDEMIDDLE EAST AFRICAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)NEPALESE JOURNAL OF OPHTHALMOLOGY (list date 4/5/10)NEW FRONTIERS IN OPHTHALMOLOGY (NFO) (list date 3/31/17)NEW ZEALAND JOURNAL OF OPHTHALMOLOGYNIGERIAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)OMAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)OPEN ACCESS JOURNAL OF OPHTHALMOLOGY (OAJO) (list date 10/9/18)OPHTHALMIC RESEARCH (list date 3/6/17)OPHTHALMIC SURGERY, LASERS AND IMAGING (list date 3/30/10)OPHTHALMOLOGICA (list date 3/6/17)OPHTHALMOLOGY (list date 9/26/17)OPHTHALMOLOGY AND ALLIED SCIENCES (list date 7/26/16)OPHTHALMOLOGY AND EYE DISEASES (list date 2/1/12)OPHTHALMOLOGY AND VISION SCIENCE (list date 2/12/18)OPHTHALMOLOGY RETINA (list date 9/26/17)RMJ CLINICAL OPHTHALMOLOGY (list date 6/9/15)RUSSIAN OPHTHALMOLOGICAL JOURNAL (list date 11/28/17)SAUDI JOURNAL OF OPHTHALMOLOGY (list date 1/25/10)SUDANESE JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)TAIWAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)THE EGYPTIAN JOURNAL OF CATARACT AND REFRACTIVE SURGERYTHE OPHTHALMOLOGY - OPEN JOURNAL (list date 10/16/17)TNOA JOURNAL OF OPHTHALMIC SCIENCE AND RESEARCH (list date 5/31/18)TURKISH JOURNAL OF OPHTHALMOLOGY (list date 5/3/16)US OPHTHALMIC REVIEW (list date 1/9/18)WORLD JOURNAL OF OPHTHALMOLOGY (list date 5/20/14)
CASE REPORTS IN OPHTHALMOLOGY (list date 3/6/17)CHINESE JOURNAL OF OPHTHALMOLOGYCLINICAL AND EXPERIMENTAL VISION AND EYE RESEARCH (list date 1/9/18)CLINICAL OPHTHALMOLOGY (list date 9/4/14)DELHI JOURNAL OF OPHTHALMOLOGY (list date 7/14/15)DELTA JOURNAL OF OPHTHALMOLOGY (list date 5/29/18)DIGITAL JOURNAL OF OPHTHALMOLOGYEC OPHTHALMOLOGY (list date 2/18/16)EGYPTIAN RETINA JOURNAL (list date 5/29/18)EUROPEAN MEDICAL JOURNAL - OPHTHALMOLOGY (list date 7/30/14)EXPERT REVIEW OF OPHTHALMOLOGY (list date 12/13/11)EYE AND BRAIN (list date 9/4/14)EYE REPORTS (list date 10/30/14)HONG KONG JOURNAL OF OPHTHALMOLOGYINDIAN JOURNAL OF CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY INDIAN JOURNAL OF OPHTHALMOLOGYINTERNATIONAL JOURNAL OF GLAUCOMAINTERNATIONAL JOURNAL OF OPEN ACCESS OPHTHALMOLOGYINTERNATIONAL JOURNAL OF OPHTHALMOLOGY & EYE SCIENCE (IJOES) INTERNATIONAL JOURNAL OF OPHTHALMOLOGY & VISION RESEARCH INTERNATIONAL JOURNAL OF OPHTHALMOLOGY AND CLINICAL RESEARCHINVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE (list date 7/12/10)JOURNAL KLINISCHE MONATSBLÄTTER FÜR AUGENHEILKUNDEJOURNAL OF CLINICAL & ACADEMIC OPHTHALMOLOGY (list date 10/21/15)JOURNAL OF CLINICAL OPHTHALMOLOGY AND RESEARCH (list date 5/31/18)JOURNAL OF CLINICAL RESEARCH AND OPHTHALMOLOGY (list date 6/5/18)JOURNAL OF GLAUCOMA (list date 6/24/14)JOURNAL OF OPHTHALMIC AND VISION RESEARCH (list date 5/31/18)JOURNAL OF OPHTHALMIC DISEASES (list date 1/20/16)JOURNAL OF OPHTHALMIC SCIENCE (list date 3/8/16)JOURNAL OF OPHTHALMOLOGY & EYE CARE (list date 9/14/18)JOURNAL OF PEDIATRIC OPHTHALMOLOGY & STRABISMUS (list date 3/30/10)JOURNAL OF REFRACTIVE SURGERY (list date 3/30/10)JOURNAL OF THE EGYPTIAN OPHTHALMOLOGICAL SOCIETY (list date 10/16/13)JOURNAL OF VISION (list date 7/12/10)KARGER KOMPASS OPHTHALMOLOGIE (list date 3/6/17)KERALA JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)KLINISCHE MONATSBLATTER FUR AUGENHEILKUNDEMIDDLE EAST AFRICAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)NEPALESE JOURNAL OF OPHTHALMOLOGY (list date 4/5/10)NEW FRONTIERS IN OPHTHALMOLOGY (NFO) (list date 3/31/17)NEW ZEALAND JOURNAL OF OPHTHALMOLOGYNIGERIAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)OMAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)OPEN ACCESS JOURNAL OF OPHTHALMOLOGY (OAJO) (list date 10/9/18)OPHTHALMIC RESEARCH (list date 3/6/17)OPHTHALMIC SURGERY, LASERS AND IMAGING (list date 3/30/10)OPHTHALMOLOGICA (list date 3/6/17)OPHTHALMOLOGY (list date 9/26/17)OPHTHALMOLOGY AND ALLIED SCIENCES (list date 7/26/16)OPHTHALMOLOGY AND EYE DISEASES (list date 2/1/12)OPHTHALMOLOGY AND VISION SCIENCE (list date 2/12/18)OPHTHALMOLOGY RETINA (list date 9/26/17)RMJ CLINICAL OPHTHALMOLOGY (list date 6/9/15)RUSSIAN OPHTHALMOLOGICAL JOURNAL (list date 11/28/17)SAUDI JOURNAL OF OPHTHALMOLOGY (list date 1/25/10)SUDANESE JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)TAIWAN JOURNAL OF OPHTHALMOLOGY (list date 5/31/18)THE EGYPTIAN JOURNAL OF CATARACT AND REFRACTIVE SURGERY (list date 5/31/18)THE OPHTHALMOLOGY - OPEN JOURNAL (list date 10/16/17)TNOA JOURNAL OF OPHTHALMIC SCIENCE AND RESEARCH (list date 5/31/18)TURKISH JOURNAL OF OPHTHALMOLOGY (list date 5/3/16)US OPHTHALMIC REVIEW (list date 1/9/18)WORLD JOURNAL OF OPHTHALMOLOGY (list date 5/20/14)
Guidelines - ICJME
ICMJE
• Authorship criteria• Conflicts of Interest• Trial registration, • Timely publication
(≤12 months of completion)
“Briefly, the ICMJE requires, and recommends that all medical journal
editors require, registration of clinical trials in a public trials
registry at or before the time of first patient enrollment as a condition of
consideration for publication.”
4753 journals adhere (to date)
JRS - yes
JCRS - no
Guidelines
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Guidelines: GPP – Good Publication Practice
GPP
Authorship criteria, transparency of
results +Follow ICMJE!
Guidelines
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For RCTs – but basic principles holdTo enforce » Transparency» True randomization» Sample size generation» No improper LTFU – higher the
rate, the greater the concern» Follow the patients!
CONSORT
Guidelines
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Vigorously debated when presented orally at previous CXL Experts’ meetingsClaim:
The hot manuscript right now
“Epithelium-on CXL using this new protocol halted the progression of keratoconus and ectasia after LASIK. It was safer and provided more rapid visual recovery than CXL with epithelial removal, allowing routine bilateral, simultaneous treatment.”Epi-on manuscript
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Epi-off vs Epi-on (currently)
Epi-on
Epi-off =
=
Epi-on manuscript
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• Prospective observational study• Single-arm, open-label
Study design
+
CT ≥300 µm
CXLUSA Treatment
KC or FFKCn=512
PLE n=80
UDVACDVA
SnellenRefractionPentacam
iTrace1
day1
week1
month3
months6
months12
months24
months
UDVACDVA
Snellen
RefractionPentacam
iTrace
UDVACDVA
Snellen
RefractionPentacam
iTrace
UDVACDVA
Snellen
RefractionPentacam
iTrace
UDVACDVA
Snellen
RefractionPentacam
iTrace
UDVACDVA
Snellen
RefractionPentacam
iTrace
UDVACDVA
Snellen
RefractionPentacam
iTrace
UDVACDVA
Snellen
RefractionPentacam
iTrace
END
N=592
Trial Design
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Patients
Keratoconus or
forme fruste keratoconus
n=512
Post-LASIK ectasia n=80
Unilateraln=363(61%)
N=592
Bilateral (sequential) treatment
n=134 (23%)
Bilateral simultaneous
n=95 (16%)
N=592
Total bilateral n=229 (39%)
300
400
500
600
*
*
Base
line
corn
eal t
hick
ness
(µ
m)
651 µm
302 µm
474.8 ± 54.9 µm(mean ± SD)Median: 474.0 µm
!
Patient Enrolment
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CXLUSA Treatment protocol
Instill proparacaine drops
“Gentle brushing” with proparacaine-infused sponge for 15 seconds
(pH=4.64)
Protocol
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CXLUSA Treatment protocol
1 drop CXLUSA riboflavin q2 minutes onto a different, bespoke sponge for 15–20 minutes
Estimate stromal riboflavin concentration at slit lamp with white + cobalt blue light; compare against reference images
Adequate concentration (~15 µg/gm)?
No
Yes
Instill proparacaine drops
“Gentle brushing” with proparacaine-infused sponge for 15 seconds
(pH=4.64)
Protocol
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1 drop CXLUSA riboflavin q2 minutes onto a different, bespoke sponge for 15–20 minutes
Estimate stromal riboflavin concentration at slit lamp with white + cobalt blue light; compare against reference images
Adequate concentration (~15 µg/gm)?
No
Yes
BSS rinse
365 nm UV at 4 mW/cm2, 30 mins,cycled on/off with a proprietary light
“The total energy delivered by this system (3.6 J/cm2)”
No drops during illumination
Instill proparacaine drops
“Gentle brushing” with proparacaine-infused sponge for 15 seconds
(pH=4.64)
CXLUSA Treatment protocol
Protocol
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No dextran
Specific pH
Specific concentrationSpecific osmolarity
NaI “as an excipient”*
Their proprietary riboflavin, as described:
1 drop CXLUSA riboflavin q2 minutes onto a different, bespoke sponge for 15–20 minutes
Estimate stromal riboflavin concentration at slit lamp with white + cobalt blue light; compare against reference images
Adequate concentration (~15 µg/gm)?
No
Yes
BSS rinse
365 nm UV at 4 mW/cm2, 30 mins,cycled on/off with a proprietary light
“The total energy delivered by this system (3.6 J/cm2)”
No drops during illumination
Instill proparacaine drops
“Gentle brushing” with proparacaine-infused sponge for 15 seconds
(pH=4.64)
CXLUSA Treatment protocol
*”Riboflavin penetration enhancer”
Protocol
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• UDVA, CDVA, Kmax• Total higher-order aberrations (HOAs) and coma• Progression defined as an increase of >1 D Kmax and >1 line CDVA loss in
same eye
Methods: Outcome measures
“In healthy eyes the repeatability limit, of the maximal corneal curvature Kmax (with the Pentacam HR®) were reported to be 0.8 Dioptres (D), however, we found repeatability limits in keratoconic eyes to be 1.97 D [1, 2]. This result means that the current main criteria for progression detection and CXL is inadequate (i.e. a change of 1 D in Kmax after one year of follow-up) [1, 3].
General question: is > +1 D Kmax + 1 line CDVA loss a good enough endpoint assessment?
Outcome measures
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CXLUSA (JCRS 2018) trial dates
2013 2014 2015 2016 2017 2018
Oct 17,2013
May 16,2016
Feb 20,2017
2 years, 6 months, 29 days9 months, 4
days
Jan 28, 2018
11 months, 8 days
1
3
2
4
0
Max
& M
in P
artic
ipat
ion
+ fo
llow
-up
(yea
rs)
“The study comprised 512 eyes of 308 patients with keratoconus or forme fruste keratoconus and 80 eyes of 55 patients with ectasia after LASIK, who underwent epi-on CXL between October 17, 2013 and May 16, 2016, and were followed through February 20, 2017.”
• 512 eyes• 308 patients
COMPLETION TO
SUBMISSION
<12 MONTHS !Trial Dates
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‘N’s throughout the study
KC, keratoconus; PLE, post-LASIK ectasia
Age ≤18 y0
100
200
300
400
500
600
229 bilateral
95 simultaneous
of which
512 KC
+80 PLE
592N
UDVACDVAKmax
133N83N
Total HOAComa
UDVACDVAKmax
341N
217NTotal HOA
Coma
UDVACDVAKmax
26N19NTotal HOA
Coma
UDVACDVAKmax
12N9NTotal HOA
Coma
Age ≤18 y
Consistent cohort (n=115N)
EnrolledUDVACDVA
367NTotal HOA
Coma
308 KC
+59 PLE
592NKmax
588N
Eyes
Months0 2412
Dropout/ LTFU
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And expressed as Kaplan-Meier curvesKC, keratoconus; PLE, post-LASIK ectasia
0
100
200
300
400
500
600UDVACDVAKmax
Total HOAComa
Consistent cohort
Eyes
Months0 2412
Dropout/ LTFU
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Short follow-ups?
1
3
2
4
0
Max
& M
in P
artic
ipat
ion
+ fo
llow
-up
(yea
rs)
Why are these patients in the trial if
none of the outcomes assessments are at
1 years?
Cannot be part of the “consistent cohort”.Dropout/ LTFU
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• 308 patients (592 eyes)
• October 17 2013 – Feb 20, 2017
• Keratoconus/post-LASIK ectasia
Wait! What about clinicaltrials.govregistration?
Trial Registration
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NCT Number Title Status
Study Result
sConditions Interventions Outcome Measures
Sponsor/ Collaborat
orsAge Phase
sEnroll-ment
Funded Bys Study Type Study Designs Other
IDsStart Date
Primary Completion Date
Completion Date
First Poste
d
Results First Posted
Last Updat
e Posted
NCT01956474
CXL-04 A Study of Collagen Crosslinking With Ultraviolet-A in Asymmetric Corneas
Terminated No Keratoconu
s
Other: Theralight crosslinking and Riboflavin
Change in Best Spectacle Corrected Visual Acuity (BSCVA)|Change in Uncorrected Visual Acuity (UCVA)|Change in Corneal topography|Change in Manifest Refraction|Change in Keratometry on topography and Pentacam|Change in Wavefront Refraction and aberrations
Cxlusa≥8
Years to older adult
Phase 2 1324 Industry Intervention
al
Intervention Model: Single Group Assignment | Masking: None (Open Label)|Primary Purpose: Treatment
CXL-04 Jan.13 February 3, 2017
February 3, 2017
October 8, 2013
nullOctober 12, 2018
NCT03029104
COLLAGEN CROSS-LINKING WITH ULTRAVIOLET-A IN ASYMMETRIC CORNEAS
Recruiting NoKeratoconus Corneal Diseases
Combination Product: CXLO Corneal Strengthening Solution and UVA Illumination Device
Corrected Distance Visual Acuity (CDVA)|Uncorrected distance visual acuity (UCVA)|KMax
Cxlusa≥8
Years to older adult
Phase 2 3000 Industry Intervention
al
Allocation: Randomized| Intervention Model: Parallel Assignment |Masking: Single (Outcomes Assessor) |Primary Purpose: Treatment
CXL-005Decemb
er 21, 2016
January 1, 2020
January 1, 2020
January 24, 2017
nullOctober 12, 2018
NCT01739673
Ultraviolet-A and Riboflavin Treatment for Infectious Keratitis
Completed No Infectious
KeratitisOther: Ultraviolet-A and riboflavin
Resolution of Signs and Symptoms of Infectious Keratitis Cxlusa
≥18 Years to
older adult
N/A 13 Industry Interventional
Intervention Model: Single Group Assignment|Masking: None (Open Label)|Primary Purpose: Treatment
iCXL Aug.11 Jul.14 Jul.14
December
3, 2012
null
September
26, 2018
NCT01726283
Combined CXL//UV and PRK or LASIK in Forme Fruste Keratoconus or Eyes With Potential Risk of Ectasia
Completed No
Fruste Keratoconu
s Risk of Ectasia
Device: Corneal Cross-Linking|Drug: Riboflavin
Postoperative Best-Corrected Visual Acuity|Residual Refractive error at the 1, 3 and 6 month visits
Cxlusa≥18
Years to older adult
22 Industry Observational
Observational Model: Case-Only|Time Perspective: Prospective
CXL-RSR Oct.11 Jul.14 Jul.14
November
14, 2012
nullAugust
24, 2015
NCT01189864
Cross-linking of Corneal Collagen (CXL) With Ultraviolet-A in Asymmetric Corneas
Terminated No
Keratoconus Ectasia
Degeneration
Drug: Ciprofloxicin or Vigamox or other.|Drug: Nonsteroidal (Acular, Acuvail, Voltaren Xibrom, etc)|Drug: Steroid (FML, Pred Forte, Flarex, etc.)
Increase the biomechanical and biochemical stability of the cornea by inducing additional cross-links within|Increase the biomechanical and biochemical stability of the cornea between collagen fibers using UVA light and the photo-mediator riboflavin
Cxlusa≥12
Years to older adult
3493 Industry Observational
Observational Model: Cohort|Time Perspective: Prospective
CXL (12 & older)
February 1, 2010
February 3, 2017
February 3, 2017
August 27, 2010
nullOctober 12, 2018
NCT01097447
Collagen Crosslinking With Ultraviolet-A in Asymmetric Corneas (2)
Terminated No
Keratoconus Ectasia
Degeneration
Increase the biomechanical and biochemical stability of the cornea by inducing additional cross-links within|increase the biomechanical and biochemical stability of the cornea between collagen fibers using UVA light and the photo- mediator riboflavin
Cxlusa≥8
Years to older adult
2619 Industry Observational
Observational Model: Cohort|Time Perspective: Prospective
CXL (2)Decemb
er 1, 2009
April 30, 2017
April 30, 2017
April 1,
2010null
October 11, 2018
NCT01024322
Collagen Crosslinking With Ultraviolet-A in Asymmetric Corneas
Terminated No
Keratoconus Ectasia
Degeneration
Drug: Ciprofloxicine or Vigamox or other.|Drug: Nonsteroidal (Acular, Voltaren Xibrom, etc)|Drug: Steroid (FML, Pred Forte, Flarex, etc.)
Increase the biomechanical and biochemical stability of the cornea by inducing additional cross-links within|increase the biomechanical and biochemical stability of the cornea between collagen fibers using UVA light and the photo- mediator riboflavin
Cxlusa≥8
Years to older adult
1189 Industry Observational
Observational Model: Cohort|Time Perspective: Prospective
CXL October 1, 2009
February 3, 2017
February 3, 2017
December
2, 2009
nullOctober 11, 2018
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NCT Number Title Status
Study Results
Conditions Interventions Outcome Measures
Sponsor/ Collaborators
Age Phases
Enroll-ment
Funded Bys Study Type Study Designs Other
IDsStart Date
Primary Completion Date
Completion Date
First Posted
Results First Posted
Last Update Posted
NCT01956474
CXL-04 A Study of Collagen Crosslinking With Ultraviolet-A in Asymmetric Corneas
Terminated No Keratocon
us
Other: Theralightcrosslinking and Riboflavin
Change in Best Spectacle Corrected Visual Acuity (BSCVA)|Change in Uncorrected Visual Acuity (UCVA)|Change in Corneal topography|Change in Manifest Refraction|Change in Keratometry on topography and Pentacam|Change in Wavefront Refraction and aberrations
Cxlusa≥8 Years to older adult
Phase 2 1324Industry Intervention
al
Intervention Model: Single Group Assignment|Masking: None (Open Label)|Primary Purpose: Treatment
CXL-04 Jan.13February 3, 2017
February 3, 2017
October 8, 2013
nullOctober 12, 2018
NCT03029104
COLLAGEN CROSS-LINKING WITH ULTRAVIOLET-A IN ASYMMETRIC CORNEAS
RecruitingNo
Keratoconus Corneal Diseases
Combination Product: CXLO Corneal Strengthening Solution and UVA Illumination Device
Corrected Distance Visual Acuity (CDVA)|Uncorrected distance visual acuity (UCVA)|KMax
Cxlusa≥8 Years to older adult
Phase 2 3000Industry Intervention
al
Allocation: Randomized| Intervention Model: Parallel Assignment |Masking: Single (Outcomes Assessor) |Primary Purpose: Treatment
CXL-005December 21, 2016
January 1, 2020
January 1, 2020
January 24, 2017
nullOctober 12, 2018
NCT01739673
Ultraviolet-A and Riboflavin Treatment for Infectious Keratitis
Completed No Infectious
KeratitisOther: Ultraviolet-A and riboflavin
Resolution of Signs and Symptoms of Infectious Keratitis Cxlusa
≥18 Years to older adult
N/A 13Industry Interventional
Intervention Model: Single Group Assignment|Masking: None (Open Label)|Primary Purpose: Treatment
iCXL Aug.11 Jul.14 Jul.14
December 3, 2012
null
September 26, 2018
NCT01726283
Combined CXL//UV and PRK or LASIK in Forme Fruste Keratoconus or Eyes With Potential Risk of Ectasia
Completed No
Fruste Keratoconus Risk of Ectasia
Device: Corneal Cross-Linking|Drug: Riboflavin
Postoperative Best-Corrected Visual Acuity|Residual Refractive error at the 1, 3 and 6 month visits
Cxlusa≥18 Years to older adult
22Industry Observational
Observational Model: Case-Only|Time Perspective: Prospective
CXL-RSR Oct.11 Jul.14 Jul.14
November 14, 2012
nullAugust 24, 2015
NCT01189864
Cross-linking of Corneal Collagen (CXL) With Ultraviolet-A in Asymmetric Corneas
Terminated No
Keratoconus Ectasia Degeneration
Drug: Ciprofloxicin or Vigamox or other.|Drug: Nonsteroidal (Acular, Acuvail, Voltaren Xibrom, etc)|Drug: Steroid (FML, Pred Forte, Flarex, etc.)
Increase the biomechanical and biochemical stability of the cornea by inducing additional cross-links within|Increase the biomechanical and biochemical stability of the cornea between collagen fibers using UVA light and the photo-mediator riboflavin
Cxlusa≥12Years to older adult
3493Industry Observational
Observational Model: Cohort|Time Perspective: Prospective
CXL (12 & older)
February 1, 2010
February 3, 2017
February 3, 2017
August 27, 2010
nullOctober 12, 2018
NCT01097447
Collagen Crosslinking With Ultraviolet-A in Asymmetric Corneas (2)
Terminated No
Keratoconus Ectasia Degener-ation
Increase the biomechanical and biochemical stability of the cornea by inducing additional cross-links within|increase the biomechanical and biochemical stability of the cornea between collagen fibers using UVA light and the photo- mediator riboflavin
Cxlusa≥8 Years to older adult
2619Industry Observational
Observational Model: Cohort|Time Perspective: Prospective
CXL (2)December 1, 2009
April 30, 2017
April 30, 2017
April 1, 2010
nullOctober 11, 2018
NCT01024322
Collagen Crosslinking With Ultraviolet-A in Asymmetric Corneas
Terminated No
Keratoconus Ectasia Degener-ation
Drug: Ciprofloxicine or Vigamox or other.|Drug: Nonsteroidal (Acular, Voltaren Xibrom, etc)|Drug: Steroid (FML, Pred Forte, Flarex, etc.)
Increase the biomechanical and biochemical stability of the cornea by inducing additional cross-links within|increase the biomechanical and biochemical stability of the cornea between collagen fibers using UVA light and the photo- mediator riboflavin
Cxlusa≥8 Years to older adult
1189Industry Observational
Observational Model: Cohort|Time Perspective: Prospective
CXL October 1, 2009
February 3, 2017
February 3, 2017
December 2, 2009
nullOctober 11, 2018
PACK-CXL
N=22
Starts 4 y too early
?? CLOSEST MATCH
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Does this mean the Kaplan-Meier curves…
0
100
200
300
400
500
600UDVACDVAKmax
Total HOAComa
Consistent cohort
Eyes
Months0 2412
Dropout/ LTFU
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Should it look like this?
0
100
200
300
400
500
600 UDVACDVAKmax
Total HOAComa
Consistent cohort
700
800
900
1000
1100
1200
1300
????
Or was this a completely different trial, unregistered on clinicaltrials.gov?
(not eyes)
Eyes
Months0 2412
Dropout/ LTFU
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Is it harsh to apply the same conditions to ~4 surgeons running a trial as is done to a pharmaceutical or device company?
But this is a physician-led study
“Epithelium-on CXL using this new protocol halted the progression of keratoconus and ectasia after LASIK. It was safer and provided more rapid visual recovery than CXL with epithelial removal, allowing routine bilateral, simultaneous treatment.”
?Claims
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“The 12-month and 24-month data analyses included only eyes with preoperative and 12-month or 24-month examinations, respectively.”
“Trends over time were studied using the consistent cohort (eyes with preoperative and 3-, 6-, 12-, and 24-month examinations) to avoid artifacts created by analyzing different eyes at different timepoints.”
Analyses
Pre-op
12months
24 months
UDVACDVA
SnellenRefractio
nPentaca
miTrace
UDVACDVA
SnellenRefractionPentacam
iTrace
UDVACDVA
SnellenRefractionPentacam
iTrace
Pre-op
UDVACDVA
SnellenRefractio
nPentaca
miTrace
AND
AND
OR
3months
6months
12months
24months
UDVACDVA
SnellenRefractionPentacam
iTrace
UDVACDVA
SnellenRefractionPentacam
iTrace
UDVACDVA
SnellenRefractionPentacam
iTrace
UDVACDVA
SnellenRefractionPentacam
iTrace
Pre-op
UDVACDVA
SnellenRefractio
nPentaca
miTrace
✓ ✓
✓ ✓
✓ ✓ ✓ ✓ ✓“Consistent cohort” – n=115
Is 115 patients the ”real” analysis population?Is this enough to investigate these claims with sufficient sensitivity?
Analysis
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Documentation of progression was not required for inclusion in this study;
however, progression was documented by medical history in 283 (92%) patients
and by progressive increase in myopic spherical equivalent (>1 D), cylinder (>1 D), or Kmax (>1 D) in the previous 2 years in 172 (56%) patients with keratoconus or forme fruste keratoconus.
“Documentation of progression was not required for inclusion in this study;”
Keratoconus or
forme fruste keratoconus
n=512 eyesPost-LASIK ectasia n=80 eyes
N=592 eyes
Hard to reconcilepatient and eye
numbersAnalysis
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“This does not match with out experience”– Seiler, Hafezi, Randleman, Vinciguerra.
“Only ~1 in every 3 patients that come to our clinics have progressive KC”
“If we cross-linked all of them, 2/3 were stable and would not have progressed!”
“How can you claim that the method works to halt keratoconus progression when you’re treating many patients who are stable?”
“Documentation of progression was not required for inclusion in this study;”
Person with stable keratoconus
Person with progressive keratoconus
Treat
Progression !Success!Weren’t progressing anyway!
"
Is this a fair criticism of the CXLUSA study?
Analysis
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Treating non-progressive patients skews the numbers
“Documentation of progression was not required for inclusion in this study;
however, progression was documented by medical history in 283 (92%) patients
and by progressive increase in myopic spherical equivalent (>1 D), cylinder (>1 D), or Kmax (>1 D) in the previous 2 years in 172 (56%) patients with keratoconus or forme fruste keratoconus.”
[later]
“At 24 months postoperatively, Kmax increased by more than 1 D in 11 (8.3%) of 133 eyes”
Person with stable keratoconus
Person with progressive keratoconus
Progressive KC Treatment failure
Progressive KC Treatment success
Stable KC treatment “success”
These people weren’t progressive!
Then logically, in a truly progressive cohort, the progression rate was
~15%– equivalent/similar to
all other epi-on protocols reported to date”
If 56% of the cohort may have been progressive
AND
8.3% progressed by common definition
THEN
Analysis
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Statistical methods
Entire section:
• “Significant” results are presented with very low patient numbers • Pediatric eyes:• 12 months, n=26 / n=19• 24 months, n=12 / n=9
Analysis
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AbstractIntro
FiguresDiscussion
ResultsMethods
Statistical methods
How does a busy person read a manuscript?
Most likely
Least likely
“Therefore, these error bars and plots should not be usedto assess the statistical significance of the true differences in these values between timepoints.”
Analysis
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Figure 1. Trend in visual acuities over 24 months after CXL. Columns show UDVA and CDVA obtained at 3, 6, 12, and 24 months after CXL for eyes in the consistent cohort (n = 115). Error bars represent standard error of the mean (CDVA = corrected distance visual acuity; CXL = corneal crosslinking; UDVA = uncorrected distance visual acuity).
Figure 2. Trend in Kmax over 24 months after CXL. Columns show Kmax measured at 3, 6, 12, and 24 months after CXL for eyes in the consistent cohort (n = 115). Error bars represent standard error of the mean (CXL = corneal crosslinking; Kmax = maximum keratometry).
Figure 3. Trend in pediatric visual acuities over 24 months after CXL. Columns show UDVA and CDVA measured at 3, 6, 12, and 24 months after CXL for eyes in the consistent cohort (n=11). Error bars represent standard error of the mean (CDVA = corrected distance visual acuity; CXL = corneal crosslinking; UDVA = uncorrected distance visual acuity).
Figure 4. Trend in pediatric Kmax over 24 months after CXL. Columns show Kmax obtained at 3, 6, 12, and 24 months after CXL for eyes in the consistent cohort (n=11). Error bars represent standard error of the mean (CXL = corneal crosslinking; Kmax = maximum keratometry).
Figure 5. Eyes with more than 1 D change in Kmax 12 and 24 months after CXL. Columns show the number of eyes with an increase or decrease in Kmax at 12 and 24 months after CXL (CXL = corneal crosslinking; Kmax = maximum keratometry).
Figure 6. Corrected distance visual acuity in eyes with a more than 1 D increase in maximum keratometry 12 months after corneal crosslinking. Columns show the number of eyes with a change in CDVA as shown on the horizontal axis (n = 24) (CDVA = corrected distance visual acuity).
Figure 7. Corrected distance visual acuity in eyes with a more than 1 D increase in maximum keratometry 24 months after corneal crosslinking. Columns show the number of eyes with a change in CDVA as shown on the horizontal axis (n = 11) (CDVA = corrected distance visual acuity).
Figures
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Figure 1. Trend in visual acuities over 24 months after CXL. Columns show UDVA and CDVA obtained at 3, 6, 12, and 24 months after CXL for eyes in the consistent cohort (n = 115). Error bars represent standard error of the mean (CDVA = corrected distance visual acuity; CXL = corneal crosslinking; UDVA = uncorrected distance visual acuity).
Figure 2. Trend in Kmax over 24 months after CXL. Columns show Kmax measured at 3, 6, 12, and 24 months after CXL for eyes in the consistent cohort (n = 115). Error bars represent standard error of the mean (CXL = corneal crosslinking; Kmax = maximum keratometry).
Figure 3. Trend in pediatric visual acuities over 24 months after CXL. Columns show UDVA and CDVA measured at 3, 6, 12, and 24 months after CXL for eyes in the consistent cohort (n=11). Error bars represent standard error of the mean (CDVA = corrected distance visual acuity; CXL = corneal crosslinking; UDVA = uncorrected distance visual acuity).
Figure 4. Trend in pediatric Kmax over 24 months after CXL. Columns show Kmax obtained at 3, 6, 12, and 24 months after CXL for eyes in the consistent cohort (n=11). Error bars represent standard error of the mean (CXL = corneal crosslinking; Kmax = maximum keratometry).
Figure 5. Eyes with more than 1 D change in Kmax 12 and 24 months after CXL. Columns show the number of eyes with an increase or decrease in Kmax at 12 and 24 months after CXL (CXL = corneal crosslinking; Kmax = maximum keratometry).
Figure 6. Corrected distance visual acuity in eyes with a more than 1 D increase in maximum keratometry 12 months after corneal crosslinking. Columns show the number of eyes with a change in CDVA as shown on the horizontal axis (n = 24) (CDVA = corrected distance visual acuity).
Figure 7. Corrected distance visual acuity in eyes with a more than 1 D increase in maximum keratometry 24 months after corneal crosslinking. Columns show the number of eyes with a change in CDVA as shown on the horizontal axis (n = 11) (CDVA = corrected distance visual acuity).
Small proportion of cross-linked eyes in figures
16%
84%
16%
84%
2%
98%
2%
98%
7%
93%
14%
86%
4%
96%
2%
98%
Eyes in figureEyes enrolled, not in figure
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Carporissi et al. JCRS 2013 (TE-CXL, Ricrolin TE) had only 26 eyes» Found only 12 months of stability» No control arm» Progression: ≥2 of the following:
- UDVA and/or CDVA loss >1 line;- ↑ sph and/or cyl >0.5 D; - ↑ Kmax > 1 D; - ≥10 mm reduction on thinnest
point using AS-OCT pachymetrySouters et al., JCRS 2015 (TE-CXL, Ricrolin TE)» Compared 35 eyes (Ricrolin TE) vs.
26 eyes epi-off CXL» 1 D Kmax threshold – no CDVA
requirement» 23% progressed after 12 months
Etc.
Is this harsh? Are other epi-off trials any better?
~8 trials in literature» Generally small n’s – no large LTFU either» Few have epi-off control arms» Many have only 1-year data published
NOT REALLY(ALTHOUGH SOME DEFINE
PROGRESSION BETTER)
NONE CLAIM SUPERIORITY EITHER
Analysis
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Let’s review the abstract
1. DPS O’Brart, Eur J Ophthalmol (2017), 27:253-269.
Not proven in this manuscript
David O’Brart: even non-treated keratoconic eyes can improve in
visual acuity. Why? Patients learning the chart during the trial (1)
Remember:“Consistent cohort”
= 115 eyes
Very small n’s
Real effect?The inter-
measurement variability increases
in more highly asymmetric corneas
- and 0.48 D is definitely within that variability (which is
about 0.7 D)
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What this paper adds
Misses the fact that this is incredibly rare
Presented data not robust enough to support this;the follow-up is 2 years, and the drop-out/LTFU rate is phenomenal.
This paper reports pain, progression, possible activation of HSV keratitis, and one PK was required. This statement is far too strong.
Analysis
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General concerns:• Defining progression (common to most studies)
Specific concerns:• Drop-out rate• Treating non-progressive patients (that wouldn’t have progressed)• No control arm• Claimed outcomes that are “significant” – but fall within instrumentation noise• Epi-off CXL’s effects last longer than the 24 month data shown here
(CXLUSA have been performing studies since 2009)• No clinicaltrials.gov registration• Declarative statements and claims being made that are stronger than the data
supports
Issues
Conclusions
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• Small group of good people involved running the trial• Surgeon-led study• Limited resources• No academic/ corporate statistician available?• No large pharma/device support expertise
• Still a sensible rationale for how it might work• There’s still a potential that this could be the “Holy Grail” of CXL…• No manuscript or trial design is perfect.
• Next steps? Easy. External validation, as per basic scientific principles.• Reduces concerns, shows technique is viable
Nevertheless…
What do you think?
Conclusions
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• It’s important to stay current
• Read the journals
• Wait to adapt your clinical protocols until these
publications have been shown to be safe and effective
• If you want to publish, follow the guidelines and be as
transparent as possible
Take-home
Conclusions