Low-cost Enabling Technology for Image-guided Photodynamic Therapy (PDT) of Oral
Phase: PHASE1
Conditions: Oral Cancer
Sponsor: Massachusetts General Hospital

 
PROTOCOL NCT NCT03638622 
 
 
 
Protocol Title: 
Low-cost enabling technology for image-guided photodynamic therapy (PDT) of oral 
cancer 
 
NCT number: 
NCT03638622 
 
Document date: 
Dec 17, 2020 
 
 
 

DETAILED PROTOCOL 
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Low-cost enabling technology for image-guided photodynamic therapy 
(PDT) of oral cancer 
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Principal Investigators: 
 
Tayyaba Hasan, Ph.D. 
Professor of Dermatology and of Health Sciences and Technology Wellman Center 
Harvard Medical School 
Massachusetts General Hospital 
Boston, MA02114 
Phone: 617-726-6996  
Email: thasan@partners.org 
 
Jonathan P. Celli, Ph.D.  
Assistant professor of Physics  
University of Massachusetts Boston  
Boston, MA 02125 
Phone: 617-287-5715 
Email:Jonathan.celli@umb.edu 
 
 
 
 
 
Principal Investigators (Clinical Trial site) 
 
Shahid Ali Siddiqi, MBBS, M.D. 
Professor of Radiotherapy, 
 Department of Radiotherapy, J.N. Medical College Hospital, Aligarh Muslim University 
 Aligarh-202002, UP, India 
Phone: 0571-2700927 
Email: sasjnmc@yahoo.com 
 
Syed Abrar Hasan, MBBS, M.S. 
Professor of Otorhinolaryngology 
 Department of Otorhinolaryngology (ENT), J.N. Medical 
College Hospital, 
Aligarh Muslim University, Aligarh-202002, UP, India 
Phone: 0571-272-0588 
Email: profahasan@yahoo.com 
 

Low-cost enabling technology for image-guided photodynamic therapy (PDT) of oral 
cancer 
!!!!!
BACKGROUND  AND  SIGNIFICANCE:  Oral  cancer  is defined  as the  cancer  of the  lip, 
mouth, tongue, and buccal cheek. Based on these criteria, oral cavity cancer is the 8th most 
frequent cancer in the world among males and 14th  among females, the main risk factors 
being tobacco and alcohol use. ‘Oral cancer’ OR ‘mouth cancer’ OR ‘tongue cancer’; the use 
of these terms generated a list of numerous MeSH entry terms, which included subheadings 
of these main terms to include mouth neoplasms, oral neoplasms, cancer of the mouth, and 
head  and  neck  cancers.  Oral  cancer  is a heterogeneous  group  of cancers  arising  from 
different  parts  of  the  oral  cavity,  with  different  predisposing  factors,  prevalence,  and 
treatment outcomes. It is the sixth most common cancer reported globally with an annual 
incidence of over 300,000 cases, of which 62% arise in developing countries. There is a 
significant difference in the incidence of oral cancer in different regions of the world, with the 
age-adjusted rates varying from over 20 per 100,000 population in India, to 10 per 100,000 
in the USA, and less than 2 per 100,000 in the Middle East. In comparison with the U.S. 
population, where oral cavity cancer represents only about 3% of malignancies, it accounts 
for over 30% of all cancers in India (1). More than 80,000 new cases are reported every year 
and it is the leading cause of cancer death among Indian men (2, 3). Oral cancer in India 
affects mostly those from the lower socioeconomic groups, that is, people from the lower 
socioeconomic strata of society due to a higher exposure to risk factors such as the use of 
tobacco, zarda, khaini, chewing gutka, mawa, and kharra, which are all dry mixtures of 
flavorings, areca nut flakes and powdered tobacco. 
!
Earlier detection of oral cancer offers the best chance for long-term survival and has the 
potential  to  improve  treatment  outcomes  and  make  healthcare  affordable.  Even  though 
clinical diagnosis occurs via examination of the oral cavity and tongue, which is accessible 
by current  diagnostic  tools, the majority  of cases  present  to a healthcare  facility  at later 
stages of cancer subtypes, thereby reducing chances of survival due to delays in diagnosis. 
Current treatment options, primarily surgery and/or radiation, can be curative if cancer or 
dysplasia is caught at a sufficiently early stage. Though even in these cases treatment may 
be disfiguring  with significant  impact upon quality of life, and many patients  do not seek 
medical  attention  until the disease  has progressed  to a point where  radical  operation  is 
required (Stage III/IV), often entailing block dissection and removal of the entire lymphatic 
drainage of the neck. Despite the radical operation, disease still recurs, leading to an overall 
survival rate of less than 70% of these cases (4). Even the less drastic excisional surgeries 
for early stage disease  often cause cosmetic  issues and persistent  chewing,  swallowing, 
speech  problems.  Radiotherapy,  when feasible,  typically  preserves  more tissue,  but side 
effects in the oral cavity, including xerostomia, mucositis, ulceration, alterations in taste, and 
fibrosis, can also present major quality of life issues. 
!
Furthermore, it is crucial to note that even given the limitations of these approaches, both 
surgery  and  radiotherapy   require  significant  medical  infrastructure   and  highly  trained 
clinicians   that   are   often   not  available   in  the   resource-limited   settings   where   these 
malignancies are disproportionately prevalent. In fact it is estimated that approximately 100 
million  people  globally  do  not  have  access  to  radiotherapy  machines,  which  cost  about 
$6,000,000 and last for 8–10 years if maintained properly, which they are often not. As a 
result of these limitations, patients who do not have immediate access to high quality health 
care will far too often not receive timely intervention. All of these factors point to the urgent 
need for the pursuit of therapeutic strategies that are not only effective, but can feasibly be 
adapted for implementation with low-cost components in rural areas with little or no access 
to electricity, let alone the medical resources of a major clinical center. 
!
With these considerations in mind, the present proposal makes the case that photodynamic 

therapy  (PDT)-based  treatment  of  oral  cancer,  already  shown  to  be  effective  in  the 
traditional  clinical  setting  (5–10),  is  inherently  conducive  to  adaptation  into  a  low-cost 
battery-powered platform that addresses the requirements for EMERGING ECONOMY 
implementation. 
!
PDT Background: PDT is a photochemistry-based modality for the treatment of cancer and non-
cancer diseases that works by preferential light-mediated cytotoxicity to target tissues (11). PDT is 
based on the observation that certain photosensitizers (PS) accumulate preferentially in malignant 
tissues. PDT is clinically approved for the treatment of a number of carcinomas (12, 13) and 
shown to be effective with remarkable healing of the mucosa in oral cancer and pre-cancer 
applications while surgical procedures frequently result in scar formation (chen et al 2012). 
 
PDT involves delivering visible light of the appropriate wavelength to excite the PS to an excited 
state, leading to intersystem crossing to the long-lived triplet state which can produce singlet 
oxygen or other cytotoxic species, in addition to fluorescence emission for tumor imaging (14). It is 
also well established that PDT is inherently a theranostic modality whereby the photosensitizing 
compounds function simultaneously as imaging and cytotoxic agents. The modest preferential 
accumulation and activation of photosensitizers in neoplastic tissues provides both site-specific 
cytotoxicity, and selective visualization of tumors using fluorescence contrast to demarcate the 
boundaries of cancerous and healthy tissues, which have been studied by our group and others 
(14), i.e., PDT is a localized therapy and has minimal side effects unlike systemically delivery 
chemotherapy.  
 
Early work led by Dr. Stephen Bown and Dr. Colin Hopper in the UK (clinical consultants on this 
proposal) showed that PDT for treatment of oral cancer and dysplasia produced consistent 
epithelial necrosis and excellent healing after treatment (5, 6). In their initial study of 18 patients 
presenting with squamous cell carcinoma (SCC) or premalignant lesions of the buccal mucosa, 
floor of the mouth, tongue or alveolus, the maximum depth of necrosis was 1.3mm and complete 
epithelial necrosis was achieved. Yet no necrosis in muscle was reported for all cases.6 Patients 
received analgesia during therapy but importantly there was excellent healing in all cases, with 
even the largest lesions completely healed in 3-5 weeks and none of the patients had perceived 
changes in sensation within the oral cavity after healing.  
 
Similar results from PDT therapy on oral lesions have been reproduced by other groups and at 
other centers in Europe and Asia (7-9, 15, 16). In a study by Tsai et al (provide reference here), 
patients with oral lesions had minimal to no scarring  with excellent cosmetic outcome. At 6 month 
followup, post therapy, in the five hyperplasia subjects, complete response was observed in four 
subjects while partial response in the remaining one subject.  This study and others (5) showed 
that LED light-mediated topical ALA-PDT is as effective as the laser light-mediated topical ALA-
PDT for treatment of oral lesions. 
 
A review of the 5-Aminolevulinic acid-mediated photodynamic therapy for oral cancers and 
precancers has been provided in Chen et al 2012 (5). This clinical literature collectively concludes 
that PDT is a safe and effective approach, with remarkable healing and is especially effective for 
early stage cancerous and precancerous lesions of the oral cavity. It is for this reason that the 
clinical validation of the present proposal focuses on treatment of patients with T1N0M0 disease 
with no lymph node involvement or distant metastasis. That being said, this is a highly active and 
rapidly evolving field, in which new photosensitizers and light delivery methods indicate promise in 
achieving greater depths of penetration.  
 
To the best of our knowledge, most of the previous ALA-PDT studies used laser light to treat a 
variety of premalignant and malignant human lesions; Tsai et al and Yu et al first tested the 
efficacy of an LED light-mediated ALA-PDT on oral premalignant lesions, however these were not 
battery operated. Laser machines can provide light with specific mono-wavelength; the laser 
system is well designed, more stable, and power adjustable. However, it is heavier, more bulky, 
and more expensive. An LED light device can provide light with a range of wavelengths and has 
the advantages of being a simpler, smaller, lighter, less expensive, and more portable light source 
than the laser machine. The present project however focuses on developing a technology for the 
situations in which PDT is already satisfactorily shown to be safe and effective. Furthermore, by 
coordinating the clinical validation with efforts at broader dissemination, it is hoped that the ability 
to treat relatively early stage disease in a manner that is actually available, accessible and 
attractive (not too expensive or painful or requiring good infrastructure or costly travel to a major 

medical center and possible disfigurement) will in fact reduce the number of patients presenting at 
late stages whose treatment require highly demanding surgical procedures.  
 
Motivated by all these factors and excellent studies by several research groups around the world, 
here is a compelling case for PDT in rural India, not only because it has excellent results for early 
stage disease relative to the other options, but also for patients in rural areas who might otherwise 
get no treatment at all due to the cost, logistics of travel to a clinic, etc.   
Photosensitization 
by 
5-aminolevulinic 
acid 
(ALA)-induced 
accumulation 
of 
protoporphyrin IX (PpIX): In this proposal, we adopt the well-established technique of 
photosensitization  by  administration  of  ALA  5-aminolevulinic  acid  (ALA)  (17,  18).  This 
approach  has been widely  used in dermatology  PDT applications  (19–23)  and in all the 
clinical   oral   cancer   PDT   studies   cited   above.   In   fact,   the   first   clinical   report   of 
photosensitization  by oral, systemic administration  of ALA was by Drs. Bown and Hopper 
and their colleagues, and it was for oral cancer patients. Because administration of ALA only 
temporarily overloads the natural heme synthesis pathway, photosensitization lasts no more 
than several hours. This is a crucial consideration  in a setting where sunlight exposure is 
difficult to avoid. 
!
LED-based light source for PDT therapy: The light source to be used for PDT treatment is 
a fiber-coupled, 635nm (peak wavelength) LED housed inside a small aluminum enclosure, 
which contains the LED itself and all associated electronics. The device is battery powered 
and provides a stable output power of 42mW continuously for approximately 8 hours before 
battery change is required. A simple on/off switch controls it and also has a power selector 
dial that can reduce  the internal  current  through  the LED  to regulate  power  to 4 preset 
settings  between  approximately  10 and 42mW.  The fexible fiber bundle  (approx.  1cm 
diameter) extends  approximately  one meter  from  the enclosure.  The distal  end of the 
fiber,  which delivers  light to the oral cavity,  is fitted with an interchangeable  light delivery  
applicator, which  attaches  to  the  end  of  the  fiber.  The  applicators  have  variable  size  
light  output apertures from 0.5,1.0,1.5 and 2cm that can be selected based on lesion size. 
These are plastic [poly(methyl methacrylate) (PMMA)] or other  similar material  pieces that 
contain an internal reflector to direct light at a 90-degree angle from the fiber bundle with 
external dimensions  of  1cm  by  2cm.  During  treatment  the  distal  end  of  the  fiber,  
including  the applicator, will be covered to approximately 10 cm down the fiber bundle from 
the end by a transparent hygienic plastic sheath. This device is adapted from an earlier 
prototype battery- operated  LED  PDT  light  source  that  has  been  characterized  and  
shown  to  produce tumoricidal efficacy comparable to a turn-key laser system in two recent 
peer-reviewed publications (24,25). 
!
The device described here has been built and tested in the US and is to be imported to India 
for the proposed study. As an investigational device, the process for obtaining a Certificate 
of  Exportability  (COE)  from  the  United  States  Food  and  Drug  Administration  (FDA)  is 
described  under  section  801(e)(1)  of  the  FD&C  Act  Chapter  VIII:  Imports  and  Exports. 
Pending ICMR review of this protocol, a letter from the Secretary of Commerce at the Indian 
Embassy in Washington, D.C. may be provided to the FDA to provide assurance that the 
device is not in conflict with the laws of India, the Indian government has full knowledge of 
the status of the device in the U.S.; and import is permitted or not objected to. Once this 
assurance  has  been  provided,  the  investigators  will  provide  additional  technical 
documentation  to the  US  FDA  who  may  then  provide  a COE  for this  device.  Once  the 
required documentation, including a letter from the Secretary of Commerce, is provided to 
the FDA, it is anticipated that a COE can be granted within 20 days. 
!
!

 
Figure 1: Battery operated light source for oral cavity PDT treatment. The fiber coupled 
battery-powered device is shown with two different prototype light applicators (left panel). 
!
Smart-phone based fluorescence imaging: An inherent advantage of this PDT approach 
is that the therapeutic agent (PpIX, via ALA administration) also doubles as a fluorescence 
contrast agent. After administration of ALA and allowing a 2-3h period of PpIX conversion 
and accumulation in the malignant tissue, imaging can be performed to gain a more 
sensitive/specific view of tumor margins that will primarily be used in the current application 
to  guide  the  precise  placement  of  the  fiber-coupled  applicator  for  PDT  treatment.  A 
secondary priority, will be a forward looking validation study of high contrast baseline and 
follow-up  fluorescence  images  of the treatment  site that will be compared  with 
histopathological evaluation of corresponding biopsies. This study will evaluate the feasibility 
of using PpIX fluorescence images to monitor treatment response in the clinic and, as the 
technology is considered for dissemination into, neighboring rural villages. In the long-term 
and with the proper resources and development, this approach may also serve as a rapid 
source of documentation for potential telemedicine interaction between a clinician and a field 
healthcare worker to provide additional guidance if needed. 
!
This proposal  develops  an approach  in which  photosensitizer  (PpIX)-based  fluorescence 
images can be obtained via smartphone or using an adaptation of a standard commercial 
intraoral camera. So, following a single administration of a photosensitizing agent, the oral 
cavity can be illuminated with blue light to more clearly identify margins on the smartphone 
screen  before  proceeding  with  the  PDT  treatment  without  need  for  application  of  any 
additional  exogenous  agents.  The  latter  follows  using  the  compact,  hand-held,  red-light 
system  in  which  a  sheathed  fiber  optic  with  a  light  diffusing  applicator  is  placed  in  the 
patient’s  mouth  for the  duration  of therapy  (approximately  30-45  minutes  total  exposure 
broken into 10 minute exposure segments with a 2-3 minute breaks after each segment). 
The smartphone-mounted LED array to be used for PpIX fluorescence imaging in this study 
is  characterized  in  a  recent  publication  (24).  The  smartphone-mounted   illuminator  or 
intraoral  camera,  to enable  non-invasive  fluorescence  imaging  of the  oral  cavity  can  be 
exported   by  the  same  FDA  export  request  mechanism   discussed   in  the  preceding 
paragraph. 
!
In fact it is reasonable to envision a more ambitious implementation  of PpIX imaging as a 
global health technology for oral cancer screening. For the sake of focus, the emphasis on 
treatment  rather  than  diagnosis  here  is  a  decision  based  on  the  realistic  scope  of  the 
proposal rather than capability of the technology, and we will apply for additional funding to 
develop the diagnostic potential of this approach for emerging economy settings. 
!
SPECIFIC AIMS/OBJECTIVES: 
!
Aim 1: Adaptation and calibration of existing PDT treatment and imaging technologies 
for oral cancers to a low-cost, battery powered format. In dialog with design criteria from 
emerging economy site clinical collaborators, we will develop a low-cost light delivery device 
by adapting high-output 635 nm LED(s) coupled to a multimode fiber with an oral insert 
applicator to illuminate a sufficient area (for typical lesion sizes) with the necessary 
power  density  (~50mw/cm2)  for  clinically  feasible  PDT  treatments.  The  required  power 
density  over  these  areas  will  be  verified  by  a  series  of  calibration  experiments  using 
established optical tissue phantoms. Leveraging the well-established tumor selectivity and 

multifunctional capability of ALA-PpIX to serve also as a contrast agent for optical tumor 
imaging, a simple approach using low cost filters and the imaging capability of a smartphone 
to ascertain disease margins (also on follow- up) and guide fiber applicator placement will 
also be developed in Aim 1 building on prelim data. All engineering design will be conducted 
in close dialog with PSI. 
!
Aim 2: Optimization of LED-based ALA-PpIX PDT and Imaging.  In dialog with Aim 1, we 
will (A) conduct preclinical PDT studies in an established mouse model to 1) validate tumor 
depth  of  necrosis  in  an  implanted  tumor  model  by  histology  (B)  We  will  conduct  pilot 
sessions in healthy subjects at AMU in India, to assess uniformity  of light delivery in the 
human oral cavity. 
!
Aim  3:  To  validate  clinical  performance  of  PDT  treatment  of  oral  cancers  and 
dysplasia at emerging economy sites. Initially we will conduct clinical studies on 30 
eligible patients with T1N0M0  oral  lesions  on  location  at  AMU,  which  treats  
approximately  500  oral  cancer patients  per  year.  All  patient  studies  will  be  conducted  
according  to  local  institutional guidelines that are also compliant with the NIH 
requirements. Ultrasound and/or biopsy will also  see  patients  at  the  hospital  for  follow-
up  examination  and  to  assess  therapeutic response. 
!
Aim 4: To establish a long-term business, dissemination and healthcare training plans 
for sustainable implementation. This is facilitated by our industry partners, DUSA 
pharmaceuticals   (subsidiary  of  India-based  SunPharma)  and  PSI.  Our  team  includes 
expertise in international oncology care and global health delivery and will forge partnerships 
with smaller care providers in surrounding villages to “train the trainers” in implementing our 
technology, establish relationships with local organizations and develop a more detailed 
business plan for distribution of both the PDT agent (ALA) and the low-cost device for PDT 
treatment. If successful, the PDT-based cancer treatment technology established here could 
have broader impact in neighboring countries in South Asia (Pakistan, Sri-Lanka) where oral 
cancer is also disproportionately prevalent. It would also have impact on other cancers such 
as cancers of the uterine cervix, which is still a significant problem in rural India. 
!
Study  Recruitment  and  Procedures:  Study  participants  will  be  recruited  from  patients 
referred to JN Medical College with histologically confirmed T1N0M0 oral lesions. The sites 
of these lesions, which are typically squamous cell carcinoma, are in order of occurrence: 
the gingivobuccal sulcus, cheek, floor of mouth and tongue. All of these lesion sites in the 
oral cavity should be accessible for light delivery with the proposed fiber-coupled applicator 
system. 
!
1.  Pre-study procedures/Screening:  Patients come to ENT/Oral and Maxillofacial/Plastic 
and  Reconstructive  surgery  outpatient  facilities.  Typically,  an  ENT  specialist  handles 
early cases (biopsy proven malignancies),  while ENT and plastic surgeons jointly deal 
with advanced cases. Patient screening will take place in outpatient departments. The 
investigator/s will interview each subject to develop a brief, relevant medical history and 
determine that all selection criteria are met. The subject will receive an explanation of the 
study objectives, possible risks and benefits of the study. After history evaluation of the 
patients, Blood work will be done to check liver functions Test. After the blood report and 
inclusion  and  exclusion  criteria,  the  consultant  will  discuss  and  educate  the  patients 
about photosensitization and PDT therapy. If patients are willing to take part in the study, 
co-investigator will obtain a signed consent form. After obtaining a signed consent form, 
the consultant will schedule an appointment for PDT therapy. 
!
!
!
Questions asked of participants before treatment will seek to understand: 
!
1.   Why is the patient seeking treatment? 
2.   What are the bothersome symptoms: pain, difficulty eating, swallowing, speaking, etc.? 
3.   What medications,  treatments,  ayurvedic  and herbal  supplements  are currently  being 
taken? 

4.   What  is  the  patient’s  previous  health  history,  including  liver  problems,  tuberculosis, 
yellowing of skin or eyes (often undiagnosed hepatitis A or B), etc.? 
5.   What is the patient’s current use of NSAIDs? 
6.   Practical   considerations   such   as   the   availability   of   transportation,   cost,   home 
environment and availability of caregivers. 
7.   What is the patient’s current use of tobacco, including willingness to quit and what is their 
access to tobacco and nicotine treatments and treatment programs? 
!
Subject enrollment: 
!
1. If a potential subject is eligible and still interested, identifiable healthcare information may 
be collected including: last name, address, and birthdate, contact information, etc. This 
method ensures that identifiable healthcare information will be collected only from those 
persons who likely meet eligibility criteria. Those people who do not meet entry criteria 
will have only given non-identifiable health information. 
2. For those subjects who have given identifiable healthcare information and have signed a 
consent form, but are not subsequently enrolled, a failure log will be maintained. 
3. Logs for pre-screening,  enrollment  and failure to enroll will be used to track relevant 
information. 
4. The subjects  must verbally  acknowledge  understanding  of the informed  consent,  and 
sign the consent form accordingly. 
!
Study Facility: The study is to be conducted at one location within the JNMC hospital. All 
procedures will be performed at the Department of Radio-diagnosis. The following sections 
describe the procedures to be followed for this clinical study. The study does not necessitate 
the use of any invasive interventions at the test sites. All data collection and procedure 
techniques are standard medical practice and are known to be safe. 
!
Inclusion Criteria: 
!
1.   Age above 21 years, males or females 
2.   Subject has read and signed a written informed consent form 
3.   Subject is willing to have ALA administered and wait for 2-3 hours 
4.   Subject is willing to receive red light irradiation in the mouth via the fiber probe/applicator 
and is willing to have the fiber probe/applicator  in the mouth for a maximum time of 1 
hour 
5.   Subject is willing to allow investigators to take measurements using smart phone imaging 
before, during and after light treatment 
6.   After the procedure, the subject is willing to avoid spicy, hot, or oily foods for at least 6 
hours 
7.   Subject willing to wear full sleeve shirt and full-length garments for couple of hours. 
!
Exclusion Criteria: 
!
1.   Pregnancy or nursing (ALA is a drug that belongs to FDA pregnancy category C). 
2.   History of photosensitivity diseases (e.g., lupus erythematosus, porphyrias). 
3.   Therapy with any photosensitizing  medication, e.g., thiazides (for the treatment of high 
blood pressure), fluoroquinolones, griseofulvin, or sulfonamides (for the treatment of 
infections),   sulfonylureas   (for  the  treatment   of  diabetes),   phenothiazines   (for  the 
treatment  of  emotional  problems),  and  other  medications  reported  to  cause 
photosensitivity within the last 6 months. 
4.   Subject is unable or unwilling to comply with the study requirements. 
5.   Subject has any conditions or scars within the location of the test sites that may interfere 
with the treatment or evaluation. 
6.   Allergy to porphyrins or ALA. 
7.   Subject has received laser treatment within 6 months in the area of the treatment. 
8.   Subject is participating in other potentially confounding research, e.g., currently enrolled 
in a clinical study of any other unapproved investigational drug or device. 
9.   Any other condition  or laboratory  value that would, in the professional  opinion  of the 

investigator, potentially affect response or participation in this clinical study. 
10. Subject has inadequate organ function. 
11.  Subject has co-morbid systemic illnesses or severe concurrent disease. 
12. Subject is being treated for vascular disease. 
13. Subject is an employee of the participating sites directly supervised by the investigator. 
14. Subject with invasive deep carcinoma evaluated by biopsy. 
15. Subject is currently being treated for other cancers with medical or radiation therapy. 
16. Subject  has  AIDS  or  other  infectious  diseases,  including  tuberculosis,  hepatitis  or 
herpetic lesions (oral herpes). 
17. Subject has oral submucous  fibrosis (OSF) resulting in patient inability to comfortably 
hold the light applicator in mouth. 
18. Subject has HPV positive tumor. 
19. Subject has the tumor at Oropharynx area.  
20. We will exludes the patients  of the all other oral lesions at sites except: the gingivobuccal  
sulcus, cheek, floor of the mouth and tongue. 
!
Procedure  after enrollment:  We plan to enroll 30 patients with oral cancer in this study. 
The study will take place at JNMC, Aligarh. A timeline of key steps in the clinical protocol is 
shown in Figure 2. This timeline of procedures considers that many patients may need to 
travel from remote rural areas with poor access to transportation, so it cannot be assumed 
that patients have convenient access to return to the clinic for multiple repeated biopsies. 
!
Day One: 
Baseline imaging; Fluorescence measurement: PpIX fluorescence will be recorded using 
405nm excitation light delivered from an LED source powered by a smartphone. This is a 
non-invasive  system.  The  PpIX  fluorescence  will  be  photographed  using  the  camera 
embedded  in the smartphone.  The advantage  of this step is that in the long term it will 
obviate the need for biopsies to establish PpIX concentrations and could allow for online 
dosimetry  customized  to  individual  patients.  Three  photographs  will  be  taken  in  each 
subject: first photograph will be taken prior to given ALA to the patients, second photograph 
after 2-3 hours of ALA incubation, and third photograph will be taken immediately after PDT 
treatment. 
!
 
Figure 2: Timeline of procedures for clinical PDT protocol 
!
ALA  preparation  and  administration:  The  FDA-approved  ALA  from  DUSA 
Pharmaceuticals,  Inc., Wilmington,  MA will be used in powder  form. Patients  will initially 
receive a baseline ultrasound of the oral cavity prior to ALA administration. One hour prior to 
ALA administration, analgesic (Aceclofenac, HIFENAC-SR (200mg);Intas Pharmaceuticals, 
India) and antiemetic (Domperidone, Domperon, 10mg; Cadila Pharmaceuticals, Inc., India) 
will be given to patients orally to avoid nausea and pain. ALA, totaling 60 mg/kg, will be 
administered orally via three repeated doses of 20 mg/kg of ALA dissolved in either orange 
juice or a soft drink, which lowers the pH of the solution, at 0, 1 and 2 hours. 
!
 
 

Imaging  Procedure  before treatment: After allowing 2–3 hours for PpIX conversion and 
accumulation in the malignant tissue, a baseline image of the tumor will be obtained using 
the  smartphone  PpIX  imaging  approach.  In  this  clinical  validation  study,  these  PpIX 
fluorescence images will be used to make treatment decisions beyond visual guidance for 
applicator placement on the lesion. 
!
PDT Procedure: Immediately after the brief imaging session (approximately 5 minutes), the 
PDT treatment will proceed. Depending on the exact fractionation schedule determined, a 
total fluence of 100J/cm2  at the lesion surface will be delivered with an area of applicators or 
compressed applicator in for approximately 30-45 minutes. Placement will be such that the 
full extent of the lesion falls within a 1mm margin of the applicator area. Every 10 minutes, a 
2-3 minute break is provided to the patient and the study personal will check for the correct 
placement of the probe. The clinician will conduct applicator placement with the assistance 
of a nurse as needed so that it fits tightly in contact with the active surface facing the lesion. 
Care will be required when pressing an applicator tipped light delivery system hard against 
tissue. If one presses too hard and the tissue is rendered temporarily hypoxic, there will be 
no PDT effect. During therapy patients will leave their mouth closed around the optical fiber. 
Depending on the exact orientation of the lesion within the oral cavity a mouth guard may be 
used  to  aid  applicator  positioning,  or  if  this  improves  patient  comfort.  Also,  to  aid  in 
stabilization  of  the  fiber  and  improve  patient  comfort,  an  ergonomic  external  positioning 
mount may be employed to help maintain the optical fiber in position. Provided that care is 
taken that no incidental body movements during irradiation lead to significant shifting of 
movement of the applicator, patients will be able to read a magazine, watch TV (if available) 
or other  similar  activities  from  a seated  position.  Small  lesions  may  receive  a complete 
treatment  in this time interval, while (as noted above), larger lesions may require one or 
more additional applications. Patients will receive analgesic Aceclofenac, HIFINAC-SR (200 
mg); Intas Pharmaceuticals,  India to avoid pain. Appropriate Laser safety glasses will also 
be provided to the patients during irradiation. 
!
Post-treatment imaging: At the conclusion of the PDT treatment, the light delivery fiber will 
be  removed  and  a  follow-up  smartphone  fluorescence  image  will  be  obtained  for  later 
analysis of PpIX photo bleaching. Patients will receive guidance on resumption of normal 
activities. After the procedure, patient will be advised to avoid foods that are spicy, hot or oily 
for at least 6 hours and advised to take analgesic as needed Aceclofenac,  HIFENAC-SR 
(200 mg); Intas Pharmaceuticals, India. to avoid pain. Patients will also be advised to stop 
smoking, and chewing tobacco product. 
!
Questions for participants on survey to be administered after treatment, and at follow- 
up will seek to understand: 
!
1.   The  tolerability  of the  treatment  and,  in particular,  any  side  effects  such  as nausea, 
vomiting,  pain  after  treatment,  ability  to  eat  and  drink  after  treatment,  and 
photosensitivity. 
2.   What  are  current  symptoms  and  their  severity,  in  order  to  capture  trajectory  and 
worsening/no change/resolution of previously identified bothersome symptoms? 
3.   Pragmatic issues associated with cost, transportation for follow-up (including non-PDT) 
treatments, lab work to monitor LFTs (bilirubin, biliverdin, AST), and follow-up visits. 
4.   Adherence to recommended plan of treatment (literacy, cultural variation). 
5.  Current tobacco use, access to tobacco and nicotine treatment programs/treatments. 
(Information about quitting tobacco chewing will also  be made available to patients as 
needed). 
!
Day  Two  to  Three: Routine  complete  blood investigations  including  a liver function  test 
(LFT) will be performed at 1 to 2 days following ingestion of ALA. If abnormalities are noted, 
follow-up blood work will be conducted that includes a renal function test (blood urea, serum 
creatinine, uric acid) and blood electrolytes measurement. 

!
Day Seven to Ten: At a follow-up examination, 7 days after treatment, ultrasound of the oral 
cavity will be conducted to assess treatment response by lesion area (cm2) and depth (mm). 
As part of this study, ALA will also be re-administered  (unless a particular patient had an 
adverse reaction to ALA in the initial treatment) so that follow-up fluorescence imaging can 
also be conducted. Again, at this stage, fluorescence imaging is included for validation of the 
procedure itself, not to decide the next steps in treatment for this patient cohort. However, as 
shown in Figure 2, the follow-up ultrasound will be a decision point to determine whether a 
given patient needs to undergo surgical excision of residual tumor (possibly with additional 
radio- and/or chemotherapy as determined by the clinician team), or if no residual disease is 
present, a biopsy will be conducted at the original disease site for histological confirmation of 
treatment response, and/or disease progression (development of invasive disease). If the 
radiologist  reports  residual  tumor  after  the  ultrasound  procedure,  an  ENT  surgeon  will 
perform biopsy and the tissue will be preserved in formalin and sent for histopathology 
assessment. The depth of necrosis evaluated from the histopathology will serve as end dpoint for 
evaluating the technology. This  histopathology  data  will  also  be  used  for  validation  of  
imaging  to  establish   fluorescence   contrast   agreement   with   histologically   confirmed 
malignant tissue.  
 
Follow-up Model: 
Patients who have good response to PDT will not need to undergo surgery, which  would  
compromise  the  excellent  healing  of  the  mucosa  that  has  been reported  with  this 
modality (7,9).  At the same  time,  patients  whose  disease  has partial  or no response to 
PDT will still receive the same standard of care (surgical excision, chemo/radiation) they would 
have if they had not enrolled in the study. It is also possible that the PDT treatment, even if 
response was not complete, could reduce the scope of excision required in these subjets. 
Therefore at the end of the study we will have established the utility of this technology without 
interrupting the flow of treatment/management of the patients whose disease has partial or no 
response to PDT. Regardless of the flow of this study, additional follow-up on all patients will 
be carried out at 3 months, 6 months, 9 months and 1 year after treatment. All patient data 
obtained will be appropriately de-identified as per local institutional guidelines before off-site 
analysis, which will continue throughout the study. !
  
The clinical validation study will also serve as an opportunity to gather patient data that will 
be invaluable in two capacities 1) to obtain important information immediately relevant to 
individual patient care and 2) with a mind toward sustainability we will seek to understand 
cultural barriers to acceptance or compliance with the proposed PDT treatment that will be 
accounted for in outreach and training plans. The present validation study is not powered to 
make comparison between different interventions, but rather to provide a validation that the 
safety  and  efficacy  of  the  low  cost  approach  is  equivalent  to  previous  reports  of  PDT 
treatment for oral cancer in traditional medical settings at JNMC. 
 
Role of Clinicians 
Role in recruitment and prescreening: Oral malignancy cases reporting in our OPD will be 
examined, evaluated and screened for enrolling under the study. 30 patients with T1N0M0 and 
fulfilling other inclusion criteria will be considered for PDT. Each patient will undergo thorough 
clinical examination and investigation as per protocol. All the patients will be explained the 
objectives, benefits and possible risks of the study. The physician will also discuss and educate 
the patients on PDT therapy and its procedure. Once they agree co-investigator along with a 
person with no conflict of interest will take consent under video graphic recording. 
 
Role in conducting the study and followup: Dr. Hasan, in conjunction with Dr. Siddiqui, will be 
responsible for recruiting patients and defining the selection criteria for patients. Dr. Hasan will be 
one of the physicians responsible for performing photodynamic therapy of oral cancer in the 
clinical trial proposed and also prescribing the required analgesic and antiemetic drugs. He will 
also contribute to the coordination of education programs focused on training physicians and 
healthcare workers to deliver the treatment protocols. Dr. Hashmi is the co-Investigator of the 
project and collaborating on the surgeries and treatment performed for the clinical studies during 
trial. After first PDT regimen we will follow-up the study for the out come. In the follow up study 
If the radiologist reports residual tumor after the  ultrasound  procedure,  an  ENT  surgeon 
will 

perform biopsy and the tissue will be preserved in formalin and sent for histopathology 
assessment. Based on the histopathalogical analysis, the clinicians will determine the patients 
who have good response to PDT will not need to undergo surgery, as it would compromise the 
excellent healing of the mucosa that has been reported with this modality. At the same time, 
patients whose disease has partial or no response to PDT will still receive the surgical excision, 
chemo/radiation by the clinicians. It is also possible that the PDT treatment even if response was 
not complete could reduce the scope of excision required in these subjects. Regardless of the 
flow and output of this study, the clinicians will followup on all patients at 3 months, 6 months , 9 
months and 1 year after treatment.  
 
!
Objective  drop  criteria  for  the  removal  of  a  subject  from  the  study  include  the 
following: 
!
1.   Subject verbalizes desire to no longer participate in the study, which will be monitored by 
utilizing “ongoing consent” during the study. 
2.   PIs reserves the right to terminate any subject based on his expert judgment of potential 
increased risk and/or non-compliance with the study protocol 
!
 
Bio-statistical analysis:    
 
1. 
Number of patients required for the study: The estimated study size of 30 patients is based on 
an estimated effect size of 1.2 (p-value, two-tailed students t-test) to measure significance of 
change between pre and post treatment mean lesion surface area in cm2 from published 
estimates of variance in PDT response in oral lesions (reference to Fan et al paper). This 
estimate assumes a statistical power of 0.80 and alpha level of 0.05 and accounts for an 
attrition rate of 10–15% of patients not completing the study.” 
 
 
2. 
Analysis on follow up response data: “ We emphasize that the intent of the study is to test the 
technology for future clinical trials and each patients’ pre-treatment biopsy will serve as control 
to his/her post-treatment biopsy data. Statistical comparisons between the pre and post-
treatment histopathological images will be performed via two-tailed paired student’s t-test.  The 
biostatistician assigned to this project will be consulted to perform comprehensive statistical 
analysis on the data. 
 
 
Risks and possible discomforts: 
!
1.   Potential effects experienced during the irradiation: stinging or burning sensations. We 
do not expect major discomfort or severe pain during the irradiation. If a study subject 
feels  major   discomfort   or  pain   during   the   treatment,   we   will   provide   analgesic 
ceclofenac, HIFENAC-SR (200 mg); Intas Pharmaceuticals, India. If major discomfort is 
constant despite the changes, we will stop the treatment immediately. 
2.   Potential   effects   experienced   after   the   irradiation:   Swelling   and   reddening.   The 
reddening and swelling is a response to the light irradiation, which is the intent of the 
treatment. This response will usually fade within 48–72 hours but may persist longer. 
3.  Cutaneous photosensitivity: ALA-induced PpIX causes cutaneous photosensitivity. So 
avoidance of inadvertent exposure to sunlight or artificial light is recommended for 24–48 
hours.  Patients  will be  provided  with  the  appropriate  clothing,  including  a full sleeve 
gown, to cover skin totally. In addition, patients will also get the sunglasses to wear and 
will be advised to stay indoors. 
4. There is a risk of adverse reactions to ALA. Cutaneous photosensitivity after the 
administrations of ALA last approximately 24–48 hours. High doses of ALA have been 
associated  with transient elevations  of serum transaminase,  nausea and vomiting. To 
reduce the side effect of nausea for patients taking oral ALA dose, we will provide an 
anti-emetic   drug.  On  the  day  of  procedure,   patients   will  be  pre-medicated   with 
Domperidone (Domperon, 10mg; Cadila Pharmaceuticals, Inc., India), one hour prior to 
oral administrations of ALA. 
5.   Psychosocial  (non-medical)  risks:  psychological  risks  are  not  anticipated  during  this 

study. However if any participants experience emotional distress during the study, the 
study  staff  will assist  them  to resolve  this  stress  with  appropriate  referrals.  Steps  to 
prevent this outcome will include detailed explanation of the study, what to expect from 
the study treatments and careful screening of subjects who may be at higher risk of 
experiencing distress from the study procedures as described. 
6.   Patients who participate may experience discomfort from venipuncture to obtain 10ml of 
blood, which is required pre- and post-study procedure to perform a liver function test. A 
trained   phlebotomist   will   perform   the   procedure   here   to   reduce   the   associated 
discomfort. 
7.   Cardiovascular   effects:   though   these   are  rare  events,   patients   might  experience 
hypotension and bradycardia. 
!
Details of Funding agency/ Sponsors and fund allocation: 
National Institute of Health, USA, 
!
Subcontract was awarded by Massachusetts General Hospital, Boston, USA 
Fund Allocation: 
Budget in Indian currency: 
Total Budget 
Budget for Indian Investigator 
!
i) 
ii) 
iii) 
Staff 
Equipment 
Contingency (including 
Rs.41,610,240 
!
Rs.2,028,600 
9,321,984 
1,955,016 
Chemicals, reagents etc.) 
!
iv) 
Travel (including 
Rs.2,520,000 
1,323,000 
Manpower training) 
!
v) 
Miscellaneous 
!
Total 
Rs.46,158,840 
Rs.12,600,000 
!
!
 
Methods for ensuring safety of subjects 
!
1.   Small sample size (n = 30). 
2.   Exclusion  of  patients  who  are  prone  to  higher  risk  of  side  effects  associated  with 
photosensitization  - as  defined by inclusion/exclusion  criteria (i.e. lupus erythematous, 
porphyries). 
3.   Baseline study tasks: history and abbreviated physical exam. 
4.   All subjects will be informed that their participation is strictly voluntary. 
5.   Ongoing “Process of consent” to ensure continued voluntary participation throughout the 
study. 
6.   Extensive   explanation   of  procedures   and  expected   results   prior  to  consent   and 
throughout the study. 
7.   Close follow-up of all study patients during study participation,  including monitoring  of 
vital signs during light exposures. 8.   24-hour availability of co-investigators and study 
nurse during the study. 
9.   Anonymity and confidentiality will be kept strictly confidential; only authorized research 
staff will have access to study data (including all photographs taken of their test sites). 
10. All subjects will be asked to sign an informed consent form detailing the risks, benefits, 
the nature of their participation and the estimated time involved in the study. 
11. Subjects will be informed that adverse events are unlikely and unexpected.  However,  
subjects will be instructed to report any adverse effects immediately. 
12. Periodic  monitoring  visits by study sponsor,  weekly  research  meetings  of study staff, 
continuing review of data by the principal investigator (PI). 
13. We  will utilize  previously  defined  safe  parameters  as determined  in previous  human 
study (IRB  2004-9-002217) which  was  done  by  our  Massachusetts  General  Hospital 
collaborators. 
 
Consent Procedures: 30 patients with T1N0M0 and fulfilling other inclusion criteria will be 
considered for PDT. Each patient will undergo thorough clinical examination and 

investigation as per protocol .The subjects will meet with one of the licensed physician 
investigators to discuss the study and the entire research in detail. All the patients will be 
explained the objectives, benefits and possible risks of the study. The informed consent 
document will be reviewed with the subject orally and the potential subject will be allowed 
to read the entire document. The physician will also discuss and educate the patients on 
PDT therapy and its procedure. Subjects will have as much time as necessary to consult 
with family members or their physician before enrolling in the study. If the subject 
understands and accepts the document, they will sign it or, when appropriate, they will 
make their thumb print upon it. The estimated time for the review and the explanation of 
the consent form is about 45 minutes. Once they agree co-investigator along with a person 
with no conflict of interest will take consent under videographic recording. After the subject is 
enrolled, the baseline evaluation and treatments may commence after signing the consent 
form. 
!
Publication  of  the  Results:  The  results  of  this  study  may  be  published  in  a  medical 
publication, journal, or may be used for teaching purposes. Additionally, this study and its 
results may be submitted for inclusion in all appropriate health authority study registries, as 
well as publication on health authority study registry websites, as required by local health 
authority regulations. Selection of first authorship will be based on several considerations, 
including, but not limited to study participation, contribution to the protocol development, and 
analysis  and  input  into  the  manuscript,  related  abstracts,  and  presentations  in  a  study. 
However study participants’ names or other identifying information will not be used for these 
purposes without their permission. 
!
 
Maintenance of the data collected during trial: All study subjects will be assigned a study 
number which will be the only subject identifier used throughout the study. A log of subject 
names and study numbers will be kept in a locked file in a locked office accessible only to 
study staff. As data is collected, it will be entered into case report forms by the study nurse 
and stored in a password protected computer database, identifiable only by subject study 
number.  All  photographs  taken  of  the  treatment  site  will  be  identified  by  subject  study 
numbers and will be kept in patient specific study records in the same locked file as other 
study logs. Photographs will be taken of the test site and will not include subject faces. We 
will cover the face or region if any identifiable marks are in the photograph. Photos may be 
used for publications at the end of the study, but names will not be included. 
!
Proposed compensation and reimbursement of incidental expenses and management 
of research related and unrelated injury/ illness during and after research period: We 
will offer you the care needed to treat any injury that directly results from taking part in this 
research study. We reserve the right to bill your insurance company or other third parties, if 
appropriate, for the care you get for the injury. We will try to have these costs paid for, but 
you may be responsible for some of them. For example, if the care is billed to your insurer, 
you will be responsible for payment of any deductibles and co-payments required by your 
insurer. Injuries sometimes happen in research even when no one is at fault. There are no 
plans to pay you or give you other compensation for an injury, should one occur. However, 
you are not giving up any of your legal rights by signing this form. If you think you have been 
injured or have experienced  a medical problem as a result of taking part in this research 
study, tell the person in charge of this study as soon as possible. The researcher's name 
and phone number are listed in the consent form. 
!
Monitoring and Quality Assurance: 
!
a. Independent monitoring of source data:  A study coordinator at MGH shall monitor all 
source data and ensure that the data are accurately documented on the study case report 
forms.  All  source  data  shall  be  organized  and  filed  into  individual  subject  binders.  Any 
pertinent notes to file regarding the subject shall be documented by the study coordinator 
and  kept  in the  applicable  subject  binder.  The  PI shall  review  data  on  an  ongoing  and 
consistent basis throughout the duration of the study. All subjects must be assigned a study 

identification   number  that  is  the  only  item  that  appears  on  the  subject  binder  and 
photographs. 
!
The  study  shall  be  performed  in  accordance  with  all  applicable,  Ministry  of  Health  and 
Family Welfare, Government of India act (Drugs & Cosmetics Act 1945) which was amended 
in June 16th, 2015, the requirements of the Food, Drug and Cosmetics Act (the “FDCA”) 
and similar   or   successor   legislations,   any   policed   issued   by   the   U.S.   Food   and   
Drug Administration   (the  FDA),  the  ICH  Guidelines   for  Good  Clinical  Practice  (the  
“GCP Guidelines”) and the Health Insurance Portability and Accountability Act of 1996 
(“HIPAA”) and any regulation and official promulgated here under. 
b. Safety monitoring: 
Data to be used for safety monitoring will include the following: 
•   Review of any adverse events. 
•   Review of enrollment, dropout rates, any protocol deviations and protocol adherence. 
• 
Review of medical history to ensure patient safety: medical history, and ongoing clinical 
evaluations   (including   participant’s   objective   and   subjective   response   to   cooling 
exposure). 
•   Review of any subjective report of discomfort experienced by participants. 
 
The Data Safety Monitoring Board will consist of 7 members namely: 
1. Prof. Anjum Pervez, Department of Medicine, JNMC (Physician) 
2. Prof. Moied Ahmad, Department of Anesthesia, JNMC (Intensivist) 
3. Prof. Asif Ali, Department of Biochemistry, JNMC (Scientist) 
4. Mr. Salman Khalil, Asst. Prof., Department of Community Medicine (Statistician) 
5. Dr. Ruhi Khan, Department of Medicine, JNMC (Medical Oncologist) 
6. Dr. G.S. Hashmi, Assoc. Prof, Dept. Of Oral & Maxillofacial Surgery, ZADC, AMU (Surgical 
Oncologist) 
7. Dr. Mohd. Akram, Assoc. Prof., Department of Radiotherapy, JNMC (Radiation Oncologist) 
 
 
c. Outcome monitoring: The validity and integrity of the data will be ensured by close 
adherence to the protocol and meticulous documentation of the data as it is collected. Case 
report forms will be completed within hours to days after the subject’s visits. Separate source 
documents will be utilized during the actual data collection and carefully reviewed after 
completion of the study visit and prior to entry into the final case report forms. Completeness 
and accuracy of study documents will be supervised by the study nurse and reviewed by the 
principal investigator on a weekly basis. Each subject will have two study books. One will 
serve as the source document, the other as the final study record. Additionally, study staff 
will participate in a weekly study meeting, which will serve to provide a collaborative review 
and analysis of subject recruitment, selection, enrollment, retention, participant’s response to 
treatment, safety profile and data collection and documentation. The study sponsor (NIH) will 
source of integrity and validation of data and protocol adherence. 
!
d. Adverse event reporting guidelines: Serious, expected/unexpected, adverse events will 
be reported to the IRB within 24 hours of the event followed by a full written report within 10 
working days/14 calendar days. Mild/moderate, expected/unexpected adverse events will be 
reported to the IRB in writing within 20 working days/30 calendar days. Adverse events will 
also be summarized in a progress report at the time of continuing review. The Principal 
Investigator acknowledges the following PHRC & FDA definitions of adverse events which 
will be utilized to guide recognition  and management  of such events in the trial. Serious 
adverse  events:  are  events  that  result  in  any  of  the  following  outcomes:  death;  a  life 
threatening experience; inpatient hospitalization or prolongation of existing hospitalization; a 
persistent or significant disability/incapacity; or a congenital anomaly/birth defect. In addition, 
events that may not result in death, but may be life threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
!
Mild adverse events: Awareness of signs or symptoms, but easily tolerated; are of minor 
irritant type; causing no loss of time from normal activities; symptoms would not require 

medication or a medical evaluation; signs and symptoms are transient. 
!
Moderate adverse events: Discomfort severe enough to cause interference with usual 
activities; persistent or requiring treatment. 
!
Unexpected adverse events are defined as any event, the specificity or severity of which is 
not consistent with the current investigator brochure; or, if an investigator brochure is not 
required  or  available,  the  specificity  or  severity  of  which  is  not  consistent  with  the  risk 
information   described   in  the  general   investigative   plan  or  elsewhere   in  the  current 
application, as amended. "Unexpected", as used in this definition, refers to an adverse drug 
experience  that  has  not  been  previously  observed  (e.g.,  included  in  the  investigator 
brochure) rather than from the perspective of such experience not being anticipated from the 
pharmacological properties of the pharmaceutical product. 
!
Expected adverse events are defined as any event, the specificity or severity of which is 
consistent  with  the  current  investigator  brochure;  or,  if  an  investigator  brochure  is  not 
required  or  available,  the  specificity  or  severity  of  which  is  consistent  with  the  risk 
information   described   in  the  general   investigative   plan  or  elsewhere   in  the  current 
application, as amended. 

resection of malignant glioma: a randomised controlled multicentre phase III trial. 
 
!
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