Evaluation of the Role of Vibrational Spectroscopy in the Diagnosis of Premalignant and Malignant Disease of the Thyroid RAFTER (RAman For Thyroid cancER)
Conditions: Thyroid Diseases, Thyroid Cancer
Sponsor: Gloucestershire Hospitals NHS Foundation Trust

 
 
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Evaluation of the role of vibrational spectroscopy in the diagnosis of 
premalignant and malignant disease of the thyroid 
RAFTER (RAman For Thyroid cancER) 
 
Research Protocol 
Version 1.4 
04/09/2018 
R&D Ref: 18/044/GHT 
 
 
Sponsor: Gloucestershire Hospitals NHS Foundation Trust 
Funders: University of Exeter Proof of Concept Fund 
Protocol reviewed by: Gloucestershire Hospitals Scientific Peer Review 
Committee 
 
Investigators 
 
Chief Investigator: 
Dr Alex Dudgeon 
Post-Doctoral Research Fellow 
Biophotonics Research Unit 
Gloucestershire Hospitals NHS FT 
Gloucester Royal Hospital 
Great Western Road 
GL1 3NN 
 
 
Co-investigators: 
 
Dr Catherine Kendall 
Head of Biophotonics 
Biophotonics Research Unit 
Gloucestershire Hospitals NHS FT 
Gloucester Royal Hospital 
Great Western Road 
GL1 3NN  
 
Ms Maryam Nowghani 
ENT Speciality doctor 
Department Of Otolaryngology 
Gloucestershire Hospitals NHS FT 
Gloucester Royal Hospital 
Great Western Road 
GL1 3NN 
 
 
 
 
Mr Charlie Hall 
Consultant ENT Surgeon 
Gloucestershire Hospitals NHS FT 
Gloucester Royal Hospital 
Great Western Road 
GL1 3NN  
 
 
 
 
 

 
 
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Sponsor 
Gloucestershire Hospitals NHS Foundation Trust is the main research sponsor 
for this study. For further information regarding the sponsorship conditions, 
please contact: Mr Charlie Hall. 
Funders 
The Biophotonics Research Unit, and Cheltenham and Gloucester Hospitals 
Charity (FOCUS) funded this project. 
 
Every care was taken in drafting this protocol, but corrections or amendments 
may be necessary. Problems relating to this trial should be referred, in the first 
instance, to the Chief Investigator. 
This study will adhere to the principles outlined in the NHS Research 
Governance Framework for Health and Social Care (2nd edition). It will be 
conducted in compliance with the protocol, the Data Protection Act and other 
regulatory requirements as appropriate. 
 
 
 

 
 
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Table of Contents 
 
STUDY SUMMARY................................................................................................... 5 
Background ........................................................................................................... 6 
AIMS & OBJECTIVES .............................................................................................. 8 
STUDY DESIGN AND METHODS ............................................................................ 8 
Study Design ......................................................................................................... 8 
Setting and Recruitment of Patients ...................................................................... 9 
Handling of Tissue ............................................................................................... 10 
Spectral & Statistical Analysis ............................................................................. 10 
OUTCOME MEASURES ......................................................................................... 12 
Primary Outcome Measures ................................................................................ 12 
Secondary Outcome Measures ........................................................................... 12 
REGULATORY ISSUES ......................................................................................... 12 
Adverse Events ................................................................................................... 12 
Ethics Approval ................................................................................................... 12 
Patient and public involvement ............................................................................ 12 
Consent ............................................................................................................... 13 
Confidentiality ...................................................................................................... 13 
Human Tissue Act ............................................................................................... 13 
Indemnity ............................................................................................................. 13 
Audit .................................................................................................................... 13 
Publication Policy ................................................................................................ 13 
REFERENCES ........................................................................................................ 14 
Appendix 1 
RAFTER Study Consent Form ..................................................... 15 
Appendix 2 
Participant Information Sheet Copy .............................................. 16 
Appendix 3 
Patient Histology Report ............................................................... 20 
Appendix 4 
Adverse Event Reporting Form .................................................... 21 
Appendix 5 
Personnel Delegation and Signature Log ..................................... 22 
 
 

 
 
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GLOSSARY OF ABBREVIATIONS 
LDA 
PCA 
VS 
FTIR 
RS 
Linear Discriminant Analysis 
Principal Component Analysis 
Vibrational spectroscopy 
Fourier Transform Infrared spectroscopy 
Raman spectroscopy 
FNA 
Fine needle aspiration 
 
 
 
 
 
 
 
 
 
 
 
 
 
KEYWORDS 
Raman spectroscopy 
Infrared spectroscopy 
Spectrum Analysis 
Raman probe 
Optical 
Diagnosis 
Cancer 
Multivariate analysis 
Thyroid cancer 
Papillary thyroid cancer 
Follicular thyroid cancer 
Anaplastic thyroid cancer  
Medullary thyroid cancer 
 

 
 
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STUDY SUMMARY 
Title 
Evaluation of the role of vibrational spectroscopy in the diagnosis and 
management of premalignant and malignant disease of the thyroid. 
Design 
Ex vivo vibrational spectroscopy (VS), including Raman spectroscopy (RS) of 
thyroid tissue samples, collected from patients undergoing routine diagnostic 
thyroid biopsies for diagnosis of potential thyroid cancer. Raman spectra are to 
be correlated with consensus histopathology and clinical outcomes. 
Multivariate analysis to be used to evaluate the classification accuracy of VS 
ex vivo. 
Aims 
1. To establish VS signal characteristics across a range of known thyroid 
cancer types. 
2. To evaluate the ability of VS to detect thyroid cancer. 
3. To evaluate the ability of VS to detect diseased lymph nodes in patients 
undergoing surgery for thyroid cancer. 
4. To develop a minimally-invasive Raman probe to aid the diagnosis and 
follow up of patients with thyroid cancer. 
5. To investigate thyroid nodules by comparing with histopathological results 
6. To further the understanding of biochemical changes in a range of known 
thyroid cancers. 
7. To evaluate the ability of VS to give prognostic information on the 
progression of thyroid cancer. 
Outcome Measures 
Measurement of thyroid nodules using the needle probe 
Diagnostic performance of VS for differentiation of key thyroid cancer types: 
• Papillary thyroid cancer 
• Follicular thyroid cancer 
collectively known as the differentiated thyroid cancers 
• Anaplastic thyroid cancer  
• Medullary thyroid cancer 
Diagnostic performance of VS for differentiation between normal and diseased 
thyroid carcinomas. 
Prognostic performance of VS to indicate the risk of thyroid cancer progression. 
Population 
Patients undergoing investigation of thyroid cancer within Gloucestershire 
Hospitals NHS Foundation Trust. 

 
 
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INTRODUCTION 
Background 
Cancer is a major cause of morbidity in the United Kingdom (UK). Each year 
more than a quarter of a million people are newly diagnosed with cancer. 
Overall it is estimated that one in three people will develop some form of cancer 
during their lifetime. 
There are more than 200 different types of cancer. Thyroid Cancer is a rare 
cancer (1% of all new cancer cases) with approximate 3500 new cases in the 
UK per annum (5/100,000 population). It is more common in females (73%). All 
age-groups are affected with the peak incidence in women at 35-39 years and 
men at 65-70 years. Overall the incidence is increasing (150% in 20 years).1 
There are four main types of thyroid cancer. Papillary and follicular thyroid 
cancer, known collectively as the differentiated thyroid cancers, carry a good 
prognosis and are usually curable. Conversely anaplastic thyroid cancer is a 
very aggressive tumour usually presenting in the elderly with a very poor 
prognosis. Finally, medullary thyroid cancer is a rare form with a strong genetic 
preponderance and a prognosis dependent on stage at presentation. Most 
thyroid cancers metastasize initially to the cervical lymph nodes, however 
follicular thyroid cancer has a tendency to metastasize via the blood stream to 
distant sites, commonly lung and bone. 
Whist thyroid cancer is rare, the presence of thyroid nodules is extremely 
common (in around 50% of people, by autopsy).2 In many cases this represents 
background multinodular change in an otherwise normal thyroid. Occasionally 
a thyroid nodule will grow in an otherwise normal thyroid gland to become 
palpable in the neck, this is known as a solitary nodule. Alternatively, a nodule 
within a multinodular thyroid can grow or expand to form a palpable “dominant 
nodule”. In both these situations, the patient will present with a lump in their 
neck. In most cases a thyroid cancer will also present with a lump in the thyroid 
or occasionally a cervical lymph node representing a nodal metastasis. There 
is therefore a clinical need to be able to differentiate between benign nodule 
and malignant nodules presenting as a neck lump. Around 13% of nodules 
presented clinically are cancerous.3 
Currently, patients presenting with a neck lump are assessed with clinical 
history and examination followed by an ultrasound scan and fine needle 
aspiration for cytology. This results in a spectrum of outcomes ranging from 
definitely benign to definitely malignant. However, a large proportion of patients 
fall into an indeterminate group with lower risk patients requiring interval 
scanning and higher risk patients a diagnostic lobectomy (removal of thyroid 
node for diagnosis). The latter is a surgical procedure to remove half the thyroid 
gland performed under general anaesthetic that usually necessitates an 
overnight stay in hospital. It is a low-morbidity procedure, but does carry a risk 
of vocal cord weakness due to nerve damage of up to 5%. In most cases this 
results in a temporary weak voice that resolves within 6 months. 
 

 
 
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Every year there are approximately 10,000 thyroid operations performed in 
England of which 17% are for thyroid cancer. While approximately half of the 
rest are for patients with symptomatic enlargement of the thyroid (goiter) or for 
the management of thyrotoxicosis, 20-30% are diagnostic procedures for the 
evaluation of a thyroid nodule.4 
There is therefore a clinical and socio-economic need for improved diagnosis 
of thyroid nodules. The ability to differentiate between malignant and benign 
nodules in the outpatient setting will shorten diagnostic pathways, reduce the 
need for diagnostic operative procedures and reduce the cost of managing 
these patients. 
Minimally invasive, near-instantaneous diagnosis of thyroid cancer would 
relieve patients of the anxiety whist awaiting results and, if required, allow for 
treatment planning to begin immediately. 
Vibrational Spectroscopy  
Vibrational spectroscopy (VS) utilises light to probe the composition of tissue. 
The sample is illumined with a source (often a laser), and the scattered or 
adsorbed light is measured by a detector. The amount light collected, along 
with the wavelength can be used to determine the composition and 
concentration  of molecules in of the tissue. Small changes in these values can 
be used to compare different samples and monitor changes in tissues. The 
technique is non-destructive and non-invasive. 
The potential benefits of VS in the management of thyroid conditions range 
from initial diagnosis to surveillance and treatment.  These are outlined below. 
1. VS offers a potential real time non-invasive diagnostic technique which 
could be used in the outpatient setting to avoid the need for invasive 
tissue biopsies in the following situations: 
a. The initial diagnosis of thyroid cancers. 
b. The monitoring of malignant changes in women with premalignant 
thyroid cancer. 
2. VS offers a potential real time intraoperative diagnostic tool to detect 
non-visible disease margins and improve complete excision rates and 
avoid disease recurrence whist minimising the extent of surgical 
excisions. 
3. In the management of thyroid cancer VS offers a potential tool for 
intraoperative objective assessment margins and of sentinel lymph 
nodes. 
4. VS offers the potential to give prognostic information that can be used to 
evaluate the risk of progression of thyroid cancers. 
Raman Spectroscopy 
Raman spectroscopy (RS) is a non-destructive analytic tool that uses the 
inelastic scattering of light to identify the molecular composition of different 
tissues or materials.  Incident light of a known frequency interacts with the target 
tissue and alters the vibration mode of the molecules within it by the transfer of 
energy. This results in light emitted from the tissue with a frequency dependent 
on the change in vibrational energy in the tissue. Measuring the frequency of 

 
 
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the emitted light produces a spectra which is unique to the molecular 
composition of the target tissue.7 VS has been shown to be effective in the 
diagnosis of other cancers including colon,5 lymphoma,6 skin7 and prostate.8 
The Raman Needle Probe 
We have previously demonstrated that it is possible to differentiate healthy and 
diseased tissue in the laboratory by measuring the light emitted when a low 
power laser is shone upon the tissue; a technique called Raman spectroscopy 
(RS). Our results have shown it is possible to obtain an “optical biopsy” or 
fingerprint of disease that can be used to diagnose cancer to a high level of 
accuracy within 2 seconds. This work was funded by the NIHR i4i and LINC 
from 2012-2016. We have submitted a second stage application to the NIHR, 
to fund a single centre in vivo trial of our device for lymphoma diagnosis, but 
would like to collect pilot data using the device for the diagnosis of other cancers.  
We (The Biophotonics Research Unit, University of Exeter and University of 
Bristol) have developed these “smart needle” probes, consisting of fibre-optics 
within a fine needle for investigating cancer below the skin's surface. It is 
difficult to create a sensitive probe to fit inside a needle; however, we have 
demonstrated this approach in lymph node tissue samples from 68 patients in 
the laboratory, where we showed that our probe could detect cancer with a high 
level of accuracy. 
Following on from our success with lymph nodes we wish to trial our smart 
needle on excised thyroid to demonstrate the device in another ENT cancer. 
Earlier studies have shown that thyroid cancer can be diagnosed using RS 
under a microscope with an accuracy greater than 78%.9 By eliminating the 
need for unnecessary surgery by diagnosis with our device, we will minimise 
the risk to patients, eliminate delays in obtaining results and reduce the cost of 
surgery and overnight stay in the hospital. We wish to advance this device 
closer to the clinic for a new cancer to improve the patient care pathway and 
remove the need for unnecessary surgery, by facilitating the work of the one-
stop ENT diagnostic outpatient clinics. 
AIMS & OBJECTIVES 
1. To demonstrate that the smart Raman needle probe can be used to 
measure spectra from excised thyroid nodules 
2. To establish VS signal characteristics across a range of known thyroid 
cancer types. 
3. To evaluate the ability of VS to detect thyroid cancers. 
4. To further the development of a minimally-invasive Raman probe to aid the 
diagnosis and follow up of patients with thyroid cancer. 
5. To further the understanding of biochemical changes in a range of known 
thyroid cancer types. 
6. To evaluate the ability of VS to give prognostic information on the 
progression of thyroid cancer conditions. 
STUDY DESIGN AND METHODS 
Study Design 
The study consists of measuring spectra of new tissue taken during routine 
diagnostic surgical thyroid lobectomy.  

 
 
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New tissue for this project will be collected during routine biopsy will be rapidly 
analysed 
by 
a 
spectrometer 
before 
proceeding 
with 
conventional 
histopathological analysis. The new tissue will consist of thyroid and adjacent 
tissue biopsies. No additional tissue will be taken for this research, we only plan 
to measure samples taken during routine diagnosis in under 5 minutes, before 
passing the sections back to the surgical team for routine histopathological 
analysis. 
Patient consent for immediate spectroscopic analysis can be found in Appendix 
1 and the participant information leaflet in Appendix 2. 
Anonymous background information relevant to known risk factors, family 
history and details of any treatment, menopausal status, details relevant 
medical procedures, and any treatment for thyroid cancer will be provided with 
the samples. An example of the report can be found in Appendix 3. Tissue 
specimens taken during routine clinical care are to be subjected to ex vivo 
vibrational spectroscopic analysis immediately prior to being sent for routine 
histopathological analysis. Vibrational spectra are to be correlated with 
consensus histopathology of adjacent sections. Multivariate analysis is to be 
used to evaluate the classification accuracy of VS ex vivo.  The vibrational 
spectra will be assessed for both prognostic as well as diagnostic information. 
Setting and Recruitment of Patients 
Identification of Participants 
Eligible patients will be identified by any of the clinicians working within 
Gloucestershire Hospitals NHS Foundation Trust. With the patients consent, 
the clinicians will contact the Experimental Medicine Research Officer to 
arrange for the potential participant to be approached for consent to be 
included in the collection. The consent process will not delay the patient’s 
routine care. 
Patients who wish to consider participation in the study are approached by 
a member of the study clinical team for consent to be recruited. Patients will 
be given the opportunity to read the participant information sheet (see 
appendixes) and ask questions about the study. 
All patients who will have biopsies taken with consent for inclusion in 
research studies whist undergoing investigation or treatment for thyroid 
cancer within Gloucestershire Hospitals NHS Foundation Trust may be 
considered for inclusion in this study. 
The decision that a biopsy is necessary is usually made in the outpatient 
setting during thyroid examination. These decisions will have either lead to 
an immediate FNA biopsy in outpatients or arrangements were made for the 
patient to attend for a specialist clinic appointment or operating list, to have 
the biopsy taken. 
Inclusion criteria 
• Patients undergoing biopsy or excision for thyroid cancer as part of their 
routine clinical care within Gloucestershire Hospitals NHS Foundation 
Trust. 

 
 
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Exclusion Criteria 
• Less than 18 years of age 
• Patients unable to consent to the study due to communication difficulties 
• Patients unable to consent to the study due to lack of capacity 
Handling of Tissue 
All tissue samples will be handled in line with Gloucestershire Hospitals NHS 
Foundation Trust’s standard procedures. 
For the samples, the fresh tissue will be immediately measured in a room 
adjacent to the surgical procedure location, in less than 5 minutes, before 
passing the tissue back to the surgical team for conventional histopathological 
analysis. 
The samples used in this study will be identified with a study identifier number 
on a pre-printed sticker to be attached to the pathology sample submission form. 
This will allow the histopathology team to identify the node is involved in this 
project, and allow them to report the histology back to the research team in 
pseudo-anonymised form. 
In the event of multiple nodules being removed from the patient, the surgical 
team will position a marker suture identifying the nodule examined using the 
probe, so the histopathologist can confidently identify the nodule you are 
interested in (likely to be the nodule of clinical concern in the majority of cases). 
Only one nodule per case will be used with the probe, to ensure the correct 
identification and pairing with the correct histology. 
“Normal” tissue will be identified as lobes which the histology reports are 
returned as having no cancer. 
Surplus tissue (not required for routine histopathology) from patients 
undergoing surgical excision of thyroid cancer dissection may be retained by 
the research team for analysis. 
Spectral & Statistical Analysis 
The spectral data will be correlated with gold-standard routine histopathology 
of the biopsy sample. The spectral variance will be explored using principal 
component analysis. This will facilitate exploration of the biochemical 
differences between the pathology groups. A multivariate discriminant 
classification model will then be developed using methods (e.g. Principal 
Component Analysis and Linear Discriminant Analysis) to extract the subtle 
spectral differences between tissue types. The background patient information 
and clinical outcomes will be included within the analysis to further develop the 
classification model. The classification model will be tested with leave one out 
cross-validation. 

 
 
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Figure 1 – study overview flow chart 
Version 1.0, 7 August 2018 
 
Patient assessed with possible thyroid cancer 
Biopsy of thyroid tissue or dissection required as part of 
routine care 
Yes 
Biopsy taken 
Specimens to undergo Raman 
spectroscopic analysis 
Routine patient care and specimen 
processing 
Participant background information 
data collection completed 
Consent given? 
No 
Yes 
Routine histological analysis 
Routine clinical follow up 
Clinical and pathological 
correlation 
Data Analysis 
Classification Model 
Patient invited to surgery via letter, study patient 
information sheet enclosed with letter 
Tissue returned to surgical team in <5 min 
Unique label attached to histology processing form 
Specimen handed to research team 
Patient Excluded, Routine patient care, 
specimen processing analysis  
STUDY OVERVIEW 

 
 
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OUTCOME MEASURES 
Primary Outcome Measures 
Demonstration and evaluation of the spectroscopic measurement of ex vivo 
thyroid tissue using the Raman needle probe. 
Secondary Outcome Measures 
Diagnostic performance of VS for differentiation of thyroid cancer vs normal 
benign (no cancer). 
Diagnostic performance of VS for differentiation of thyroid cancer types. 
• Papillary thyroid cancer 
• Follicular thyroid cancer 
• Anaplastic thyroid cancer  
• Medullary thyroid cancer 
Prognostic performance of VS to indicate the risk of thyroid cancer progression. 
REGULATORY ISSUES 
Adverse Events 
Failure of histological diagnosis due to sample processing errors is not 
expected and is reportable. All failure of histological diagnosis should be 
reported to the chief investigator using the form in Appendix 4. 
This study is observational and will not alter the routine management of patients, 
therefore adverse events as a result of treatment received is outside the remit 
of the study and not reportable. 
The histopathology team at Gloucestershire Hospitals NHS FT are aware of 
this study and its design and propose that there will be little chance of tissue 
damage (some patients may have undergone an FNA procedure prior to 
surgery). The histopathologists will inform the research team at once if the use 
of the probe affects the macroscopic or microscopic assessment of the tissue.  
The first 5 biopsy samples will be subject to thorough damage assessment by 
the histopathology team. 
Ethics Approval 
The chief investigator has applied for approval from a Research Ethics 
Committee. The study has been submitted for approval by the Gloucestershire 
Hospitals Scientific Peer Review Committee. 
Patient and public involvement 
Patients at Gloucestershire Hospitals NHS Foundation Trust have been 
contacted. A patient helped review the patient information sheet, and comment 
on the study. Other patients have been invited to complete a questionnaire after 
reading the information sheet and being given the opportunity to ask questions. 
Members of the group commented that they supported this research into the 
new technique especially if it led to more-rapid diagnosis using a minimally-
invasive technique. Several commented on how anxious they felt whilst 
awaiting results. 

 
 
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Consent 
Consent for inclusion in the study will be taken either by the principal 
investigator, co-investigators or named clinician to whom that duty has been 
delegated. 
Consent to enter the study will be sought from each participant only after a full 
explanation has been given, an information sheet offered, and time allowed for 
consideration. Signed participant consent will be obtained prior to analysis of 
tissue samples. The right of the participant to refuse to participate without giving 
reasons will be respected. 
All participants are free to withdraw at any time from the study without giving 
reasons and without prejudicing further treatment. 
See appendices for participant information sheet and participant consent form. 
Confidentiality 
The Chief Investigator will preserve the confidentiality of participants taking part 
in the trial according to the Data Protection Act 1998. 
Human Tissue Act 
This study complies with the regulations set out in the Human Tissue Act 2004. 
Indemnity 
Gloucestershire Hospitals NHS Foundation Trust holds standard NHS Hospital 
Indemnity and insurance cover with NHS Litigation Authority for NHS Trusts in 
England, which apply to this study. 
Audit 
The study may be subject to inspection and audit by Gloucestershire Hospitals 
NHS Foundation Trust as sponsor and other regulatory bodies to ensure 
adherence to GCP and the NHS Research Governance Framework for Health 
and Social Care (2nd edition). 
Progress reports will be submitted to the bi-annual Gloucestershire Hospitals 
Research and Innovation Forum. 
Publication Policy 
Results to be submitted for publication in peer reviewed journals and for 
presentation at relevant scientific meetings. 
 
 
 

 
 
14
REFERENCES 
 
1 
Cancer 
Research 
UK, 
Thyroid 
cancer 
statistics, 
http://www.cancerresearchuk.org/health-professional/cancer-
statistics/statistics-by-cancer-type/thyroid-cancer. 
2 
J. 
Norman, 
Fine 
Needle 
Biopsy 
of 
Thyroid 
Nodules, 
https://www.endocrineweb.com/conditions/thyroid/fine-needle-biopsy-
thyroid-nodules, (accessed 5 February 2018). 
3 
S. C. Kamran, E. Marqusee, M. I. Kim, M. C. Frates, J. Ritner, H. Peters, 
C. B. Benson, P. M. Doubilet, E. S. Cibas, J. Barletta, N. Cho, A. 
Gawande, D. Ruan, J. Moore Francis D., K. Pou, P. R. Larsen and E. K. 
Alexander, J. Clin. Endocrinol. Metab., 2013, 98, 564–570. 
4 
NHS Digital, Hospital Episode Statistics. 
5 
C. A. Jenkins, P. D. Lewis, P. R. Dunstan and D. A. Harris, World J. 
Gastrointest. Oncol., 2016, 8, 427. 
6 
G. R. Lloyd, L. E. Orr, J. Christie-Brown, K. McCarthy, S. Rose, M. 
Thomas and N. Stone, Analyst, 2013, 138, 3900–3908. 
7 
X. Feng, A. J. Moy, H. T. M. Nguyen, J. Zhang, M. C. Fox, K. R. Sebastian, 
J. S. Reichenberg, M. K. Markey and J. W. Tunnell, Biomed. Opt. Express, 
2017, 8, 2835. 
8 
P. Crow, B. Barrass, C. Kendall, M. Hart-Prieto, M. Wright, R. Persad and 
N. Stone, Br. J. Cancer, 2005, 92, 2166–2170. 
9 
J. V. Rau, M. Fosca, V. Graziani, C. Taffon, M. Rocchia, M. Caricato, P. 
Pozzilli, A. Onetti Muda and A. Crescenzi, Sci. Rep., 2017, 7, 14970. 
 
 
 

 
Project Title:  RAFTER 
 
Project Title (Full): RAman For Thyroid cancER 
                                   Biophotonics Research Unit 
Gloucestershire Royal Hospital 
Great Western Road 
Gloucester 
GL1 3NN 
Switchboard: 0300 422 2222 
 
When completed: 1 for participant; 1 for researcher site file; 1 to be kept in medical notes. 
 
 
Appendix 1 
RAFTER Study Consent Form 
IRAS ID: 245612 
Participant Identification Number for this trial: 
CONSENT FORM 
Title of Project: RAFTER (RAman For Thyroid cancER) 
Name of Researcher: Dr Alexander Dudgeon 
Version 1.2, 04 September 2018 
Please 
initial box  
1. I confirm that I have read the information sheet dated. 04/09/2018 (version. 1.2) for the 
above study. I have had the opportunity to consider the information, ask questions and have 
had these answered satisfactorily. 
 
2. I understand that my participation is voluntary and that I am free to withdraw at any time 
without giving any reason, without my medical care or legal rights being affected. 
 
3. I understand that the information collected about me will be used to support 
other research in the future, and may be shared anonymously with other researchers. 
 
4. I agree to take part in the above study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Participant 
 
Date 
 
 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Person 
 
Date 
 
 
 
Signature 
taking consent 

 
Project Title:  RAFTER 
 
Project Title (Full): RAman For Thyroid cancER 
                                   Biophotonics Research Unit 
Gloucestershire Royal Hospital 
Great Western Road 
Gloucester 
GL1 3NN 
Switchboard: 0300 422 2222 
 
 
 
 
 
 
 
 
Appendix 2 
Participant Information Sheet Copy 
Participant Information Sheet: RAFTER 
Version 1.2, 04/09/2018 
Study Title: RAman For Thyroid cancER 
(Developing a new technique for the assessment of swollen thyroid nodule 
conditions) 
You are being invited to take part in a research study.  Before you decide it is important 
for you to understand why the research is being done and what it will involve.  Please 
take time to read the following information carefully and discuss it with others if you wish.  
Ask us if there is anything that is not clear or if you would like more information.  Take 
time to decide whether or not you wish to take part. 
Thank you for reading this. 
What is the purpose of the study? 
This study is being undertaken to develop a new minimally-invasive method for use in the 
diagnosis of thyroid cancer. It is hoped that this technique will improve the care of patients 
by reducing the need for an invasive surgical procedure if no malignant cancer is found. 
Why have I been chosen? 
You have been chosen to take part in this study because your doctor would like you to 
have surgery to investigate the lump in your neck. You may have already had a needle 
biopsy (FNA) and this does not stop you from participating in the study. 
What is the technique that is being tested? 
The diagnostic technique being tested is called Raman spectroscopy. This technique 
allows us to determine the biochemical composition of tissues by measuring the changes 
to specific colours of light shone onto the tissue. This technique is currently also being 
investigated as a way of diagnosing medical conditions in other parts of the body such as 
the lymph nodes, breast and oesophagus. 
We have not used this technique in the thyroid before and this is an initial study to try and 
establish if the type of thyroid diseases that can be identified using this technique. If the 
study were successful, then we would aim to make a device to assess several types of 
thyroid disease using a fine needle technique without the need for tissue biopsies during 
invasive surgery. 

 
 
Do I have to take part? 
It is up to you to decide whether or not to take part.  If you do decide to take part you will 
be given this information sheet to keep and be asked to sign a consent form. If you decide 
to take part you are still free to withdraw at any time and without giving a reason. A 
decision to withdraw at any time, or a decision not to take part, will not affect the standard 
of care you receive. 
What will happen to me if I take part? 
If you decide to take part in the study your normal care will not be affected. The study 
involves an additional test of your biopsy specimen or tissue removed at the time of 
surgery. Participation in the study will not significantly affect or delay the results of your 
routine tests. The research team will then anonymously match the test with your 
pathology results to identify what type of tissue we are measuring. After completing the 
consent form, you will not be required to contribute any more of your time to the study. 
The research team will be provided with your pathology report annonomously , without 
contacting you further. It will not be possible for the researchers to identify who you are 
from these results. 
If you take part in the study then your tissue sample will immediately be measured with 
the new diagnostic test, in theatres. The sample will then continue with standard routine 
diagnosis (histopathology). After the new test has been performed on samples from many 
different participants, analysis will be carried out to see if the test can be used to diagnose 
different thyroid diseases without the need for invasive surgical biopsies. 
Who else will be taking part? 
The research team anticipate that a total of 40 patients will participate in the study. 
What are the possible disadvantages and risks of taking part? 
We do not anticipate that taking part in this study will affect the care you receive from your 
doctor. The pathology team do not expect the additional measurements to affect your 
diagnosis. Samples from participants in the study will be undergo routine testing at the 
same time as samples from patients not participating in the study. It is therefore not 
anticipated that participation in this study will cause a delay in the issuing of 
histopathological results and should not affect the timing of any further treatment you may 
require. 
As we are comparing the new diagnostic technique to the standard analysis the research 
findings will not affect your care or give additional information on your case, but could 
contribute to improved diagnostic tests for the future. 
What are the possible benefits of taking part? 
There is no benefit to your care if you participate in the study, however you will be 
contributing to the development of a new diagnostic technique. If successful this will give 
patients access to instant diagnosis of conditions of the thyroid, without the need for 
invasive surgical tissue biopsies.  
Will my taking part in this study be kept confidential? 
All information which is collected about your diagnosis during this research will be 
provided anonymously to the research team, with the linking to pathology reports will be 

 
 
done with a unique study code. Only your direct care team will have access to your 
personal data. 
What will happen to the results of the research study? 
You will not be identified in any report or publication produced as part of this study.  
Results will be submitted for publication in scientific journals and may be presented at 
scientific meetings. Initial results will be submitted for publication. If you would like a copy 
of the results of the study please contact the principal investigator or project supervisor 
listed at the end of this information sheet. 
Who is organising and funding the research? 
The study is being organised by the Biophotonics Research Unit at Gloucestershire 
Hospitals NHS Foundation Trust and is funded by Focus, the charitable fund for the 
Gloucestershire Oncology Centre the Research and Innovation Forum, part of 
Cheltenham and Gloucester Hospitals Charity, (registered charity no. 1051606). 
Who has reviewed the study? 
This study has been reviewed by the London-West Research Ethics Committee. 
What if something goes wrong? 
Any complaint about the way you have been dealt with during the study or any possible 
harm you might suffer will be addressed. Please raise your concerns in the first instance 
with the Principal Investigator (that is the lead researcher), Dr Alexander Dudgeon, his 
contact details are at the end of this form. If you wish to make a more formal complaint, 
please contact the hospital’s Patient Advice and Liaison Service (PALS) (PALS Office, 
Gloucestershire Royal Hospital, Great Western Road, Gloucester, GL1 3NN, telephone:  
0800 019 3282, e-mail: ghn-tr.pals.gloshospitals@nhs.net). 
What could I do to help researchers use my own experience more when they are 
planning their next project?  
Do you want to get more involved and help researchers improve future project ideas and 
research information leaflets? Please contact “People in Research – Opportunities for 
public involvement in research” http://www.peopleinresearch.org/. If you would like to 
help, you can also contact INVOLVE which is a national advisory group, funded by the 
National Institute for Health Research (NIHR). Its role is to support and promote active 
public 
involvement 
in 
NHS, 
public 
health 
and 
social 
care 
research. 
http://www.invo.org.uk/ or INVOLVE, Alpha House, University of Southampton Science 
Park, Chilworth, Southampton, SO16 7NS, Telephone: 023 8059 5628 Email 
involve@nihr.ac.uk 
 
Thank you for taking the time to read this information and considering 
participation in this research study. 
 
Contact for Further Information 
Principal Investigator 
 

 
 
Dr Alexander Dudgeon 
Post-Doctoral Research Fellow 
Biophotonics Research Unit 
Gloucestershire Royal Hospital 
Great Western Road, 
Gloucester, 
GL1 3NN 
Tel: +44 (0)300 422 5476 
email: alex.dudgeon@nhs.net 
 
Version 1.2 04/09/2018 
 
 

 
 
Appendix 3 
Patient Histology Report 
Example sample information report 
 

 
 
Appendix 4 
Adverse Event Reporting Form 
 
Study Title - RAFTER (RAman For Thyroid cancER) 
Research department use only 
Case reference number: 
Date report received: 
Person making report 
 
 
 
Name: 
 
 
 
 
Job title/role in study: 
 
 
 
 
Contact address: 
 
 
 
 
 
Email address: 
 
 
 
 
Telephone No: 
 
 
 
 
Details of adverse event: 
  
 
 
 
 
 
 
 
 
 
￼  
Signature of person making report:  
_______________________________Date:____/____/____ 
Please send completed reporting form to: 
Dr Alex Dudgeon 
Biophotonics Research Unit 
Leadon House 
GH NHS FT 
GL1 3NN 
 
 
Version 1.0, 7 August 2018 
 
 

 
 
Appendix 5 
Personnel Delegation and Signature Log 
Study title: RAFTER (RAman For Thyroid cancER). 
All those involved in the above study must read the protocol (and amendments if applicable) and 
understand their role as outlined in the protocol 
Name 
(print) 
Job title 
Signature 
Signed 
Initials 
List duty 
categories 
PI signature 
ONLY & date 
Start 
date 
Date of 
leaving 
(if appl.) 
 
Principal 
Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Key for list of duty categories: 
1. Maintaining investigator file 
2. Review & reporting Adverse events & SAE 
3. Archiving 
4. Resolving data queries 
 
 
 
 
 
 
5. Other duties specific to the study, please specify below: 
 
 
 
 
Version 1.0 - 7/08/2018