HAMMERSMITH, QUEEN CHARLOTTE’S & CHELSEA AND ACTON HOSPITALS

RESEARCH ETHICS COMMITTEE

GUIDANCE NOTES

THE COMMITTEE

1.	The Research Ethics Committee (the “REC” or the “Committee”) reports to Ealing, Hammersmith and Hounslow District Health Authority (“the Authority”).  The REC is responsible for ensuring that all research involving human subjects carried out within the School or the Hammersmith Hospitals NHS Trust [excluding Charing Cross Hospital, which is the responsibility of the Riverside Research Ethics Committee] (“the Trust”) conforms to the highest ethical standards.  Details of the Committee membership and Standing Orders are available from the office of the Secretary of the Research Ethics Committee; “the Secretary”.

2.	The Committee expects that all research carried out under its auspices will be in accordance with recognised standards of good clinical practice; in particular the Declaration of Helsinki (Annex 1), the Nuremberg Code (Annex 2) and the ICH/GCP guidelines (copies available from the Secretary or from REC web page: www.geocities.com/hammersmith_lrec/index.html). The Committee will expect all investigators to be aware of the contents of these documents.

PROCEDURE FOR SEEKING APPROVAL

3.	When an investigator wishes to undertake a research project involving human subjects (including studies involving questionnaires, medical notes (Annex 3), fetal tissue (Annex 4) and the recently dead), the investigator must obtain the Research Ethics Committee’s approval before commencing any investigations.

4.	Committee approval is obtained by the investigator first completing one copy of the application form and submitting it for approval to his/her Head of Division and to his/her Divisional Scrutiny Committee (ICSM/Hammersmith Hospital/QCCH/Acton Hospital staff only).  Once the protocol has been approved by the Divisional Scrutiny Committee the original application plus 18 photocopies should be sent to the Secretary.  

NB. All applications must be accompanied by an electronic version (unless hand-written) on disk/e-mail attachment to c.collett@ic.ac.uk. 

The Committee meets every month (except August) and the closing date for each month's meeting is normally eleven working days before the meeting.  The dates of meetings and submission deadlines are published annually and these can be obtained from the Secretary's office/website.

5.	The Committee's decisions are categorized as follows: Approved - the protocol is satisfactory and needs no amendment or correction; Approved in Principle - the protocol is not essentially unethical, but the investigator needs to make some minor amendments before it can be approved (normally by Chairman's action);  Deferred - the Committee decides not to reach a decision but to seek further advice;  Not Approved - the protocol is seriously flawed and requires major revision before it can be reconsidered.  Protocols in this category have to be considered by the full Committee if resubmitted.  Rejected - the study is unethical. 

6.	If the Committee approves the project for registration without amendment, the protocol will be signed by the Chairman and an approval letter and signed copies of the information sheet(s) returned to the principal investigator.  The original submission will be retained in the Secretary's office.

7.	If the Committee defers approval, the Secretary will notify the Principal Investigator in writing and, when appropriate, discuss the amendments necessary to secure approval.

INSTRUCTIONS FOR COMPLETING THE APPLICATION FORM

8.	The Application Form is read by all members of the Committee, the majority of whom are not expert in your particular field.  Consequently, you must make every effort to complete the form in lay terms and only use jargon when there is no alternative.  When having to use jargon, remember that each term must be explained.

9.	Sections 1 to 10 are relevant to the majority of applications to the Research Ethics Committee.  Investigators wishing to carry out studies using patient case notes should refer to Annex 1.  Protocols proposing the use of fetal material will need to adhere to the Polkinghorne Code of Practice (Annex 4).

10.	Section 1: Title of proposed research:  It is important that the title is relatively short and written in language easily understood by a lay readership.  In addition, it is important that the title on the protocol is the same as that on the Information Sheet.

11.	Section 2:  Investigators:  It is important that this section is completed as accurately as possible. It is important that the person responsible for coordinating the research is named as the Principal Investigator as all correspondence will be addressed to him/her.

12.	Section 3:  Compensation for death or personal injury:  This section must be completed.  If the project is to be sponsored by a commercial company, it is important that the Committee is made aware of this.  It is important that you give a contact name and address and note that the company will be invoiced to pay an administration charge of £750 (£500 for MREC approved submissions). Applications lacking this information will not be accepted. N.B. If the study is covered by a sponsoring company's indemnity a copy of the "Form of Indemnity for Clinical Studies" (appendix 3) must be submitted bearing BOTH Trust and Company signatures. Studies will not be approved until a signed copy this indemnity form is received.

13.	The question of the compensation of participants who suffer harm as a result of taking part in a research project is a complex one, in which the NHS Indemnity, the membership of the investigator of a medical negligence insurance organization, and guarantees provided by sponsoring organizations all play a part.  Approval will only be given to drug company-sponsored research projects where the company concerned has agreed to accept the ABPI Guidelines for compensation, under which the sponsoring company undertakes to compensate patients or volunteers who may be harmed without the necessity for the patient or volunteer first to prove negligence.  The School has taken out insurance of its own to offer further protection to healthy volunteers who cannot be covered by the APBI Guidelines. Any trial conducted under the auspices of Imperial College is covered under the Imperial College "no-fault" indemnity scheme.  Under this scheme a claimant does not need to show negligence on behalf of the investigators, nor that the drug/device used was inherently faulty, they need only show that there was a causal link between their participation in a study and they adverse reaction they had suffered. Any person involved in conducting such a study - whether an employee of the College or an associated NHS trust, or indeed anyone else who is acting on the College's behalf - is individually protected (under the normal rules of vicarious liability).

14.	The Committee has decided that it is important that participants in research studies are fully informed of compensation arrangements.  Consequently it is important that this information is included on the information sheet given to potential participants when consent is being taken. Investigators should be clear that these compensation arrangements apply only to participation in research projects approved by the Research Ethics Committee.

15.	The Committee has agreed that the following forms of words are appropriate for use on Information Sheets:
a)	Commercially sponsored studies: “The sponsoring company (..........) has agreed to abide by the Association of the British Pharmaceutical Industry's (ABPI) Good Practice guidelines with regard to compensation in the event of your suffering any adverse effects as a consequence of your participation in this study.”

b)	In the case of non-therapeutic studies involving volunteers (ie healthy subjects and some patients): “In the event of your suffering any adverse effects as a consequence of your participation in this study, you will be compensated through the Imperial College School of Medicine’s “No Fault” Compensation Scheme.” 

c)	Therapeutic research or research carried out by employees of Hammersmith Hospitals NHS Trust:  “Hammersmith Hospitals NHS Trust (“the Trust”), like Government and many other publicly funded bodies, does not insure.  In the absence of any other arrangements, therefore, the Trust will give sympathetic consideration to claims for compensation for adverse effects suffered as a result of participation in any study organized by it or its employees.”

d)	Clinical research is to be undertaken under the sole medical direction of MRC-employed consultants:  “The Medical Research Council (MRC), like Government and many other public-funded bodies, does not insure.  In the absence of any other arrangements, therefore, the MRC will give sympathetic consideration to claims for compensation for adverse effects suffered as a result of participation in any study organized by the MRC or its employees.”

16.	Section 4:  Research:  This section allows you to give a full description of your proposal, including the hypothesis you wish to test (it is advisable to have only one per application), the scientific or clinical background and rationale to the proposal and the design and methodology of the study (including statistical analysis).

a)	Section 4(5)i:  Drugs:
i)	The manufacture, sale and importation of drugs is controlled by statute administered by the Medicine Controls Agency.  There is, however, often confusion as to when a Product Licence (PL), Clinical Trial Certificate (CTC), Clinical Trial Exemption Scheme (CTX) or Doctors and Dentists Exemption Scheme (DDX) are appropriate when applying for ethical approval of a clinical trial involving the giving of medicines to patients (studies on healthy volunteers do not require certification).  The REC will expect applicants to have the appropriate certificate/exemption before final approval of their protocol will be given.  A summary of the different certificates/exemptions is at Annex 5.
ii)	Pharmacy should have copies of all protocols of clinical trials using drugs and will hold randomisations for emergency code breaks.  All clinical trial supplies must be stored in the Pharmacy and prescriptions written for them in the normal way.  The Clinical trial protocol must specify who is entitled to administer the drug.
iii)	Investigators should make every effort to persuade the sponsoring companies of drug trials to agree to continue to supply the study drug on a named patient basis to those patients who feel they have benefited from it. Such negotiations should be completed before submission of the application form to the Committee.

b)	Section 4(5)ii:  Devices: Since 1 January 1993 regulations governing the use of active implantable devices (eg cardiac pacemakers, neurostimulators and infusion pumps) have been in force. On 1 January 1995 further regulations came into force implementing another, more wide-ranging, directive, which covers all other implantable devices.  A third directive will cover any medical device, reagent, reagent product, kit, instrument, apparatus or system which is intended to be used in vitro for the examination of substances derived from the human body.  It seems likely that this directive will come into force sometime after 1996.  These directives are enforced in the UK by the Medical Devices Directorate from which more information can be obtained.  Unlike the MCA, the MDD  expects research protocols to have been approved by a REC before it will consider giving a device approval for use in an experimental situation.

c)	4(5)(iii)(e): Anonymisation of samples for genetic studies
	
Definitions of types of tissue sample:  
Anonymous (unidentified) samples come from unknown or unidentifiable sources. There is no way of tracing them to any particular person. 

Anonymised (unlinked) samples previously had individual identifiers (proper names or codes) but these have been deliberately removed before giving the samples to the researchers.

Coded (‘linked’ or ‘identifiable’) samples can be matched with individuals through a numbered code. Access to the code linking numbers to names is restricted to a small number of people, researchers receive only the number, not the names.

Identified samples contain either a name or a patient number that researchers can match with a name.

An alternative terminology is used in the MRC’s Guidelines on Personal Information in Medical Research (October 2000):

Unlinked anonymised data contains no information that could reasonably be used, by anyone, to identify people.

Linked anonymised data is anonymous to the people that receive and hold it (eg a research team) but contains information or codes who would then allow others (eg those responsible for the individual’s care) to identify people from it.

Coded data is identifiable personal information in which the details that could identify people are concealed in a code, but which can be readily de-coded by those using it. It is not anonymised data.

d)	Section 4(5)vii: Irradiation:  Guidelines have been issued which cover the irradiation of human subjects for the purposes of research.  The main points are summarized below:

i)		irradiation of humans for research purposes requires the approval of the local ethics committee;
ii)		"irradiation" includes both radioisotopes and X-rays;
iii)		where radioisotopes are being administered, a certificate issued by the Department of Health’s Administration of Radioactive Substances Advisory Committee (ARSAC) will be required.  Application to the REC should refer to the number of the Certificate and a copy of the Certificate should be included with the submission.  Investigators should note that final approval will only be given after presentation of the ARSAC Certificate to the REC;
iv)	the total radiation dose [expressed as the effective dose equivalent (EDE) in mSv] must be calculated beforehand, and must be broken down into the dose (if any) resulting from the clinical procedure and the dose arising from the research procedure;
v)		research projects are categorized (see Table below) according to the radiation dose arising from the research procedure;
vi)	projects involving doses higher than Cat. III will not normally be permitted;
vii)	investigators should consider recruiting older subjects whenever possible in an attempt to minimize the long term risks of irradiation;
viii)	persons under 18 will be accepted only if the project is specific to their age group;
ix)	irradiation of the under 18 age group is permissible only for Category I projects and with the permission of the parents or guardians;
x)	pregnant women will not be accepted unless the project concerns pregnancy specifically;
xi)	the minimum number of subjects should be used to avoid unnecessary irradiation;
xii)	volunteers (i.e. patients and controls) should be asked whether they have participated in other projects, particularly those involving radiation, during the preceding year, so that their total dose can be limited.  The irradiation of controls must be recorded in duplicate books available from the Radiation Protection Service.  On each irradiation a record should be made in the forms contained in the book, the original being retained by the Investigator, one copy being retained by the control concerned, the other copy being sent to the Radiation Protection Service;
xiii)	Information Sheets should give radiation exposures in terms of multiples of the annual background radiation exposure in the UK (2.5 mSv per annum);
xiv)	classified workers should not normally volunteer.
xv)	Categories of Research Project Involving the Irradiation of Human Beings:

Category	Radiation Dose 	Level of Risk
			(mSv EDE)
	I (low)		<0.2		Trivial:  within the variations in the 							natural background radiation between 						different regions of the UK.
	II (med.)	0.2 - 2		Small:  comparable with natural 
				background radiation. Within the annual				dose limits for members of the public.
III (high)	2 - 20		Significant:  risk of a fatal induced cancer 					is between 1 in 10,000 and 1 in 1,000.  					Investigator should be aware that 						projects in this category are likely to be					examined closely by the Committee. The 					Committee is likely to recommend that 					subjects of 35 years and older be recruited 					to studies in category III unless adequate 					justification for the recruitment of younger 					subjects is given.
		
17.	Section 5: The Subjects

a)	Section 5(4)f&g: Payments: Payments may be made to participants for reimbursement of traveling and out-of-pocket expenses and loss of earnings.  An investigator who wishes to make any other payment must state his reasons for wishing to do so at the time of submission of the research project for approval.

b)	Section 5(5):  Consent: The Committee will not authorize any experimental procedure, invasive or non-invasive, in subjects or controls unless fully informed consent is obtained prior to the procedure being carried out.  Oral consent will be approved by the Committee only for trivial or minimal risk procedures (e.g. questionnaires or a blood sample; not including genetic studies): for all other procedures written consent will be required. 

c)	In accordance with the definition in the MRC publication "Responsibility in Investigations on Human Subjects" (Cmnd 2382), fully informed consent in this context means consent freely given with proper understanding of the nature and consequences of what is proposed.  Normally this means that the participant needs to be given time to consult with a third party (e.g. a genetic counsellor, a priest etc), relatives or his/her GP before giving consent.

d)	If it is proposed that research be conducted on persons who are not able to give fully informed consent on their own behalf justification for this must be clearly stated; furthermore, it is expected that the “consent” of the key carer will be sought.  The application should specify if key carer “consent” will be required and a relative/carer information sheet written. In this case the relative/carer should sign the "Statement for Relatives/Carers" sheet. 

(NB. 	It should be noted, however, that under English law nobody may give consent on behalf of another. The “consent” of a relative/carer on behalf of the patient has no legal basis and indeed the Law Commission has stated that “As a matter of law such “consent” is meaningless”)

e)	Important special considerations relate to research projects involving children and the Committee has adopted the recommendations of the Institute of Medical Ethics Working Group Report "Medical Research with Children: Ethics Law and Practice" in respect of the consent of children to their taking part in research projects.  These recommendations are summarized in the following paragraphs:
•	the assent of parents or guardians of children must always be obtained; the consent of children aged 7-18 should be sought;
•	consent should be deemed not to have been given if the parent or guardian of a child below 16 refuses assent, or if a child over 14 years refuses consent;
•		notwithstanding the desirability of seeking the child's consent, for a child aged 7 to 14 years the decision of a parent or guardian to give assent for a therapeutic research procedure (i.e. a procedure intended to benefit the person on which the research is carried out) may be deemed to override the refusal of the child to consent;
•		a non-therapeutic research procedure (i.e. one which could not benefit the person on which it was carried out) should not be carried out if a potential child subject aged 7 to 14 refuses to consent.

f)	Information Sheet and Consent Form/Statement for Relatives/Carers etc.

	The Information Sheet for Patients and Healthy Volunteers and the “Participant Consent Form” and “ Statement for Relatives/Carers etc.” can be found at Appendices 1 and 2(a)&(b) of the application form.  The Information Sheet must be completed with a statement from the Investigator.  

		In preparing your Information Sheet you might find the following checklist useful.  The Committee will expect the following points (as appropriate) to be addressed in your Information Sheet:

•	rationale and objectives of the research (including a statement of your hypothesis in lay language);
•	what is to be learnt/potential benefit to subject (if any; explain)/potential benefit to others;
•	exclusion criteria (e.g. pregnancy, breastfeeding);
•	what will happen to the subject if he/she volunteers;
•	how long will their involvement take/how many extra visits to hospital/how long will each visit be;
•	drug or device - expected side effects/what stage of testing (e.g. phase I-IV)/how many people have experienced the drug/device before;
•	will subjects be randomized to different treatment/placebo arms;
•	will subjects be exposed to ionizing radiation;
•	what are the standard/alternative treatments;
•	what are the risks/discomforts/inconvenience;
•	confidentiality/privacy/anonymity in published data;
•	compensation arrangements;
•	how will subjects be told of results;
•	communication with GPs/before/after/with results.

The Hammersmith REC require all information sheets to be written using the following guidelines originally prepared by the Scottish Office/COREC:

Information Sheet - Guidance

The guidance that follows applies primarily to multi-centre pharmaceutical studies and encompasses the ICH Good Clinical Practice guidelines. However, the principles and much of the content will be of use to researchers writing information sheets in their particular fields, for trials involving patients, patient volunteers and healthy volunteers. You will find it helpful to refer also to other guidelines produced for writing patient information sheets.

Potential recruits to your research study must be given sufficient information to allow them to decide whether or not they want to take part. An Information Sheet should contain information under the headings given below where appropriate, and in the order specified. It should be written in simple, non-technical terms and be easily understood by a lay person. Use short words, sentences and paragraphs. ‘The readability’ of any text can be roughly estimated by the application of standard formulae. Checks on readability are provided in most word processing packages.

Consumers for Ethics in Research (CERES) publish a leaflet entitled ‘Medical Research and You’. This leaflet gives more information about medical research and looks at some questions potential recruits may want to ask. You may obtain copies from CERES, PO Box 1365, London N16 0BW.

Information Sheet for Research Participants

You will be given a copy of this Information Sheet

1.	Study title
Is the title self explanatory to a lay person? If not, a simplified title should be included.
2.	Invitation paragraph
This should explain that the patient is being asked to take part in a research study. The following is a suitable example:

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.

We will be happy to let you have a copy of the leaflet entitled ‘Medical Research and You’ published by Consumers for Ethics in Research (CERES). This leaflet gives more information about medical research and looks at some questions you may want to ask. (NB. Investigators may obtain copies from CERES, PO Box 1365, London N16 0BW.)

Thank you for reading this.’

3.	What is the purpose of the study?
The background and aim of the study should be given here. Also mention the duration of the study.
4.	Why have I been chosen?
You should explain how the patient was chosen and how many other patients will be studied.
5.	Do I have to take part?
You should explain that taking part in the research is entirely voluntary. You could use the following paragraph:-
‘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.
6.	What will happen to me if I take part?
You should say how long the patient will be involved in the research, how long the research will last (if this is different), how often they will need to visit a clinic (if this is appropriate) and how long these visits will be. You should explain if the patient will need to visit the GP (or clinic) more often than for his/her usual treatment and if travel expenses are available. What exactly will happen e.g. blood tests, x-rays, (over and above those involved in standard diagnosis and treatment), interviews etc.? Whenever possible you should draw a simple flowchart or plan indicating what will happen at each visit. What are the patient’s responsibilities? Set down clearly what you expect of them.
You should set out simply the research methods you intend to use - the following simple definitions may help:-
Randomised Trial:
Sometimes because we do not know which way of treating patients is best, we need to make comparisons. People will be put into groups and then compared. The groups are selected by a computer which has no information about the individual – i.e. by chance. Patients in each group then have a different treatment and these are compared.
You should tell the patients what chance they have of getting the study drug/treatment e.g. a one in four chance.
Blind trial:
In a blind trial you will not know which treatment group you are in. If the trial is a double blind trial, neither you nor your doctor will know in which treatment group you are (although, if your doctor needs to find out he/she can do so).
Cross-over trial:
In a cross-over trial the groups each have the different treatments in turn. There may be a break between treatments so that the first drugs are cleared from your body before you start the new treatment.
Placebo:
A placebo is a dummy treatment such as a pill which looks like the real thing but is not. It contains no active ingredient.
7.	What do I have to do?
Are there any lifestyle restrictions? You should tell the patient if there are any dietary restrictions. Can the patient drive?, drink?, take part in sport? Can the patient continue to take their regular medication? Should the patient refrain from giving blood? What happens if the patient becomes pregnant?
Explain (if appropriate) that the patient should take the medication regularly.
8.	What is the drug or procedure that is being tested?
You should include a short description of the drug or device and give the stage of development.
You should also state the dosage of the drug and method of administration. Patients entered into drug trials should be given a card (similar to a credit card) with details of the trial they are in. They should be asked to carry it at all times.
9.	What are the alternatives for diagnosis or treatment?
For therapeutic research the patient should be told what other treatments are available.
10.	What are the side effects of any treatment received when taking part?
For any new drug or procedure you should explain to the patients the possible side effects. If they suffer these or any other symptoms they should report them next time you meet. You should also give them a contact name and number to phone if they become in any way concerned. The name and number of the person to contact in the event of an emergency (if that is different) should also be given.
The known side effects should be listed in terms the patient will clearly understand (e.g. ‘damage to the heart’ rather than ‘cardiotoxicity’; ‘abnormalities of liver tests’ rather than ‘raised liver enzymes’). For any relatively new drug it should be explained that there may be unknown side effects.
11.	What are the possible disadvantages and risks of taking part?
For studies where there could be harm to an unborn child if the patient were pregnant or became pregnant during the study, the following (or similar) should be said: 
‘It is possible that if the treatment is given to a pregnant woman it will harm the unborn child. Pregnant women must not therefore take part in this study, neither should women who plan to become pregnant during the study. Women who are at risk of pregnancy may be asked to have a pregnancy test before taking part to exclude the possibility of pregnancy. Women who could become pregnant must use an effective contraceptive during the course of this study. Any woman who finds that she has become pregnant while taking part in the study should immediately tell her research doctor.’
Use the pregnancy statement carefully. In certain circumstances (e.g. terminal illness) it would be inappropriate and insensitive to bring up pregnancy.
There should also be an appropriate warning and advice for men if the treatment could damage sperm which might therefore lead to a risk of a damaged fetus.
If future insurance status e.g. for life insurance or private medical insurance, could be affected by taking part this should be stated (if e.g. high blood pressure is detected.) If the patients have private medical insurance you should ask them to check with the company before agreeing to take part in the trial. They will need to do this to ensure that their participation will not affect their medical insurance.
You should state what happens if you find a condition of which the patient was unaware. Is it treatable? What are you going to do with this information? What might be uncovered?

The following paragraph should be used in studies where the possibility exists that information might be discovered which could have implications for the participants’ health (e.g. MRI/PET studies):

You should be aware that there is a possibility that the methods used in this study may produce an unexpected result that may have relevance for your health. In the unlikely event of this happening, we will discuss this with you and, if necessary, provide any support that you may require, such as arranging follow-up tests and/or treatment.

12.	What are the possible benefits of taking part?
Where there is no intended clinical benefit to the patient from taking part in the trial this should be stated clearly.
It is important not to exaggerate the possible benefits to the particular patient during the course of the study, e.g. by saying they will be given extra attention. This could be seen as coercive. It would be reasonable to say something similar to:
‘We hope that both (all) the treatments will help you. However, this cannot be guaranteed. The information we get from this study may help us to treat future patients with (name of condition) better.’
 13.	What if new information becomes available?
If additional information becomes available during the course of the research you will need to tell the patient about this. You could use the following:-
‘Sometimes during the course of a research project, new information becomes available about the treatment/drug that is being studied. If this happens, your research doctor will tell you about it and discuss with you whether you want to continue in the study. If you decide to withdraw your research doctor will make arrangements for your care to continue. If you decide to continue in the study you will be asked to sign an updated consent form.
Also, on receiving new information your research doctor might consider it to be in your best interests to withdraw you from the study. He/she will explain the reasons and arrange for your care to continue.’
14.	What happens when the research study stops?
If the treatment will not be available after the research finishes this should be explained to the patient. You should also explain to them what treatment will be available instead. Occasionally the company sponsoring the research may stop it. If this is the case the reasons should be explained to the patient.
15.	What if something goes wrong?
You should inform patients how complaints will be handled and what redress may be available. Is there a procedure in place? You will need to distinguish between complaints from patients as to their treatment by members of staff (doctors, nurses etc.) and something serious happening during or following their participation in the trial i.e. a reportable serious adverse event.
Where there are no Association of the British Pharmaceutical Industry (ABPI) or other no-fault compensation arrangements, and the study carries risk of physical or significant psychological harm, the following (or similar) should be said:
‘If you are harmed by taking part in this research project, there are no special compensation arrangements. If you are harmed due to someone’s negligence, then you may have grounds for a legal action but you may have to pay for it. Regardless of this, if you wish to complain, or have any concerns about any aspect of the way you have been approached or treated during the course of this study, the normal National Health Service complaints mechanisms should be available to you.’
Where there are ABPI or other no-fault compensation arrangements the following (or similar) should be included:
‘Compensation for any injury caused by taking part in this study will be in accordance with the guidelines of the Association of the British Pharmaceutical Industry (ABPI). Broadly speaking the ABPI guidelines recommend that ‘the sponsor’, without legal commitment, should compensate you without you having to prove that it is at fault. This applies in cases where it is likely that such injury results from giving any new drug or any other procedure carried out in accordance with the protocol for the study. ‘The sponsor’ will not compensate you where such injury results from any procedure carried out which is not in accordance with the protocol for the study. Your right at law to claim compensation for injury where you can prove negligence is not affected. Copies of these guidelines are available on request.’
Research carried out by employees of Imperial College: “In the event of your suffering any adverse effects as a consequence of your participation in this study, you will be compensated through the Imperial College School of Medicine’s “No Fault” Compensation Scheme.”
16.	Will my taking part in this study be kept confidential?
You will need to obtain the patient’s permission to allow restricted access to their medical records and to the information collected about them in the course of the study. You should explain that all information collected about them will be kept strictly confidential. A suggested form of words for drug company sponsored research is:
‘If you consent to take part in the research any of your medical records may be inspected by the company sponsoring (and/or the company organising) the research for purposes of analysing the results. They may also be looked at by people from the company and from regulatory authorities to check that the study is being carried out correctly. Your name, however, will not be disclosed outside the hospital/GP surgery.’
or for other research:-
‘All information which is collected about you during the course of the research will be kept strictly confidential. Any information about you which leaves the hospital/surgery will have your name and address removed so that you cannot be recognised from it.’
You should always bear in mind that you, as the researcher, are responsible for ensuring that when collecting or using data, you are not contravening the legal or regulatory requirements in any part of the UK. This is not the responsibility of the REC.
You should explain that for studies not being conducted by a GP, the patient’s own GP will be notified of their participation in the trial. This should include other medical practitioners not involved in the research who may be treating the patient. You should seek the patient’s agreement to this. In some instances agreement from the patient that their GP can be informed is a precondition of entering the trial.
17.	What will happen to the results of the research study?
You should be able to tell the patients what will happen to the results of the research. When are the results likely to be published? Where can they obtain a copy of the published results? Will they be told which arm of the study they were in? You might add that they will not be identified in any report/publication.
18.	Who is organising and funding the research?
The answer should include the organisation or company sponsoring or funding the research (e.g. Medical Research Council, Pharmaceutical Company, charity, academic institution).
The patient should be told whether the doctor conducting the research is being paid for including and looking after the patient in the study. This means payment other than that to cover necessary expenses such as laboratory tests arranged locally by the researcher, or the costs of a research nurse. You could say:-
‘The sponsors of this study will pay (name of hospital department or research fund) for including you in this study’ or
‘Your doctor will be paid for including you in this study.’
19.	Who has reviewed the study?
You may wish to give the name of the Research Ethics Committee(s) which reviewed the study (you do not however have to list the members of the Committee).
20.	Contact for Further Information
You should give the patient a contact point for further information. This can be your name or that of another doctor/nurse involved in the study.
Remember to thank your patient for taking part in this study!
The patient information sheet should be dated and given a version number.
The Patient Information Sheet should state that the patient will be given a copy of the information sheet and a signed consent form to keep.

THIS INFORMATION SHEET IS VALID FOR USE UNTIL : 

Signed (REC Chairman)           Date:

18.	A copy of the Information Sheet must be given to the subject to keep.  The signed copy of the form of consent or statement for relatives/carers etc. should be retained, along with the other forms relevant to the project and bound together in book form and kept in the laboratory, accessible for inspection by the Secretary if required.  A copy of the consent form should also be filed among the patient's notes and in addition copies of ALL signed patient consent forms must be sent to the Hammersmith Hospitals Trust's central repository for safe-keeping. Signed consent forms should be sent to:

Consent Form Repository
R&D Office
Hammersmith House
Hammersmith Hospital

	Responsibility lies with the principal investigator to produce, when required by the Committee, evidence that informed written consent has been obtained.  In submitting an application Investigators must ensure that the Information Sheet(s) and the Consent Form(s) are on separate sheets.

19.	Section 5(6): General Practitioners: The GP of every participant in a study approved by the Committee should normally be informed by letter.  The letter should provide sufficient information about the study to enable the GP to answer queries from his/her patient and should give a reliable contact name and telephone number.

20.	Recording in Patients’ Notes: If a patient agrees to participate in a research project a note to this effect, and the appropriate Research Ethics Committee study number, must be recorded in the patient's notes (inside front cover).

21.	Section 6:  Financial and other arrangements:  In this section should be described the financial basis on which a particular project is to proceed.  For example the Committee will wish to know the value of the contract and the payment being made to the investigators for each patient recruited to a clinical trial.

22.	Section 7: Curriculum Vitae of Investigator(s):  Under ICH Guidelines the REC is required to obtain the CV's of all investigators involved in the study so as to be able to consider their qualifications for the proposed trial.

23.	Sections 8,9&10:  Declaration, Signatures and Divisional Approval: It is important that all the applicants sign the application form as this confirms their involvement in the project and their acceptance of the protocol as submitted.  Similarly, applications from ICSM staff will not be accepted unless they have been approved by the principal investigator’s Division(s).  In this regard, it is important that all applications are considered by the relevant ICSM Divisional scrutiny committee, before submission to the REC.  The role of the Divisional committee is primarily to assess the scientific validity of the project, although consideration of ethical issues will also take place.  Lastly, applications will not be accepted unless they have been signed by the chair of the Divisional committee and by the Divisional head or his/her designated signatory.

24.	Notes of Guidance and Application Form in Electronic Media: The text of the Notes of Guidance for Investigators and the Application can be copied on to pre-formatted 3½" floppy disks in Word for Windows for IBM compatible PCs. Alternatively the Application Form and Guidance Notes may be obtained from the REC Web page or via e-mail attachment from c.collett@ic.ac.uk 

	NB. All applications must be accompanied by an electronic version (unless hand-written) on disk/e-mail attachment. Please contact the Office of the Secretary/see website for details.

25.	Any queries about the application form, or approval procedures in general, should be directed to the Secretary.
26.	Summary of Investigators’ Responsibilities:

i)	To read the notes of guidance carefully and submit an application form to the Research Ethics Committee if appropriate.

ii)	To obtain informed consent - in most cases in writing.

iii)	To keep the signed consent forms with the research records for 15 years as well as keeping copies in the patient’s medical records for the statutory life of the records so that they may be inspected on request ( Royal College of Physicians guidelines: para 7.47).

iv)	To inform the Research Ethics Committee immediately of any adverse events even if they occurred at some other centre taking part in the research.

v)	To obtain the Research Ethics Committee’s approval for any changes to the protocol. This includes any increase in the number of subjects whom it is desired to study.

vi)	To maintain the confidentiality of information obtained about the subjects studied 

vii)	To provide data about the subjects studied and to produce the signed consent forms when requested by the Research Ethics Committee for audit purposes.

	In cases of uncertainty, consult with the Research Ethics Committee’s secretariat or with the Chairman.

Annex 1

WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI

WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 

Adopted by the 18th WMA General Assembly
Helsinki, Finland, June 1964
and amended by the
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
and the
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
A. INTRODUCTION 
1. 
The World Medical Association has developed the Declaration of Helsinki as a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects. Medical research involving human subjects includes research on identifiable human material or identifiable data.
2. 
It is the duty of the physician to promote and safeguard the health of the people. The physician's knowledge and conscience are dedicated to the fulfillment of this duty.
3. The Declaration of Geneva of the World Medical Association binds the physician with the words, "The health of my patient will be my first consideration," and the International Code of Medical Ethics declares that, "A physician shall act only in the patient's interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient." 4. 
Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects.
5. 
In medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society.
6. The primary purpose of medical research involving human subjects is to improve prophylactic, diagnostic and therapeutic procedures and the understanding of the aetiology and pathogenesis of disease. Even the best proven prophylactic, diagnostic, and therapeutic methods must continuously be challenged through research for their effectiveness, efficiency, accessibility and quality. 7. 
In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic procedures involve risks and burdens. 
8. 
Medical research is subject to ethical standards that promote respect for all human beings and protect their health and rights. Some research populations are vulnerable and need special protection. The particular needs of the economically and medically disadvantaged must be recognized. Special attention is also required for those who cannot give or refuse consent for themselves, for those who may be subject to giving consent under duress, for those who will not benefit personally from the research and for those for whom the research is combined with care. 
9. 
Research Investigators should be aware of the ethical, legal and regulatory requirements for research on human subjects in their own countries as well as applicable international requirements. No national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections for human subjects set forth in this Declaration.
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 10. 
It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human subject. 
11.
Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, where appropriate, animal experimentation.
12. Appropriate caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research must be respected.
13. The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol. This protocol should be submitted for consideration, comment, guidance, and where appropriate, approval to a specially appointed ethical review committee, which must be independent of the investigator, the sponsor or any other kind of undue influence. This independent committee should be in conformity with the laws and regulations of the country in which the research experiment is performed. The committee has the right to monitor ongoing trials. The researcher has the obligation to provide monitoring information to the committee, especially any serious adverse events. The researcher should also submit to the committee, for review, information regarding funding, sponsors, institutional affiliations, other potential conflicts of interest and incentives for subjects. 14. The research protocol should always contain a statement of the ethical considerations involved and should indicate that there is compliance with the principles enunciated in this Declaration. 15. Medical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given consent. 16. 
Every medical research project involving human subjects should be preceded by careful assessment of predictable risks and burdens in comparison with foreseeable benefits to the subject or to others. This does not preclude the participation of healthy volunteers in medical research. The design of all studies should be publicly available.
17. Physicians should abstain from engaging in research projects involving human subjects unless they are confident that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians should cease any investigation if the risks are found to outweigh the potential benefits or if there is conclusive proof of positive and beneficial results. 18. Medical research involving human subjects should only be conducted if the importance of the objective outweighs the inherent risks and burdens to the subject. This is especially important when the human subjects are healthy volunteers. 19. Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research. 20. 
The subjects must be volunteers and informed participants in the research project.
21. 
The right of research subjects to safeguard their integrity must always be respected. Every precaution should be taken to respect the privacy of the subject, the confidentiality of the patient's information and to minimize the impact of the study on the subject's physical and mental integrity and on the personality of the subject.
22. In any research on human beings, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. The subject should be informed of the right to abstain from participation in the study or to withdraw consent to participate at any time without reprisal. After ensuring that the subject has understood the information, the physician should then obtain the subject's freely-given informed consent, preferably in writing. If the consent cannot be obtained in writing, the non-written consent must be formally documented and witnessed. 23. 
When obtaining informed consent for the research project the physician should be particularly cautious if the subject is in a dependent relationship with the physician or may consent under duress. In that case the informed consent should be obtained by a well-informed physician who is not engaged in the investigation and who is completely independent of this relationship. 
24. For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a legally incompetent minor, the investigator must obtain informed consent from the legally authorized representative in accordance with applicable law. These groups should not be included in research unless the research is necessary to promote the health of the population represented and this research cannot instead be performed on legally competent persons. 25. When a subject deemed legally incompetent, such as a minor child, is able to give assent to decisions about participation in research, the investigator must obtain that assent in addition to the consent of the legally authorized representative. 26. 
Research on individuals from whom it is not possible to obtain consent, including proxy or advance consent, should be done only if the physical/mental condition that prevents obtaining informed consent is a necessary characteristic of the research population. The specific reasons for involving research subjects with a condition that renders them unable to give informed consent should be stated in the experimental protocol for consideration and approval of the review committee. The protocol should state that consent to remain in the research should be obtained as soon as possible from the individual or a legally authorized surrogate.
27. Both authors and publishers have ethical obligations. In publication of the results of research, the investigators are obliged to preserve the accuracy of the results. Negative as well as positive results should be published or otherwise publicly available. Sources of funding, institutional affiliations and any possible conflicts of interest should be declared in the publication. Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication. C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE 28. The physician may combine medical research with medical care, only to the extent that the research is justified by its potential prophylactic, diagnostic or therapeutic value. When medical research is combined with medical care, additional standards apply to protect the patients who are research subjects.

29. The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists. 30. 
At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.
31. 
The physician should fully inform the patient which aspects of the care are related to the research. The refusal of a patient to participate in a study must never interfere with the patient-physician relationship.
32. 
In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not exist or have been ineffective, the physician, with informed consent from the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. Where possible, these measures should be made the object of research, designed to evaluate their safety and efficacy. In all cases, new information should be recorded and, where appropriate, published. The other relevant guidelines of this Declaration should be followed.

	Annex 2
THE NUREMBERG CODE

The Nuremberg Code arose as part of the trial of the United States v. Karl Brandt. Karl Brandt and others were tried at Nuremburg for crimes against humanity committed in their roles as the Nazi high command. The code has ten requirements: 

1.The voluntary consent of the human subject is absolutely essential. This means that  the person involved should have legal capacity to give consent: should be so situated as to be able to exercise free power of choice without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and their effects upon his health or person which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs, or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity. 

2.The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature. 

3.The experiment should be so designed and based on the results of animal
experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment. 

4.The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury. 

5.No experiment should be conducted where there is a prior reason to believe that death or disabling injury will occur, except perhaps, in those experiments where the experimental physicians also serve as subject. 

6.The degree of risk to be taken should never exceed that determined by the
humanitarian importance of the problem to be solved by the experiment. 

7.Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability or death. 

8.The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment. 

9.During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible. 

10.During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill, and careful judgment required of him, that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

Annex 3

RESEARCH STUDIES INVOLVING HOSPITAL CASE NOTES

1.	The Department of Health has stipulated in its published guidance for Local Research Ethics Committees that LRECs must be consulted about any research proposal involving access to the records of past or present NHS patients.

2.	Where it is proposed therefore to conduct a research study involving the case notes of current or ex-patients, the following guidelines must be observed:

a)	All such studies must be submitted to the Research Ethics Committee for approval.  Applications where the study only involves an examination of case notes may be made to the Committee in the form of a letter to the Chairman.  

b)	This letter should state:

i)	in simple terms the purpose of and justification for the study;
ii)	the number of patients to be studied and the methods of statistical analysis to be used (if relevant);
iii)	that permission has been obtained from the doctor responsible for the relevant aspect of the patient's care to study the case notes (a copy of the relevant authorization should be attached);
iv)	if it is proposed to contact patients, what methods will be used; in particular, what measures will be used to ensure that letters are not addressed to deceased patients.  As a general rule, the Committee expects contact to be made through the patient's GP and not direct with the patient.  (No approach should be made to the patient concerned without the agreement of the doctor currently responsible for their care.).

3.	If, however, the study will include other procedures involving human subjects (e.g. interviews with patients or their relatives) the standard application form for Research Ethics Committee approval must be submitted with the letter.

4.	The REC protocol number given to the study should be written on the inside front cover of the patients' notes.

RESEARCH OR AUDIT?

5.	It has been agreed by the DoH that the use of patients' notes for audit purposes does not require LREC review. However, it is often difficult to decide under which heading a particular project falls. Audit may be defined as "the investigation of clinical practice and institutional systems, usually against a given or accepted standard". Research, on the other hand, concerns "the scientific investigation of a predicted but not necessarily proven relationship between or among variables". It has been said that "Research is finding out what you ought to be doing; audit is seeing whether you are doing what you ought to be doing".

6.	Where there is any doubt concerning a project's classification as either "research" or "audit" it should be submitted to the Secretary of the REC for the Chairman to decide whether the study needs to be seen by the Committee or classed as audit not requiring review. 

7.	Medical Records staff may refer any project to the REC that they feel has been incorrectly identified as "audit" by an investigator. In such cases access to patients' records will be denied until the Chairman has made a decision. It would be prudent, therefore, for investigators to submit all studies involving access to patients' records to the Chairman for classification/approval.

Annex 4

USE OF FETUSES AND FETAL MATERIAL IN RESEARCH AND TREATMENT

1.	The Department of Health notified Health Authorities in July 1989 (circular HC(89)23 refers) that the Government had accepted the main recommendations of the Polkinghorne Committee, as set out in the Committee's Report (cm 762).  These included a new Code of Practice, to replace the 1972 Peel Code; Health Authorities were required to ensure that the provisions of the new Code were followed.

2.	The Research Ethics Committee requires that all research studies involving fetal material should be collected in accordance with the provisions of the Polkinghorne Code and will require assurances to this effect.  In particular the Committee is concerned that an appropriate maternal consent has been given, and investigators are strongly advised to satisfy themselves fully on this point.

CODE OF PRACTICE ON THE USE OF FETUSES AND FETAL MATERIAL IN RESEARCH AND TREATMENT

3.	The guidance in this Chapter is taken from the Review of the Guidance on the Research Use of Fetuses and Fetal Material ("The Polkinghorne Report") CM 762, HMSO 1989 and the figures in brackets refer to the relevant paragraph in the text of the Report.

4.	In this Code fetus means the embryo or fetus from the implantation until gestation ends and, unless qualified by the words in utero, includes the fetus outside the womb.  (1.3)

5.	Treatment of the fetus

a)	Two categories of fetus are recognized:

i)	The live fetus, whether in utero or ex utero, which should be treated on principles broadly similar to those which apply to treatment and research conducted with children and adults.  (2.4, 3.2).

ii)	The dead fetus.  The determination of death shall be by reference to the absence of vital functions, as indicated by the absence of spontaneous respiration and heartbeat after consideration of possibly reversible factors, such as the effects of hypothermia in the fetus, or of drugs or metabolic disorders in the mother.  This determination shall be made or confirmed by a doctor responsible for the clinical management of the mother and the fetus and not involved with the subsequent unconnected use of fetal tissue.  (3.7).

b)	Only tissue from the dead fetus is ethically available for use in therapy.

c)	It is unethical to administer drugs or carry out any procedures during pregnancy with the intent of ascertaining whether or not they might harm the fetus.  (3.3).

d)	In the case of nervous tissue only isolated neurons or fragments of tissue may be used for transplantation.  (3.11).

6.	Contents of the uterus other than the fetus.

The contents of the uterus resulting from pregnancy other than the fetus (ie the placenta, fluid and membranes) may be used for research or therapeutic purposes subject to the conditions relating to screening at section 4.5 of this Code and those relating to finance at section 7.  (3.12).

7.	Separation of the supply of fetal tissue from the practice of research and therapy.

a)	The decision to carry out an abortion must be reached without consideration of the benefits of subsequent use.  The generation or termination of pregnancy to produce suitable material is unethical.  (4.1).

b)	The management of the pregnancy of any mother should not be influenced by use of the fetus in research or therapy.  In this context, management of the pregnancy should be taken to include:

i)	the method and timing of an abortion;

ii)	the clinical management of a mother whose fetus dies in utero or who has a spontaneous abortion.

c)	No inducements, financial or otherwise, should be put to the mother or to those who are in a position to influence her decision to have her pregnancy terminated, or to allow fetal tissue to be used.  (4.4).

d)	The mother should not be informed of the specific use which may be made of fetal tissue, or whether it is to be used at all.  (4.2, 4.6).

e)	Those involved in the process of abortion and responsible for the clinical care of the mother should not knowingly be involved in research on the fetus or fetal tissue collected.  Dissection of the dead fetus, research on it, or transplantation of fetal tissue should, when practicable, be on separate premises and certainly not in the same room.  However, ethically acceptable exceptions to this degree of separation occur when research is concerned with the investigation of cases of fetal death in utero, or spontaneous abortion or analogous post-mortem concerns arising from previous medical history.  (5.7).

f)	The source must keep records indicating the next destination of any fetal tissue which is released for purposes of research or therapy, and it should have a  means of satisfying itself that anyone to whom tissue is sent has satisfied the requirement of this Code.  The mother's identity should not be revealed when fetal tissue is released, although some coding will be necessary which will enable her to be traced by those responsible for her clinical management, should relevant information come to light through examination of the fetal tissue.  (5.3).

g)	Any intermediary or tissue bank which receives or passes on fetal tissue must keep a record of the destination and origin of all tissue and not reveal details of the identity of the source to the user and vice versa.  (5.4).

h)		On the same principle the user should be able to satisfy itself that any material it receives has been procured in accordance with the requirements of this Code.  It must keep records indicating the proximate source of any fetal tissue and the use to which it is put, but should not reveal details of the use to the source.  (5.5).

i)	Details about a fetus (eg gestational age) which might be of significance for research but could not be used for identification may be released by the source, but it is not acceptable for the source to be approached with requests for fetuses with particular characteristics.  (5.6)

8.	Consent.

a)	The written consent of the mother must be obtained before any research or therapy involving the fetus or fetal tissue takes place.  Sufficient explanation should be offered to make the act of consent valid.  (6.3).

b)	Consent to the termination of pregnancy must be reached before consent is sought to the use of fetal tissue, and without reference to the possibility of that use.  Provided the question of use is not introduced until consent to the termination of pregnancy has been obtained, it is permissible to deal with the two issues on the same occasion.  (6.5)

c)	It may be desirable to consult the father since, for example, tests on fetal tissue may reveal a finding of potential significance to him, and because he may have knowledge of a transmissible or hereditary disease, but his consent shall not be a requirement nor should he have the power to forbid research or therapy making use of fetal tissue.  (6.7).

d)	In the case of spontaneous abortions (or where death of the fetus has occurred in utero) consent to use fetal tissue should preferably be sought only after the fetus has died.  (6.4).

e)	Consent should be obtained from the mother to tests if any screening is to take place for transmissible disease or if any procedure is contemplated which could have similar consequences for the mother and affect her clinical management.  Any such tests, and the counseling to accompany them, should be conducted according to the best current practice and guidance, in a manner which ensures that the principles of separation are maintained.  (6.9).

9.	Conscientious objection.

	No member of the medical or nursing staff should be under any duty to participate in research or therapy involving the fetus or fetal tissue if he or she has conscientious objection.  This right of non-participation  does not extend to the prior or subsequent care of a patient thus treated.  (2.11).

10.	Ethics Committee.

	All research or therapy of an innovative character involving the fetus or fetal tissue should be described in a protocol and be examined by an ethics committee.  Projects should be subject to review until the validity of the procedure has been recognized by the committee as part of routine medical practice.  The ethics committee has a duty to examine the progress of the research or innovative therapy (eg by receiving reports).  It should have access to records and be able to confirm that the material is in fact being used for the purpose set out in the protocol.  It should also be able to examine the record of any financial transactions involving fetal issue.  Before permitting research the ethics committee must satisfy itself:  (7.4).

a)	of the validity of the research or use proposed;

b)		that the objectives of the proposed use cannot be achieved in any other way;

c)	that the researchers or clinicians have the necessary facilities and skill.

11.	Finance.

	There should be no monetary exchange for fetuses or fetal tissue.  Profit from any dealing in fetal tissue or other contents of the uterus is unethical.  (8.1, 8.3).

 Annex 5

NEED FOR CTC, CTX OR DDX

1.	There is clearly some confusion as to when a Clinical Trial Certificate (CTC), Clinical Trial Exemption Scheme (CTX) or Doctors and Dentists Exemption Scheme (DDX) are appropriate when applying for ethical approval of a clinical trial involving the giving of medicines to patients (studies on healthy volunteers do not require certification).

Clinical Trial Certificate (CTC)

2.	The Medicines Act 1968 contains provisions for preventing clinical research unless there is in force a clinical trial certificate permitting such a study (no CTC is required for studies on healthy volunteers).  Usually, holders of CTCs are pharmaceutical companies.  The data required for a CTC is extensive, including chemical, pharmaceutical, pre-clinical and clinical data.  Consequently it often takes a long time to obtain.  Similarly it often takes up to a year before the Medicines Control Agency grants a CTC.  In considering studies carried out under a CTC, the Research Ethics Committee will normally wish to see a copy of the certificate, which should be submitted with the protocol.

Clinical Trial Exemption (CTX)

3.	In 1981 a new scheme was introduced under the provisions of `The Medicines (Exemption from Licences) Order 1981', which does not replace the CTC scheme, but clears the way for quicker responses to requests from researchers for certificates allowing them to conduct research.  Under this scheme data are submitted in summary form to the Medicines Control Agency, with the signature of a medical practitioner declaring that it is reasonable for the trial to take place.  The Medicines Control Agency has 35 days to consider any application and to raise any objections; it can extend this period by a further 28 days if deemed necessary.  The applicant will receive a letter acknowledging his application and allocating him a CTX number.  If he then does not hear anything from the Medicines Control Agency within 35 days he can assume that he has a CTX.  The Research Ethics Committee will again normally wish to see a copy of the letter indicating that a CTX number has been given and confirmation from the investigator that he/she has not received any indication from the Medicines Control Agency, within 35 days of submission, that a CTX has not been granted.

Doctors and Dentists Exemption Scheme (DDX)

4.	The data required for a CTC application are usually outside the scope of most hospital or university departments especially with regard to toxicological data.  Therefore, if a doctor or dentist wishes to conduct a clinical trial with an unlicensed product under his own aegis he should apply for a DDX.  It is also necessary for him to apply for a DDX if he wishes to study a product with a Product Licence but for an indication which is outside the PL.  A DDX is usually supplied in a form of a letter to the researcher, a copy of which should be submitted with applications to the Research Ethics Committee.  As with CTXs, the practitioner must inform the Medicines Control Agency of any serious or adverse reactions which occur and ethics committee approval must be obtained.  Copies of the DDX application form are available from the Secretary's office.

5.	The general question to ask when deciding whether a DDX or a CTX is appropriate is "who has instigated/written the protocol for the study?". If it is the Doctor then a DDX is required. If the Sponsoring Company has instigated the study then a CTX will be required. 

Annex 6
IMPLEMENTATION OF THE MEDICAL DEVICES 
DIRECTIVES OF THE EUROPEAN COMMUNITY

Guidance to Local Research Ethics Committees from the
Department of Health

A series of three Medical Device Directives, regulating the safety and marketing of medical devices throughout the European Community, started to come into effect from the beginning of 1993.  These Directives will eventually replace existing national systems in each Member State and will benefit both the manufacturer, by creating harmonisation of controls within a single system, and purchasers and users by providing reassurance that devices marketed anywhere throughout the European Community will meet standards of performance and safety.

The first of these Directives, the Active Implantable Medical Devices Directive (AIMDD), encompasses all implantable powered devices within its scope, eg pacemakers and implantable defibrillators, and came into force on 1 January 1993.  The Medical Devices directive (MDD) covers most other medical devices and will come into effect, subject to the Parliamentary process, in January 1995.  The In Vitro Diagnostic Medical Devices Directive (IVDDD) will cover any equipment or reagent intended to be used in-vitro for the examination of substances derived from the human body.  This Directive is currently being drafted by the Commission and is not expected to come into force until 1996 at the earliest.

Under the provisions of these Directives, no device may be sold freely on the market in the EC without a CE (Communaute European) marking apart from two specific exceptions where devices are either custom-made or are undergoing clinical investigation.  With the exception of Class I (low-risk) devices, in order to obtain this marking, the manufacturer must go through a conformity assessment procedure in order to confirm that the device in question complies with the relevant Essential Requirements.  These are designed to ensure that a device:

(i)		does not compromise the clinical condition or safety of the patient;
(ii)		presents minimum risk to device users or, where appropriate, to any third party; and
(iii)		achieves its intended purpose as designated by the manufacturer.

In order to demonstrate these features satisfactorily, clinical data may be required, particularly with the higher risk devices.  This data may be obtained from previous clinical experience with the device, or may be a complication of scientific literature relating to the device or a similar device.  If this clinical data is, however, not available, eg in the circumstances of a new device being produced, evidence from a specifically designed clinical investigation may be required in order to demonstrate performance and/or determine any undesirable side effects.  Under the provisions of the AIMDD and MDD, all such clinical investigations must be notified to the Competent Authority (the body set up in each Member State to enforce the regulations of the Directives - in the case of the UK, the Secretary of State of Health acting through the Department of Health's Medical Devices Directorate) of the Member State(s) in which the investigation(s) is(are) being performed, and the required documentation submitted, the details of which are laid out in the Directives.  Under the terms of the MDD, Part of the required documentation must be a copy of the opinion of the relevant LREC(s).

The Competent Authority then has 60 days in which to make an assessment of the documentation and inform the applicant of any objections, aided by a number of assessors, expert in a wide range of subjects relating either to clinical research or aspects of the device itself.  If within this period no objections are raised, the clinical investigation may then proceed.  The only grounds on which the Competent Authority may raise objections under the terms of the Directive are in a situation where the investigation is felt to prejudice either public health or public safety.  Whilst this has the effect of preventing a proposed clinical investigation proceeding, it is envisaged that such grounds will arise mainly in respect of technical and material problems relating to the particular device.  In no case will the Competent Authority give authorization for a clinical investigation to proceed locally in circumstances where an unfavourable LREC opinion has been received.  In the case of a proposed multicentre trial, where one or more LRECs have raised ethical objections, the Competent Authority will only consider the application in terms of the centres where a favourable LREC opinion has been delivered.

All clinical trials of CE marked devices will not require notification to the Competent Authority unless such a device is being proposed for a use other than that intended under its existing authorization.

The relevant sections of the Directives that lay out the provisions relating to clinical investigation of devices are:

	-	AIMDD: Article 10, Annex VI, Annex VII;

	-	MDD: Article 15, Annex VIII, Annex X.

If you have any queries or require further information concerning these requirements, please contact:
			 		Dr S M Ludgate
					Senior Medical Officer
					Medical Devices Directorate
					Room 110
					14 Russell Square
					LONDON WC1B 5EP
These notes were distributed to Local Research Ethics Committees by the Department of Health in December, 1993.