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ISAC

ISAC (Independent Scientific Advisory Committee)

Following a recent review of the operating procedures of the ISAC , the Committee has implemented a number of changes relating to the review and approval of GPRD ISAC applications. These are outlined in the following document ISAC circular and will take place with immediate effect.

The current ISAC application form can be accessed here (Right click here and choose Save Target As for an electronic copy). To submit, please email the completed form together with your protocol to the ISAC secretariat: ISAC@gprd.com

Membership of ISAC

In response to the growing demand to use GPRD to undertake public health research, the membership of ISAC was expanded in November 2006. The Committee currently consists of 10 professional members and 2 lay members.

For further information about ISAC including a list of members please click here.




Submission of GPRD protocols to ISAC

All protocols submitted to ISAC are be required to follow the guidance on “Instructions on Content of Protocols”, drawn up by the GPRD Group in consultation with ISAC. These instructions, which are broadly based on the ISPE’s Good Pharmacoepidemiology Practices, and have been implemented to ensure that the issues considered essential for ISAC evaluation are covered in the protocol.

The current GPRD ISAC application form includes a checklist on protocol content which must be completed prior to submission of the application. There are also additional questions to be completed on the experience and expertise available within the team undertaking the proposed research.

The Instructions on Content of Protocols and the latest application form must be used for all new protocols submitted from 15th September 2007. Protocols submitted from this date which do not use the updated form, or follow the instructions for protocol content, may be returned to the applicant.

If you have any questions about the new procedures, please contact the ISAC Secretariat.


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Standard Operating Procedures for GPRD Protocol Evaluation

  1. Any studies using the GPRD which are destined for publication or for which it is intended to communicate the results to third parties, must receive ISAC approval before proceeding.
  2. Proposed studies should be presented as a protocol (see below, Submission Procedures and Instructions on contents of Protocols) and addressed to the ISAC secretariat. On receipt, they will be allocated a protocol number, which will be notified to the applicant with acknowledgement of the protocol's receipt. The protocol number will be quoted in all future correspondence about the study.
  3. Where investigators wish to send a questionnaire to GPs as part of a study, this must also be submitted to ISAC (see below, Submission Procedures). This can be done either at the time of protocol submission, or at a later date. The questionnaire must be provided in the format in which it is intended to be presented to GPs, together with any covering letter or guidance on completion which will be provided with the questionnaire.
  4. Note that organizations receiving historical data extracts via EPIC should submit their protocol/questionnaire via the data provider. We shall send ISAC’s response via the data provider.
  5. The ISAC secretariat distributes protocols/questionnaires to ISAC members. Specifically, members assess whether:


    1. There is compliance with the requirement to ensure protection of practice and patient confidentiality;
    2. There is a well defined hypothesis or clear question to be addressed;
    3. The GPRD is a suitable database in which to conduct the research;
    4. The methodology is considered appropriate, including consideration of possible bias and confounding;
    5. Original case record verification is necessary
      For Questionnaires, members assess whether:
    6. The questions are clear and unambiguous and that the content is appropriate given the nature of the study;
    7. GPs will be provided with sufficient information to identify the patients/events about which the questionnaire is answering;
    8. There is clear information on how the questionnaire should be completed in general, and on what information needs to be provided in answering each question;
    9. GPs are provided with sufficient information on the purpose and importance of the questionnaire;

  6. ISAC members provide their comments to the Chairman. These are collated and a response is forwarded to the ISAC secretariat. This feedback is communicated directly to the applicant or via the data provider, as appropriate.
  7. The time between receipt of a protocol/questionnaire by the Secretariat and distribution of the response from ISAC is about three weeks. The ISAC Secretariat monitors progress of protocol reviews. Please do not hesitate to contact the Secretariat if you have any concerns.
  8. ISAC may make proposals for modifications to study protocols/questionnaires as a condition of approval.
  9. Applicants are entitled to request a discussion at the ISAC meeting following the initial evaluation of their protocol/questionnaire. Discussion at the meeting does not guarantee an approval, but provides an opportunity for in depth discussion of issues raised by ISAC in its response to the protocol/questionnaire. If you require further information, please contact the ISAC Secretariat.
  10. If having discussed the protocol/questionnaire with ISAC at one of its meetings, the applicant feels that the decision of ISAC is unfair, he/she is entitled to an appeal.
  11. We strongly encourage GPRD users to publish the results of their studies. Although we do not require manuscripts to be submitted to ISAC prior to publication, we do request that on publication, a copy of the published article is provided to the ISAC secretariat together with the protocol number to which the article relates. This will enable us to keep the GPRD Bibliography up to date.

Confidentiality

Protocols/Questionnaires are submitted to ISAC in confidence, and are not disclosed to third parties.

Protocol Review Appeals Process

If the MHRA accepts the advice of ISAC to turn down an application for data, the unsuccessful applicant will be sent a letter setting out the reasons why. The applicant will be told that he/she has 28 days from the date of the letter to make representations, and that these should be made in writing to the Yellow Card/GPRD ISAC Secretary as appropriate. The applicant will be informed that once this 28 day period has expired, he/she will have to make a fresh application. If an appeal is to be carried out then the Licensing Authority will appoint a person or persons to undertake a review of the documentation. A letter will be sent to the applicant with the outcome of the appeal. The decision of the Licensing Authority will be final.

Duplicate Studies

At the request of the applicants, when a new protocol is submitted, the ISAC Secretariat will review approved protocols to determine whether the same or very similar topic has been studied previously. If it has been, the new applicant will be informed. The Secretariat will also inform the other investigator(s) studying the topic that a further protocol has been approved. Both parties will be asked whether they are content for their name and contact details to be disclosed to the other group. Confidentiality will be respected at the request of either party.

Submission Procedures

  1. Protocols and questionnaires can be submitted to the ISAC Secretariat at any time and irrespective of the Group's meeting dates. It is hoped that protocols will be evaluated within 3 weeks from receipt.
  2. Protocols should be submitted electronically, in the format of a Word document to the following address: ISAC@gprd.com . Annexes to the protocols, when submitted, should be sent as separate attachments.
  3. Questionnaires may be submitted alongside the protocol to which they relate, or at a later date. They should be submitted electronically, in the format of a word document to the following address: ISAC@gprd.com . The questionnaire should be accompanied by the covering letter or other information that will be provided to the GP alongside the questionnaire. When a questionnaire is submitted after the protocol, the relevant protocol number should be given in order that the questionnaire can be linked to the protocol.
  4. Protocols/questionnaires will be acknowledged within 2 working days of receipt. Applicants should contact the ISAC secretariat to check that the protocol was received if an acknowledgement is not sent within time.
  5. It is now mandatory that at submission each protocol is accompanied by its completed APPLICATION FORM. This is intended for rapid administration of the submitted proposals and to facilitate the recording of ISAC activity for management purposes. An electronic copy of the ISAC Application form (Right click here and choose Save Target As for an electronic copy) can be obtained from this website.

Expedited Review

A 'fast track' system for evaluating protocols is available, at the investigator's request, for studies which concern a serious, urgent public health issue. Only such studies will be considered for expedited review. The Chair of ISAC will determine whether a protocol meets the criteria for fast-tracking. Requests for expedited review of a protocol should be made at the time of protocol submission. The reasons for requesting expedited review should be briefly explained. On receipt, the protocol will be forwarded to the Chair, together with the reasons for the request for expedited review, for a decision on fast tracking within 24 hours. If, following review of a protocol under the expedited review process, ISAC request revision and resubmission of a protocol, then the amended protocol must be submitted to ISAC within five working days. If the amended protocol is received later than this, it will not be accepted for expedited review and will be subject to review within the standard time frames (see above).


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Instructions on Content of Protocols

The GPRD ISAC form has been further updated to request additional information on study protocols. If you are submitting your protocol after the 15th September 2007, please ensure that you are using the latest version of the application form and that your protocol complies with the instructions on content of protocols.

These instructions are intended to identify issues that are essential for ISAC evaluation. We welcome feedback from researchers on the instructions. Please note that the application form includes a checklist which must be completed to confirm that all issues required by ISAC have been addressed in the protocol. Protocols that do not comply with these criteria, including those where the checklist has not been completed, may be returned to investigators.

Please click here to download INSTRUCTIONS ON PROTOCOL CONTENT.

Prior to developing the protocol, it is suggested that it may be helpful to talk to staff within the GPRD Group about the feasibility of the proposed research. This may be particularly important for researchers with limited experience of either the GPRD or of UK primary health care.

Issues to be covered in the protocol

Lay Summary of Research (Max 200 words)

Please provide a simple overview of your proposed research including purpose, background, methodology, possible results and their significance.

Objectives, Specific Aims, and Rationale

Include:

(i) a description of the knowledge/information to be gained from the study (research objectives)

(ii) a list of the measurements to be made, and any hypotheses to be tested (specific aims). The protocol should distinguish between a priori research hypotheses and hypotheses that are generated based on knowledge of the source data.

(iii) an explanation of how achievement of the specific aims will further the research objectives (rationale).

Background

Explain the reason for the study and include any other essential background information, e.g. the findings of similar studies and other related research.

Study design

Describe the overall research design, strategy, and reasons for choosing the proposed study design. Research designs include, for example, case-control, cohort, cross-sectional, nested case-control, or hybrid designs.

Study population

Define the source and study population, in terms of persons, place, time period, and listing the criteria which will be used to select the study population from the GPRD, e.g. exclusion, inclusion criteria. The rationale for the inclusion and exclusion criteria (including any age limits) and their impact on the number of subjects available for analysis should be described. If any sampling from a base population is undertaken, provide details of sampling methods. Include information describing the study period, i.e. total calendar time to be investigated and the observational period, i.e. information on the exposure window of interest. An estimate of the expected number of relevant patients in the GPRD should be included.

Selection of comparison group(s) or controls

If applicable, describe and give justification for the procedure for control selection.

Sample size/ power calculations

Where possible, please provide some indication of the sample size /power calculation needed to detect an effect within the proposed study population. This is especially important for those studies evaluating rarer exposures and/or outcomes.

Exposures, Outcomes, and Covariates

Describe the strategies and data sources for determining the main exposures, key health outcomes, and all other variables relevant to the study objectives including all key covariates considered to be potential confounding variables and effect modifiers, using validated measurements whenever possible. Include operational definitions for each important exposure, health outcome, and key covariates (both clinical and non-clinical).

Data sources might include, for example, questionnaires, hospital discharge files, abstracts of primary clinical records, administrative records such as eligibility files, prescription drug files, biological measurements, exposure/work history record reviews, or exposure/disease registries.

An operational definition is one that can be implemented independently using the data available in the proposed study. For example "PCP episode" is not an operational definition; a better description would be “a record of a Read or OXMIS code indicating a PCP episode as listed in Annex X”. Operational definitions will not always be limited to a clinical code set; in defining patients with a particular condition, test results or therapy may need to be considered.

It is recognised that considerable effort is often put into the development of code lists. Given the nature of the coding system, it is advised that where possible, a clinician with experience of UK primary care is involved in the process. The logic and procedure used to develop the code list, including appropriate QA steps, should be outlined in the protocol. While code lists may be included as annexes to the protocol, ISAC will not review these in any detail.

Comment on how the exposure, outcome, or covariate of interest is going to be ascertained, e.g. whether it is intended to obtain additional clinical information from the GP to validate the clinical outcome(s) defined by OXMIS, Read codes or MedDRA clinical terms. .Similarly, non-clinical exposure, outcomes, and covariates of interest, e.g. new prescription, blood pressure measurement or electrocardiogram also require operational definitions.

Data analysis

Outline the methodology to be used for data management and the statistical approaches to be used in data analysis in the study; this should include the data management and statistical software programs and hardware to be used in the study. Mention any procedures to address bias, misclassification, confounding and missing data, any sensitivity analyses, and provisions to account for reverse causality where this is felt to be a potential issue.

Patient or user group involvement

It is expected that many studies will benefit from the involvement of patient or user groups in their planning and refinement stages, and/or in the interpretation of results and plans for further work. This is particularly, but not exclusively true of studies with interests in the impact on quality of life. Where possible, please provide some indication of whether patients/users group will be engaged in any of the aforementioned ways.

Limitations of the study design, data sources, and analytic methods

At a minimum, issues relating to bias and confounding, misclassification, random error and generalisability should be considered. The likely success of efforts taken to reduce errors should be discussed.

Plans for disseminating and communicating study results, including the presence or absence of any restrictions on the extent and timing of publication

There is an ethical obligation to disseminate findings of potential scientific or public health importance (e.g., results pertaining to the safety of a marketed medication). Authorship should follow guidelines established by the International Committee of Medical Journal Editors (http://www.icmje.org/). The Consolidated Standards of Reporting Trials (CONSORT) statement (http://www.consort-statement.org/Statement/revisedstatement.htm) refers to randomized studies, but provides useful guidance applicable to nonrandomized studies as well.

Points to remember

Please
  1. Be succinct where possible, you should aim for no more than 5 sides of A4, excluding annexes.
  2. Use annexes to list all codes used for the definition of exposure(s) and outcome(s)
  3. Number pages
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Extended role of the new committee

In addition to GPRD research protocols, ISAC is responsible for the scientific review of research protocols seeking to use data from the Yellow Card Scheme*. The GPRD Group supports this extended role of the committee however; we are conscious of the importance of keeping the nature and content of GPRD research protocols confidential within the GPRD Group, which is separate from the regulatory function of the MHRA.

For this reason, though the same committee will be reviewing the protocols for both data sources, administrative/Secretariat support for the two aspects of ISAC’s work will be provided by entirely distinct groups of staff within the MHRA. Staff of the GPRD Group will form the Secretariat support for GPRD protocols, with responsibility for receiving, logging, and distributing protocols for review as well as liaising with applicants, including the provision of feedback from the committee. ISAC meetings will also have separate sessions for the discussion of GPRD and Yellow Card protocol-related issues; the only MHRA staff permitted to attend the sessions for GPRD protocol-related matters will be staff from the GPRD Group. This will ensure that, as at present, knowledge of the nature of research that applicants propose to conduct using GPRD remains confidential to the GPRD Group and to ISAC members, who will be required to sign confidentiality agreements.

The MHRA’s Vigilance and Risk Management of Medicines (VRMM) division will provide equivalent support to ISAC for Yellow Card protocols; such protocols will remain confidential to relevant staff in VRMM and to ISAC members.

On occasion, it is possible that a research protocol proposal will propose the use of data from both the Yellow Card Scheme and from GPRD; such protocols will be seen by relevant staff from both the GPRD Group and the VRMM Division and will remain confidential to these staff and to ISAC members.

*The Yellow Card Scheme is the UK’s spontaneous reporting scheme to which notifications of suspected adverse drug reactions can be made by healthcare professionals and, more recently, patients; the MHRA is responsible for the operation of this Scheme.


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Ethical review for GPRD Protocols

The GPRD Group has obtained ethical approval from a Multi-centre Research Ethics Committee (MREC) for all purely observational research using GPRD data; namely, studies which do not include patient involvement (which is the vast majority of GPRD studies). ISAC will be responsible for reviewing protocols for scientific quality, but may recommend that study-specific MREC approval is sought if ethical issues arise in relation to an individual study. Separate MREC approval will be required for any study which includes any form of direct patient involvement.


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National Research Register

The National Research Register (NRR) is a register of ongoing and recently completed projects funded by, or of interest to, the UK National Health Service. ISAC strongly recommends that UK researchers using GPRD and Yellow Card data consider registering as NRR data providers, in order that others engaged in research within the UK can be made aware of current works. Registration with the NRR is entirely voluntary and will not replace information on ISAC approved protocols published in summary minutes or in the ISAC Annual Report.


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ISAC Secretariat (GPRD protocols)

Tarita Murray-Thomas
ISAC Secretariat
GPRD Group, Medicines & Healthcare products Regulatory Agency
1 Nine Elms Lane, London SW8 5NQ
United Kingdom
Tel: +44 (0)20 7084 2013
Fax: +44 (0)20 7084 2041
Electronic submission of protocols and emails to: ISAC@gprd.com

Please click here to download INSTRUCTIONS ON PROTOCOL CONTENT.