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Clinical Study Reports- Medical Writing

Structure and Content of Clinical Study Reports ICH Topic E3:

Source: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/e3-eng.pdf

Commonly used Medical Dictionaries during coding- Clinical Trials

The most commonly used medical coding dictionaries used for coding medical terms are MedDRA and WHO DDE.

The other standardised medical dictionaries are:

COSTART - Coding Symbols for Thesaurus of Adverse Reaction Terms
2. ICD9CM - International Classification of Diseases 9 Revision Clinical Modification
3. MedDRA – Medical Dictionary for Regulatory Activities
4. WHO-ART – World Health Organisation Adverse Reactions Terminology
5. WHO-DDE– World Health Organisation Drug Dictionary Enhanced

Reporting to the Ethics Committee- Safety Reporting during Clinical trials

The Ethics Committee that gave a favourable opinion for the trial should routinely receive the following reports:
• Expedited reports of all SUSARs occurring in a clinical trial of an investigational medicinal product for which the sponsor is responsible. This includes SUSARs associated with active comparator drugs. Expedited reports should be sent to the relevant Ethics Committee within the timelines as stated below.
• A sponsor shall ensure that all relevant information about a suspected unexpected serious adverse reaction (SUSAR) which occurs during the course of a clinical trial in the United Kingdom and is fatal or  life-threatening is reported as soon as possible to the MHRA, the competent authorities of any EEA State, other than the United Kingdom, in which the trial is being conducted, and the relevant Ethics Committee. This needs to be done not later than seven days after the sponsor was first aware of the reaction. Any additional relevant information should be sent within eight days of the report.
• A sponsor shall ensure that a suspected unexpected serious adverse reaction (SUSAR) which is not fatal or life-threatening is reported as soon as possible, and in any event not later that 15 days after the sponsor is first aware of the reaction.
• Quarterly safety reports on all clinical trials for which the sponsor is responsible for worldwide, with a global line listing of SUSARs occurring in these trials in the reporting period.
• Annual safety reports on the safety of subjects in all clinical trials for which the sponsor is responsible worldwide, with an aggregated global line listing of all suspected serious adverse reactions (SSARs) occurring in these trials to date.
• Reports and recommendations of any independent data monitoring committee established for the trial.

Safety reports may be submitted by the sponsor, or by the sponsor’s representative, or by the chief investigator.

Case Report Form (CRF) - Clinical Trials

The ICH GCP Guidelines say: The reason for having CRFs in a study is to (collect the necessary information about:

• the patients
•  the administration of the study drug
• the outcome of the assessments.

CRFs are the official documentation of the trial for the authorities, and together with the source documents will be closely examined during audits and inspections.The data on the CRFs will be entered into a computer system and the statistical analyses will then be performed. The data on the CRFs is therefore the basis for the trial report and also for any publications, as well as making up part of the data for regulatory approval of a new drug.

When completing the form use a black ball point pen to complete the CRF. If the CRFs are printed on carbonless duplication paper, always make sure that a suitable separator is inserted under the form being completed. If for some reason you cannot complete part of the form, you shouldn’t just leave a blank space ~ this is impossible for the people doing the data entry into the computer to interpret. Instead write unknown, uncertain, missing or test not donr as appropriate, or similar unambiguous words. Avoid using the ambiguous phrase, ‘not available’.The CRFs must be signed where indicated by the Principal Investigator to indicate that
he/she believes they are complete and correct. Some Sponsors require a signature on each page of the CRF, some only a signature on the final page.

Ensure legibility of all data entries. Corrections should be made as follows:

• Cross out the incorrect entry with a single line - the incorrect entry should still be readable, on no account use liquid correcting fluid.
• Enter the correct data.
• Initial and date the correction, and give an explanation of the correction if it is not obvious why it was changed.

Informed Consent form- Signature

The consent form should be signed and dated by the following people:

• A medically qualified person providing the information, this being the Investigator
• The subject.
•  A witness, if this is possible and if required for the study. 

A witness is defined as someone who records that the subject has provided consent of their own free will and has been fully informed of the study. The best witness is a subject’s friend or family member who has sat in when the study was being explained to the patient. A witness must have no vested interest in the study; therefore a research assistant/SSC/Sub-Investigator is not suitable as a witness.All signatures should be dated by the person who is signing and under the signature or Sub-Investigator. they should write their name in block capitals.

Obtaining Personal Written Informed Consent during Clinical Trials

When describing the study the physician /SSC should cover the following:

•  That it is a research procedure, and which aspects are experimental - it may or may not be beneficial to the subject - e.g. placebo.
•   The purpose of the trial.
•  Details about the drug under investigation. If there is a placebo arm to the study, this must be carefully     explained.
• The design of the trial, for example ‘double dummy’ or ‘crossover’. Often a
•  The number of people involved.
•  Duration of the trial. If the trial is a long-term one, enthusiasm is required.
•  Number of visits involved and duration of the visits. The area where the patient will be seen and by whom.
• Procedures involved, for example blood tests, ECGs, urine samples and chest x-rays - how many and how often.
•  The responsibilities of the subject if he/she participates.
•  Out of pocket expenses and the receipt procedure. If a taxi account is set up for thestudy, then this will be explained. If payments are entailed, the details must be covered, including the arrangements for pro-rated payments.
•  The risks involved to the subject and any benefit that might be expected. If no clinical benefit is intended, the subject must be told.
• Questions about the patient’s medical history will be asked and disclosure of all medication the patient is taking, which will be kept up to date if changes occur.
• Alternative procedures or treatments.
• If the study has a specific exclusion criterion, for example a left ventricle ejection fraction <350/0, but this is measured only after the patient has given written consent, this exclusion will be carefully explained, Providing written informed consent does not mean definite progression into the study.
• The availability of compensation and treatment if needed.
• That, because it is a study, written consent is needed which is voluntary and there is no penalty for refusal.
• The right to withdraw from study medication at any time without affecting their future medical care. Similarly, if the Investigator thinks that the study medication is not suiting the patient, then the medication would be stopped.

Patient Recruitment- Clinical Trials

The first step is to define exactly what is meant by patient recruitment. This is not as straightforward as it sounds. There are several steps from the patient being identified and contacted to starting the study treatment. These include screening the patient, obtaining informed consent. randomising the patient, a possible baseline assessment and then initiation of treatment. Exactly when the patient is said to be enrolled in the trial should be
defined in the protocol.The recruitment period, i.e. starting and finishing date of recruitment for the entire study, may also be defined in the protocol.

Intention to Enrol list:For the purpose of this SOP, an ‘Intention to Enroli st’ is a record of all patients who were considered, were eligible for the study, but who, for one reason or another, were not included. This list enables a comparison of the potential patient population with the patient population actually enrolled in the study. It is helpful when questions of bias arise during evaluation of the data.

Study Files and Filing - Clinical Trials

A Study File may consist of more than one distinct file. Too many different files should be avoided. It is usually unnecessary that each individual patient has a separate file. The Investigator’s Brochure may also need to be located separately; if so, the Study File should indicate where. Each patient’s informed consent form should be filed in the patient’s medical notes.

The Study File will be sub-divided. For example:

• Correspondence.
• Protocol and Amendments.
• Investigator’s Brochure.
• Drug accountability.
• Ethics Committee.
• List of patients entered (to enable easy identification of individuals in the future. The list should also include those actively considered for the trial but not entered, with reasons for non-entry where appropriate).
• Code envelopes may be stored in the Study File, but may be stored separately, e.g. at Pharmacy. The location should be recorded.
• Where required, registration of clinical trial with the regulatory authorities and/or local management.
• Completed serious adverse event forms (if not included in the CRFs).
• Financial agreement, unless stored elsewhere.
• Records of telephone conversations and notes of study meetings should also be filed.
• The Sponsor will also keep records of telephone conversations and make written reports after each visit. During an audit, these records will be checked for consistency.
• Completed consent forms (or copies).
• Study-specific SOP checklists.
• The completed CRFs will usually be stored in a separate file.

Outline of an Standard Operating Procedures- ICH

The general outline of an SOP is as follows:

• Number and title of procedure
• Purpose (brief summary in a few lines)
• Other procedures simultaneously involved
• Personnel involved and procedure: Who is responsible for carrying out the procedure?
• When and How should the procedure be carried out?
• Date of version in use plus ‘replaces previous version of . . .’
• Name of author and person in charge who approved this version
• Each SOP has a number. Not every SOP has an accompanying checklist. Please note that the checklists are numbered according to the corresponding SOP number.

Revision and updating of Standard Operating Procedures : SOPs must be reviewed and updated on a regular basis. When they are first introduced to the department, they may need revision after a few months. However, once they have been adjusted to your needs they will probably only need revising every two years or so, but we recommend an annual review. Revision is best done as a team task. The procedures should be examined and rewritten where appropriate, then approved and signed. The old version should be archived. It should not be disposed of because it can be of use  some time after a study is completed that Regulatory Agency questions might arise, and you may be required to show the procedures you used to follow.

Standard Operating Procedures- ICH

SOPs are defined in the ICH GCP Guidelines as ‘detailed, written instructions to achieve uniformity of the performance of a specific function’.

SOPs should be detailed enough so that a procedure can be correctly carried out in a reproducible manner, but not so specific that they can only be applied to one project and then have to be rewritten for the next. It is almost always necessary to adapt SOPs to an individual department, and the SOPs here can be tailored to suit your needs,as long as the requirements of GCP are maintained.

The SOPs here can be broadly divided into the following sections:

• General study organisation
• Pre-study
• During study
• End of study

ICH Guidances

The ICH process results in guidance documents that create consistency in the requirements for new drug approval. Guidance documents represent the Agency ’ s current thinking on a particular subject. These documents provide guidance on the processing, content, evaluation, and approval of applications. They also establish policies intended to achieve consistency in the Agency ’ s regulatory approach and establish inspection and enforcement procedures. Because guidances are not regulations or laws, they are not enforceable, eitherthrough administrative actions or through the courts. An alternative approach may be used if such an approach satisfi es the requirements of the applicable statutes, regulations, or both.

ICH guidances are developed through a fi ve - step process: (1) consensus building, (2) start of regulatory action, (3) regulatory consultation, (4) adoption of text, and (5) implementation.

When a guidance document reaches Step 2 or Step 4 in the ICH process, the FDA publishes a notice of
availability in the Federal Register . Guidances are posted on the Internet and placed in the Docket for viewing and public comment. Notices for Step 2 guidances include a date for receipt of written comment. Because Step 2 documents are drafts, they do not conform with the Agency ’ s Good Guidance Practices (GGP) policy. Step 4 guidances must be reformatted and edited to be consistent with the GGPs. This is because the 1997 U. S. Food, Drug and Cosmetic Act required the Agency to make GGPs the law.

ICH(International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use)

ICH is the shortened name for The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. It works to bring together government regulators and drug industry representatives from the United States, the EU, and Japan to make the international drug regulatory process more effi cient and uniform. This work will help make new drugs available with minimum delays to both American consumers and those in other countries.

The drug regulatory systems in all three regions share the same fundamental concerns for the safety, effi cacy, and quality of drug products. However, many time - consuming and expensive clinical trials have had to be repeated in all three regions. An ICH goal is to minimize unnecessary duplicate testing during the research and development of new drugs. Another goal is to develop guidance documents that create consistency in the requirements for new drug approval. Some ICH projects include the following:

• Medical Dictionary for Regulatory Activities (MedDRA). MedDRA is a new international medical  terminology designed to improve the electronic transmission of regulatory information and data worldwide. It will be used to collect, present, and analyze information on medical products during clinical and scientifi c reviews and marketing. It will be particularly critical in the electronic transmission of adverse event reporting and coding of clinical trial data. The FDA is already using MedDRA in its Adverse Events Reporting Systems.
• Common Technical Document. This document will provide an international standard format for submitting safety and effi cacy information about a new drug.

Reporting Time Frames- ICSR

Reporting Time Frames: In general, expedited reporting of serious and unexpected ADRs refers to 15 calendar days. Time frames for other types of reports vary among countries.


Minimum Criteria for Reporting:Minimum required data elements for an ADR case are: an identifiable reporter, an identifiable patient, an adverse reaction, and a suspect product. Lack of any of these four elements means that the case is incomplete; however, MAHs are expected to exercise due diligence to collect the missing data elements. It is recommended that as much information as possible be collected at the time of the initial first report.

 Time Clock Start Point:The regulatory reporting time clock (in calendar days) starts on the date when any personnel of the MAH first receive a case report that fulfills minimum criteria as well as the criteria for expedited reporting. In general, this date should be considered as day 0.When additional medically significant information is received for a previously reported case, the regulatory reporting time clock begins again for submission of the follow-up report.

 Non-serious ADRs:Cases of non-serious ADRs are not normally reportable on an expedited basis. The spontaneous reports of non-serious ADRs should be reported in the periodic safety update report.

STANDARDS FOR EXPEDITED REPORTING- ICSR

Single Cases of Serious ADRs:Cases of adverse drug reactions from all sources that are both serious and unexpected are subject to expedited reporting. The reporting of serious expected reactions in an expedited manner varies among countries. Non-serious adverse reactions, whether expected or not, would normally not be subject to expedited reporting.For reports from studies and other solicited sources, all cases judged by either the reporting healthcare professional or the MAH as having a possible causal relationship to the medicinal product qualify as ADRs. For the purposes of reporting, spontaneous reports associated with approved drugs imply a possible causality.

Reporting Guidelines for Other Observations:In addition to single case reports, any safety information from other observations that could change the risk-benefit evaluation for the product should be promptly communicated to the regulatory authorities.

Lack of Efficacy:Reports of lack of efficacy should not normally be expedited, but should be discussed in the relevant periodic safety update report. However, in certain circumstances reports of lack of efficacy should be treated as expedited cases for reporting purposes. Medicinal products used for the treatment of life-threatening or serious diseases, vaccines, and contraceptives are examples of classes of medicinal products where lack of efficacy should be considered for expedited reporting. Clinical judgment should be used in reporting, with consideration of the approved product labeling/prescribing information.

Overdose: Reports of overdose with no associated adverse outcome should not be reported as adverse reactions. They should be routinely followed up to ensure that information is as complete as possible with regard to symptoms, treatment, and outcome. The MAH should collect any available information related to its products on overdose, and report cases of these that lead to serious adverse reactions according to expedited reporting criteria.

Regulatory Authority Sources- Sources of Individual Case Safety Report

Individual serious unexpected adverse drug reaction reports originating from foreign regulatory authorities are always subject to expedited reporting. Re-submission of serious ADR cases without new information to the originating regulatory authority is not usually required, unless otherwise specified by local regulation.

Licensor -Licensee Interaction- Sources of ICSR

When companies co-develop, co-market, or co-promote products, it is considered very important that explicit contractual agreements specify the processes for exchange of safety information, including timelines and regulatory reporting responsibilities. Whatever the contractual arrangement, the MAH is ultimately responsible for regulatory reporting.

It is particularly important to ensure that processes are in place to avoid duplicate reporting to the regulatory authority, e.g. assigning responsibility to one company for literature screening. The time frame for expedited regulatory reporting should normally be no longer than 15 calendar days from the first receipt of a case meeting minimum criteria by any of the partners, unless otherwise specified by local regulation. Any subsequent follow-up information sent to the regulators should be submitted by the same MAH that reported the case originally.

Solicited Sources

Solicited reports are those derived from organized data collection systems, which include clinical trials, post-approval named patient use programs, other patient support and disease management programs, surveys of patients or healthcare providers, or information gathering on efficacy or patient compliance. Adverse event reports obtained from any of these should not be considered spontaneous.

For the purposes of safety reporting, solicited reports should be handled as if they were study reports, and therefore should have an appropriate causality assessment. Further guidance on study-related issues such as managing blinded therapy cases can be found in ICH E2A.

Unsolicited Sources- Sources of ICSR

Unsolicited Sources:


Spontaneous Reports: A spontaneous report is an unsolicited communication by healthcare professionals or consumers to a company, regulatory authority or other organization (e.g. WHO, Regional Centers, Poison Control Center) that describes one or more adverse drug reactions in a patient who was given one or more medicinal products and that does not derive from a study or any organized data collection scheme. Stimulated reporting may occur in certain situations, such as a notification by a "Dear Healthcare Professional" letter, a publication in the press, or questioning of healthcare professionals by company representatives. These reports should be considered spontaneous.

Consumer reports:Consumer adverse reaction reports should be handled as spontaneous reports irrespective of any subsequent "medical confirmation", a process required by some authorities for reportability. Even if reports received from consumers do not qualify for regulatory reporting, the cases should be retained. Emphasis should be placed on the quality of the report and not on its source.

Literature:The Marketing Authorisation Holder (MAH) is expected to regularly screen the worldwide scientific literature, by accessing widely used systematic literature reviews or reference databases. Cases of ADRs from the scientific and medical literature, including relevant published abstracts from meetings and draft manuscripts, might qualify for expedited reporting. A regulatory reporting form with relevant medical information should be provided for each identifiable patient. The publication reference(s) should be given as the report source; additionally a copy of the article might be requested by the local regulatory authority to accompany the report. All company offices are encouraged to be aware of publications in their local journals and to bring them to the attention of the company safety department as appropriate. The regulatory reporting time clock starts once it is determined that the case meets minimum criteria for reportability. MAHs should search the literature according to local regulation or at least once a month. If the product source, brand, or trade name is not specified, the MAH should assume that it was its product, although reports should indicate that the specific brand was not identified.

Internet:MAHs are not expected to screen external websites for ADR information. However, if an MAH becomes aware of an adverse reaction on a website that it does not manage, the MAH should review the adverse reaction and determine whether it should be reported. Unsolicited cases from the Internet should be handled as spontaneous reports. MAHs should regularly screen their websites for potential ADR case reports. MAHs and regulators should consider utilising their websites to facilitate ADR data collection, e.g. by providing ADR forms for direct reporting or by providing appropriate contact details for direct communication. For the determination of reportability the same criteria should be applied as for cases provided via other ways.

Other Sources:If MAHs become aware of a case report from non-medical sources, it should be handled as a spontaneous report.

Sources of Individual Case Reports- Pharmacovigilance

Sources:

• Unsolicited Sources: Spontaneous Reports,Consumer reports, Literature, Internet, Other Sources.
• Solicited Sources: data collection systems, which include clinical trials, post-approval named patient use programs, other patient support and disease management programs, surveys of patients or healthcare providers, or information gathering on efficacy or patient compliance.
• Licensor-Licensee Interaction
•  Regulatory Authority Sources