Case Report Form

A Case Report Form (CRF) is a printed, optical or electronic questionnaire-document sheets, designed for recording of all the protocol mentioned information, which is required to be reported to the sponsor for each trial participants, specifically used in clinical trial research. The Case Report Form is a part of clinical data management, a data collection tool and is used by sponsor to collect the clinical trial data at each clinical trial site. The case report form collects all data relevent to each participating patient in a clinical trial, including adverse events,

The sponsor designs and develops the CRF to collect clinical trial specific data needed to support their hypotheses or to answer their research questions. The size of the CRF vary and it will depend on the clinical trial treatment periods, follow up periods, treatment cycles and data needed to assure the effectiveness and safety of the investigational drug.

The Case record form is used for several purposes:

1. to ensure data collection in accordance with the Study protocol;
2. to ensure fulfilling of the regulatory authorities' requirements for data collection;
3. to facilitate the effective, comprehensive data processing and analysis, results reporting, and to promote the safety data sharing between the study team and other departments of the institution.

The data collected in the study site during the course of a study should be comprehensive and provide true and fair information on what happened to each study subject. Only if the above criteria are met, the study will reliably answer the questions concerning the efficacy and safety of the investigational drug.

The purpose of a CRF is to ensure efficient and complete data collection in accordance with the protocol. This facilitates analysis and clear reporting of the data and finally, the outcome determines efficacy and safety of a product. If you think about why sponsors design studies, it is obviously to gather information on efficacy and safety. Since the CRF is the primary vehicle for collecting this data, it is a very critical and important part of the study process.

The sponsor is solely responsible for designing, developing and production of the CRF which accurately comply and collect data as required by the clinical trial protocol, also monitoring and auditing of the data collection and the content of the filled-in CRFs.

The conent of the case repport form includes the two part of the as below mwntioned :

• The Generic Case Report Form Completion Guidelines
• CRF complition guidelines

All CRF's should include the following data:

• study title and number;
• Investigator's name;
• study subject/patient ID (number and initials);
• inclusion / exclusion criteria;
• demographic data;
• detailed description of dosage regimens of investigational drug;
• concomitant treatment;
• adverse events (side effects and intercurrent diseases);
• conclusion on subject's health;
• Investigator's signature and date.

Additionally, the CRF's should include special pages to record the following information:

• past medical history;
• results of physical examination;
• primary and secondary diagnoses;
• relevant previous treatment;
• baseline characteristics, results of interim assessments, evaluation of efficacy endpoints, laboratory tests, description of study procedures etc.

All CRF's should be legible and suitable for duplication and possible additional sharing.

Case report forms contain data obtained during the patient's participation in the clinical trial. Before being sent to the sponsor, this data is usually de-identified (not traceable to the patient) by removing the patient's name, medical record number, etc., and giving the patient a unique study number. The supervising Institutional Review Board (IRB) oversees the release of any personally identifiable data to the sponsor.

From the sponsor's point of view, the main logistic goal of a clinical trial is to obtain accurate CRFs. However, because of human and machine error, the data entered in CRFs is rarely completely accurate or entirely readable.

When the study administrators or automated mechanisms process the CRFs that were sent to the sponsor by local researchers, they make a note of queries. Queries are non-sensible or questionable data that must be explained. Examples of data that would lead to a query: a male patient being on female birth control medication or having had an abortion, or a 15-year old participant having had hip replacement surgery. Each query has to be resolved by the individual attention of a member of each local research team, as well as an individual in the study administration. To ensure quality control, these queries are usually addressed and resolved before the CRF data is included by the sponsor in the final clinical study report. Depending on variables relating to the nature of the study, (e.g., the health of the study population), the effectiveness of the study administrators in resolving these queries can significantly impact the cost of studies.

Informed Consent Form

Informed consent can be defined as a volunteer process through which the person or subject provide his or her willingness to take part in clinical trial. Before giving the consent for participation, the participants have been informed with all aspects of the clinical trial that are necessary and relevant to the subject's voluntarily decision to participate. Informed consent is the process, which includes documentation of a written, signed and dated informed consent form.

In other words, informed consent, a process of learning, or understanding of key facts regarding the clinical trial and making a decision to take part or not. Also it is a process, which continues through out the trial period, providing necessary information. The process involves discussion regarding detailed aspect of clinical trial between the site personnel and subject or in presence subject’s legal representative. The discussion carried out in subject’s local and understandable language.

Also the Informed consent form provided in the understandable local language, which includes the study details such as a study purpose, total number of study participants, duration, study procedures, risks, potential benefits, financial implications and contact person name. The participant then decides whether or not to sign the document. Informed consent is not a contract, and the participant may withdraw from the trial at any time.

Informed consent is one of the most important elements of system ensuring the ethics of medical experiments and protection of the rights of the study subjects.

Informed consent is a process by which a subject voluntary confirms his/her willingness to participate in one or another clinical trial, after having been informed of all aspects of the study. Informed consent should be documented by means of a written, signed and dated Informed Consent Form (ICF).

Potential subjects should be informed of the objectives and methods of the study, the drug product and treatment regimen, the available alternative treatments, potential risks and benefits, and of possible complications and discomforts, which may arise from participation in the study.

Based on information that he/she had received and understood, the potential subject freely gives consent to participate in a study. The informed consent should not be obtained through inducement or coercion. The subject should be aware that he/she may withdraw from the study at any time, and this will not affect his/her future medical care in any way.

The main principles of Informed consent

The subject should be informed of the following:

• the purposes of the trial;
• the methods of the trial;
• the study drug(s) and treatment regimens;
• available alternative treatment(s);
• the potential risks and benefits, and possible discomforts.

The subject should understand:

that informed consent should be given freely; that consent should not be obtained through inducement or coercion; that he/she may withdraw from the study at any time; that withdrawal from the study will not affect his/her future medical care.

Investigator's Brochure (IB)

Investigator Brochure contains pre-clinical and clinical information related to an investigational drug. The information should be presented in a concise, simple, objective, balanced form that should be taken into account during translation.

The Investigator's Brochure includes Title Page, which provides the Sponsor's name, the identity of investigational product (products), an edition number and date, and the number and date of the edition it supersedes as well. The Sponsor may wish to include a Confidentiality Statement instructing to treat the IB as a confidential document. A standard Investigator's Brochure usually includes the following sections:

• List of Abbreviations
• Contents
• Summary – a brief description of significant physical, chemical and pharmaceutical properties of the investigational product, and also pharmacological, toxicological, pharmacokinetic, metabolic and therapeutic information that is relevant to the appropriate stage of clinical trial.
• ntroduction provides the chemical name (and generic and trade names, if approved) of the investigational product, all active components, pharmacological class, the rationale for performing further research with the investigational product and anticipated indications for its use. This section should provide the general approach to be followed in evaluating the investigational product.
• hysical, chemical and pharmaceutical properties and formulation of the medicinal product.
• Non-clinical studies - this section provides the data from animal studies regarding non-clinical pharmacological, pharmacokinetic, metabolic and toxicological characteristics of the investigational drug.
• Clinical studies – this section provides information on pharmacokinetics, biotransformation, safety and efficacy in humans; data on post-marketing experience if the product under investigation has been already approved for use for other indications.
• Conclusions and Guidance for the Investigator
• References (the references should be provided at the end of each section)

The Investigator's Brochure should be reviewed at least annually and revised as necessary in compliance with a standard procedures established by drug development company.

Clinical Trial Protocol

A Clinical Trial Protocol is a document or a predetermined written set of rules which includes that study objective(s), design, methodology, statistical considerations, and organization of a clinical trial. Also the protocol contains the background information and reasons for why the clinical trial or study being conducted, but these could be provided in other protocol referenced documents.

The purpose of the protocol writing is development and noting down of predetermined steps for clinical trial which will going to conduct. The protocol contains study plan on which the whole clinical trial is based. The protocol describes the clinical trial background information, answer study specific research questions, and also it is planned to escort a safety of clinical trial participants.

The format and content of clinical trial protocols sponsored by pharmaceutical, biotechnology or medical device companies in the United States, European Union, or Japan has been standardized: they are written to follow the Good clinical practice guidance issued by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Regulatory authorities in Canada and Australia also follow the ICH guidance.

Clinical trial protocols for other clinical trials do not necessarily follow the standard format.The existence of a clinical trial protocol allows researchers at multiple locations (in a multicenter trial) to perform the study in exactly the same way, so that their data can be combined as though they were all working together. The protocol also gives the study administrators (often a contract research organization) as well as the local researchers a common reference document for the researchers' duties and responsibilities during the trial.

The contents of a clinical trial protocol should generally include the following topics. However, site specific information may be provided on separate protocol page(s), or addressed in a separate agreement, and some of the information listed below may be contained in other protocol referenced documents, such as an Investigator's Brochure.

General Information

1. Protocol title, protocol identifying number, and date. Any amendment(s)should also bear the amendment number(s) and date(s).
2. Name and address of the sponsor and monitor (if other than the sponsor).
3. Name and title of the person(s) authorized to sign the protocol and the protocol amendment(s) for the sponsor.
4. Name, title, address, and telephone number(s) of the sponsor's medical expert (or dentist when appropriate) for the trial.
5. Name and title of the investigator(s) who is (are) responsible for conducting the trial, and the address and telephone number(s) of the trial site(s).
6. Name, title, address, and telephone number(s) of the qualified physician (or dentist, if applicable), who is responsible for all trial-site related medical (or) dental) decisions (if other than investigator).
7. Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical department(s) and/or institutions involved in the trial.

Background Information

1. Name and description of the investigational product(s).
2. A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial.
3. Summary of the known and potential risks and benefits, if any, to human subjects.
4. Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s).
5. A statement that the trial will be conducted in compliance with the protocol, GCP and the applicable regulatory requirement(s).
6. Description of the population to be studied.
7. References to literature and data that are relevant to the trial, and that provide background for the trial.

Trial Objectives and Purpose

A detailed description of the objectives and the purpose of the trial.

Trial Design

The scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design. A description of the trial design, should include:

1. A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial.
2. A description of the type/design of trial to be conducted (e.g. double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures and stages.
3. A description of the measures taken to minimize/avoid bias, including:
   • Randomization.
   • Blinding.
4. A description of the trial treatment(s) and the dosage and dosage regimen of the investigational product(s). Also include a description of the dosage form, packaging, and labelling of the investigational product(s).
5. The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any.
6. A description of the "stopping rules" or "discontinuation criteria" for individual subjects, parts of trial and entire trial.
7. Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if any.
8. Maintenance of trial treatment randomization codes and procedures for breaking codes.
9. The identification of any data to be recorded directly on the CRFs (i.e. no prior written or electronic record of data), and to be considered to be source data.

Selection and Withdrawal of Subjects

1. Subject inclusion criteria.
2. Subject exclusion criteria.
3. Subject withdrawal criteria(i.e. terminating investigational product treatment/trial treatment) and procedures specifying:
1. When and how to withdraw subjects from the trial/ investigational product treatment.
2. The type and timing of the data to be collected for withdrawn subjects.
3. Whether and how subjects are to be replaced.
4. The follow-up for subjects withdrawn from investigational product treatment/trial treatment.

Treatment of Subjects

1. The treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration, and the treatment period(s), including the follow-up period(s) for subjects for each investigational product treatment/trial treatment roup/arm of the trial.
2. Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial.
3. Procedures for monitoring subject compliance.

Assessment of Efficacy

1. Specification of the efficacy parameters.
2. Methods and timing for assessing, recording, and analysing of efficacy parameters.

Assessment of Safety

1. Specification of safety parameters.
2. The methods and timing for assessing, recording, and analysing safety parameters.
3. Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnesses.
4. The type and duration of the follow-up of subjects after adverse events.

Statistics

1. A description of the statistical methods to be employed, including timing of any planned interim analysis(ses).
2. The number of subjects planned to be enrolled. In multicentre trials, the numbers of enrolled subjects projected for each trial site should be specified.Reason for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justification.
3. The level of significance to be used.
4. Criteria for the termination of the trial.
5. Procedure for accounting for missing, unused, and spurious data.
6. Procedures for reporting any deviation(s) from the original statistical plan (any deviation(s) from the original statistical plan should be described and justified in protocol and/or in the final report, as appropriate).
7. The selection of subjects to be included in the analyses (e.g. all randomized subjects, all dosed subjects, all eligible subjects, evaluable subjects).

Direct Access to Source Data/Documents

The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s), providing direct access to source data/documents.

Quality Control and Quality Assurance

Ethics

Description of ethical considerations relating to the trial.

Data Handling and Record Keeping

Financing and Insurance

Financing and insurance if not addressed in a separate agreement.

Publication Policy

Publication policy, if not addressed in a separate agreement.

Supplements

(NOTE: Since the protocol and the clinical trial/study report are closely related, further relevant information can be found in the ICH Guideline for Structure and Content of Clinical Study Reports.)

Protocol Amendment

Protocol amendment describes major changes to the initial Study Protocol. Protocol amendment must be again approved by the Ethics Committee.

Phases of Clinical Research

Clinical Trial is performed in four phase for step wise evolution. The new phase of commenced only after getting satisfactory and good result from previous phases. The clinical studies started only on the satisfactory base of preclinical studies.

Phase 0

Phase 0 is a recent designation for exploratory, first-in-human trials conducted in accordance with the U.S. Food and Drug Administration’s (FDA) 2006 Guidance on Exploratory Investigational New Drug (IND) Studies.

Phase 0 (micro dose study)is included to speed up the drug development process of promising drugs or imaging agents by establishing very early on whether the drug or agent behaves in human subjects as was anticipated from preclinical studies. Micro dosing studies permit collection of human pharmacokinetic (PK) and bioavailability data earlier in the drug development process. This human data is combined with preclinical data to select the best candidates to advance to further, more expensive and extensive clinical development.

Subject number is small (10 to 15) to gather preliminary data. Microdosing uses accelerator mass spectroscopy (AMS) to count radioactive carbon atoms (¹⁴C) in blood, urine and or faecal samples from volunteers who have taken radiolabelled doses of test compounds.

A micro dose is defined as less than 1/100^th of the dose calculated to yield a pharmacological effect of a test substance and a maximum dose of <100>

Phase I

Phase I trials are the first stage of testing in human subjects. The study performed in small group (20-80) of Healthy Volunteer and usually done with non-therapeutic objectives. It evaluates safety profile, tolerability of dose range, pharmacokinetics, and pharmacodynamics of a drug. Phase I trials conducted in an inpatient under clinical supervision. The subject who receives the drug is usually observed until several half-lives of the drug have passed.

Phase I trial normally includes dose-ranging, also called dose escalation, studies so that the appropriate dose for therapeutic use can be found. The dose range will be decided the animal testing data. Phase I carried on the healthy volunteers or certain types of patients, e.g. patients with mild hypertension. Drugs with significant potential toxicity, e.g. cytotoxic drugs, are usually studied in patients.

Phase II

Once the initial safety of the study drug has been confirmed in Phase I trials, Phase II is initiated with primary objective to explore therapeutic efficacy in patients. Therefore phase II trials also called as Therapeutic Exploratory phase.

Phase II trials are performed on larger groups (20-300) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients.

Phase II studies are sometimes divided into Phase IIA and Phase IIB. Phase IIA is specifically designed to assess dosing requirements (how much drug should be given), whereas Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)).

Phase III

Phase III studies have primary objective to confirm preliminary evidence which assessed in the Phase II studies. Phase III trials are randomized controlled multicenter trials on large patient pool (300–3,000 or more depending upon the disease/medical condition studied), and compared with current standard treatment. Phase III trials are the most expensive and time-consuming in drug development process.

These studies are intended to provide an adequate basis for marketing approval. Studies in Phase III may also further explore the dose-response relationship, to obtain additional safety data, or explore the drug's use in wider populations, in different stages of disease, or in combination with another drug. This trial allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Other reasons for performing trials at this stage include attempts by the sponsor at "label expansion" (to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing), or to support marketing claims for the drug.

While not required in all studies, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, in order to obtain approval from the appropriate regulatory agencies (FDA (USA), TGA ( Australia ), EMEA (European Union), etc.).

Phase IV

Phase IV initiated after drug approval, which involves studies to go beyond the prior demonstration of the drug’s safety, efficacy and dose definition. Phase IV trials involve all studies or safety surveillance performed after drug approval and ongoing technical support for the approved indication of a drug after it receives permission to be sold. They are studies that were not considered necessary for approval but are often important for optimising the drug's use.

Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials). The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being no longer sold, or restricted to certain uses.

Types of Clinical Trial

Clinical Trials are divided in different type includes,

Treatment Trials : Comparison of a new treatment to an existing treatment (Standard Care) or to a placebo (looks like a real Treatment but contains no real Treatment) to prove that it is Safe and Effective. The only way to test whether a new Treatment actually is better is to compare it to existing Treatment or no Treatment at all (Placebo).

Prevention Trials : A Treatment, procedure, or lifestyle change is studied to see if a medical condition or disease can be prevented. For example, vaccine studies show whether or not a vaccination will actually prevent the disease.

Diagnosis Trials : Some Clinical Trials conducted to find better tests or procedures for diagnosing a particular disease or condition.

Screening and Early Detection Trials : Clinical Trials which assess new detection techniques in early phase of disease in healthy people

Quality of Life/Supportive Care Trials : Some Clinical Trials measure ways to improve comfort and the quality of life for individuals with a chronic illness, classified as Quality of Life Trials.

Genetic Makeup Trials : Studies, which determine how one’s genetic makeup can influence detection, diagnosis, prognosis, and treatment

History of Clinical Studies

First recorded clinical trial describes the person called as Daniel who followed a pulses diet and water to show that the diet is better than the meat-wine combination which was recommended by King Nebuchadnezzar II at that time.

The first clinical trial of a novel therapy was conducted unintentionally by the Renaissance surgeon Ambroise Parè in 1537. He used a concoction of turpentine, rose oil and egg yolk to prevent the infection of battlefield wounds, noting that the new treatment was much more effective that the traditional formula.

The father of clinical trial (James Lind) introduced the first control group in his clinical experiments to demonstrate the fact that citrus fruits were useful and effective in prevention of scurvy disease. The study performed at sea on board the Salisbury (1747). All scurvy patients treated with same general diet with additional items like cider, elixir seawater, vitriol, vinegar, nutmeg, oranges and lemons etc. within six days of therapy, the patients shows relief from scurvy who were taking citrus fruits.

The modern clinical studies are begun from 1800 onwards, in which more attention given to design the study. In addition, the placebos and idea of randomization were first introduced in 1863 and 1923, respectively.

The first clinical trial with randomization control group design performed in 1948 by the MRC (Medical Research Council) to demonstrate the use of streptomycin in the treatment of pulmonary tuberculosis. Also the study used the double blind assessment method to enable the unbiased method of analysis of the clinical study results.

From 1945 onwards, the ethical and patients welfare has become increasingly important in clinical trials, which yield strict rules and regulation, compiled in form of documents such as the Nuremburg Code (1947), the Declaration of Helsinki (1964, amended in 1975, 1983, 1989, 1996, 2000 and 2001).

The current clinical trials have thus developed in the process of standard procedures; strictly focus on patient safety; voluntary participation and informed consent process to all participants.

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Medical Writing

What is medical writing?

In general, medical writing is about communicating clinical and scientific

data and information to a range of audiences in a wide variety of different

formats. Medical writers combine their knowledge of science and their research skills with

an understanding of how to present information and pitch it at the right level for the

intended audience.

What qualifications and skills do you need?

Companies may expect you to have a first degree in a life science (e.g.

biology, biochemistry, physiology, or chemistry) and some may require a

PhD. However, there are many medical writers who have entered the profession with

backgrounds in language rather than science (see the section headed What is it really like?).

You don’t necessarily need a medical qualification, although a good understanding of

basic human anatomy and physiology is important. Knowledge of diseases and their

treatment is an advantage, but in most jobs you can learn about specific disease areas as

you get involved with different projects.

You’ll need very good writing and word processing skills. Most employers will ask you to

do a writing test before, or as part of, your interview so that they can judge your writing

skills. The format of this test will vary depending on the type of medical writing the

company is involved with.

You’ll also need to have good inter-personal skills. Medical writers work as part of

inter-disciplinary teams and, in some cases, with people outside of their company. You

need to be comfortable communicating with people from a range of backgrounds.

Most advertisements that you’ll see will also ask for good attention to detail. This is

important for reviewing and editing documents, and also for spotting the important

points in pages of clinical data.

Where do medical writers work and what do they do?

You’ll find medical writers in pharmaceutical companies, contract research organisations (CROs), and communications agencies. CROs conduct clinical studies and help pharmaceutical companies to get their products registered with international regulatory authorities. In general, medical writers in CROs are involved with preparing a range of documents for these regulatory submissions, including protocols and final reports for clinical trials, and clinical expert reports. They may also be involved in the preparation of manuscripts for publication in medical

journals.

The situation is generally similar in a pharmaceutical company with medical writers preparing documents for submission to the regulatory authorities and manuscripts for publication. However, depending on the company, they may also be involved in other writing projects such as training manuals, promotional material for marketing purposes, and websites.

Writers in communications agencies generally prepare manuscripts for publication, items

for conferences (e.g. posters, abstracts, and slide presentations), promotional items for

pharmaceutical marketing, training material, and multimedia (e.g. websites). The work in

this environment is likely to be more creative.

Many writers also work on a freelance basis, which is an attractive option for some

people. If you’re new to medical writing, it’s better to start off as an employee working

for a company. This will allow you to develop the skills that you need, and gain some

contacts and experience.

For more information about medical writing, download : www.emwa.org/Mum/Career.pdf, which is the source of this article.