Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting research that involves the participation of human subjects. Compliance with this standard provides assurance that the rights, safety and well-being of research subjects are protected; consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.
When considering applications that involve human subjects, it is important for reviewers and researchers to keep a number of definitions of terms in mind:
Human subjects: A “human subject” is defined as a “living individual about whom an investigator obtains (1) Data through intervention or interaction with the individual, or (2) Identifiable private information.”
The regulations extend to the use of human organs, tissue and body fluids from individually identifiable human subjects as well as to graphic, written, or recorded information derived from individually identifiable human subjects. A subset of research involving human subjects may qualify for the exemption, but justification must be provided
Children: For purposes of this policy, a child is an individual under the age of eighteen (18) years.
Clinical research is defined as:
(1) Patient-oriented research, i.e., research conducted with human subjects (or on the material of human origins such as tissues, specimens and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects. (Excluded from the definition of patient- oriented research are in vitro studies that utilize human tissues that cannot be linked to a living individual).
Patient-oriented research includes: (a) mechanisms of human disease, (b) therapeutic interventions, (c) research projects, and (d) development of new technologies; (2) epidemiologic and behavioural studies; or (3) outcomes research and health services research. A clinical trial is operationally defined as a prospective biomedical or behavioural study of human subjects that is designed to answer specific questions about biomedical or behavioural interventions.
Investigator: A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator.
Co-Investigator: Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g. research associates/ coordinators, residents, research fellows etc.).
Sponsor : An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial
Contract Research Organization: A person or an organization (commercial, academic, or other) contracted by the research sponsor to perform one or more of a sponsor’s trial-related duties and functions
Randomization: The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias.
Blinding/Masking: A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). Single-blinding usually refers to the subject(s) being unaware, and double-blinding usually refers to the subject(s), the investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s).
A clinical trial is a broadly based prospective clinical investigation, involving human subjects, for the purpose of evaluating an experimental intervention in comparison with a standard or control intervention or comparing two or more existing treatments. Often the aim of such investigation is to provide evidence leading to a scientific basis for consideration of a change in health policy or standard of care. The definition includes pharmacologic, non-pharmacologic, and behavioural interventions given for disease prevention, prophylaxis, diagnosis, or therapy. Community trials and other population-based intervention trials are also included.
A valid analysis is required for all research projects. This means an unbiased assessment. Such an assessment will, on average, yield the correct estimate of the difference in outcomes between two groups of subjects. Valid analysis can and should be conducted for both small and large studies.
A valid analysis does not need to have high statistical power for detecting a stated effect. The principal requirements for ensuring a valid analysis are:
Adverse Event (AE): Any untoward medical occurrence in a research participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR): Any untoward medical occurrence that at any dose:
– results in death,
– is life-threatening,
– requires inpatient hospitalization or prolongation of existing hospitalization,
– results in persistent or significant disability/incapacity,
or
– is a congenital anomaly/birth defect.
If the proposed research involves human subjects, reviewers must evaluate the plan to protect human subjects. The applicant’s research plan should include details about the protection of human participant from research risk. Reviewers are asked to evaluate the following elements of human research participant protection:
Risks to the research participants: discussion of research participant involvement and characteristics, source of material, and potential risks. This includes a discussion of the likelihood and seriousness of the potential risk to subjects including, if applicable, risks to vulnerable populations and hospital staff (such as the potential for coercion and undue influence).Where appropriate, alternate treatments and procedures, including risks and benefits, should be considered. If a test article (Investigational New Drug, device, or biologic) is involved, or if the applicant proposes using a drug or device in a method that may not have regulatory approval, the test article must be named and the status with regard to regulatory approval by international (e.g. Food and Drug Regulation Authority, FDA) and local (Drug Regulatory Authority of Pakistan, DRAP) regulatory bodies must be stated.
Adequacy of protection against risks: discussion of plans to protect against or minimize potential risks and assessment of their likely effectiveness. Where appropriate, this should include discussion of plans for ensuring necessary medical or professional intervention in the case of adverse effects.
Also included are recruitment plans and description of the process for obtaining informed consent, including the information to be provided to subjects. It will be ensured that for any collaborative/sponsored research study/trial, appropriate indemnity is in place. For institutional research projects, the hospital will provide management of adverse effects.
The potential benefit of the proposed research to the research participant and others: discussion of why the anticipated risks are reasonable in relation to the anticipated benefits to the subjects and to others.
Importance of the knowledge to be gained: discussion of why the risks to subjects are reasonable in relation to the importance of the knowledge to be gained.
There is a fifth level of protection involving data and safety monitoring if a clinical trial is proposed. All such applications should include plans for data and safety monitoring and should follow the institutional policies and procedures for adverse event reporting.
Based on the evaluation of whether the applicant has adequately addressed human subjects protection according to these criteria and subsequent discussion, the reviewer may score the application with no concerns or with comments or concerns that may affect the score to a level commensurate with the seriousness of the concern.
The investigator and the sponsoring institution are responsible for protecting the environment and research personnel from hazardous conditions. As with research involving human subjects, reviewers are expected to apply the collective standards of the professions in identifying potential hazards, such as inappropriate handling of oncogenic viruses, chemical carcinogens, infectious agents, radioactive or explosive materials, or recombinant DNA. If applications pose special hazards, these hazards will be identified and any concerns about the adequacy of safety procedures highlighted. The inventory, handling, storage, and use of hazardous materials and waste in research studies will be carried out as per hospital policies.
All materials pertinent to the applications being reviewed are privileged communications prepared for use only by consultants and other SKMCH&RC staff, and should not be shown to or discussed with other individuals. Review group members must not independently solicit opinions or reviews on particular applications or parts thereof from experts outside the pertinent initial review group. Members may, however, suggest scientists from whom the SRC may subsequently obtain advice. Consultants are required to leave all review materials with the SRC secretary at the conclusion of the review meeting. Privileged information in grant applications shall not be used to the benefit of the reviewer or shared with anyone.
Under no circumstances shall consultants advise investigators, their organizations, or anyone else of recommendations or discuss the review proceedings while the review process is ongoing. The investigator may be led to unwise actions on the basis of premature or erroneous information. Such advice also represents an unfair intrusion into the privileged nature of the proceedings and invades the privacy of fellow consultants serving on review committees. A breach of confidentiality could deter qualified consultants from serving on review committees and inhibit those who do serve from engaging in a free and full discussion of recommendations.
Ordinarily, there must be no direct communications between consultants and investigators. Consultants’ requests for additional information and telephone inquiries or correspondence from investigators must be directed to the SRC, who will handle all such communications.
” Research Misconduct” or “Scientific Misconduct ” is defined as fabrication, falsification, plagiarism, or other practices that seriously deviate from those that are commonly accepted within the scientific community for proposing, conducting or reporting research. It does not include honest error or honest differences in interpretation or judgments of data.
The reviewers should not review an application about which an allegation of misconduct has been made . The SRC/IRB secretary should report the allegation to the MD. In all cases of suspected misconduct, it is essential that the SRC/IRB secretary stress to the reviewers the seriousness of such allegations and the potential harm that may result if confidentiality is not strictly maintained. In addition, it is important for the SRC/IRB to assure the reviewers that the suspicions identified will be taken seriously and pursued by the MD.
Conduct of research at SKMCH&RC needs to be of high standards and calls for the declaration of conflict of interest, enabling further actions to either eliminate, reduce or manage such conflicts, as appropriate. It is in line with the hospital policy on conflict of interest.This policy applies to both researchers as well as reviewers of research and those making funding decisions.
A conflict of interest (COI) exists when a reviewer or chair of review committee has certain relationships to research protocols that the Institutional Review Board (IRB) or Scientific Review Committee (SRC) reviews.
This includes participating in or supervising the research project, a financial interest, a personal interest, or some other situation giving rise to a conflicting interest.Peer review system is subject to academic conflict of interest when one reviewer may critique or delay competitor’s research proposal to strengthen his or her own chances of funding or promotion or may respond positively to one proposal which may lead to intangible personal gain.
The reviewer conflict of interest declaration should be signed by all reviewers as well as chair of
review committee, after they have reviewed the agenda (list of research studies under review). Medical director would make the final determination. No reviewer will be allowed to participate in the review of research in which the member has a conflicting interest, except to provide the information requested by the SRC/IRB.
All researchers must identify and declare any conflicting interests related to their research at the time of submitting it to for review. Conflicting interests exists when professional judgment/practice concerning a primary interest (such as patients’ welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or professional rivalry). It may arise for researchers when they have a relationship with sponsoring company (paid or honorary position on advisory board or steering committee, sponsorship of symposium or meeting, or a travel grant), which may influence their interpretation of efficacy of the product of the sponsor or reporting of serious adverse events.
Researchers are required to disclose such relevant information while submitting their studies via a COI form available at the research office. Medical Director will make final determination and advice on the matter under review.
Clinical research office will educate all reviewers and researchers to complete and submit a signed conflict of interest forms in a timely manner and ensure compliance to above. Following are the examples of possible financial conflicts of interest;
The conflict of interest declaration will be evaluated by relevant heads of department before final review by the Medical Director who will evaluate such conflicts and if necessary, determine
The medical director will communicate when it is determined that interest must be disclosed and/or further managed. Monitoring reports of conflict of interest is presented to Clinical Exective Board (CEB).
Each research activity undertaken at the SKMCH&RC hospitals needs a prior review and approval by relevant research committees. Researchers are encouraged to review Appendix I for detailed guidance for research review requirements and process.
An independent hospital committee, which is responsible for reviewing the scientific content of research protocols. Research projects which are conducted at SKMCH & RC need approval from the SRC prior to IRB presentation.
Clinical Research Administrator
Shaukat Khanum Memorial Cancer Hospital & Research Centre
7 – A, Block R – 3, Muhammad Ali Johar Town, Lahore
Tel: +92 (0)42 35905000 Ext. 4280
Fax: +92 (0)42 35945209
E-mail: [email protected]
You are being asked to evaluate the scientific merit of a research proposal. The institution appreciates your valuable role in this review process. Two weeks before the meeting, you will receive a package containing all of the applications except for those that pose a conflict of interest for you. Included will be a list of applications on which you are expected to focus as a reviewer. It is critical that you promptly alert the SRC (within 48 hours is optimal) to unforeseen conflicts or questionable assignments concerning the matching of your expertise.
Conflict of Interest: The clinical research office will attempt to identify conflicts of interest involving you and any application. Your assistance is necessary. Consider the following as potential conflicts: investigators are listed with whom you have a financial relationship; the funding decision on any application would benefit you directly; you feel there may be a perception of conflict. Notify the SRC in such cases. The SRC will make the final determination after discussion with the medical director (MD). All reviewers will sign a conflict of interest form as a record of their declaration.
Confidentiality: The applications are to be considered confidential, and it is important to respect the privacy of the investigators’ ideas. If consultation with an expert is appropriate, contact the secretary SRC who can recruit an outside opinion and secure a signed conflict of interest form.
Expectations of Reviewers : Each application is assigned to at least two reviewers. As a reviewer, you will be expected to write a complete critique.
Amended and Renewal Applications: For revised applications, your critique should include an evaluation of the changes made in response to the last review. You should consider the response by the investigator to the previous criticisms as one component in your overall evaluation of the current application. Note, however, that you are not tied to previous critiques and can raise new criticisms and/or disagree with previous comments on strengths and weaknesses. If the application is a competing renewal, you should include an evaluation of progress over the past project period.
The Written Critique: Consider all aspects of the application. Do not describe the investigator’s plans; rather make evaluative statements about the strengths and weaknesses of the proposal. A strong application will contain good ideas, address important issues, and generate confidence that the investigator(s) will make a significant impact. Do not insist on a hypotheses-driven approach if the research is sound and will move the field forward. Focus is important, especially for new investigators. Avoid emphasizing minor technical details, making tutorial comments, or redesigning the investigator’s experiments. Put the requirement for preliminary data in perspective such that bold new ideas, young investigators, and risk-taking are encouraged rather than stymied. Be concise; longer reviews are not necessarily better. Sample critiques are less than two (2) pages long. Where possible, try to put the strengths and weaknesses in perspective by indicating their relative magnitude. Do not consider issues outside of scientific merit in your critiques, such as current or past funding levels or personal situations of the investigator.
Scoring: Each scored application is assigned a single, global score (A-E) that reflects the overall impact that the project could have on the field based on consideration of the five review criteria (significance, approach, innovation, investigator, and environment). The emphasis on each criterion may vary from one application to another, depending on the nature of the application and its relative strengths.
Scientific Misconduct: It is vital that you not make allegations of potential misconduct at the meeting or in the critique. Such concerns must be brought to the attention of the SRC in a confidential manner, preferably before the SRC meeting.
Discussion of Applications: The scientific discussion of the proposal will begin with a brief description of the overall goals of the application. Subsequently, reviewers should avoid repeating detailed descriptions of strengths and weaknesses already provided. Identify major issues with which you disagree and raise any issues not brought up previously that you feel should influence the score of the application. It is important that you listen carefully to each presentation and be prepared to defend or change your point of view based on scientific arguments. Keep an open mind, but don’t give in just to reach consensus. Do not be afraid to express your view, but avoid statements that might be considered offensive. You are strongly encouraged to participate in the discussion of applications not assigned to you. A vigorous discussion involving multiple panel members is ideal.
The consensus is not an absolute necessity, and the chair will decide when further discussion is not likely to resolve scientific differences of opinion. In such cases, it is important to establish the foundation of the disagreement. It is important, however, that you articulate your reasons for assigning a particular score. Consider human subject issues, if any, before scoring. Budget recommendations are addressed after scoring, followed by issues of compliance with regulations and policies regarding animals and biohazards. Please note that, in the event that your views are altered as a result of the discussion, you are encouraged to modify your critique appropriately so that the summary statement reflects your final evaluation of the application.
The SRC makes recommendations concerning the scientific merit of applications. The specific criteria used to assess the merit of research project applications will vary with types of applications reviewed.
The chairperson of the SRC introduces each application designated for discussion and calls upon the individuals assigned by the SRC to present their evaluations. The assigned reviewers are then called upon for their comments, and group discussion follows. After sufficient discussion has ensued, the chairperson calls for a priority rating to be assigned to the application. Ratings will be assigned by those serving as reviewers of a study who are encouraged not to abstain from assigning a score. Regular members of the SRC can give their feedback about any submitted proposal.
In addition, if there are comments or serious concerns regarding the use of human subjects or animal welfare or biohazards, a motion may be initiated that the application should be coded to reflect these comments or concerns, and an appropriate note will be included in the summary statement.
If additional information is needed before a review group can make a recommendation, a motion for a deferral may be entertained. The review group may, by majority vote, defer an application for additional information, if the information necessary to evaluate the application can be obtained only by visual inspection of the facilities, for a project site visit. Any member may nominate an application for deferral.
