Ensuring Good Clinical Practices

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.

2.1  Definitions

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:

  • Allocation of study participants of both sexes/genders and different racial/ethnic groups to the intervention and control groups by an unbiased process such as randomization (applicable for studies using a randomised controlled design)
  • Unbiased evaluation of the outcome(s) of study participants, and
  • Use of unbiased statistical analyses and proper methods of inference to estimate and compare the intervention effects among the sex/gender and racial/ethnic groups.

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.

2.2 Protection of Human Subjects

If the proposed research involves human subjects and does not qualify as being exempt, it is considered clinical research (see definition above) and 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.

2.3  Biohazards

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.

2.4 Confidentiality and Communications with Investigators

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.

2.5 Scientific Misconduct

” 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.

2.6 Conflict of Interest

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.

2.6.1 Guidance for Reviewers:

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.

2.6.2 Guidance for Researchers:

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;

  • A fee for speaking
  • A fee for organizing educational activity
  • Reimbursement for attending a symposium/conference/meeting etc
  • Sponsorship of your research or that of your trainees
  • Paid or honorary position on advisory board or steering committee
  • Employment
  • Any sponsorship/funding that investigators may have received to help conduct a study.

2.6.3 Monitoring Process for Conflict of Interest Declaration :

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

  1. Whether the conflict is permissible in the context of the proposed research
  2. Whether the conflict warrants disclosure to potential participants as part of informed consent process or
  3. Warrants further management to reduce or eliminate the interest.

The medical director will communicate when it is determined that interest must be disclosed and/or further managed.

2.7 Process for Scientific and Ethical Review of Research

Each research activity undertaken at the SKMCH&RC hospitals needs a prior review and approval by relevant research committees. Researchers are encouraged to review the document titled “Process to get IRB approval” for detailed guidance for research review requirements and process.

2.8 Scientific Review Committee

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.

2.8.1  Terms of Reference

  1. The Scientific Review Committee will be headed by the medical director (MD) and will be based on the nature and subject of the project. A fulltime secretary to the SRC will assist the principal investigator (PI) in obtaining approval from the SRC.
  2. The secretary of the SRC will initially review all proposals received and forward complete applications to the MD, recommending the names of two scientific reviewers.
  3. All necessary documentation must be completed & submitted to the secretary SRC by the principal investigator at least four weeks prior to the scheduled date of the meeting.
  4. The MD will nominate a scientific review committee for the project. All SRC’s constituted will include MD, secretary SRC, secretary IRB, at least two members from the consultant staff and at least one representative each from the basic science research lab and cancer registry and clinical data management (CRCDM). The committee will advise and facilitate the investigators and may support, oppose or suggest modifications to the proposal. SRC will ensure that the proposed study is appropriate for the institution

a) Target patient population, infrastructure and facilities are available

b) Investigator and research team suitability for carrying out the research study

5. The SRC will meet once per month or frequently if needed.

6. The secretary SRC will make sure that final versions of the following documents are sent to reviewers at least two weeks prior to the meeting:

    • Copy of clinical research protocol (and any amendments)
    • A copy of investigator brochure and any available safety information
    • Proposal review request
  1. In the meeting, the Principal investigator will present the protocol under review and answer any questions posed by the reviewers. In the event of serious objections, re-submission of the protocol, with amendment will be necessary. Ordinarily, the purpose of the second meeting will only be to address issues raised following the first meeting.
  2. The assigned scientific reviewers must ensure submission of their complete critique of the submitted proposal before the SRC meeting and presentation by the PI.
  3. Decisions in the SRC will be based on consensus. The Medical Director will have final authority in case of a dispute.
  4. If required, the medical director (MD) may obtain assistance and advice from outside reviewers.
  5. No protocol will be presented to the IRB before the SRC issues its written approval, except in the following circumstances
  • Studies qualifying for exempt status are submitted directly to IRB (see the section on IRB review for details)
  • For international investigational new drug (IND) / device or biologics trials, the scientific review will be carried out during the initial feasibility assessment process coordinated through the clinical research office. The process involves assessment of scientific validity, availability of target population, infrastructure and facilities which is carried out by proposed investigators who are subject area experts, in liaison with clinical research office.
  1. The secretary SRC will be responsible for maintaining all relevant records (e.g. written procedures, submitted documents, minutes of meetings & correspondence) for a period of at least three (3) years after the completion of the study and make them available if required by regulatory authorities.
  2. Toobtain the application template, guidelines for SRC approval and for any further information regarding SRC approval contact:

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: crc3@skm.org.pk

2.8.2 Guidelines for Reviewers

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.

2.8.3 Review procedures for SRC meetings

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.

2.9 Institutional Review Board

An Independent Hospital Ethical Committee, responsible for reviewing and approving all clinical research projects undertaken at SKMCH&RC or involving hospital patients/patient’s data.

The principal duty of the IRB is to safeguard the patient’s or test subjects’ interest including those identified as vulnerable such as children, prisoners, pregnant women, persons who are mentally disabled, persons who are economically or educationally disadvantaged, and others (e.g. hospital staff) who may be at risk for coercion or undue influence.

It primarily evaluates the ethical aspects of the planned study, and deliberates on a research proposal only after it’s scientific content has been validated. The IRB bases its work on principles that have their origin in the Declaration of Helsinki (first written in 1964 & recently at the General Assembly in October 2013) and that are consistent with Good Clinical Practice (GCP) guidelines & applicable regulatory requirements.

The IRB judges:

  • The investigator’s suitability and prospects for performing the study. Research investigator and the team should be sufficiently qualified by training, education and experience to carry out the study . This is evaluated through a review of the qualification of the principal investigator which are submitted alongside the research proposal.Trial related medical decisions should be made by a suitably qualified physician or physician designee. The investigator may delegate other trial-related duties to other qualified staff such as pharmacist for drug dispensing , nurses for drug administration etc.
  • Whether the risks that the patients are being subjected to have been minimized and are proportional to the expected advantages of the results of the study
  • Whether the patients are correctly selected and informed about the study.

IRB review is required for any research protocol involving:

  1. Patients and users of the SKMCH&RC. This includes all potential research participants recruited by virtue of the patient or user’s past or present treatment by, or use of SKMCH&RC. It includes SKMCH&RC patients treated under contracts with private sector institutions
  2. Individuals identified as potential research participants because of their status as relatives or carers of patients and users of the SKMCH&RC, as defined above.
  3. Access to data, organs or other bodily material of past and present SKMCH&RC patients.
  4. Foetal material involving SKMCH&RC patients.
  5. The recently deceased in SKMCH&RC premises.
  6. The use of, or potential access to, SKMCH&RC premises or facilities.
  7. SKMCH&RC staff recruited as research participants by virtue of their professional role. Hospital staff can partcipate in any IRB approved hospital research after eligibility assessment and as per procedures outlined in that protocol.

2.9.1 Terms of Reference

  1. At the time of review in a convened meeting a quorum meeting following requirements must be present
  • The IRB must have at least five members.
  • The IRB must include at least one scientist and at least one non-scientist.
  • The IRB must include at least one person who is not affiliated with the institution or in the immediate family of a person affiliated with the institution.
  1. The IRB of SKMCH&RC will be composed of at least ten (10) members and each member will be appointed for a minimum period of two years. The IRB will meet monthly or earlier if needed.
  2. A clinical research office member will function as the secretary to the IRB and will assist the principal investigator (PI) & the sponsor in obtaining ethical approval from the IRB.
  3. The scientific content of all research projects presented to the IRB must have been validated prior to submission to the IRB.
  4. All the necessary documents must be completed and submitted to the secretary to the IRB by the concerned parties at least four weeks prior to the proposed date of the meeting.
  5. An IRB processing fee must be submitted to the clinical research office before the meeting. The fee is Rs.30,000 for pharmaceutical sponsored trials and Rs.3,000 for external postgraduate student projects. Undergraduate students and investigator initiated studies by SKMCH&RC staff  and are not subjected to an IRB processing fee.
  6. The secretary will make sure that final versions of the following documents are sent to all IRB members for review:

IRB application (Online IRB application can be accessed at link:

https://apps.shaukatkhanum.org.pk/online/irb/index.php)

    • A copy of synopsis along with the attached Scientific Review Committee approval and the IRB approval request
    • study protocol (and any amendments)
    • consent form & subject information sheet both in English & Urdu
    • Study questionnaire/data collection form/interview guide as applicable
    • A copy of the Investigator Brochure and any other available safety information
    • Information about payments and compensation available to subjects
    • The Investigator’s current curriculum vitae.
    • Any other documents specifically requested by the IRB
  1. After reviewing the above documents, the IRB will issue a letter confirming that it has reviewed the concerned documents (adding the dates & version seen) and outlining its decision with regard to the proposal.
  2. During a convened meeting, all IRB members will perform the review of each study and will be expected to
    • explicitly state that, in his/her opinion, the criteria required for approval have been met, and vote (for/against)
    • propose a specific frequency for continuing review
    • carefully describe the proposed conditions or basis for requiring changes or in disapproving research, in cases where approval is not granted
    • IRB decision will be made by majority vote, and voting information will be recorded in meeting minutes
  1. Using the above procedures, the IRB may approve, reject, modify or defer any application, pending further information. The decision of the IRB will be conveyed to the principal investigator (PI) and the sponsor and a copy will be retained in the Investigator’s Study File & IRB folder.
  2. Only those IRB members who are independent of the investigator teams and the sponsor of the study/trial can vote/proffer an opinion on a study/trial-related matter.
  3. Only those members who actually participate in the IRB review & discussion can cast a vote/provide an opinion or advice
  4. In special circumstances, the IRB can invite non-members with particular expertise for assistance.
  5. No subject will be enrolled in any study/clinical trial before the IRB issues its written approval of the study protocol.
  6. No deviations from, or changes to, the protocol will be initiated without prior written IRB approval of any proposed amendments, except when necessary to eliminate immediate hazards to the subjects or when the change involves only logistical or administrative aspects of the research projects (e.g. change of the investigator).
  7. The investigator will be required to report to the IRB any instance of:
    • Deviation from, or changes to, the protocol designed to eliminate immediate hazards to the study/trial subjects.
    • Changes increasing the risk to subjects and/or affecting the conduct of the study/trial significantly.
    • All adverse drug reactions that are serious and/or unexpected.
    • New information that may affect the safety of the subjects or the conduct of the study/trial adversely.
    • The investigator will also inform the IRB if there are any changes to the consent document as a result of any new safety concerns as the participants will need to be re-consented in that case. Any amendment to the informed consent document will be submitted to the IRB for its review and approval prior to its implementation.
  1. The secretary to the IRB will be responsible for maintaining all relevant records (e.g., written procedures, membership lists, submitted documents, minutes of meetings and correspondence) for a lifetime period after the completion of the study and make them available upon request from any appropriate regulatory authority(ies). The secretary IRB is also responsible for submitting an annual report of research review activities to the clinical executive board (CEB) for a review of the research review function.
  2. A subset of human subject research involving no more than minimal risk qualifies for exemption. It means that the proposed research activity is exempt from full quorum review by IRB, and no further correspondence is required. A quick review by IRB chairperson and one of his designee is required, and it is completed in two to four (2-4) weeks of submission. This type of review is applicable when research involves the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, and if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects Investigators should not make final determination that their research is exempt. IRB is an authorized body to make the final determination of exemption.
  3. IRB review also ensures that informed consent in research is documented as per GCP requirements and hospital policy on informed consent. A template document outlining requirements for consent in research is available with the clinical research office for investigator use. The investigator should ensure that the following is covered during the process of informed consent for research studies
    • an explanation of the research, duration of patient participation, and procedures to be followed by patients;
    • expected benefits;
    • potential discomforts and risks;
    • alternative treatments and procedures that might also be beneficial;
    • the extent to which confidentiality of records will be maintained;
    • compensation or medical treatments available if an injury occurs;
    • a statement that participation is voluntary;
    • assurance that refusal to participate or withdrawal from participation will not compromise care or access to the hospital’s services; and who to contact with questions about the research.

A sub-set of research activities may qualify for a waiver of written consent. The research applications requesting a waiver of consent requirement should include the following details

  • The research involves no more than minimal risk to subject and involves no procedures for which informed consent is normally required outside of the research context.
  • The waiver or alteration will not adversely affect the rights and welfare of the subjects.
  • The research could not practically be carried out without the waiver or alteration.
  • Whenever appropriate, the subjects will be provided with additional information after participation.

Review of application during Pandemics & Public Health Emergencies

IRB will use its best efforts to continue to function during a pandemic. It will provide a rapid but robust review. IRB will adapt to meet by video conferencing and accept online reviews (in place of signed forms)

IRB will further ensure that practical and meaningful consent process is in place for patients affected by diseases outbreak. If appropriate, alterations in the informed consent process, including waiver of informed consent and verbal consent can be approved by IRB.

To obtain an application template, guidelines for IRB approval and for any further information regarding IRB approval, please contact:

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:crc3@skm.org.pk

2.9.2 Guidelines for IRB reviewers:

Criteria for IRB Approval of Research

Institutional Review Board (IRB) is responsible for reviewing and approving all Clinical Research Projects undertaken in the hospital or involving the hospital’s patients or patient data.

The principal duty of the IRB is to safeguard the welfare of patients who participates in research (participants). It primarily evaluates the ethical aspects of the planned study.

The IRB judges that the investigator is suitable to conduct this research (sufficiently qualified and experienced), and ensures that the rights of study participants are protected from possible risks of research.

In order to approve research under review, IRB should determine that all of the following requirements are satisfied

  1. Risks to subjects are minimized by using:
    i) procedures consistent with sound scientific design and which do not unnecessarily expose subjects to risk
    ii) whenever appropriate by using procedures already being performed on subjects for diagnostic or treatment purposes
  2. Risks to subjects are reasonable in relation to the anticipated benefits
  3. Selection of subjects is equitable (Are these participants appropriate to the research question)
  4. Informed consent will be sought from each prospective subject or the subject’s legally authorized representative
  5. Informed consent will be appropriately documented
  6. When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects
  7. When appropriate, there are adequate protections to protect the privacy of subjects and to maintain the confidentiality of data.

Note: When some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as hospital staff, children, prisoners, pregnant women, mentally disabled, or economically or educationally disadvantaged persons, IRB should ensure that appropriate safeguards have been included in the study to protect the rights and welfare of these subjects. In cases where research involves the participation of hospital employees, IRB should ensure that mechanisms are in place to obtain voluntary participation and appropriate confidentiality. Informed consent must state that refusal to participate will not result in any loss of privileges or negative impact on evaluation.

2.9.3 Investigator Responsibilities and Responsible Conduct of Research

As per ICH-GCP, all researchers involved in research must ensure the following as part of responsible conduct of research

  • The investigator(s) should be qualified by education, training, and experience to assume responsibility for the proper conduct of the research
  • The investigator should be thoroughly familiar with the research protocol, should be aware of, and should comply with, GCP and the applicable regulatory requirements.
  • The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority (ies) where applicable.
  • The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties
  • The investigator should ensure availability of adequate resources for conducting a research study such as adequate time allocation to research activities, qualified and trained staff as members of research team and other logistics as per study need.
  • The principal investigator of a study has ultimate responsibility for maintaining study oversight (including but not limited to ensuring protocol compliance, investigational products accountability) and for supervising any individual or party to whom the investigator delegates trial-related duties and functions.
  • A qualified physician (or dentist, when appropriate), who is an investigator or a sub-investigator for the trial, should be responsible for all trial-related medical (or dental) decisions.
  • During and following a subject’s participation in a trial, the investigator should ensure that adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory values, related to the trial.
  • The investigator is responsible for ongoing ethics and regulatory communication as applicable with relevant committees following initial approval of the study.
  • Investigators are responsible for obtaining and documenting informed consent from research participants as per approved protocol consent procedures. In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. Neither the investigator nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in a trial. Once consent has been obtained, research participation should be clearly recorded in the research subjects’ hospital records, and a copy of the signed consent must be retained in the research files.
  • The investigator should maintain adequate and accurate source documents and research related records.
  • The investigator should submit written summaries of the trial status to the IRB at least annually, or more frequently, if requested by the IRB.
  • All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g., Investigator’s Brochure) identifies as not needing immediate reporting.
  • If a clinical trial is prematurely terminated or suspended for any reason, the investigator should promptly inform the trial subjects, should assure appropriate therapy and follow-up for the subjects, and, where required by the applicable regulatory requirement(s), should inform the regulatory authority(ies).
  • Upon completion of the research study, the investigator, where applicable, should inform the IRB with a summary of the trial’s outcome, and the regulatory authority(ies) with any reports required.
  • For research projects undertaken as part of training requirements , following are the supervisor responsibilities for oversight of such research activities
    • Supervisor to only allow project initiation once IRB approval is confirmed and should conduct regular project update meetings
    • Promptly notify the institution in case of any research misconduct which may lead to suspension of the study or termination of ethics approval for that study.