Ensuring Good Clinical Practices

Definitions

When considering applications that involve human subjects it is important for reviewers 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 exemption, but justification must be provided under the heading “Protection of Human Subjects from Research Risk”. The use of autopsy materials is governed by various laws overseas.

Clinical research is defined as: (1) Patient-oriented research, i.e., research conducted with human subjects (or on material of human origin 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 behavioral studies; or (3) Outcomes research and health services research.

A Clinical Trial is operationally defined as a prospective biomedical or behavioral study of human subjects that is designed to answer specific questions about biomedical or behavioral interventions.

An NIH-defined Phase III clinical trial is a broadly based prospective clinical investigation, usually involving several hundred or more 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 behavioral 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 in phase III 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 a 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,

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.

Children: For purposes of this policy, a child is an individual under the age of 18 years.

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 four elements under the heading “Protection of Human Subjects from Research Risk”. Reviewers are asked to evaluate each of the four elements:

Risks to the subjects: discussion of human subject involvement and characteristics, source of material, and potential risks. This includes discussion of the likelihood and seriousness of potential risk to subjects including, if applicable, risks to special populations. 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 FDA approval, the test article must be named and the status with regard to FDA submission/approval 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 section 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, hospital will provide management of adverse effects)

Potential benefit of the proposed research to the subjects 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 applications proposing research projects research (see definition above) should include plans for Data and Safety Monitoring that describe the entity to be responsible for the monitoring as well as the policies and procedures for adverse event reporting. An NIH defined Phase III clinical trial (see definition above) also requires establishment of a Data and Safety Monitoring Board to provide this oversight.

Based on the evaluation of whether the applicant has adequately addressed Human Subjects Protection according to these criteria and subsequent discussion, the study section 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.

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 represented within the SRC 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 as a special note (BIOHAZARD) on the summary statement.

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 RSG may subsequently obtain advice. Consultants are required to leave all review materials with the RSG 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. The investigator may be led into 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 and site visit teams. A breach of confidentiality could deter qualified consultants from serving on review committees and inhibit those who do serve from engaging in 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 RSG, who will handle all such communications.

Scientific Misconduct

“Misconduct” or “misconduct in science” 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 SRC should not review an application about which an allegation of misconduct has surfaced from one of its members. The RSG should report the allegation to the MD.

In all cases of suspected misconduct, it is essential that the RSG 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 RSG to assure the reviewers that the suspicions identified will be taken seriously and pursued by the MD. In no instance shall the RSG or a reviewer communicate the SRC’s concerns to the principal investigator or applicant.

Scientific Review Committee

Independent Hospital committee responsible for reviewing scientific content of research protocols. Research projects which are conducted at SKMCH & RC need approval from the SRC prior to IRB presentation.

Terms of Reference

1. The Scientific Review Committee will be headed by the Medical Director and will be based on the nature and subject of the project. A full-time Secretary to the SRC (usually a Clinical Research Officer) will assist the Principal Investigator 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, Sec SRC, Sec IRB, at least two members from the Consultant staff and at least one representative from the basic science research group. The committee will advise and facilitate the investigators and may support, oppose or suggest modifications to the proposal. SRC will ensure that proposed study is appropriate for the institution
   • Target patient population, infrastructure and facilities are available
   • Research investigator and team is sufficiently qualified to carry out the study and the qualification of the research team are explicitly stated in research
5. The SRC will meet on the first and third Friday of every month.
6. The Secretary SRC will make sure that final versions of the following documents are sent to all reviewers at least two weeks prior to the meeting:
   • copy of clinical trial protocol (and any amendments)
   • copy of consent form & subject information sheet both in English & Urdu
   • a copy of investigator brochure and any available safety information
   • proposal review form
7. 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, following amendment, will be necessary. Ordinarily, the purpose of the second meeting will only be to address issues raised following the first meeting.
8. The two scientific reviewers must be present at the time of the SRC meeting and the presentation by the PI.
9. Decisions in the SRC will be based on consensus. The Medical Director will have final authority in case of dispute.
10. If required, the Medical Director may obtain assistance and advice from outside reviewers.
11. No protocol will be presented to the IRB before the SRC issues its written approval.

12. 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 3 years after the completion of the study and make them available if required by regulatory authorities.
13. To obtain the application template, guidelines for SRC approval and for any further information regarding SRC approval contact:

Clinical Research Administrator
Shaukat Khanum Memorial Cancer Hospital and Research Center
7 – A, Block R – 3, Muhammad Ali Johar Town, Lahore
Tel: +92 42 35905000 Ext. 4280
Fax: +92 42 35945207
E-mail: crc3@skm.org.pk

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 or Discussant. It is critical that you promptly alert the RSG (within 48 hours is optimal) to unforeseen conflicts or questionable assignments concerning the matching of your expertise.

Conflict of Interest: The RSG 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 RSG in such cases. The RSG will make the final determination.

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 RSG who can recruit an outside opinion and secure a signed conflict of interest form.

Expectations of Reviewers and Discussants: 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 reviewers’ 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 hypothesis-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 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 critique 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. Abstaining members and those not present during the discussion do not assign a rating and are not counted in calculating the average of the individual ratings.

Scientific Misconduct: It is vital that you not make allegations of potential misconduct at the study section meeting or in the critique. Such concerns must be brought to the attention of the RSG in a confidential manner, preferably before the study section meets.

Discussion of Applications: The scientific discussion of the proposal will begin with a brief description of the overall goals of the application. Subsequent 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. Consensus is not a 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. Each reviewer present for the discussion will vote on each application. Your score should be based on your level of enthusiasm. It is important, however, that you articulate any plan to give a score outside the range indicated by the assigned reviewers. 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 written critique appropriately so that the summary statement reflects your final evaluation of the application.

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 discussants 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 regularly appointed members of the SRC and by those serving as temporary members. Reviewers are encouraged not to abstain.

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 deferral may be entertained. The review group may, by majority vote, defer an application for additional information or, if 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.

Institutional Review Board

An Independent Hospital Ethical Committee, responsible for reviewing and approving all Clinical Research Projects undertaken in the Hospital or involving Hospital patients or patient data.

The principal duty of the IRB is to safeguard the patient’s or test subjects’ interest including those identified as vulnerable. 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 by the Scientific Review Committee. The IRB bases its work on principles that have their origin in the Declaration of Helsinki (first written in 1964 & most recently revised at General Assembly in October 2013) and that are consistent with Good Clinical Practice guidelines & applicable regulatory requirements.

The IRB judges:

• The investigator’s suitability and prospects for performing the study
• 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.

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.
2. The IRB will meet after every two months or earlier if needed.
3. A Clinical Research Officer will function as the Secretary to the IRB and will assist the Principal Investigator & the sponsor in obtaining ethical approval from the IRB.
4. The scientific content of all research projects presented to the IRB must have been validated by the Scientific Review Committee prior to submission to the IRB.
5. All the necessary documents must be completed & submitted to the Secretary to the IRB by the concerned parties at least four weeks prior to the proposed date of the meeting.
6. 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 postgraduate student projects. Undergraduate students and investigator initiated trials and are not subjected to an IRB processing fee.
7. The Secretary will make sure that final versions of the following documents are sent to all IRB members for review:
   • 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
8. 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.
9. 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
10. Using 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 and the sponsor and a copy will be retained in the Investigator’s Study File & IRB folder.
11. 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.
12. Only those members who actually participate in the IRB review & discussion can cast a vote / provide an opinion or advice.
13. In special circumstances, the IRB can invite non-members with particular expertise for assistance.
14. No subject will be enrolled in any study / clinical trial before the IRB issues its written approval of the study protocol.
15. 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 hazards to the subjects or when the change involves only logistical or administrative aspects of the research projects (e.g. change of the investigator).
16. 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 significantly the conduct of the study/trial.
    • All adverse drug reactions that are either serious or unexpected.
    • New information that may affect adversely the safety of the subjects or the conduct of the study/trial.
17. 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 period of at least three years after the completion of the study and make them available upon request from any appropriate regulatory authority(ies).

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 and Research Center
7 – A, Block R – 3, Muhammad Ali Johar Town, Lahore
Tel: +92 (0)42 35905000 Ext. 4280
Fax: +92 (0)42 35945207
E-mail: crc3@skm.org.pk