Conducting a clinical study: A guide for good research practice

he number of prospective randomized trials in proposed randomized controlled trial (RCT). orthopedic surgery is increasing. To assure that the developers of the protocol should perform a systematic the rights, safety and wellbeing of trial subjects (i.e. review (and/or meta-analysis) to gather the available patients) are protected, the guideline for good clinical evidence. Orthopedic devices are sometimes introduced practice (GCP) was developed. This guideline has its into the market without thorough evaluation. This approach origin in the Declaration of Helsinki. Furthermore, it assures may result in unnecessary risk for patients. In addition, that the clinical trial data are credible. The objective of the not all new surgical treatments are improved from current International Conference on Harmonization (ICH) GCP standards. guideline is to provide a unified standard for research in Europe, Japan, United States, Australia, Canada and the Investigators considering a new study must ask the key Nordic countries. A copy of the entire guideline can be question: do we need a research trial to examine if a downloaded from the following website: http:// treatment works or doesn’t? Is there sufficient uncertainty www.emea.eu.int/pdfs/human/ich/013595en.pdf. about the relative effects of “investigational” and current standard treatments on patient importance outcomes? To In this article we provide an overview of the guideline for ensure that no relevant published studies already exist, a GCP in the context of conducting an orthopedic clinical thorough literature search is mandatory. trial. Our emphasis focuses upon those issues most relevant should use a systematic approach to find the available to orthopedics. evidence. Often, a systematic review may already exist. The Cochrane library is one extensive database of THE PRINCIPLES OF ICH GCP systematic reviews on a variety of topics. The conduct of a meta-analysis helps to systematically appraise the The key principle of the GCP guideline is the ethical available evidence as well as to frame an answerable conduct of a trial. The trial cannot be initiated before all research question for future research. foreseeable risks and inconveniences are weighted against the anticipated benefit for the individual trial subject and Clinical trials should be scientifically sound and described society. Patient safety is the cornerstone of the GCP in a clear, detailed protocol. The British Medical Journal The safety and wellbeing of the trial subjects mandates the protocol of a trial to be reviewed together are most important and should prevail over the interest of with the final manuscript to identify protocol deviations. science and society. The trial should be conducted in compliance with the Therefore, T

he number of prospective randomized trials in proposed randomized controlled trial (RCT). 3 orthopedic surgery is increasing. 1 To assure that the developers of the protocol should perform a systematic the rights, safety and wellbeing of trial subjects (i.e. review (and/or meta-analysis) to gather the available patients) are protected, the guideline for good clinical evidence. Orthopedic devices are sometimes introduced practice (GCP) was developed. 2,3 This guideline has its into the market without thorough evaluation. This approach origin in the Declaration of Helsinki. Furthermore, it assures may result in unnecessary risk for patients. 4,5 In addition, that the clinical trial data are credible. The objective of the not all new surgical treatments are improved from current International Conference on Harmonization (ICH) GCP standards. 6 guideline is to provide a unified standard for research in Europe, Japan, United States, Australia, Canada and the Investigators considering a new study must ask the key Nordic countries. A copy of the entire guideline can be question: do we need a research trial to examine if a downloaded from the following website: http:// treatment works or doesn't? Is there sufficient uncertainty www.emea.eu.int/pdfs/human/ich/013595en.pdf. about the relative effects of "investigational" and current standard treatments on patient importance outcomes? To In this article we provide an overview of the guideline for ensure that no relevant published studies already exist, a GCP in the context of conducting an orthopedic clinical thorough literature search is mandatory. 7 trial. Our emphasis focuses upon those issues most relevant should use a systematic approach to find the available to orthopedics.
evidence. Often, a systematic review may already exist. The Cochrane library is one extensive database of THE PRINCIPLES OF ICH GCP systematic reviews on a variety of topics. 7 The conduct of a meta-analysis helps to systematically appraise the The key principle of the GCP guideline is the ethical available evidence as well as to frame an answerable conduct of a trial. 3 The trial cannot be initiated before all research question for future research. 8 foreseeable risks and inconveniences are weighted against the anticipated benefit for the individual trial subject and Clinical trials should be scientifically sound and described society. Patient safety is the cornerstone of the GCP in a clear, detailed protocol. 3 The British Medical Journal The safety and wellbeing of the trial subjects mandates the protocol of a trial to be reviewed together are most important and should prevail over the interest of with the final manuscript to identify protocol deviations. 9 science and society.
The trial should be conducted in compliance with the Therefore, The available nonclinical and clinical information on an investigational product should be adequate to support the protocol that has received prior institutional review board or independent ethics committee approval. Some journals facilitate review of a protocol before the trial starts. 10,11 Protocol publication ensures that investigators follow the guidelines of the protocol they initially proposed. Furthermore, it reduces the potential for sudden changes to the protocol and random analyses (i.e. "data-dredging") to find a difference between treatment groups. 10, 12 Observational studies or case series are most suspect to data-dredging and post-hoc revisions. 10 Therefore, protocols of these studies should be published before the conduct of the study. Legislation in some countries now requires registration of trials. Details can be found at: http:/ /www.controlled-trials.com/.

METHODOLOGICAL ISSUES IN CLINICAL STUDIES
Key aspects of a methodological sound study design are randomization, allocation concealment and blinding. 13 Randomization ensures that both known and unknown prognostic factors are equally distributed in the treatment and control groups. Allocation concealment prevents undermining of random, unpredictable assignment sequences resulting in overestimated treatment effects. 14 in surgical RCTs the "expertise-based trial" has been Blinding of outcome assessors is mandatory, especially if promoted by Devereaux and colleagues. 18 In an expertisesoft outcomes are used, as is often the case in orthopedic based randomized trial subjects are allocated to a treatment provider, not to a treatment. 18 This ensures treatment by Treatment effects are known to be overestimated in un-blinded studies. 13,16,17 qualified and motivated surgeons who believe in the technique they are using, thus reducing potential bias.

Key administrative issues Informed consent
The following principles are straightforward but should be followed in every trial. The medical care given to and Freely given informed consent should be obtained from medical decisions made on behalf of, subjects should every subject prior to clinical trial participation. 3 always be the responsibility of a qualified physician. 3 Each orthopedic RCTs patient recruitment can be difficult. [19][20][21] individual involved in conducting a trial should be qualified Low recruitment can lead to small sample size and by education, training and experience to perform his or therefore, insufficient statistical power. The results of an her respective tasks. 3 Therefore, copies of licenses should underpowered clinical trial will not be able to provide be kept in the trial documentation. Before subjects can be clinically important answers the trial was designed for, while enrolled in your study several prestudy documents must it risks adverse events of the participants. 22 be compiled by the study coordinator and placed in the should try to identify potential recruitment problems study operations manual. If this is an FDA trial, a form beforehand and modify their approaches accordingly. 22

Expertise-bias: A key consideration when conducting an orthopedic trial
Skepticism about surgical RCTs found its roots in questions adverse event occurs during the trial this needs to be documented for detailed evaluation. Moreover, it will be easier for investigators to collect the results and analyze them. RCTs almost always have some missing data. Inadequate handling of these missing data in the analysis can cause substantial bias in the treatment effect estimates. 23 One way of preventing this possible source of bias is detailed and accurate documentation. The success and integrity of a trial depends on the data quality and data management. 1 Data collection in multi-center trials is challenging. Designated coordinating centers use centralized computer data collection systems that can be fax-based or Internet-based. 1,24 Study documents should be created and are summarized in [ Table 2]. Each subject who is enrolled in your study must have a folder that contains documents necessary for patient education,

Document Description
Investigator brochure (summary of device or method)* Delegation of responsibilities form (from PI to others) Source documents The first recording of any observations made or data generated about a study subject during his/ her participation. 8 Source documentation is the foundation of all studies as they confirm the completeness and accuracy of data collection and that the study follows the protocol and is ethically administered. "Facts About Source Documents" can be found at the following FDA website: http://www.fda.gov/cder/present/dia-699/wollen-dia99/ Subject enrolment forms Forms listing all subjects to aid in the scheduling of subject visits and serves as a checklist to ensure all necessary CRFs are completed for each visit. Case report forms (CRF) Documents that provide for a seamless transfer of data from the source documents to the study database. CRFs are preprinted pages that allow the investigator or study coordinator to document data regarding demographics, medication use, prognostic factors and all follow-up outcomes being measured. Adverse event forms Forms that allow for the documentation of medical complaints and possible side-effects of any degree that may or may not be attributed to the study procedure. Authorized signature record List of names of those individuals who are authorized to complete or make changes to the CRFs. Site visit log (monitor log) A form used to record visits by the study monitor to each study site.

Telephone log
Used to record all telephone contacts that pertain to the study. All correspondence to and from sponsor* informed consent and proper data collection [ Table 3]. and stored in accordance with applicable good Each document within the subjects work folder should have manufacturing practice. They should be used in accordance the subject unique identifier. For example, 2C-322 may with the approved protocol. 3 In orthopedic trials this issue indicate Protocol 2C, site number 3, subject number 22.
should be discussed with, for example, the implant The confidentiality of records that could identify subjects manufacturer and documented accordingly. should be protected, respecting the privacy and confidentiality rules in accordance with the applicable Systems with procedures that assure the quality of every regulatory requirements. 3 For this reason subjects should aspect of the trial should be implemented. 3 To facilitate this be given a unique identification number as described "study operations manual" is created. This manual will be above. Data will be checked in the coordinating centers helpful to oversee the day-to-day operations of a study. 25 It for missing information, implausible data and will provide detailed instructions for all study procedures. inconsistencies at an early stage. Research coordinators This manual should include the step-by-step process for from each clinical site should be contacted by phone to enrolling and following patients, entering and managing data ensure that problems are corrected. Failure to resolve and monitoring the process. Copies of all study materials, problems urgently will violate the GCP guideline and can including study protocol, consent forms, questionnaires, etc, result in termination of the trial by the authorities as a worst-should also be included in the manual. Procedures for case scenario.
maintaining confidentiality and quality assurance and control should be covered. 25   COMMITTEES AND TRAIL PERSONNEL TO ENSURE ADHERENCE TO THE GCP GUIDELINE Especially, the complexity of a multi-center trial requires key organizing committees to overlook the conduct of the trial, to assure patient safety and to limit bias in outcome assessment, in other words: adherence to the GCP guideline. 1

Steering committee
The steering committee is responsible for the overall design and conduct of a trial. 1 Although not all trials require safety

Element Description
Study protocol Read and understand all sections of the protocol and ensure that all investigators have reviewed it, given input and agreed to following the procedures (signature is recommended and sometimes required) Compile prestudy documents These are documents that are absolutely necessary to have on record before conducting a study to ensure patient confidentiality and legal protection. Create study documents These are documents that you and all study personnel will be using to document the day-to-day study activities including data collection. Create subject work folder Each subject will need a folder that includes all documents they must read, understand and sign.
monitoring by a formal committee external to the trial trials on an ethical basis. For investigators it requires a large investigators, all trials need safety monitoring.
time commitment but will result in pure data collection while patient safety is maintained. Adherence to this Data safety monitoring board guideline will safeguard patient trust in science. A data safety monitoring board (DSMB) is usually required for large multi-center trials that evaluate interventions