Welcome back to trial management and advanced operations. My name is Sheriza Baksh and I am an Assistant Scientist at the Center for Clinical Trials and Evidence Synthesis at the Johns Hopkins University. In this lecture, we'll be discussing standardization of research practices, transparency of study activities , and research reproducibility. Before we begin I wanted to highlight some key points that you should keep in mind throughout this lecture. The first of these is that standardization of reporting practices across trials internationally improves dissemination of the results. This eases the possibility of selective reporting between trials and allows for a complete view of the entire scientific body of evidence underneath the particular study question. In addition to this, standards for both data collection reporting practices, as well as a research practice, enable replication of these studies. If there are other investigators who might want to duplicate your results to verify that in fact the association you're seeing is true, this enables them to do so. The third point is that transparency in trials allow for the effective adjudication of study results by journal editors and others who might wish to consume your study data. Finally, protocol development and the use of trial registries often hold the investigators to whatever outcomes they pre-specified in their protocol development and so when they come to actually publish the trial results they can ensure that what they said they would do is in fact what they did do. Our underlying lesson for today is that standardization of study procedures and data collection leads to better reporting of trial procedures and results, which then leads to the ability to replicate studies both in the same population, and other populations, and the ability to synthesize multiple studies more effectively. Together, this leads to better health care decision-making. We can't have a discussion around standardization in clinical trials without mentioning the International Council for Harmonization, also known as ICH. The ICH harmonizes guidelines and practices for the goal of improving pharmaceutical product quality safety and efficacy. While this group has a primary focus on harmonization within the context of product development, their technical documents have been used as the basis for regulating clinical research within many contexts. ICH was formed in 1990 and consists of members from both industry and regulatory agencies as well as regional harmonization groups. The ICH consists of both members and observers interested in developing standards for the conduct of regulatory trials. The difference between members and observers comes down to who is actually involved with the development of set guidelines and who has a say in whether or not they're actually approved and moved on to the next step. While this may be the focus, these standards have been adopted for a variety of clinical trials and observational studies. The standardization process has proved useful for dissemination of results in a very digestible manner for various audiences. The ICH guidelines and standards are developed in a step-wise fashion shown here, and we'll go through each of these. The process first begins with the formation of an expert working group, and from this working group, a consensus is built around a particular topic. Once that consensus has been built, it's then brought to the General Assembly for their agreement and their consensus on a particular topic. This may mean some back and forth with editing but eventually, they will come to a draft guideline. This draft guideline is then presented for regulatory consultation, discussion, and a finalization. This is where we might bring in some of the other external regulatory officials to see if this meets their needs. At this point, the finalized draft guidance is then adopted and different regulatory agencies may choose to incorporate this into their guidelines for any submissions. After the adoption of these harmonized guidelines, it is then implemented by those who are actually submitting the products for regulatory approval. Each of the guidelines fall into one aspect of the guideline library, and you'll see here we have four buckets. We have quality, safety, efficacy, and a catch-all, a multi-disciplinary bucket. The quality guidelines include key documents covering the conduct of stability studies defining relevant threshold for impurity testing and a more flexible approach to pharmaceutical quality based on good manufacturing practice risk management. The safety guidelines are a little bit more pertinent to clinical trials and they are comprehensively used to identify potential risks such as carcinogenicity, genotoxicity, and lipotoxicity. The efficacy guidelines are concerned with mainly the design conduct and safety of reporting for clinical trials. Finally, the multi-disciplinary guidelines include those for MedDRA dictionaries as well as common technical documents, and it really is a catch-all for anything that doesn't fall under the other three. Common technical documents are one of the products that the ICH commits to cementing. Common technical documents are the agreement to assemble quality, safety, and efficacy data into a standard format. It's typically the format you use for submission of study documents to regulatory agency, and it consists of five different modules. Those of you who do have some experience with regulatory submissions will be quite familiar with these. The first module is the Regional Administrative Information. This particular one is very regionally specific. Depending on which regulatory agency you might be submitting to, these documents will defer. Module 2 is more of a quality summary. This can be non-clinical and clinical data that are submitted as an overview and summarized for review. Module 3 is a quality assessment of whatever product is being submitted, and module 4 is a compendium of all the non-clinical study reports, while module 5 contains all of the clinical study reports. Together, these common technical documents and their standard formatting allows for regulatory agencies to both communicate with each other when necessary and to look at different product approval packages in the same light as all of them should technically be submitting very similarly formatted documents. Another product that ICH creates is MedDRA, the Medical Dictionary for Regulatory Activities. This is a very highly used, highly specific standardized medical terminology dictionary. It's used for both safety reporting and for any type of communication of the adverse events that are associated with the clinical trial. It can be used within the context of registration, formal documentation, or study monitoring activities, and it's been adopted worldwide by many regulatory agencies. MedDRA is maintained by the Maintenance and Support Services Organization and it's freely available for non-commercial use. There is one tool that is also linked to the MedDRA dictionary called Standardized MedDRA Queries. These SMQs as they're called, are grouping of various MedDRA terms that are commonly found in patient populations. They tend to occur concomitantly within a particular patient population and can be analyzed as such. What you see on the right-hand side is an example of how the MedDRA dictionary is structured. We start at a very high level with the system organ class, then we go down to a slightly lower level with the higher-level group term. In this example, we have cardiac disorders, then coming down to cardiac arrhythmias. After these, we have the high-level term. Again, it's a little specific but not too specific. In this example, we have rate and rhythm disorders. Then we move to a preferred term, and this is probably the term you're most familiar with, with medical conditions. In this example, we have arrhythmias. Finally, we get truly granular with the lowest level term. In this example, we have dysrhythmias. As you can see, depending on the level of analysis you wish to perform, using a major term for collection of adverse events can be truly informative if you're trying to aggregate different adverse events or if you want to look at them at a very high level you would be able to analyze based on the structure of the MedDRA dictionary
