By Diganta Bose, BE, MS (Bioinformatics), Clinical Programmer
The Idea
Writing SAS programs for SDTM conversion could be a cumbersome process when the raw data are not CDASH compliant or is a legacy data that did not follow any particular standard for data capture (in CRF and during Data Entry into a designed DBMS screen). This task could be simplified to a great extent if clinical programmers have utility macros (substitution of programming lines) handy with them. Let us see how and why utility macros may be used.
- Utility macros Fine Tunes Programming Tasks
- Utility macros can be used for Avoiding Repetitive Programming Tasks
- Major objective is to reduce a moderately major programming task to just filling in (passing) parameters to a function (or a macro) that will do the clinical programming for you.
- To develop a utility program, we need to understand and analyze the variation of the data that the program is supposed to handle.
The idea is to study extensively how a SDTM variable (or a group of similar SDTM variables) in question is captured across studies. This should span all possibilities in which the variable(s) are defined. A clinical programmer can then create the variable(s) in a way that all possible algorithms or rules are taken into consideration when creating the variable(s). This program can then turn into a macro with parameters which can be called in to do the programming for you whenever you need to create SDTM variable(s). Imagine the ease of a regular SAS programmer’s job when prewritten executable programs are available, in the form of macros, for 60-80% of SDTM programming tasks. If such macros are developed, it can save a lot of programming time during stringent timelines.
Some Implementation Examples
Before a clinical programmer starts to develop a utility macro, he or she should first understand how the SDTM variable(s) in question has to be derived using a rule or a simple assignment. Let us consider some of the SDTM timing variables (AESTDTC, AEENDTC, LBDTC, and so on) that capture dates and times from raw data in ISO8601 format. A utility macro can be developed which considers all possible date and time formats as inputs, including partial dates and times that can be captured in raw data, and converts to ISO8601 format. This utility macro can be called in each time a clinical programmer wants to create DTC variables across all applicable SDTM domains and across all studies.
Similarly let us consider the variables which haves numeric coded formats such as AESER in AE domain and SEX in DM domain. For instance the variable AESER may have codes 1=Mild, 2=Moderate and 3=Severe or codes has codes 0=Mild, 1=Moderate and 2=Severe and variable SEX may have codes 1=M and 2=F or codes 0=M and 1=F. A utility macro can be developed so each of the numeric coded formats can be passed as parameters and the values can be controlled when a clinical programmer runs the macro.
There are numerous opportunities to program utility macros for all or at least most SDTM variables that follow similar rules or algorithms. Thus time can be saved because repetitive clinical programming tasks are avoided.
Conclusion: Reusability and Flexibility
A utility program, provided it takes into consideration the broad spectrum of data, rules, and algorithms it needs to handle as input, and generate the desired output, should not only be flexible and reusable but also should be robust to work under multiple conditions. Such macros should be stress tested thoroughly before releasing for production. Robust and powerful utility macros can make the SDTM mapping process very flexible and quick. Enough documentation should be provided so that any clinical programmer, other than the developer, can use the macros by understanding the parameters, functioning and so on. Implementing updates should be quick; the clinical programmer just has to make minor updates to the utility macro and run it rather than going to each line of individual programs and manually programming the updates. In this way tedious clinical programming tasks can be reduced to defining macro parameters for this kind of “Modular Programming” approach.
Macros are useful to define “canned” code that may be made available to other users in an organization. But, there are also simple, less sophisticated macros that are useful in your day to day coding efforts, if only to reduce keystrokes. We often find ourselves reaching for the same, familiar tools as we deal with the typical coding and data analysis tasks common to many of our occupations. While robust, parameterized macros may be overkill for much of what we do, there’s enough repeatable coding activity taking place that are smaller; utility macros can save us development time, typing effort and reduce errors.
References
Paper SBC-125 Quick ‘n Dirty - Small, Useful Utility Macros Harry Droogendyk,
Stratia Consulting Inc., Lynden, ON
*Note that the above article talks about feasibility of macros in the SAS language and not macros in general.
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By Malarkodi S. Moorthy, M.Sc., M.Phil., Medical Writer
In 2010, the International Conference on Harmonization (ICH) rolled out its E2F Development Safety Update Report (DSUR) guideline. The DSUR is similar to the US’s Investigational New Drug Annual Report (IND-AR) and the EU’s Annual Safety Report (ASR) in that its purpose is to provide a brief overview of safety for a project on an annual basis.
Although both the Food & Drug Administration (FDA) and EU Clinical Trial Directive required what is termed as IND AR and ASR, respectively, the content, format and timings differed between the US and EU reports. Considering that most contemporary trials are multinational, a need was felt towards harmonizing these requirements and to provide a uniform standard acceptable to all regulatory agencies across the world. The concept of a DSUR was first introduced by the CIOMS VI working group and taken forward by the CIOMS VII working group. In 2008, the ICH published a draft guideline E2F on DSUR, which has been updated in August, 2010, incorporating background, objective and scope of DSUR and providing guidance on DSUR contents.
This report is now expected annually by the EMA (implemented from September 1, 2011) and is accepted annually by the FDA (released in August 2011 although the FDA still accepts IND-ARs). There are numerous similarities among the DSUR, IND-AR, and ASR since they share a common purpose. However, some of the ways in which they achieve that purpose differ in the details. Major features of the DSUR are that it covers an entire Investigational Medicinal Product (IMP) rather than just an indication, and that much of its information is cumulative from inception of the project.
FDA’s planned updates for Module 1
Among these is a new Section 1.13.15, for the DSUR, but FDA’s Module 1 update is not expected to be implemented until early 2013.
As per Connie Robinson (FDA personnel), “Currently for an IND, it would be acceptable to place the DSUR as a single document in Section 1.13.3 Summary of Safety Information. You should state that the DSUR is being submitted in place of the IND annual report in the cover letter and provide a link to the document if possible. If information (other than the granular annual report information) is expected as a part of the DSUR, but the information should be placed in its own designated eCTD location.”
More information about the DSUR would be forthcoming along with the implementation of the updates to Module 1.
Usefulness of DSUR
DSURs, which are an enhanced report over the previous required reports, contain not only an evaluation of safety information collected in the past year but also includes a cumulative review of existing safety information. This evaluation allows the sponsors the ability to identify and evaluate potential risks with the drug and make appropriate adjustments to their clinical development program.
The DSUR expects more information than its predecessors (IND-ARs and ASRs) including patient data from the inception of a project, and could thus take more time for a company to prepare. As with most things, once a process is put in place and becomes familiar, subsequent reports will become smoother to produce.
Points to Remember
- A DSUR should be submitted until the last visit of the last patient in the Member States concerned, as specified within the protocol.
- The data lock point (DLP) for a DSUR reporting period is the last day (or the last day of the month, ICH E2F section 2.2) before the anniversary of the DIBD (Development International Birth Date), the date on which the product was first authorized for testing in humans anywhere in the world. IBD (International Birth Date), the date on which the product was first approved for market anywhere in the world can also be acceptable.
- The first DSUR period should not be longer than 1 year. The DSUR is always submitted on a yearly basis.
- For transitional period: The DIBD and the European Birth Date (EBD) of the previous
- ASR should be aligned in such a way that DSUR periods that are substantially longer than 12 month as well as overlapping DUSR periods are avoided.
- A DSUR is required for Phase IV clinical trials, if only such trials are conducted.
- Submission of one single DSUR is strongly recommended if the same IMP is used in the clinical trials.
- A separate DSUR for a comparator, placebo or non-IMP is not required. However, relevant safety information of the above mentioned drug types should be addressed in the DSURs of the investigational drugs.
- The Investigator Brochure (IB) or Summary of Product Characteristics (SmPC) can be updated during the DSUR reporting period.
Since CDSCO does not require DSUR, for Indian pharmaceutical companies undertaking a global trial for a locally developed drug, Indian regulators will not have real-time update of the drug's developing safety profile, while foreign regulators (such as tripartite countries) having requirement of DSURs will have this information. With the global focus on DSUR, Schedule Y needs to be revised incorporating similar provision of providing cumulative safety updates to the regulators during clinical development phase.
By Carrie Stem, MS, Medical Reviewer
Henrietta Lacks is the human source of the cell line that is today known as “HeLa.” This cell line has been used to develop numerous technologies and advances in cell biology and medicine. The source of the cells is often misidentified as “Helen Lane.” Rebecca Skloot’s book The Immortal Life of Henrietta Lacks gives an excellent overview of the life and family of Henrietta Lacks with the scientific concepts explained in layman’s terms. The socioeconomic and racial issues of the Lacks’ family history are intermixed with chapters of Skloot’s present-day quest to learn as much as she can about Henrietta’s story with the support and assistance of Henrietta’s daughter, Deborah.
However, Skloot also delves into the ethical quandaries of clinical research, and in particular, tissue research. Skloot provides informative descriptions of important events in human subjects research from historical events through recent years, which is very important for the knowledge of the general public. Although the ethical standards for clinical research are very different now than they were during the time of Henrietta Lacks, some of the questions surrounding research remain the same. While the majority of people (scientists or not) would likely agree that informed consent is completely essential, there are many other ethical complexities in research. For example, the question of compensation for tissue donors is frequently mentioned in the book. This is an especially important issue for donors whose tissue has desirable traits for the fields of medicine and pharmaceutical development. If donors should be compensated, how much is a “fair” price? Should donors whose tissue is considered more desirable be compensated more than other donors (since their tissues have more monetary value)? Also, how can tissue donors be adequately educated at the time of donation (such as through an informed consent form) on future investigations and topics involving their stored tissues? This is of particular concern in the age of genetic analyses, and the future will no doubt bring more issues as science and medicine continue to progress.
What are your thoughts? Should tissue donors be compensated based on the “value” of their tissues? Should all be compensated equally? Should they be compensated at all?
References
Skloot, Rebecca. The Immortal Life of Henrietta Lacks. New York: Crown Publishers, 2010.