Shirlee Fonda was born in 1932 in the USA as Shirlee Mae Adams. She is known for her work on Joanne Carson's VIPs (1972), Gala Opening of the American Ballet Theater (1984) and The 5th Annual Legacy Awards (1993). Alumina Limited's sole investment is in Alcoa World Alumina and Chemicals (AWAC). The AWAC joint venture was formed in 1994 and our relationship with Alcoa dates back to 1961. AWAC is the world's largest producer of alumina (the feedstock for producing aluminium) and also the world's largest bauxite miner. Alcoa (NYSE: AA) is a global industry leader in bauxite, alumina, and aluminum products, and is built on a foundation of strong values and operating excellence dating back more than 130 years to the world-changing discovery that made aluminum an affordable and vital part of modern life.
In 1920, Alcoa had a population of 3,358 people living in 700 houses. The Great Depression and World War II. Early Alcoa was a classic 'company town', with the company maintaining a paternalistic relationship with the city. The city's welfare was almost wholly dependent upon the company's fortunes. To use the interactive timeline above, click the left and right arrows to view the next event or click and drag in the grey timeline area. 1984 Alcoa, Inc., formerly the Aluminum Company of America, joins forces with Fujikura Ltd. Of Japan to form Alcoa Fujikura Ltd.
The U.S. Food and Drug Administration (FDA) has long emphasized the importance of data integrity in medical device and other regulated product development. To help companies better understand the regulation and reduce the number of violations, the agency drafted a question-and-answer-based guidance, “Data Integrity and Compliance With CGMP.”(1)
Data Integrity Definition
It’s safe to say that the FDA is particular about data management practices. This fact was reiterated by former acting FDA Commissioner Ned Sharpless in response to discovering a data integrity violation involving a high-profile drug manufacturer: “The agency relies on truthful scientific data to make regulatory decisions, and we take the issue of data integrity very seriously.”(2)
The ALCOA acronym establishes a basic formula for data integrity requirements:(3)
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- Legible
- Contemporaneously recorded
- Original or a true copy
- Accurate
Alcoa Dating Timeline Images
However, the FDA’s expectations for data handling extend beyond this benchmark. This means companies need to implement meaningful and effective strategies to manage their data integrity risks. What it boils down to is falling out of compliance with data integrity leads to:
- Companies missing critical timelines for product launches.
- Delays in the development and shortages of much-needed pharmaceutical products.
- Medical devices are unavailable to the facilities that need them.
The following questions from the agency’s Q&A guidance provides valuable insight into proper data management.
What is metadata?
Metadata is the contextual information required to understand data. It’s essentially data about data. For instance, a value by itself (e.g., 3) is meaningless without additional information about the data (e.g., 3 mg). To have relevance, documentation needs to include contextual attributes such as:
- Title
- Author
- Date
- Time stamp
Outside of providing clarifying information, metadata makes it easier to manage, retrieve and use data.
What is an audit trail?
An audit trail is a secure, computer-generated and time-stamped electronic record. It allows for easy reconstruction of the events (who, what, when and why) relating to the creation, modification, or deletion of the record.
Can electronic copies be used as accurate reproductions of paper or electronic records?
The guidance says that electronic copies can be used as true copies of paper or electronic records. It also stipulates that the copies need to preserve the content and meaning of the original data, which includes associated metadata and the static or dynamic nature of the original records.
Manufacturers are allowed to keep paper printouts or static records. However, some electronic records are dynamic in nature. In this case, the printout or static record does not preserve the dynamic nature of the original electronic record. According to the FDA, the record would fail to meet the CGMP requirements.
Does each workflow on the organization’s computer need to be validated?
The short answer is yes. The FDA’s guidance states that workflows, such as batch records and control records are an intended use of a computer system, which needs to be checked through validation. It goes on to say that if you validate your computer system, but do not validate it for its intended use, you cannot know if your workflow is running correctly.
How should access to CGMP computer systems be restricted?
Any changes to computerized MPCRs or other records as well as the input of laboratory data into computerized records must be completed only by authorized personnel. The FDA recommends that whenever possible, you should use technology to restrict the ability to alter specifications, process parameters or manufacturing and testing methods (e.g., limiting permissions for specific tasks and types of data).
When does electronic data become a CGMP record?
All data generated to satisfy a CGMP requirement is a CGMP record. The data integrity guidance states that in order to comply with CGMP requirements with manufacturing processes, you must document or save recorded data at the time a task or process is performed. Also, all data that is recorded and maintained cannot be modified or discarded.
Because of the criticality of data integrity, the FDA’s guidance expands beyond the parameters of the standard CGMP requirements. While the guidance is not binding, the agency tends to rely on guidances during inspections and when making enforcement decisions.(4)
Ensure Data Integrity Compliance With a Digital Quality Management System
The FDA is determined to ensure that consumers have confidence in the quality, safety and effectiveness of health care products. In pursuing that initiative, the agency will continue to ramp up its enforcement of data integrity compliance guidelines. That said, companies are urged to implement digitized technologies designed to automatically prevent omission, incorrect entry, unauthorized alteration, etc. of data.
A digital quality management system (QMS) will enable you to ensure the integrity of your data, easily comply with all other regulatory requirements and remain audit-ready at all times. Advantages of a digital QMS specific to data management include:
- Preserves the meaning of original records, including the associated metadata.
- Ability to restore any deleted data.
- Eliminates the common problem of out-of-sync metadata during a revision process.
- Automatically tracks all changes, the names of people who made changes and the reason for the changes.
- Tracks every signature combination and prevents duplication or reassignment of the user ID and signature combination.
To learn more about a technology-driven approach to not only ensuring data integrity, but turning data management into a business accelerator, download MasterControl’s exclusive “The Ultimate Guide to Connected Quality Data.”
David Jensen is a content marketing specialist at MasterControl, where he is responsible for researching and writing content for web pages, white papers, brochures, emails, blog posts, presentation materials and social media. He has over 25 years of experience producing instructional, marketing and public relations content for various technology-related industries and audiences. Jensen writes extensively about cybersecurity, data integrity, cloud computing and medical device manufacturing. He has published articles in various industry publications such as Medical Product Outsourcing (MPO) and Bio Utah. Jensen holds a bachelor’s degree in communications from Weber State University and a master’s degree in professional communication from Westminster College.
References
- “Data Integrity and Compliance with Drug CGMP: Questions and Answers Guidance for Industry” U.S. Food and Drug Administration (FDA), Dec. 2018 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM495891.pdf
- FDA Threatens Criminal Action Against Novartis Over Faulty Data Used In Application for $2.1 Million Gene Therapy,” Berkeley Lovelace Jr., CNBC, Aug. 6, 2019 https://www.cnbc.com/2019/08/06/fda-novartis-knew-its-application-for-2point1-million-gene-therapy-included-errors.html
- “ALCOA+ and Data Integrity,” Susan J. Schniepp, PharmTech.com http://www.pharmtech.com/alcoa-and-data-integrity
- Law Blog: “FDA’s Draft Guidance on Data Integrity: The Cupola on Tower of Guidances,” Mark I. Schwartz and Douglas B. Farquhar, FDA Law Blog, Apr. 17, 2016. http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2016/04/fdas-draft-guidance-on-data-integrity-the-cupola-on-a-tower-of-guidances.html
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FDA
electronic document management
FDA published in December 2012 a final guidance on IND and BA/BE reporting along with a brief Q&A accompanying it. See: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227351.pdf and www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM332846.pdf respectively.
The Q&A is short and not too useful but the final guidance runs 32 pages and is a very useful read. It summarizes FDA’s requirements and thinking on SAE reporting in clinical trials. The section on BA/BE reporting is at the end and is rather brief.
The document is largely without surprises though a few things actually did surprise me. We will review the key points here and in the next posting. It is a long document (over 30 pages) and many worthwhile points are made. The routine safety reporting requirements we will presume you are aware of and will not discuss unless there is something important to note.
FDA notes clearly up front that 21CFR320 (the IND safety reporting regulations) were changed to avoid excess reporting of individual cases where there is not enough evidence to suggest a reasonable possibility that the drug caused the AE. FDA notes that there is often over-interpretation of the regulatory phrase: “reasonable possibility that that the AE may have been caused by the drug” which means associated with the use of the drug. FDA points out several times that single case reports are usually not useful and should not be reported as 15 day IND safety reports.
Suspected Adverse Reactions
Several standard definitions are noted. The only one to emphasize here is “suspected adverse reaction”. This is any AE for which there is a reasonable possibility that the drug caused the AE and where “reasonable possibility” means there is evidence to suggest a causal relationship between the drug & AE. There are basically three types of suspected ARs:
- A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome).
- One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture).
- An aggregate analysis of specific events observed in a clinical trial (such as known consequences of the underlying disease or condition under investigation or other events that commonly occur in the study population independent of drug therapy) that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group.
Here is FDA’s diagram from the appendix of this guidance:
Editorial comment: What FDA is saying here is that they don’t want excessive reporting of cases that are not really suspected of being due to the drug. They imply (softly) in several areas that companies sometimes do excessive reporting to cover themselves.
Well yes indeed. The problem from the company’s point of view is that if they get it wrong and don’t report some cases that turn out to be drug related and/or if they override an investigator’s causality (see below) they will get no sympathy or succor from FDA, the press, patients or attorneys…
Having been burned several times over the years, my view is still to be conservative and over-report (or at least require really compelling reasons and data to not report).
Causality
FDA acknowledges here that the US requirements differ from ICH E2A. Specifically, the FDA requires the sponsor to determine causality (with consideration of the investigator’s opinion) whereas the E2A proposal is that both the investigator and the sponsor determine causality. In the latter case, usually the most conservative call is used (that is, if one says related and the other unrelated, the case is considered unrelated).
Unexpected
Again the FDA notes that “anticipated” AEs based on the disease or patient population under study are NOT used to determine expectedness. Rather the specific AEs listed in the IB seen with the drug are used.
Serious
In a somewhat surprising note that I’m sure was missed by many folks (myself included), the FDA requirement for “important medical events” is clarified: FDA uses “and” rather than “or” for important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in the definition.
FDA accepts both the ICH (“or”) and FDA definition (“and”).
Editorial Comment: The FDA definition seems more restricted than the ICH definition requiring that the patient be jeopardized AND require medical or surgical intervention. In practice, this probably doesn’t matter as almost all patients in such situations would require some sort of medical intervention – even if it is just observation. It also doesn’t mean that they will actually get the intervention, only that they “may require” it.
Review of Safety Information
FDA spells out the information that must be reviewed. This is not an inclusive list but seems to me to cover pretty much everything a company or investigator might run into regarding the drug:
- Animal studies or in vitro studies
- Clinical or epidemiological investigations
- Reports in the scientific literature
- Unpublished scientific papers
- Information presented at scientific meetings
- Reports from foreign regulatory authorities
- Reports from commercial marketing experience
- Safety information presented at a professional meeting
- Foreign spontaneous reports
In regard to the scientific/medical literature: “The sponsor should conduct literature searches regularly with a frequency appropriate to the drug or study design to seek safety information”.
Editorial Comment: No surprises here.
Investigator Notification
The sponsor must notify FDA & “all participating investigators” of an IND safety report (7 or 15 day report) no later than 15 calendar days. No surprise.
Clarification of “all participating investigators” is given: All investigators to whom the sponsor is providing drug under any of its INDs or under an investigator’s IND.
Editorial Comment: This may be a surprise to some readers as not all companies send the 15 day reports to investigators in ALL their INDs or to investigator initiated studies that the company has supplied drug for.
Analysis of Similar Reports
This analysis, required for 15 day expedited reports, should be based on information from all other INDs held by the sponsor and any other relevant information known to the sponsor. In addition, the suspected AR should be examined in the context of other related AEs including those in placebos, comparators and those in pre- and post-marketing studies.
Editorial Comment: FDA seems to want some context for the analysis of similar events. If there are, say, a dozen other myocardial infarctions in patients taking the study drug in other INDs but also in the comparators, this should be noted.
Review of the Safety Database
Sponsors should conduct ongoing safety evaluations, including periodic review and analyses of their entire safety database, not only for IND safety reporting purposes, but also to update investigator brochures, protocols, and consent forms with new safety information.
Alcoa Dating Timeline Photos
Editorial Comment: Call it what you will: signaling, trend analysis, life cycle risk management. It has to be done.
Investigator Initiated Studies (IISs)
The investigator is held to the same regulations as corporate sponsors including reporting on the scientific literature and foreign commercial marketing experience.
But “FDA recognizes that a sponsor-investigator may not have access to complete safety data…but sponsor-investigators are responsible for evaluating all safety information available to them… To protect human subjects, we recommend that entities that provide drug to or receive drug from other entities share safety information with each other.”
Editorial Comment: Reading through the somewhat obscure language in the last sentence, this means that pharma companies “helping” in or involved with IISs should supply the investigator with the IB, safety updates etc. It’s not clear all companies do this and it’s certainly not clear that all investigators fully comply with IND maintenance and reporting.
Serious & Unexpected Suspected ARs
This refers to what most others (and occasionally FDA itself!) call SUSARs (Suspected Unexpected Serious Adverse Reaction). However, FDA does not officially use the term SUSAR.
FDA reiterates that the sponsor must consider the investigator’s causality assessment (which is obligatory for the investigator) but that the sponsor may override that judgment and should submit “an IND safety report only for those events for which the sponsor determines that there is a reasonable possibility the drug caused the event, regardless of the investigator’s causality assessment.“ The investigator assessment should be in the safety report as well as the sponsor’s. If the investigator does not supply an assessment (even though it is required) the sponsor assessment is then used.
Editorial Comment: This has produced a lot of consternation amongst sponsors. Many companies do not feel they should override an investigator assessment (lack of trained staff, not right to disagree with the investigator, the sponsor override may appear self-serving, there may be potential legal jeopardy). No easy answer on this. I personally take a very conservative viewpoint and prefer to overreport than underreport using the most conservative assessment– not the position the FDA wants. Note that this may then produce a safety report for other regions (EMA, Canada, etc.) but not for the US FDA. This violates one of the “fundamental rules” of drug safety: Say the same thing to all regulators at the same time.
We are only about a third of the way through the guidance. More in the next posting.