Adverse event

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An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. [1]

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AEs in patients participating in clinical trials must be reported to the study sponsor and if required could be reported to the local ethics committee. Adverse events categorized as "serious" (results in death, illness requiring hospitalization, events deemed life-threatening, results in persistent or significant incapacity, a congenital anomaly, birth defect or medically important condition) must be reported to the regulatory authorities immediately, whereas non-serious adverse events are merely documented in the annual summary sent to the regulatory authority.

The sponsor collects AE reports from the local researchers, and notifies all participating sites of the AEs at the other sites, as well as both the local investigators' and the sponsors' judgment of the seriousness of the AEs. This process allows the sponsor and all the local investigators access to a set of data that might suggest potential problems with the study treatment while the study is still ongoing.

Types of adverse events

All clinical trials have the potential to produce AEs. AEs are classified as serious or non-serious; expected or unexpected; and study-related, possibly study-related, or not study-related. [2]

For example, while a study that tests the effectiveness of a new blood pressure cuff for a period of 10 minutes might seem innocuous, the potential exists for the patient's skin to be irritated by the device. Patients in that study might also die during that 10-minute period. Both skin irritation and sudden death would be considered AEs. In this case, the skin irritation would be classified as not serious, unexpected, and possibly study-related. The death would be classified as serious and unexpected (unless the patient was already at death's door). The local researcher would use his/her medical judgment to determine whether the death could have been related to the study device.

Both the skin irritation and the death are unexpected events, and should alert the researcher to the potential existence of a problem with the device (for instance, it could have malfunctioned and shocked the patient). The researcher would report these AEs to the local Institutional Review Board and to the sponsor, and await direction on whether to stop the study. If the researcher feels there is an imminent danger posed by the device, he or she can use medical discretion to stop patients from participating in the study.

An adverse event can also be declared in the normal treatment of a patient which is suspected of being caused by the medication being taken or a medical device used in the treatment of the patient.

In Australia, 'Adverse EVENT' refers generically to medical errors of all kinds, surgical, medical or nursing related. The most recent available official study (1995) indicated 18,000 deaths per year are a result of hospital care. [3] The Medical Error Action Group is lobbying for legislation to improve the reporting of AEs and through quality control, minimize the needless deaths.

Reporting of adverse events

Researchers participating in a clinical trial must report all adverse events to the drug regulatory authority of the respective country where the drug or device is to be registered [e.g. Food and Drug Administration (FDA) if it is US]. Serious AEs must be reported immediately; minor AEs are 'bundled' by the sponsor and submitted later.

The type of method used to elicit AEs reported by individuals for evidence on likely adverse drug reactions (ADRs) influences the extent and nature of data. A 2018 review conducted found that some participants in clinical drug trials were asked simple open questions (i.e. 'how are you feeling?'), while in other trials, participants were given lengthy questionnaires about physical symptoms (i.e. 'do you experience muscle soreness or headaches?'. [4] A 2022 review on adverse events in Human challenge trials found that reporting improved over time, but remains non-standardized in ways that make comparisons difficult. [5]

As there is a lack of consensus on how AEs should be assessed, there is a concern that the kinds of questions and the phrasing of questions may lead to measurement error and impede comparisons between studies and pooled analysis. However, Allen et al. [4] concluded that the impact of the AE detected by different methods is unclear.

Grades of AE

Clinical trial results often report the number of grade 3 and grade 4 adverse events. Grades are defined: [6]

Databases of adverse events

Devices

The FDA provides a database for reporting of adverse device events called the Manufacturer and User Facility Device Experience Database (MAUDE)[1]. The data consist of voluntary reports since June 1993, user facility reports since 1991, distributor reports since 1993, and manufacturer reports since August 1996, and is open for public view. Two private companies have also recently started providing access to analyzed adverse event information: Clarimed provides adverse event information for medical devices and AdverseEvents provides adverse event data for drugs.

MAUDE is incomplete. KFF Health News of the Kaiser Family Foundation reported discovering a secret set of least 1.1 million adverse events hidden in a database not known to professionals familiar MAUDE [7] Some device AEs reported to FDA can only be found in MDR Data Files of the Device Experience Network (DEN) or in Alternative Summary Report (ASR) data received by the FDA.

See also

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Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments and known interventions that warrant further study and comparison. Clinical trials generate data on dosage, safety and efficacy. They are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/benefit ratio of the trial—their approval does not mean the therapy is 'safe' or effective, only that the trial may be conducted.

A medical error is a preventable adverse effect of care ("iatrogenesis"), whether or not it is evident or harmful to the patient. This might include an inaccurate or incomplete diagnosis or treatment of a disease, injury, syndrome, behavior, infection, or other ailment.

Pharmacovigilance, also known as drug safety, is the pharmaceutical science relating to the "collection, detection, assessment, monitoring, and prevention" of adverse effects with pharmaceutical products. The etymological roots for the word "pharmacovigilance" are: pharmakon and vigilare. As such, pharmacovigilance heavily focuses on adverse drug reactions (ADR), which are defined as any response to a drug which is noxious and unintended, including lack of efficacy. Medication errors such as overdose, and misuse and abuse of a drug as well as drug exposure during pregnancy and breastfeeding, are also of interest, even without an adverse event, because they may result in an adverse drug reaction.

<span class="mw-page-title-main">Adverse drug reaction</span> Harmful, unintended result of medication

An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or may result from the combination of two or more drugs. The meaning of this term differs from the term "side effect" because side effects can be beneficial as well as detrimental. The study of ADRs is the concern of the field known as pharmacovigilance. An adverse event (AE) refers to any unexpected and inappropriate occurrence at the time a drug is used, whether or not the event is associated with the administration of the drug. An ADR is a special type of AE in which a causative relationship can be shown. ADRs are only one type of medication-related harm. Another type of medication-related harm type includes not taking prescribed medications, known as non-adherence. Non-adherence to medications can lead to death and other negative outcomes. Adverse drug reactions require the use of a medication.

An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complication is similar to adverse effect, but the latter is typically used in pharmacological contexts, or when the negative effect is expected or common. If the negative effect results from an unsuitable or incorrect dosage or procedure, this is called a medical error and not an adverse effect. Adverse effects are sometimes referred to as "iatrogenic" because they are generated by a physician/treatment. Some adverse effects occur only when starting, increasing or discontinuing a treatment. Using a drug or other medical intervention which is contraindicated may increase the risk of adverse effects. Adverse effects may cause complications of a disease or procedure and negatively affect its prognosis. They may also lead to non-compliance with a treatment regimen. Adverse effects of medical treatment resulted in 142,000 deaths in 2013 up from 94,000 deaths in 1990 globally.

Clinical monitoring is the oversight and administrative efforts that monitor a participant's health and efficacy of the treatment during a clinical trial. Both independent and government-run grant-funding agencies, such as the National Institutes of Health (NIH) and the World Health Organization (WHO), require data and safety monitoring protocols for Phase I and II clinical trials conforming to their standards.

A serious adverse event (SAE) in human drug trials is defined as any untoward medical occurrence that at any dose

  1. Results in death
  2. Is life-threatening
  3. Requires inpatient hospitalization or causes prolongation of existing hospitalization
  4. Results in persistent or significant disability/incapacity
  5. May have caused a congenital anomaly/birth defect
  6. Requires intervention to prevent permanent impairment or damage

An investigational device exemption (IDE) allows an investigational device to be used in order to collect safety and effectiveness data required to support a premarket approval (PMA) application or a premarket notification [510(k)] submission to Food and Drug Administration (FDA). Clinical studies are most often conducted to support a PMA. Only a small percentage of 510(k)'s require clinical data to support the application. Investigational use also includes clinical evaluation of certain modifications or new intended uses of legally marketed devices. All clinical evaluations of investigational devices, unless exempt, must have an approved IDE before the study is initiated.

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<span class="mw-page-title-main">Research on Adverse Drug Events and Reports</span>

Research on Adverse Drug Events and Reports (RADAR) is a pharmacovigilance team of 25 doctors who receive calls about possible adverse drug reactions (ADR) and investigate. RADAR is based at Northwestern's Feinberg School of Medicine. RADAR is led by Dennis West. Though it was without funding for its first four years, RADAR has raised about $12 million through grants from the National Institutes of Health, the American Cancer Society and other such institutions. Its work has identified safety problems with 33 drugs. Adverse drug events are a serious health problem.

A Site Management Organization (SMO) is an organization that provides clinical trial-related services to a contract research organization (CRO), a pharmaceutical company, a biotechnology company, a medical device company, or a clinical site. The site is usually a hospital or a similar health care institution that has adequate infrastructure and staff to meet the requirements of the clinical trial protocol. The scope of an SMO's responsibility is limited to the site and hence the eponymous title. Some of the responsibilities include:

A Clinical Research Coordinator (CRC) is a person responsible for conducting clinical trials using good clinical practice (GCP) under the auspices of a Principal Investigator (PI).

<span class="mw-page-title-main">Food and Drug Administration Amendments Act of 2007</span> US law

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A glossary of terms used in clinical research.

The following outline is provided as an overview of and topical guide to clinical research:

Guidances for statistics in regulatory affairs refers to specific documents or guidelines that provide instructions, recommendations, and standards pertaining to the application of statistical methodologies and practices within the regulatory framework of industries such as pharmaceuticals and medical devices. These guidances serve as a reference for statisticians, researchers, and professionals involved in designing, conducting, analyzing, and reporting studies and trials in compliance with regulatory requirements. These documents embody the prevailing perspectives of regulatory agencies on specific subjects. It is worth noting that in the United States, the term "Guidances" is used, while in Europe, the term "Guidelines" is employed.

References

  1. ↑ ICH GCP
  2. ↑ Amalberti R, Benhamou D, Auroy Y, Degos L (June 2011). "Adverse events in medicine: easy to count, complicated to understand, and complex to prevent". Journal of Biomedical Informatics. Biomedical Complexity and Error. 44 (3): 390–4. doi:10.1016/j.jbi.2009.06.004. PMID   19615466.
  3. ↑ Weingart SN, Wilson RM, Gibberd RW, Harrison B (March 2000). "Epidemiology of medical error". BMJ. 320 (7237): 774–7. doi:10.1136/bmj.320.7237.774. PMC   1117772 . PMID   10720365.
  4. 1 2 Allen EN, Chandler CI, Mandimika N, Leisegang C, Barnes K (January 2018). "Eliciting adverse effects data from participants in clinical trials". The Cochrane Database of Systematic Reviews. 1 (1): MR000039. doi:10.1002/14651858.mr000039.pub2. PMC   7098080 . PMID   29372930.
  5. ↑ Adams-Phipps, Jupiter; Toomey, Danny; Więcek, Witold; et al. (11 October 2022). "A Systematic Review of Human Challenge Trials, Designs, and Safety". Clinical Infectious Diseases. 76 (4): 609–619. doi: 10.1093/cid/ciac820 . hdl: 1887/3491506 . PMC   9938741 . PMID   36219704.
  6. ↑ Common Terminology Criteria for Adverse Events
  7. ↑ Jewett, Christina (7 March 2019). "Hidden FDA Reports Detail Harm Caused By Scores Of Medical Devices". KFF Health News.
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