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Pharmaceutical industry is a tightly regulated business, especially in the U.S. and in Europe. Before medicines reach the market, they must undergo extensive clinical testing. Upon reaching the market, approved drugs can be prescribed to any patient if the physician can reasonably expect therapeutic benefit for the specific patient.

Clinical research on human subjects can be sponsored by the industry, academic institutions, hospitals and even by individuals. A sponsor is the organization or person who initiates the study and who has authority and control over the study, including responsibility for data management and collection, evaluation and reporting of adverse events. An investigator is the entity that conducts the clinical trial according to protocol as directed by the sponsor. Investigator-sponsored studies are controlled and conducted by the same entity, typically hospitals. Roles and responsibilities of individual parties in clinical research are outlined in the ClinicalTrials.gov registry [1].

An Investigational New Drug Application (IND) is a complex undertaking that among other obligation includes preparation of the drug label based on safety and efficacy data obtained in clinical trials. Federal regulations define phases of clinical research, provide for IND content and format, protocol amendments, roles and responsibilities of individual parties and safety reporting[2].

The assessment of the benefits and risks of therapeutic interventions depends on the nature of the disease under study, patient population and the way its course is counterbalanced by therapeutic interventions. All adverse events that occur in a clinical trial are collected and evaluated for potential causal relationship with the therapeutic intervention. Serious and unexpected events (SUSARs) are subject to expedited (7 or 15 days) reporting to the FDA by trial sponsors[3]. The industry adopted processes that follow the regulations to the letter in order to meet all the regulatory requirements.

Once the drug reaches the market, monitoring of the benefit:risk profile of the drug is left to the market authorization holder. ADE reporting is voluntary for physicians, pharmacists and consumers. Adverse events that are serious[4] and unexpected[5] are subject to expedited reporting to the FDA.

The FAERS database has some serious limitations[6] that relate directly to the methods of data collection. Some of the limitations are listed on the FDA website.

  • Data from clinical trials and post-market surveillance are lumped together. In clinical trials, the reporting rate is near 100%. Post-market surveillance rates are estimated about 1 to 10%.
  • The system contains duplicate reports. Because all manufacturers have the obligation to report events relating to their products and product identification in post-market surveillance is often inaccurate, reports are often duplicated or even multiplied as a result.
  • Incomplete reports in the system are the result of aborted entries or failed follow-up. These reports are impossible to evaluate due to missing necessary information.
  • Existence of a case report does not imply causation. Concurrent conditions and concomitant medications may be the cause rather than the drug.
  • Adverse effects that develop with long delay are typically not found from expedited reports but are identified in observational studies. Cardiovascular adverse effects relating to cox-2 inhibitors are the perfect example of such safety signal.
  • Rates of occurrence cannot be established from individual case reports, as the total pool of treated patients is unknown, and the number of reported events is not representative.

The sole focus on compliance with regulations makes pharmacovigilance activities somewhat disconnected from the original purpose: to make medicines available to patients safer in the context of clinical care. New information technologies and concepts have the potential to revolutionize drug safety and make data collection fit for purpose, easier, faster and less costly.


[1] NIH. Clinical Trials Registry. https://clinicaltrials.gov/ct2/about-studies/glossary
[2] Title 21 of the Code of Federal Regulations, Section 312. https://www.ecfr.gov/cgi-bin/text-idx?SID=dce3cd762f6130037123510382f44782&mc=true&node=pt21.5.312&rgn=div5
[3] Section 312.32 https://www.ecfr.gov/cgi-bin/text-idx?SID=dce3cd762f6130037123510382f44782&mc=true&node=pt21.5.312&rgn=div5#se21.5.312_132
[4] FDA. What is a serious adverse event? https://www.fda.gov/safety/medwatch/howtoreport/ucm053087.htm
[5] Expectedness criteria: Event listed on the drug label (after approval) or in the Investigator Brochure (in clinical trials) is considered expected. Unlisted events qualify as unexpected.
[6] FDA Adverse Event Reporting System (FAERS) Public Dashboard. https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm070093.htm


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