Director, Pharmacovigilance & QPPV, Navitas Life Sciences

Philipp Hofmann, MD

EMA defines a spontaneous report as ‘An unsolicited communication by a healthcare professional or consumer to a company, regulatory authority or other organization (e.g. the World Health Organization, a regional center, a poison control center) that describes one or more adverse reactions in a patient who was given one or more medicinal products and that does not derive from a study or any organized data collection scheme.’

Such a spontaneous report for adverse drug reactions (ADRs) should be filed by doctors as a fundamental principle of their professional code of conduct. The mere suspicion of an ADR is considered enough to fulfill this obligation. However, a significant number of doctors fail to adequately comply with this responsibility.

ADRs pose a substantial health concern for individuals and society due to their role in causing illness and death, incurring significant healthcare expenses, and negatively affecting the well-being of those affected. ADRs contribute to 5% of hospital admissions and are experienced by 10% of outpatients and 10% to 20% of inpatients. Moreover, they are the fifth most common cause of death among hospitalized patients.

 The reporting of ADRs play a crucial role in identifying potential risks associated with the administration of drugs or vaccines, ultimately improving patient safety. This task poses an equal challenge to doctors, patients, pharmacists, other healthcare professionals, and pharmaceutical companies.

Identifying ADRs and building reporting strategie

Doctors and pharmacists have a professional duty to report ADRs to their respective drug commissions, specifically designated for physicians or pharmacists. These entities then transmit the reports anonymously, without disclosing the patient's or the doctor's identity, to the relevant authorities. In certain countries like Germany, a distinction is made between drugs and vaccines, with the Federal Institute for Drugs and Medical Devices (BfArM) or the Paul Ehrlich Institute for Vaccines and Biomedical Drugs (PEI) being responsible. Doctors who submit an ADR report also receive feedback from their drug commission, which includes additional information regarding the suspected drug and, if necessary, an excerpt from the ADR database and relevant literature.

Patients, along with their healthcare professionals, have the option to directly report suspected ADRs of drugs and vaccines online to the appropriate authorities.

COVID-19 and the obligation to report ADRs in Germany

During the COVID-19 pandemic, the Drug Commission of the German Medical Association emphasized that doctors have a professional obligation not only to report adverse reactions but also to inform the relevant health authorities about reactions that exceed the expected level in relation to COVID-19 vaccines.

The spontaneous reporting system is based on national or regional drug laws, which require authorities to systematically gather and evaluate the experiences related to the use of a drug or vaccine following its approval. The reporting process is designed to have low barriers: a mere suspicion that a reaction is a side effect of taking a drug or receiving a vaccination is sufficient to warrant a report. This is particularly applicable to the following cases:

ADRs that are not listed in the product information

ADRs that are more severe or frequent than what is stated in the product information

ADRs of drugs that have been on the market for less than five years

 ADRs are found and reported in a variety of healthcare settings and technologies throughout Europe.

Although the spontaneous reporting system is valuable, it cannot provide precise information on the absolute frequency of an ADR. Additionally, it does not allow for comparative evaluation of different medicinal products due to the lack of data regarding unreported ADRs and the frequency of product usage. This phenomenon is known as under-reporting.

All reports are sent to the central "European Database of Reported Suspected Cases of Adverse Drug Reactions (EudraVigilance)," located at EMA, which aims to monitor drug risks across the European Union.

As the field of artificial intelligence (AI) rapidly expands in the biopharmaceutical industry, the focus is now on maximizing the potential to create significant value by seamlessly integrating AI methods into risk assessment.

Prof. Karl Broich, MD, President of the BfArM, predicts that the use of artificial intelligence will play an increasingly important role in evaluating this data. AI can help automate the assessment of message quality. As the amount of collected data increases, it enables better assessment of the risk-benefit profile of drugs or vaccines.

In 2020, the spontaneous reporting system implemented by BfArM received a total of 18,978 spontaneous cases reported throughout Germany. Among these reports, 5,495 came directly from patients or their relatives. Health care professionals utilized the system 2,323 times, while pharmaceutical companies made 4,050 reports. This represents a significant increase compared to previous years. For instance, in 2012, only 7,216 reports were directly submitted by doctors, other health care professionals, patients, or their relatives.

The number of incoming reports at EudraVigilance, the central European database, has also shown a consistent rise. In 2021, the database recorded 82,958 spontaneous reports from patients, their relatives, doctors, and health care professionals in Germany. This is an increase from 60,323 reports in 2017 and 78,253 reports in 2018.

However, despite these numbers, the spontaneous reporting system in Germany still faces challenges in terms of effectiveness. Not all ADRs are reported, and there are various reasons for the reluctance of health care professionals and patients to report. On one hand, patients may not inform their doctors about every observed reaction following drug intake or vaccination. This could be due to their failure to recognize the association between the reaction and the drug or mistakenly attributing the ADR to their underlying medical condition.

Survey indicates lack of willingness to report

Conversely, the willingness of doctors to participate in the spontaneous reporting system is sometimes low, as indicated by a survey conducted in Germany on their attitudes towards the system from November 2017 to February 2018. Factors such as the time required to report, lack of knowledge regarding the reporting procedure and the involved organizations, as well as uncertainties about what exactly should be reported, often contribute to doctors not fulfilling their reporting obligations.

To enhance awareness and encourage reporting, drug commissions, authorities, and pharmaceutical companies regularly organize lectures or training sessions. These initiatives aim to educate healthcare professionals about the spontaneous reporting system and emphasize the importance of submitting well-documented case reports. Patients and doctors can also access information about the reporting system and the necessity of detailed case reports on the respective websites of the relevant Authorities.

Pharmacovigilance obligations for the industry

In addition to the spontaneous reporting system involving drug commissions and authorities, pharmaceutical companies have their own obligations to collect information on ADRs. The responsibility lies with the marketing authorization holder (MAH), who is required to:

Continuously monitor the safety of their medicinal products for human use.

Notify the authorities of any changes that could impact the marketing authorization.

Ensure that the product information remains up to date.

Maintain records of all suspected adverse reactions that are spontaneously reported by patients or their healthcare professionals, as well as those identified in post-authorization studies.

For all medicinal products, it is mandatory for the MAH to establish a pharmacovigilance system master file. Additionally, the MAH must provide the competent authorities with information on suspected ADRs through periodic safety update reports. Since large volume of data needs to be processed, strategic partnership with an experienced pharmacovigilance and therapeutic area expert will help in adhering to timelines and sufficient reporting.

When ADRs are successfully reported in day-to-day practice and the data gathered from across geographies, there is a significant impact along the value chain. Research systems benefit and harness synergies created by gathering such data to enhance further drug development. It is important that these systems act as feedback loops and are used to refine the predictive capability and stability, and provide enhanced patient safety.

, MD, director, Pharmacovigilance & QPPV, Navitas Life Sciences

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-annex-i-definitions-rev-4_en.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8658366/

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While underreported, ADR data offers significant value to the drug development value chain to refine the predictive capability and stability, and provide enhanced patient safety. 


Philipp Hofmann, MD

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