Express Pharma
Home  »  Management  »  Monitoring product safety beyond clinical trials – Industry practices

Monitoring product safety beyond clinical trials – Industry practices

Read Article

Dr J Vijay Venkatraman, Managing Director & CEO, Oviya MedSafe, details on the need to foster adherence to good pharmacovigilance practices within the industry to ensure its future progress

Medicinal product safety monitoring is an ongoing activity that starts long before a product is introduced into the market and continues until the product remains available in the market. In clinical trials, only a few hundreds to thousands of carefully selected people get involved for a fixed period of time. The safety data from clinical trials may therefore not necessarily suffice to assess how safe the product would be in the long-term when it will be used by millions of consumers in the real world. A medicinal product may appear to be safe and well-tolerated in the pre-marketing phases which may result in it gaining marketing approval too but the real safety profile of the product will be understood only after it has been used by large numbers of patients over a longer period of time and in different parts of the world. For this to happen, it is imperative for product safety data to be collected, organized, analysed and reported in a proper manner in the post-approval scenario also.

The term ‘Pharmacovigilance’, defined by the World Health Organization (WHO) as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem, is generally used in the context of safety monitoring beyond clinical trials. While the pharma industry is not the only stakeholder of pharmacovigilance, it is the primary stakeholder that is mandated by regulation to monitor the safety of the medicinal products it manufactures and/or markets. Although regulations may significantly vary between countries, they are usually derived from overarching guidelines which have garnered considerable acceptance across the globe. This article aims to provide an overview of the various pharmacovigilance processes in vogue in the industry without specific reference to the regulations of any particular country/region.

Pharmacovigilance system in the industry

Once a medicinal product is approved for marketing, it is the responsibility of the manufacturer/marketer to implement a pharmacovigilance system within their organisation. In addition, they must pr

oactively assess and manage the risks associated with the product throug

Figure – 1

hout the lifecycle of the product.

In the post-marketing scenario, the following processes are followed for purposes of regulatory compliance in the context of pharmacovigilance:

Adverse Event (AE) Handling

Collection of safety information

Pharmacovigilance commences with collection of safety information from various sources such as patients, consumers, healthcare professionals, company partners/ employees, e-mails, phones, fax, letters, journal publications, clinical trials, surveys of patients or healthcare providers, regulatory reports, social media, etc. Published medical and scientific literature articles are particularly considered as important sources of safety information and therefore a periodic (usually monthly) search and review of literature databases is mandated by the pharmacovigilance requirements in many countries. These sources will also give information like frequency of adverse drug reactions (ADRs), patients with highest risk of ADRs, effects in chronic and long-term use, drug-drug interactions, drug-food interactions, misuse or abuse of drug products, medication errors, etc. Each of these reports needs to be evaluated for its causal association with the product and needs to be communicated to the appropriate regulatory agencies either as an Individual Case Safety Reports or as part of Aggregate Reports within the specified timelines.

Individual Case Safety Reports

Individual Case Safety Report (ICSR) is a format and content that is used for the reporting of one or more suspected adverse reactions in relation to a medicinal product that occurs in a single patient at a specific point of time. One of the fundamental principles of single case reporting is the determination of validity. During the triage phase, the case report will be checked for validity against the four minimum criteria: an identifiable p

Figure – 2
Figure – 2

atient, an identifiable reporter, a suspect drug, and an adverse event. If any of these elements are missing or unknown, the case report will not be qualified as valid. Hence, it is the responsibility of the company to take up the appropriate measures to find out the missing data element. Once the missing element is found, the case report will be qualified as valid. Further, the seriousness and expectedness assessments will play a major role in determining the reportability of ICSRs to the relevant regulatory authority. The process flow of the steps involved in single case processing is provided below:

Signal detection

A signal is essentially a hypothesis of a risk with a medicine, with data and arguments that support it, and derived from data from one or more of many possible sources. According to the World Health Organization, a ‘signal’ is ‘reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously.’

Usually, more than one report is required to generate a signal, depending on the seriousness of the event and the quality of the information. Generally, unexpected ADRs or new aspect of a known ADR, specific adverse reactions like Steven Johnson syndrome or toxic epidermal necrolysis or some severe hematological conditions like agranulocytopenia or aplastic anaemia that do occur naturally and do have other causes but are very often associated with drug therapy, are considered signals. Reports with these kinds of reactions need to be analysed to understand if there is a reasonable possibility that the suspect drug has caused the clinical conditions.

The process of signal management must systemically address the following steps:

All steps taken and recommendations made must be accurately tracked an

Figure – 3

d documented at every stage. There are resulting legal obligations which must be fulfilled in an accurate and timely manner but the ultimate goal is to confirm or refute whether there is some new issue with the safety of a medicine so that action might then be taken to reduce the risk.

Periodic reporting

Periodic reporting is otherwise known as aggregate reporting. It provides the broader view of safety profile of the medicinal product and helps to evaluate the safety of the medicinal product in a periodic manner. It is the compilation of safety data for a particular period of time and submitted to the regulatory authorities at defined time points by the company in both pre-approval and post-approval phases of the product.

A pre-approval aggregate report is known as Development Safety Update Report (DSUR) and post-approval aggregate reports include Periodic Safety Update Reports (PSUR) / Periodic Benefit Risk Evaluation Reports (PBRER), Periodic Adverse Drug Experience Report (PADER, which is US-specific) and Addendum to Clinical Overview (ACO) in many regions including in Europe.

An aggregate report helps to evaluate the benefit-risk profile of the medicinal product and to identify the safety information that would require further investigation of the product in order to optimise the use of the product or make changes to the medicinal product label. Depending on the significance of benefit/risk profile of the product, the company may need to implement a Risk Management Plan to protect public health.

Risk management

A Risk Management Plan (RMP) is a document that describes the current knowledge about the safety and efficacy of a medicinal product. It is a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise the risk relating to medicinal products including assessment of the effectiveness of those interventions. It is ensuring that the benefits of the medicinal product exceed the risks by the greatest achievable manner for the individual patient and for the target population as a whole.

In many countries, risk management plan is required as part of the medicine’

Figure – 4
Figure – 4

s approval and renewal process and to retain the marketing approval status. Risk management plan includes the information on the medicine’s safety profile and how the medicine’s risks will be prevented or minimised in patients and describes the plans for studies and other activities to gain more knowledge about the safety and efficacy of the medicine. Also, the scope of risk management also includes the effectiveness of risk minimisation measures.

Communication of safety information

Communication is interactive exchange of information and opinions concerning risk and risk-related factors among regulatory authority, HCP and consumers. Safety communication is a broad term covering different types of information on medicines, including statutory information as contained in the product information (i.e. the summary of product characteristics (SmPC), package leaflet (PL) and the labelling of the packaging) and public assessment reports.
Safety communication aims to providing timely, evidence-based information on the safe and effective use of medicines, promoting changes to healthcare practices (including self-medication practices) where necessary, changing attitudes, decisions and behaviours in relation to the use of medicines, supporting risk minimisation behaviour and facilitating informed decisions on the rational use of medicines. In addition, high-quality safety communication boosts public confidence in the regulatory system.

Communication tools and channels have become more numerous and varied over time, offering the public more information than was previously possible. Relevant communication tools and channels should be considered when issuing a safety communication in order to reach the target audiences and meet their growing expectations. Different communication tools and channels are direct healthcare professional communication (DHPC), press communication, website, bulletins and newsletter, social media and other online communications.

The primary target audiences for safety communication issued by regulatory authorities and the company should be patients, carers and healthcare professionals who use (i.e. prescribe, handle, dispense

, administer or take) medicinal products. Effective safety communication enables them to take adequate actions to minimise risks and to give clear and useful information to their patients. This ultimately promotes patient safety and confidence in the regulatory system. Both healthcare professionals in clinical practice and those involved in clinical trials should be provided with appropriate information on any safety concern at the same time.

Regulatory consequences

Since the industry practices described above are primarily targeted towards regulatory compliance, it becomes important for us to see how the regulatory agencies respond to the safety information submitted by the industry. A regulatory agency may choose to order the manufacturer/ marketer to do any of the following, based on the gravity of the safety issue:

  • An update to the product information – warnings and contraindications;
  • Restriction to the approved indication/population;
  • Conduct of a post-authorisation safety study (PASS);
  • Perform risk minimisation activities – if risk is acceptable / preventable; and
  • Suspend/withdraw the medicinal product – if risks outweigh benefits.


The pharma industry is necessitated by regulation to carry out a wide range of pharmacovigilance activities with the sole aim of ensuring that the benefit-risk ratio of a medicinal product is always in favour of the patient who is treated with the concerned drug. Time and again, there have been several cases in which hitherto approved medicines with extraordinary efficacies had to be recalled from the market after review of the real world safety data which got accumulated post-approval. This clearly establishes the vitality of the need for fostering the further growth of good pharmacovigilance practices within the
industry and for furthering the adoption of such practices among all players in the industry.

Comments are closed.

 Introducing Smart Autoinjector: Changing the paradigm of usability, cost & size
Know More?
Know Importance of using different levels of Controls
Register Now!