Pharmacovigilance and Drug Safety

The role of this site is to provide information on how drugs are developed and the role of pharmacovigilance in ensuring drug safety throughout the lifecycle of pharmaceutical products. We cover several different topics and, should you wish to investigate further, maintain links to some of the top experts and specialists in the field of pharmacovigilance. Our expert panel includes individuals with both industry and regulatory experience. We have access to people who have helped to define and shape the science of drug safety into what it is  today and are working on what pharmacovigilance will become in the future.

Many people believe the pharmaceutical industry to be a shady cartel developing poisonous concoctions with no control from governments or the scientific community. The Pharmacovigilance Information Service is here to share information about drug safety and to explain some of the steps that pharmaceutical companies are required to take in order to get their products to market and to keep them there. It also explains the safety roles that the regulatory bodies expect the pharmaceutical companies to fulfill.

DEVELOPMENT OF MEDICINES AND PHARMACOVIGILANCE IN THE EUROPEAN UNION: a guide for the perplexed

This review is intended as a brief introduction to understanding the complex environment in which medicines are developed and their safety monitored. Much of it is applicable generally, but the focus is on the situation in the UK and the European Union.

Pharmacovigilance is the pivotal process for ensuring a company’s products remain on the market. In reality the business faces the challenges of increasingly complex and constantly changing worldwide regulations, requiring higher levels of inter-disciplinary expertise, together with demands to improve public safety. The safety arena continues to be in the media spotlight so it is important that the patient is the primary focus and Pharmacovigilance is handled effectively with the correct tools to detect and respond to any safety concerns with a product.

Many Pharma companies have increased the number of qualified staff to comply with these strict reporting requirements and increased workload but are now facing economic pressures due to shrinking budgets. Therefore it is important to scrutinize costs, as more is expected with less available resource.

Outsourcing occurs when an organisation employs a contract service provider to perform services that would normally be performed “in-house”. Outsourcing is undertaken by companies to reduce fixed overhead costs, avoid high upfront investments, secure additional capacity, increase resource flexibility or augment the performance of an activity that is not considered a core area of the business.

Off-shoring occurs when the work is outsourced to lower cost countries such as India or China rather than Europe or the US to reduce the labour costs. However there can be disadvantages as quality will suffer where staff have insufficient knowledge of the worldwide regulations and limited Pharmacovigilance experience or training.

It is possible for a company to outsource the entire Pharmacovigilance function or specific aspects only. However it is important to remember that although the Marketing Authorisation Holder (or manufacturer in the US) can delegate some or all Pharmacovigilance activities it must retain overall responsibility for the safety of the products.

What are the benefits of out-sourcing on an interim basis or for specific projects?

• To fill any gaps in a Pharmacovigilance team such as in times of sickness, maternity leave, during periods of recruitment or training of staff.
• To fill short-term skill gaps to help in times of workload peaks
• Use of a virtual team works as and when projects demand and allows for particular individuals to be brought in when specific expertise is required
• Use of interim staff can bring in strategic direction to a company without huge investment
• Benefit in expertise in a specific area by use of personnel who are effective from day one
• Ability to tap into highly specialist areas as and when needed and quickly
• Flexibility – you only pay for what you use so do not incur costs of a full-time salaried position

What are the benefits of outsourcing the Pharmacovigilance System?

• The technical requirements of operating and supporting a regulatory compliant Pharmacovigilance system can be expensive and very sophisticated and may exceed the skills of the company IT team
• The associated software and other Pharmacovigilance system costs require scalability and cost structures that Pharmacovgilance Service Providers can accommodate
• Pharmacovigilance systems upgrade or replacing an existing system can be costly and time consuming. The migration of data from different systems can be expensive and difficult
• Use of an off-site Pharmacovigilance system may be less expensive than in-house installation
• Does not require the large first year cost normally accrued with an in-house system
• Outsourcing can provide an immediate, multi-location Pharmacovigilance network with minimal IT investment

What specific Pharmacovigilance tasks can be out-sourced?

• Pharmacovigilance for a specific trial or series of studies including clinical trial site set-up
• EU Qualified Person Responsible for Pharmacovigilance (QPPV) and Deputy QPPV
• Post-Marketing Pharmacovigilance; the entire process from initial receipt of an AE through to expedited reporting
• Generation of Clinical Trial Annual Safety Reports and Periodic Safety Reports
• Adverse Event Management including holding and maintaining the Safety Database and Case Entry of AEs, coding, narrative writing, QC, expedited reporting of AEs.
• Development of Safety Specifications and Risk Management Plans
• Signal detection and evaluation
• Safety issue investigation and generation of ad-hoc reports for submission to Regulatory Authorities
• Literature Screening
• Process design and SOP development
• Pharmacovigilance audits, mock inspections and due diligence
• Pharmacovigilance training
• Generation of Safety Agreements for licensing or distribution partners or third parties involved with pharmacovigilance activities

What are the benefits and risks of outsourcing specific tasks?

Out-sourcing clinical trials can be useful when a company lacks experience in a new therapeutic area or a specific type of study. It can be especially useful for companies who may have limited experience in clinical trials as the out-sourcing company can provide expertise in study protocol, study start-up and selection of investigators. The company must determine if it will also outsource the process of handling of AEs throughout the study, entry into a safety database and expedited reporting to investigators and Regulatory Authorities. It is important to choose a partner with sufficient experience and capacity if the trials are particularly large and located in multiple sites across the globe.

Out-sourcing the QPPV can be of obvious benefit to smaller organisations. The QPPV needs to be available 24/7 and is a highly skilled individual with expertise in Pharmacovigilance. There is risk involved in out-sourcing this function if the QPPV lacks sufficient experience or company infrastructure to take on the role or has conflicting interests which may impact on their availability.

Outsourcing the Pharmacovigilance database results in reduced cost for database infrastructure and reduced license costs for software programmes.

Outsourcing the entire Post-Marketing function can be especially beneficial to new and emerging companies who may historically only have experience with products in development and have limited experience of handling Pharmacovigilance when a product comes to market. This will allow the company to buy-in expertise while developing a Pharmacovigilance department of their own and will reduce costs in terms of investment in a safety database and validation of systems and processes. Similarly this can be useful for companies with relatively small volumes of AEs reported annually as the IT costs of systems and updating these systems and re-validation when regulations change are minimised. While small and medium companies may out-source pharmacovigilance as it is not economical to have an in-house department, larger companies may out-source for efficiency. Risks involved are ensuring that the outsourcing partner has a robust, validated system capable of meeting complex requirements worldwide and sufficient processes and procedures and appropriately qualified staff in place with sufficient knowledge of the Pharmacovigilance requirements to handle the entire process.

Outsourcing allows flexibility as a company will be able to manage peaks and troughs that can occur with workload. For example with products that are taken seasonally such as products for colds and flu or hayfever – adverse events tend to peak at certain times of the year and are directly related to sales; specific adverse event reporting increases following media attention; adverse event reporting tends to be high following the launch of a new product and can increase following identification of a potential safety issue. This variation in workload requires companies to try to plan staff to meet peak demands resulting in some resources being under utilised during slack periods. For a company with older products with established safety profiles no new knowledge is likely to be gained from generating PSURs and single case processing, even though the processes must occur to maintain regulatory compliance. The benefits of out-sourcing include freeing up valuable resource time within the company allowing the company to focus attention where needed. These resources can be re-directed to strategic business objectives and not routine data discovery and data entry.

Conversely a company with a single proprietary product which accounts for a significant proportion of the company’s annual revenue may decide only to out-source specific Pharmacovigilance tasks or may decide to maintain Pharmacovigilance in-house.

Out-sourcing literature screening can be beneficial for generic companies where the frequency of searching required to meet the Pharmacovigilance requirements leads to the generation of hundreds of articles which require review to determine if the cases qualify for expedited reporting.

Out-sourcing of generation of safety agreements with third parties is especially useful for those companies operating as virtual companies. There are often complex arrangements for Pharmacoviguilance provision between multiple parties. In a pharmacovigilance inspection any partner could be interviewed by the Competent Authorities and is an area where there are often inspection findings. It is important that all responsibilities in terms of Pharmacovigilance between all parties are specified in detailed documents. Safety agreements need to be drawn up by individuals with expertise in this area and this may be lacking in virtual companies.

Out-sourcing Pharmacovigilance provides a cost effective solution especially for small and medium sized companies. Complying with Pharmacovigilance regulations requires highly trained staff to accurately code and clinically assess cases, enter the cases into a safety database and determine whether particular cases qualify for expedited reporting. This Pharmacovigilance team needs to be familiar with regulatory requirements at regional, national and international levels. An outsourcing partner can provide this capability. There are a variety of out-sourcing options available ranging from individual contractors and Pharmacovigilance consultants, specialist Pharmacovigilance consultancies, and CROs or Pharmacovigilance Service Providers. These individuals may operate from a single site or may have offices spread across several countries which could be beneficial if a presence is required in a specific territory to meet the local Pharmacovigilance requirements.

Consequently, it remains important to choose your partner wisely so check out their credibility – qualifications and experience including any previous client recommendations. Has the partner an understanding of the Pharmaceutical industry and ability to demonstrate compliance with the regulations? Are they experienced in dealing with queries from Regulatory Authorities?  Finally, ensure that there is a detailed contractual arrangement in place which clearly describes the roles and responsibilities of each party for all aspects of Pharmacovigilance to be outsourced.

Adverse Drug Reaction (ADR)
A response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, correction or modification of physiological function. A causal relationship between the medicinal product and an AE should at least be a reasonable possibility.  An ADR in post-marketing situations normally refers to ADRs occurring at therapeutic doses, but for the purposes of reporting any dosage should be considered.

Adverse Event (AE)
Any untoward medical occurrence in a patient or clinical investigation subject administered the pharmaceutical product that does not necessarily have to have a causal relationship with the treatment for which the product is used. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of the medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. A pre-existing condition which, worsened in severity after administration of the product would also be considered as an adverse event.

For clinical studies, the definition of an Adverse Event includes any untoward events occurring at any time after the subject’s formal entry into the study (being after receipt of the signed informed consent) until the follow-up period as defined in the respective study protocol.

Annual Safety Report (ASR)
An aggregate Safety Report in the context of clinical trials, taking into account all newly available safety information produced during a defined reporting period. Where several clinical trials are conducted with the same Investigational Medicinal Product (IMP) the reporter should include a concise global analysis of the actual safety profile of the tested IMP based on the experience for all the clinical trials.

Company Core Data Sheet (CCDS)
This document is prepared by the Marketing Authorisation Holder and contains, in addition to safety information, material relating to indications, dosing, pharmacology and other aspects of the product.

Consumer
A person who is not a healthcare professional such as a patient, lawyer, friend or relative/ parents/ children of a patient.

Expedited Reporting
Notification (submission) of an ICSR in a designated format to the appropriate Regulatory Authorities in compliance with the parameters and timelines specified by legislation and local regulatory guidelines. An expedited report would be an ICSR meeting the criteria for rapid transmission to a Competent Authority.

Healthcare Professional
Within the EU, a healthcare professional would be described as a medically qualified doctor, dentist, pharmacist, nurse or coroner.  When the report originates from a pharmacist or nurse, further information should be sought from a medically qualified doctor responsible for the patient.

Individual Case Safety Report (ICSR)
A report received by a company or agency which describes an adverse event.

Investigator Brochure (IB)
A compilation of the clinical and non-clinical data on the Investigational Medicinal Product relevant to the study of the product in humans.

Investigational Medicinal Product (IMP)
A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled in a different way from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form.

Marketing Authorisation (MA)
The approval granted by the Regulatory Authority to market a specific product in a particular country

Marketing Authorisation Holder (MAH)
The company named on the Marketing Authorisation for a specific product in a particular country.

Medicinal Product
A substance or combination of substances presented as having properties for treating or preventing disease in human beings; or a substance or combination which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.

Concerned Member State (CMS)
The Regulatory Authority in whose territory a clinical trial with the IMP is being conducted or is involved in the registration of a medicinal product in the EU under Mutual Recognition Procedures, as distinct from the Reference Member State that initiated the Procedure.

Non-interventional Trial
A study where the medicinal product is prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within the current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods should be used for the analysis of the collected data.

Pharmacovigilance
The process of monitoring, evaluating and improving the safety of medicines. It is carried out by pharmaceutical companies on their products and by government agencies on all medicinal products. Also, the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems (WHO).

Post-authorisation Study
A clinical study conducted within the conditions of the approved Summary of Product Characteristics or under normal conditions of use. A post-authorisation study may also be a Post-authorisation safety study (PASS).

Post-authorisation safety study (PASS)
A pharmacoepidemiological study or a clinical trial carried out in accordance with the terms of the Marketing Authorisation, with the aim of identifying or quantifying a safety hazard relating to an authorised medicinal product.

Risk Management System
A a set of Pharmacovigilance activities and interventions designed to proactively identify, characterise and prevent or minimise risks relating to Medicinal Products, including risk communication and the assessment of the effectiveness of risk minimisation and interventions.

Spontaneous Report
An unsolicited communication by a regulatory authority, healthcare professional, consumer or other person that describes an ADR/AE in a patient administered the Product and which does not derive from a study or any organised data collection scheme.