Pharmacovigilance and Drug Safety

A major change in the approach to drug safety surveillance after marketing has been introduced in the last 5 years in the EU in the form of risk management planning. This has been incorporated into EU law and is extensively covered by guidelines in Volume 9A. There has been a similar initiative by the US FDA.

For the EU, it is mandatory for companies to submit a Risk Management Plan in accordance with a detailed template and guideline at the time of application for a Marketing Authorisation for most products. Plans also have to be submitted if new safety concerns are identified for a marketed product and all plans must be updated as circumstances change.

Thus companies are required to specify at the time of first marketing areas of safety about which they are currently uncertain and how they will resolve this uncertainty. They must also indicate what measures they will take to reduce known risks and how they will test whether these measures work.

The EU Risk Management Plan (EU-RMP) has 3 main elements. First, a detailed consideration of what is known about the safety of the product, based on pre-clinical and clinical studies. This “safety specification” considers identified risks and potential risks – the latter being areas of uncertainty regarding safety. It also specifies what the limitations of the clinical research program are and what important information about safety is currently missing. In the second component, the “pharmacovigilance plan”, the company must indicate how it proposes to resolve the uncertainties – what extra studies it will carry out after marketing to fill the important gaps in knowledge. The third component is the “risk minimization plan”. This states how the company proposes to reduce the severity or frequency of known adverse reactions. This may involve special communication programs, or educational exercises, or perhaps registration programs for patients, doctors or pharmacists, or other measures. The pharmacovigilance plan and risk minimization plan must include timelines for setting up the programs and milestones for their evaluation.

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

After selection of molecules for development, the substances go through a program of pre-clinical and clinical research culminating – possibly – in an application for marketing authorisation. Most substances fail to complete the course: as few as 1 in 10,000 undergo the entire program and reach the market.

Pre-clinical Research

The research program consists of animal, ex vivo and in vitro experiments, carried out in accordance with the requirements laid down in detailed regulatory guidelines. A number of short-term animal studies must be carried out before the substance can first be tried in single doses in humans. The animal studies comprise: toxicology studies –the effects of large doses; pharmacology studies – the effects of the substance on how the body systems function; and pharmacokinetic studies – looking at how the substance is absorbed, distributed, metabolised and eliminated in the animal.

Longer duration animal toxicology studies must then be performed before multiple doses may be administered in humans, with increasing periods of exposure and a larger range of animals being studied as exposure in humans increases during clinical research.

Alongside the above animal pre-clinical studies, other studies are carried out e.g. mutagenicity studies (effects on chromosomes and on genetic processes), studies of effects on the foetus etc.

This rolling program of pre-clinical studies synchronises with the clinical study programme. At each step in the clinical trial program, there must first have been reassuring information from animal studies. However, even at the time of application for a marketing authoriztion, there may be ongoing long-term animal studies – usually carcinogenicity studies – the results of which may only become available after the product is on the market.

Clinical Research

The clinical trial program in humans can be considered as comprising four phases. In phase 1, generally involving up to about 100 subjects, there is study of the tolerability of increasing single doses of the drug and investigation of its pharmacology and pharmacokinetics. Phase 2, usually includes the first study of efficacy in patients with the disease and studies – commonly in a few hundred patients – to find a dose that is effective and well-tolerated. However, phase 1 studies may continue alongside phase 2 studies. Phase 3 potentially extends the studies into several thousand patients – although the average is around 1,500. The focus is on demonstrating efficacy and acceptable safety in the intended population. If the drug is to be used over long periods of time, there will be long-term studies. At the end of the program comes the assembly and submission of a registration dossier to regulatory authorities. This is the application for marketing authorisation (MAA in Europe, NDA in the US). The dossier is usually submitted electronically but the paper copy of the pharmaceutical, pre-clinical and clinical files often comprises many hundreds of volumes of data, each volume comprising several hundred pages. The clinical trials usually continue during the registration review period, and Phase 4 studies are set up after marketing.

Each step in the clinical research program is heavily regulated. Before first exposure in man, there is assessment by the regulatory authorities of all the animal and in vitro studies. Every trial thereafter has to be approved by the appropriate regulatory authorities –and separately by ethics committees in each country – based on summaries of the available evidence to date. All new relevant safety information arising from animal studies must be submitted to the authorities and the ethics committees during the clinical research program (and to the regulatory authorities if arising thereafter).

An investigator brochure summarising all knowledge to date about the safety and efficacy of the study drug is created by the company and updated at intervals. This is supplied to all investigators and to the ethics committees and regulators.

Serious, unexpected adverse reactions that occur during clinical trials and are suspected of being related to the study drug (SUSARs) must be submitted to the appropriate regulatory authorities within specified short time frames (expedited reports). They must also be notified to all investigators and to ethics committees. Each year during the course of the clinical trial program, annual reports (Annual Safety Reports in the EU, IND Annual reports in the US) including a summary and analysis of all the serious adverse events that have arisen during that period and all new safety findings from animal studies, as well as evaluations of benefit and risk, must be submitted to the regulatory authorities and ethics committees. All of these submissions are required by law and compliance by the companies is checked by a combination of internal company audit and regulatory authority inspection.

The review of safety in clinical trials pre-registration is performed throughout the clinical research program by R&D and pharmacovigilance departments within the sponsor companies. The conduct of the clinical trials is often contracted out to Contract Research Organizations (CROs) – but the responsibility for safety lies with the sponsor company. In addition, safety may be reviewed continuously by independent Drug Safety Monitoring Boards set up for specific studies.

A marketing authorisation for a medicinal product in more than one Member State in the EU must be sought via one of three procedures: either the “Centralised Procedure”, determined by Regulation (EC) No 726/2004, the “Mutual Recognition Procedure” or the new “Decentralised Procedure”, regulated by Directive 2001/83/EC.

In addition, national authorisations allow for products to be marketed in individual countries in the EU. A product may be authorised in several Member States by a number of national authorisations, or one of these may be used as the basis for a Mutual Recognition Procedure. The regulatory agency of the country concerned has the responsibility for monitoring and assessing the safety of products with national authorization.

Centralised Procedure

This is administered by the EMEA. It consists of one application which, if approved, grants marketing authorisation for all countries within the European Union (and the European Economic Area, i.e. the EU countries plus Iceland, Norway and Liechtenstein).The European Commission is the responsible authority for the products which come to the market through the centralised procedure. The procedure is available to all new, or innovative pharmaceuticals, and is obligatory for biotechnology medicines. It is used for products containing new substances for which the therapeutic indication is the treatment of serious disease.

The regulatory agency of a Member State is appointed as Rapporteur and carries out the initial assessment of the application for Marketing Authorisation; another agency is appointed as Co-Rapporteur. These countries remain responsible for taking the lead in the monitoring and assessment of safety of the product when it is subsequently marketed.

Mutual Recognition Procedure

Here, the marketing authorisation in one Member State, the ‘Reference Member State’, is “mutually recognised” by other ‘Concerned Member States’. There is a 90 day assessment period after which Member States grant a marketing authorisation with an identical summary of product characteristics to that in the Reference Member State, provided that they accept the assessment of the product. If a Member State raises objections and does not recognise the original marketing authorisation the matter may be referred to the EMEA for discussion among the parties: if this fails, binding arbitration is imposed.

Decentralised Procedure

This process can apply where an authorisation does not yet exist in any of the Member States. Identical dossiers are submitted in all Member States where a marketing authorisation is sought. A Reference Member State, selected by the applicant, prepares a preliminary assessment report within 120 days and sends it to the Concerned Member States. They then approve the assessment or the application will continue into a facilitation or, if this fails, a binding arbitration procedure applies.

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.

Signal detection based on spontaneous reporting involves looking for any new patterns or seemingly significant new findings in the safety database. It may be one or more reports showing particularly strong evidence of a previously unknown adverse reaction for that drug, or involving adverse events that are usually caused by drugs, such as aplastic anaemia or toxic epidermal necrolysis. More often, it is a matter of looking for patterns or clusters of reports that stand out from the background. These clusters may be identified by looking at data tables, or – for large databases, such as those held by regulatory authorities or by a company with product with many cases reported – using computerised methods involving statistical disproportion. Examples include the Proportional Reporting Ratio, Bayesian Combination Propagation Neural Network used by the WHO Uppsala Monitoring Centre and the Modified Gamma Poisson Shrinker method used by FDA and MHRA.

Having identified potential tentative signals it is necessary to evaluate them and to consider whether they are real or not. Often, an apparent signal can result just from the disease that the drug is treating – so if a drug is used in patients for the treatment of high blood pressure, it would not be surprising to find reports of high blood pressure itself, and also kidney disease, stroke and heart failure, because these are either contributory or complications of high blood pressure. This is often a difficult process: evaluating signals involves looking at the individual case reports and assessing the strength of causation of the drug in each case. Other sources of safety data are usually also checked at this time – for example, the data from clinical trials and toxicology studies.

It may then be appropriate and necessary to set up a study specifically investigating a particular signal or safety concern. Other possible actions could be to institute a review of the benefits and risks of the product; to suspend or revoke the marketing authorisation; to propose a change to the product information (SPC, labelling); to issue a warning to health professionals in the form of a Dear Health Professional communication; or perhaps just to keep the issue under review. At some point, it may become apparent that the signal was not real, and the issue can be shelved.

Organization of safety monitoring

After approval in the EU, the company holding the marketing authorisation is required by regulation to continue monitoring safety. It must enter reports of suspected ADRs on a validated safety database and review the data for signals of possible new adverse reactions or other concerns. Any change to the balance of benefits and risks must be reported to the regulatory authorities, in addition to the reporting of individual cases and periodic safety update reports.

For products with national marketing authorisation in the EU, the regulatory authority in the Member State where the product is marketed has responsibility for reviewing safety by examining the safety reports that it receives from the company and directly from health professionals working in that country. The national regulatory authority also reviews PSURs from companies. It enters the case reports it receives onto the Eudravigilance database, held by EMEA.

For mutual recognition and centrally authorised products, the responsibility for monitoring safety rests with the EU regulatory authority that acted as Rapporteur or Reference Member State. However, each national regulatory authority will still receive local reports of adverse reactions from companies and health professionals and must enter these onto the Eudravigilance database. The EMEA acts as a coordinating body for the safety activities for centrally authorised and mutual recognition products, but the safety reviews are performed by assessors in the Member State regulatory authorities.

The Committee on Medicinal Products for Human use (CHMP) – comprised of representatives of each of the EU regulatory authorities – is involved at intervals with review of the PSURs for centrally authorised products and with safety issues arising post-marketing. These are channelled through its Pharmacovigilance Working Party (PhVWP), which comprises pharmacovigilance representatives from each Member State.

Legislation provides mechanisms for referral of important safety issues potentially affecting public health throughout Europe to the CHMP by the PhVWP. There are complex procedures for examining the benefit-risk balance of products if there are major safety concerns, and for making recommendations to the European Commission for suspending or revoking marketing authorisation.

There are two main strands to the assessment of safety of marketed medicines: spontaneous reporting and post-authorisation studies. However, it should be pointed out that company-sponsored research may be continuing in countries  where the product is not yet marketed, in order to obtain marketing authorisation there. Safety information from those studies is required by regulation to be reported to the competent authorities where the drug is marketed. In the same way, studies may be set up looking at new indications for the marketed drug, or use in new populations, or with different dosage forms. All of these may generate data on adverse reactions that is relevant to the marketed product and which is legally required to be forwarded by the sponsor company to the competent regulatory authorities.