Pharmacovigilance and Drug Safety

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.

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.