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.

Issues in pharmacovigilance outsourcing and consulting

Companies may seek to outsource some or most of their drug safety surveillance activities or to obtain the services of consultants for a variety of reasons:

• To save on recurring personnel and infrastructure costs

• To provide for flexibility to cover times of high work throughput

• To cover temporary gaps in workforce

• To obtain specific expertise and support not available in house

The nature of the work and functions outsourced can include any or all of the following, both for clinical trial and post-marketing spontaneous adverse event reporting:

• Safety data receipt, triage, database entry, coding narrative and medical review

• Expedited reporting to regulatory authorities, including electronic reporting

• Preparation of periodic safety update reports, US periodic reports, annual safety reports

• Signal detection and evaluation

• Literature screening for safety issues and case reports

• Qualified Person for Pharmacovigilance for Europe and local Qualified Person

• Evaluation of benefit and risk for a product

• Preparation of development risk management plan, RMP, RiskMAP and REMS

• Preparation of Detailed Description of Pharmacovigilance System

• Preparation or review of safety data exchange agreements with third parties / business partners

• Pharmacovigilance training, inspection readiness training

• Organisation set up or organisational change

• Preparation of SOPs and other controlled quality documents

• System evaluation, database evaluation, database validation

• Pharmacovigilance audit, development of corrective action plan, implementation of CAPA

• Labelling evaluation and variations; preparation of Company Core Safety Information and Development Core Safety Information

• Responses to regulatory authority enquiries about safety

• Dossier preparation for product registration

• Crisis management

• Support for medicolegal activities and litigation defense

• Evaluation of options for pharmacoepidemiology studies

• Assessment of published reports

Clearly there are different levels of skills, experience and knowledge required for the various activities. This is reflected in the types of organisation that are available for outsourcing of pharmacovigilance work. Individual consultants or contractors may act as an interim resource, sitting in the client company for a period of days, weeks or months, working as if a member of the client pharmacovigilance team. There are also agencies (e.g. Harten Group) that specialise in this type of arrangement and have numerous pharmacovigilance freelance consultants on their books.

At the other extreme of the spectrum, the client may wish to outsource most of the pharmacovigilance activities, routine and non-routine, to a contract organisation (a “PV service provider”). These companies may be very large Contract Research Organisations (CROs) such as Quintiles or Parexel, that concentrate on clinical research, but carry out pharmacovigilance activities as well. There are also specialist PV service providers, such as PrimeVigilance Ltd, PharSafer and Vigilex, that carry out all pharmacovigilance activities but do not perform clinical trials. In the case of PrimeVigilance, there is an interesting model in that routine pharmacovigilance activities are carried out in Eastern and Southern Europe, where overheads are lower than in Western Europe and N.America, but where there is a strong emphasis on quality management. This is combined with a specialist consulting arm and a specialist phase 4 CRO to provide the possibility of a comprehensive range of services from one organisation.

Other clients may need a more limited range of routine activities, such as individual case processing, expedited reporting and PSUR preparation, but not involving other elements. Again, the large CROs may do this work, although the cost can sometimes be prohibitive. The specialist PV providers may be able to provide a competitive approach in terms of cost-effectiveness without sacrificing quality. In addition, there are a number of companies operating in India that carry out this basic work: whilst cost may be reduced there could be concerns about the ability to keep control of events and of quality this far removed geographically.

Specialist pharmacovigilance consultancies do not generally include a provision for safety database and expedited reporting, although some have made arrangements with third parties to perform this function. Again there is a range of expertise available among consultancies, some such as Elliot Brown Consulting, based in the UK, having medically trained staff as well as involving former senior regulators and an international network of pharmacovigilance associates. A similar model is provided by Pietrek Associates. Such companies are able to offer high end consulting on serious safety issues affecting a client’s products, as well as more mundane activities such as auditing, PSUR writing and review etc. While cost can sometimes seem high for these consultants, experience and knowledge may result in less time being taken to complete a project than might be the case with less experienced contractors.

There is a dilemma for companies wishing to outsource pharmacovigilance activities. On the one hand, many companies still consider pharmacovigilance merely to consist of a routine activity necessary for compliance with regulations, but basically a drain on resources and a cost with no benefit. On the other hand, there may be a recognition that safety issues, unless identified early and managed properly, can ruin a company financially. However, more enlightened companies realise that high quality safety data and effective pharmacovigilance are in effect a form of life insurance, protecting patients and products and ultimately the company itself.

Regardless of the type of pharmacovigilance service provider, contractor or consultant used, there is an important concept that the company that is holder of the marketing authorisation (manufacturer in the US) can delegate some or most pharmacovigilance activities, but must retain overall responsibility for the safety of its products. Thus, there needs to be clear accountability, a transparent management hierarchy and a robust decision-making process within the client company. In addition, it is essential that there is comprehensive and detailed contractual documentation specifying which party carries out each of the various pharmacovigilance activities. Only in this way can the legal obligations of the client company be satisfied and the patients’ interests protected.