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An efficient system can be the difference between a drug being withdrawn or delivered to market.
The implementation of an effective pharmacovigilance function is high on the list of priorities for pharmaceutical companies due to the major emphasis that is placed on ensuring drug safety. This emphasis comes as a result of the stringent legislation enforced by regulatory bodies that demands greater transparency during the pre-marketing and post-marketing of all new pharmaceuticals to protect patient safety. As a result, it is vital that manufacturers effectively document and manage data on each and every aspect of their development and marketing processes.
The advantages of an efficient pharmacovigilance system can often mean the difference between a drug that is withdrawn due to safety concerns and one that is successfully delivered to market. A comprehensive drug safety methodology will help to ensure the latter and by investing in an efficient system that will guarantee the effective processing of clinical trial safety data, pharmaceutical companies will benefit greatly in the long-term.
Traditional thinking suggests it is essential that pharmaceutical and biotechnology companies exercise complete control over their pharmacovigilance activities to make certain that any safety signals are detected effectively, that regulatory requirements are complied with and most importantly to ensure a target drug's successful progression to the final stages of development. Doing this effectively can present a number of challenges, including the expansion of drug safety departments and the associated costs. However, successful experiences of outsourcing other clinical activities are making outsourcing of safety services to specialised service providers a more attractive solution for pharmaceutical companies.
An effective pharmacovigilance function necessitates the efficient management of clinical trial serious adverse events from case assessment through to expedited reporting of suspected unexpected serious adverse reactions (SUSARs) to the regulatory authorities. It also requires development safety update reports to be compiled and submitted to regulatory authorities and ethics committees throughout the duration of the clinical trial program. Companies must also exercise the efficient management of information obtained from numerous sources including literature reviews, ongoing studies, knowledge of pharmacology and other drugs in class, preclinical data, patient population, co-morbidity profile and the disease process (pathophysiology).
Pharmaceutical companies must also meet regulatory protocols and global standards. Due to varying regulations across the globe, being compliant on a worldwide scale has become increasingly difficult and efficiently adapting processes to meet the numerous guidelines and regulations of each country is something that many organizations are struggling with. Current guidance is based upon the International Conference on Harmonization and the Council for International Organizations of Medical Sciences guidelines; in addition to the confidentiality agreement from November 2003 between the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), which covers the sharing of drug safety data. The proposed FDA guidance for a risk evaluation and mitigation strategies (REMS) program provides a new blueprint for how safety strategies should be developed, while the FDA final rule on investigational new drugs safety reporting and associated draft guidance contributes significant changes in safety reporting practices. Together with the EMA's Committee for Medicinal Products for Human Use, Guideline on Risk Management Systems for Medicinal Products for human use, these guidelines form the basis of pharmacovigilance regulations in most parts of the world.1
In all pharmaceutical companies there is a need for an appropriate approach to pharmacovigilance that is risk-based; proportionate; and feasible within resources, but which meets quality standards and protects patients. Standard operating procedures (SOPs) that meet regulatory obligations must be put into place to guarantee quality measures for recording, reporting, and managing adverse events (AEs). Systems must also be implemented for receiving both spontaneous reports and clinical trial reports from investigators and forwarding these, within the necessary timeframes, to the appropriate bodies and individuals.
Sponsors must provide the means to follow-up on safety issues, maintain records, and handle overall safety systems. Processes should be implemented to check that arrangements for projects have been established and documented correctly, and that procedures are being rigorously adhered to. It is also essential that a quantitative methodology is not used in isolation: it should be combined with expert judgment to create the safety profile of a drug.2
Until recently many pharmaceutical companies have been reluctant to outsource their drug safety activities. This was primarily due to fears among manufacturers about losing control of processes and proprietary knowledge and the legal ramifications if the outsourcing partner "got it wrong." Today's marketplace offers a broad choice of both service providers and scope of pharmacovigilance services and in the face of rising profit pressures, many companies are increasingly turning to outsourcing processes as a way to gain access to innovative new ideas, maximize the use of existing resources, and reduce expenses.
Outsourcing pharmacovigilance provides access to specialists that have the skills, technology, processes, and scale to perform tasks as well as or better than a pharmaceutical company itself. Manufacturers can benefit from specific support not available in house as and when they need it, enabling companies to save on recurring personnel and infrastructure costs while also offering the flexibility to cover times of high work throughput.
The functions that can be outsourced during the development phase of a new compound include the review of safety results from preclinical and clinical studies, expedited reporting to regulatory authorities, preparation of DSUR reports, literature screening for safety issues and case reports, surveillance of emerging data, and the evaluation of benefit and risk for a product. The preparation of development risk management plans, preparation of SOPs and other controlled quality documents, system evaluation, database evaluation, database validation, and labeling evaluation are services that can also be outsourced.
Evaluation of individual serious cases and AEs of special interest leads to the need to address important safety issues that are identified. In turn, the periodic cumulative assessment of all available clinical data (including laboratory and physical data) must be performed; this aggregate review depends on competent reviewers and auditable documentation. A specialist provider will have the capabilities to provide ongoing expert physician review to ensure the highest levels of safety are met. Such companies will be able to deliver DSUR reports that demonstrate whether or not any issues arose during a study that could have an impact on the known safety profile of a drug and can ensure that the data obtained are still consistent with the recognized profile.
Outsourcing pharmacovigilance can offer a myriad of benefits to the pharmaceutical company. They are provided with increased speed and flexibility that provides access to a virtual team that works as and when projects demand and allows particular individuals to be brought in when specific expertise is required. In addition, the input of an outside organization can bring in strategic direction and often enables operations to get up and running more quickly. Highly specialized and expensive skills are required to carry out drug safety effectively. Outsourcing to the right company provides access to experienced pharmacovigilance physicians who not only have a critical scientific eye and the ability to conform to rigorous processes, but will also have a broad view of the industry.
A further potential benefit of outsourcing safety evaluations during clinical development is that unblinding can be handled by the provider rather than the sponsor. This allows more controls and limits on who is informed of treatment assignments for reported SUSARs.
An improvement in processes is also a significant advantage of outsourcing. Service providers can offer a short cut to radical improvements in efficiency, cost, and speed by rethinking a company's ingrained habits and processes. By doing so, outsourcers can implement new and better methods as a matter of course. Through outsourcing, a company can also rely on another firm's infrastructure rather than providing the capital itself and can take advantage of the ability to avoid huge fixed costs. In addition, outsourcing non-core and transactional tasks can enable a company to focus on its core competencies.
Outsourcing to the right provider can contribute many advantages to a pharmaceutical company, however, manufacturers must remember that doing so will call for monitoring of progress; performing inspections for quality data assurance; evaluating problems; and proposing corrections, as well as preparing plans for terminating the outsourced services. Similar to outsourcing any other service, it is vital that companies evaluate all the issues that may occur as a result of contracting these services to outside organizations before choosing to work with a provider.
Though the many benefits make outsourcing a worthwhile activity, it should be approached cautiously to overcome risks and maximize success. There are a number of practices that will help manufacturers to make good outsourcing decisions and choose their partner wisely.
Pharmaceutical companies will need to give considerable thought to how best to manage the relationship between themselves, the contract research organization and the pharmacovigilance service provider. To achieve success it is essential that collaborative processes are established that will not threaten the future of a drug. A sponsor action plan should be clearly designed at the beginning of any development program setting out predetermined objectives and measures to evaluate the outsourcing solutions. The legal, training, and confidentiality requirements that will guide the relationship must also be developed at this point.
Some cases may involve the outsourcing process being divided between multiple providers meaning that the safety provider is often not in direct contact with the primary sponsor. In this instance it is important to ensure that the conduct of safety management in a clinical trial is a collaborative process requiring cooperation in evolving and implementing activities. In order to guarantee the success of the clinical program, training is of paramount importance to ensure any issues can be met with immediate action.
The continuous exchange of information between the provider and the sponsor is another key element to success. However, sponsors must be certain that this is transferred safely and that confidentiality agreements are not compromised. It is therefore vital for sponsors to thoroughly check the competency of the provider they choose to work with. A good starting point is to undertake an SOP audit alongside checking the provider's team competencies and experience.
Further to the collection, analysis, and timely reporting of safety data, an important point is the accountability for the detection of safety signals and the guarantee that signal identification is not lost due to segmentation of the analysis between providers and the company. In addition, responsibility for safety review meetings, data analyses, searches, compilation of documentation, and the ongoing creation of risk management plans needs to be defined prior to outsourcing in order to avoid misunderstandings. If it is decided that responsibility will lie with the sponsor, it is imperative that the provider is kept in the loop so all parties are aware of any new information or issues and can perform their work in line with the updated safety profile of the drug.
Working with a specialized provider that is able to contribute expert advice and medical liaison will enable these challenges to be routinely addressed. As a result, pharmaceutical companies can rest assured that the clinical experience gained in clinical trials will contribute to building the safety profile of a drug rather than being the reason for bringing its development to a halt.
Pharmaceutical companies are in a unique position to adopt the outsourcing model as a means to manage their processes more effectively and contend with pressure on profitability and a rising demand for efficiency. With a broadening array of both providers and service offerings, pharmaceutical and biotechnology organizations must remain in command, orchestrating the activities of different providers and ensuring that information is openly and continuously exchanged between all parties.
The advantages of outsourcing are clear: cost savings, access to expertise, process improvements, the avoidance of fixed costs and big capital outlays, and the ability for a company to focus on their strengths. By utilizing the services and expertise of specialist providers, companies are offered a pragmatic solution, reviewing clinical trial data from a thorough safety point of view while also having a distinct understanding of the company's objectives and the use of a drug in clinical practice. As pharmacovigilance is a pivotal process to ensure that a company's product remains on the market, investing in an efficient system will benefit the drug manufacturer greatly by defining and validating a drug's safety profile and accelerating the delivery of new therapies to the marketplace.
James Sawyer, MD, MFPM, is CEO, Prism Ideas, Regent House, Princes Court Beam Heath Way, Nantwich, Cheshire, UK, e-mail: firstname.lastname@example.org.
1. Council for International Organizations of Medical Sciences, Updates, http://www.cioms.ch/.
2. European Medicines Agency, http://www.ema.europa.eu/ema/.