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home > epc > autumn 2010 > is it safe to outsource safety?

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European Pharmaceutical Contractor Is it Safe to Outsource Safety?
Graeme Ladds at PharSafer Associates Ltd highlights the many factors to consider when deciding whether to outsource pharmacovigilance Pharmacovigilance (drug safety) is a cornerstone activity of any pharmaceutical company, or indeed anyone conducting clinical studies in patients within academia. There is a need to operate a system of pharmacovigilance which complies with both the multinational (and varied) regulations, and the highest principles of patient protection. This means that companies can face the dilemma of having products in development or on the market which do not generate many adverse events (side effects) but when they do, require experienced individuals to assess the reported events and determine if they are indeed causally related to the product, their seriousness, and whether such events are already known to occur with the product or not. Once the above assessment has been performed, the company then needs to determine who should be informed about the adverse reaction (such as regulatory authorities); whether the current labelling for the product (summary of product characteristics, product monograph, patient leaflet and investigator brochure) suffices or needs revision and, most importantly, whether there is a way to prevent such an adverse reaction occurring in the first place (risk management strategies). Highly skilled and experienced individuals are required to perform these assessments with sophisticated safety databases that record and report such events. However, few companies can afford to have idle equipment or individuals waiting in the event that adverse reactions occur, especially if the company has few products. So, what is the answer? Is it safe to outsource safety? THE BASICS For companies with products in development, or for products that already have licences (sometimes called marketing authorisations or licence holders) there is a legal requirement to have a system in place to capture, assess and, if required, give an account of all adverse reactions that are reported to the regulatory authorities. The company (referred to as the ‘sponsor’ in clinical trials) must also make their own assessment of the seriousness, predictability (either in the labelling or investigator brochure) and causality of the reported events. Additionally, the sponsor may have to provide periodic submissions to the regulatory authorities, such as annual safety reports in clinical trials or more frequent post-marketing reports, known as periodic safety update reports (PSURs). These reports examine the adverse reaction data between two time points and assess the overall benefit-risk ratio of the product to determine whether the medicines should continue to be provided to the intended patient population. It is therefore crucial that sponsors have trained safety professionals available, including safety scientists, pharmacists and physicians capable of providing such assessments. Before making any decisions about a company that can perform some or all of these activities, a checklist is needed of the actions to be taken. The list in Table 1 is not exhaustive but provides some of the key activity requirements of a licence holder and of the sponsor. Such a comprehensive set of requirements means that the service provider must have individuals suitably trained in these areas, standard operating procedures (SOPs) available to explain how such activities should be performed, and evidence that the system is operating as stated and that it complies with the necessary legislation. Ultimately, in any situation where the safety aspects for the product (investigational or marketed) have been outsourced to a CRO, the responsibility and accountability rests with the sponsor (in clinical trials) and the licence holder (for all marketed products) (1). This may seem unfair when the sponsor has approached the specialists in order to ensure compliance to safety legislation, but in Europe and the US, the legislation is clear that the licence holder or sponsor carries ultimate responsibility for patient safety. This means any outsourcing of safety should be viewed as an intimate partnership – a marriage. Divorce and bad communication are not an option. Outsourced does not mean ‘out of mind’. The only way that both parties will get the most out of such a union is through active dialogue, an understanding of what is required of each, regular reviews to ensure everything is working as it should be and clear evidence of such communication. COMPLIANCE Compliance monitoring is a legal requirement to ensure that the sponsor is reporting accurately to the various regulatory agencies. The information, timelines and format must all be correct and with the acceptable and appropriate signatories. A system should be in place (as well as specific SOPs) that will enable the various regulatory outputs to be monitored for compliance and quality. The CRO should provide evidence that it has performed everything within the regulatory timeframes on a periodic basis so that the sponsor can be assured of compliance. Any instances of non-compliance need to be investigated by both parties to ensure they will not recur. The sponsor needs to be active in this area as well, especially if the reason for late submissions is that one of their marketing partners is late providing information. AUDITS The only way to know whether the safety information provider is capable of performing the tasks that you want is to audit them. But how can you audit them when you may not have the internal expertise to do so? There are a number of possibilities. There are many individuals trained in pharmacovigilance who perform regular audits on behalf of sponsors detailing the capabilities of the proposed pharmacovigilance supplier. Some providers may also offer their own audits as part of their quality management activities. These involve the CRO getting external pharmacovigilance auditors to audit their systems in order to determine whether the systems, training and documentation are robust enough. The CRO should make the findings from such reports available to clients or proposed clients to provide them with confidence that the appropriate systems are in place. Naturally, there will be some findings from any audit, but there should never be critical failures from CROs claiming to be the experts. Lack of any audit by the sponsor would not be viewed favourably by regulatory agencies, but using the sponsor’s external quality management system or an audit from an experienced provider would be acceptable. Such audits should not be performed once and forgotten, but ought to be repeated every two years at least. Once an audit has been performed successfully, the path is then clear to appoint the CRO. THE CONTRACT As is often said, ‘the devil is in the detail’. This is very true concerning the contract between the sponsor and the CRO. There will be legal elements to every document concerning terminations, judicial aspects, confidentiality and so on, as well as the financial elements, but the contract has to focus predominantly on what the CRO is expected to do. The contract will be used by the regulatory agency when they inspect the sponsor in order for it to understand and differentiate the duties of the CRO from the responsibilities of the sponsor. In any audit of the CRO, it is the proposed contract that should be used because this details the expectations and services to be provided. Within the contract, there may be elements that are desirable as opposed to those necessary to meet regulations. In Europe, there is one individual that is responsible for the oversight of the pharmacovigilance system, and this person is referred to in legislation as the EU qualified person for pharmacovigilance (EUQPPV). The EUQPPV must be trained in all aspects of pharmacovigilance and therefore, is not a position a company should attempt to support by itself – if it does not already have such an individual in place, then asking someone to take on this role thinking it is optional is not correct. The EUQPPV must also be registered with the regulatory agencies have a suitably qualified deputy. As well as stating what activities are covered by whom, the contract should also specify which of the sponsor’s products are covered by the agreement and their current status with regard to licence submissions. Regulatory inspections do not differentiate between generic, herbals, over the counter, or innovator companies; the level of compliance to legislation and the processes to report and assess potential safety issues with the products remains the same. The contract is an essential element of this and would cover all of these various companies’ product portfolios. ADVANCED ASPECTS Large Companies versus Small Companies Large companies with extensive product portfolios tend to have their own safety systems in place, but can still require additional resources for specific projects, such as data entry, PSUR writing, risk management activities and temporary cover for maternity leave. The key to fulfilling these tasks is more person rather than process-orientated and the first question to ask is: does the person have the capabilities and training necessary to perform the task. The CRO should be able to provide a copy of the person’s training record to demonstrate their experience in the area they are being asked to perform. Copies of such records should remain with the sponsor, together with information on any additional training on company processes needed to perform the activities. Additionally, sponsors may outsource some of their pharmacovigilance to a CRO because they have old products that do not generate much safety work but still require management. The products are fully outsourced, allowing the staff to focus their energies on new launches for products where the full safety profile has not yet been established because of low patient exposure. Staff are therefore able to concentrate on these products regarding safety issues knowing that the older products outsourced are being equally well managed by the CRO. Before outsourcing to the CRO, another aspect to be considered is capacity. Can the CRO cope with the new workload being provided to them? No one likes to say no to new business, but there has to be an appreciation of competency and capacity. If capacity is exceeded, competency declines. Therefore, for any outsourced activities the sponsor has to be clear on whether this will now exceed the capabilities of the CRO. Multinational Versus National Companies Which is bigger? the company with 30 products in one country or the company with five products in six countries It would have to be the second because for each country there may be different reporting requirements, it may be managing other affiliates or marketing partners, and have multiple PSUR submissions to different countries. The company with products in one country alone has only one set of regulations to follow, the contact points are easier and there is only one language to understand. Multinational companies require more management of the processes and safety reporting elements, as well as possible translation requirements. This is why the contract is so important as it is crucial to understand where these products are marketed and by whom, as many countries differ in their safety reporting requirements. Again, for calculating capacity (as well as compliance) the more multinational the sponsor’s products, the more potential for safety reporting errors to occur. This also means you need to choose a CRO that has multinational safety reporting expertise. THE MARRIAGE OF THE COMPANY & THE CRO Once the contract has been signed and the activities begin between the sponsor and the CRO, this is when we find out whether it is a marriage of convenience or a partnership. A convenience relationship is one where the sponsor allows the CRO to perform all of the safety activities but neither monitors nor provides any input into the activities or information generated from the CRO. Safety and safety compliance are critical aspects of the sponsor’s licence holders activities and, if done improperly, can result in the sponsor licence holders receiving fines and licence suspensions. A sponsor licence holder approaching safety in this way would be wholly unacceptable to regulatory inspectors. The regulators would be looking for the fully engaged partnership approach to safety, where the sponsor is kept fully updated by the CRO with regard to any emerging safety issue and checks compliance to ensure that all safety submissions to regulatory agencies have been provided according to national regulations. The regulators would be looking for safety reviews signed jointly by the licence holder and the CRO showing that there had been thorough understanding of the issue that had been identified, a plan of what to do next, and an execution of that plan. It also provides the sponsor with full transparency concerning the safety activities and compliance. WHEN SAFE MAY BECOME UNSAFE FOR OUTSOURCING During any lifecycle of a contract, it may be that due to changes in circumstance, activities that were originally considered ‘safe’ to perform in a certain way now become ‘unsafe’. There can be various reasons for this: Company Product Portfolio If the company acquires more products in an increasing number of countries (either through new licences or the acquisition of products from other companies or company takeovers), the workload of the CRO will grow dramatically and, as a result, capacity is exceeded. Unless the company can plan ahead to warn the CRO of the potential increase, the CRO may not have the internal staff or expertise required to cope. Additionally, as the company grows in size, a threshold will be reached when the size of the portfolio and the number of countries in which the products are available will exceed the cost-effectiveness of outsourcing. The threshold for bringing pharmacovigilance to the company may be determined by: The number of products, including those in development The number of countries that market the product(s) The type of products (over-the-counter versus oncology) T he number and type of adverse events reported (serious or non-serious) The amount of follow-up of adverse events required The number of PSURs to write The number of products with risk management plans As the number of reports increases, the volume of safety processing, safety analysis and periodic submissions will all increase, and as such individuals will need to be fully employed dealing with such data. When this occurs (from a cost perspective alone), it may be more appropriate to bring this in-house. Such a transition would not happen overnight and so there must be a coordinated handover during this period to ensure that all activities are still conducted in a compliant manner. The CRO can continue to work with the client on an on-going basis because there are many external activities (such as audits of affiliates or marketing partners) that can be performed without removing staff from their daily activities. Additionally, support during staff holidays, maternity/paternity leave, recruitment and illnesses can still be supplied by the CRO. From a company risk perspective, as the portfolio of products and countries marketed in increases, the potential risk to the company may also increase as it is not in control of its own data. Although there are various systems which can be put in place to ensure that such information is shared, the sponsor may realise that it is better to be closer to the safety data than have it based externally. The Company Mantra Many small- to medium-sized companies operate under the philosophy of ‘virtual’ services and this is a valid approach to a number of aspects of the companies’ work, including regulatory and clinical, as well as pharmacovigilance and medical services (medical information). The company may also have a philosophy of establishing itself with a group of products in strategic marketplaces that will make it attractive to prospective buyers or as a development company that will develop a product in clinical trials to a certain stage and then look for a development partner. If, however, the company changes its philosophy and decides to enlarge and develop further, the question of when (rather than if) to bring pharmacovigilance in-house will be raised again and the company must have a rationale for how it will determine the point at which it will need to conduct safety internally. This has to be governed to some extent by the potential safety risks the company product portfolio has for patients, together with the cost implications of continual outsourcing. CONCLUSION There are no mathematical formulae to work out at what point a company should look seriously at conducting pharmacovigilance in-house, but a company with 200 marketed products with licences in 40 countries worldwide should conduct at least a good proportion of its pharmacovigilance internally to demonstrate oversight of the safety of its products. References Eudralex Volume IXa, Sept 2008 21 CFR 310.305, 314.80 and 314.98
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Is it Safe to Outsource Safety?