There are four distinct elements to consider in developing benefit-risk management programmes. They are: protocol design and review, active surveillance, provider and patient education and appropriate use programmes. The entire programme from design through implementation and maintenance will be overseen by programme management, quality management, continuous improvement and comprehensive communication.
Understanding the interrelationships among all key stakeholders is the critical aspect in risk management planning in today?s rapidly changing, complex global healthcare environment. These can include payers, providers, patients, care givers, patient advocacy groups, regulators and other government agencies. All these stakeholders should be considered when planning and communicating benefit and risk. In the US and Europe there have been significant updates in safety and risk management regulations. Many other countries are actively revising drug regulations such as India and China among others. In the face of these rapid and global regulatory changes one must constantly evaluate their readiness in responding with timely and compliant benefit-risk management systems. This readiness assessment will encompass several key areas but must also be comprehensive and open. The organisation must understand the principles of the culture of safety and put in place systems and processes to support this concept as a core characteristic of the company. One must identify gaps in knowledge of both risks and benefits for example, special populations both of those with identified risks and those that have not been evaluated such as the seniors and children. Given today?s advances one should also consider the implication of pharmacogenomics on the risk management programme. Is the company ready to manage a marketed product? Are there sufficient systems, processes, procedures and finally sufficient personnel both in quality and quantity?
When considering comprehensive and cross-functional benefit-risk management programmes, it is possible to organise the efforts into four key areas. They are:
These categories are used to help assure that the programme will be comprehensive and effectively designed based on all available information and utilising crossfunctional capabilities (Figure 1).
During the investigation phase, the sponsor has complete control over product distribution and use. However, he loses the control substantially as product receives marketing authorisation. With market authorisation and distribution, the product is available to licensed medical practitioners in accordance with local laws and regulations. Also, physicians could often approach the sponsor with a request to provide the medicinal product free of charge for the expressed purpose of conducting independent clinical research. In addition, a sponsor can have a programme of investigation on the medicinal product that has been designed internally to provide additional information as determined by the gap analysis noted above. These investigations could be both internal and external. The sponsor should put in place a mechanism to assure adequate design; inclusion and exclusion criteria; and adequate subject protections for each of these protocols. To focus on science and ensure that at-risk populations are protected, the sponsor can constitute a protocol review committee with adequate committee structure and document procedures. Commercial interests cannot outweigh patient protection. Key stakeholders who can be included in this committee may be from the areas of Research & Development, Medical Affairs, Regulatory, Law, and Commerce. Other groups such as public affairs may also be included. The sponsor must be inclusive and open and avoid silo behaviour.
Active surveillance programmes include a variety of methods: Consider monitoring commercial databases and insurance databases for retrospective and prospective analyses. The sponsor may also consider utilising more modern methodologies that take advantage of advanced web-based tools. One unique design taking advantage of these Internet capabilities is to create a web-based patient community. In this example a sponsor would offer access to a unique product or disease portal where the patient could enroll and opt for receiving information and also be available to participate in both prospective and retrospective research programmes. Again, the patients could be offered the opportunity to opt for the research programme on a voluntary basis. This community should then provide a platform for the sponsor to readily recruit patients for epidemiologic hypothesis generating and hypothesis testing programmes. In addition, the sponsor could consider signal detection and an evaluation programme which includes actively reviewing single case reports, case series, claims data, data warehouses, and public databases such as the World Health Organization?s Uppsala Monitoring Center, and the United States Food and Drug Association?s Adverse Event Reporting System. Sponsors need to evaluate and understand the appropriate measures to utilise, in the active surveillance programme understanding the key domains, data sources and appropriate methods to apply at each intersection.
The purpose of these programmes is to aggressively monitor and investigate events of interest, develop targeted follow-up questionnaires, establish special reporting agreements with regulators (if needed) and effectively communicate the findings to all interested parties in an open and timely manner.
Appropriate use programmes
Appropriate use programmes provide a thorough assessment of marketed product usage. These programmes monitor all uses, approved and unapproved indications. They are especially useful for monitoring known high-risk unapproved exposures. When inappropriate use is detected, a sponsor may consider holding provider and patient education programmes that would reinforce appropriate use. There are many tools available to sponsors in developing appropriate use programmes. One can develop drug and disease registries, sample use through market research, utilise publicly available databases, and commercial resources. Ultimately, the sponsor must continuously monitor usage and put appropriate measures in place when aggressive management of the medicinal product distribution is needed. The most restricted method of distribution is used in risk management programmes utilising a performancelinked access system.
These programmes ensure that only those patients who understand the specific risks are exposed to products. Notable examples of this restricted distribution in the US include the programmes for isotretinoin and natalizumab both of which have well characterised serious risk profiles.
The cornerstone of any risk management programme is the education component. It is critical that the sponsor adequately and continuously educates healthcare professionals, patients, caregivers, and patient advocacy groups with the best and latest information related to the product use. The education programme could be developed along with the entire product development programme.
The sponsor can again utilise the online patient community to both provide them with education materials directly and assess their level of comprehension of the critical elements of the programme. Patientdirected online programmes could be expanded to the level of disease communities. These programmes can provide patients access to proactive and interactive educational programmes. The online community can also be used for patient-directed physician communication wherein the patient provides permission to contact their healthcare provider for verification of specific medical information.
These complex multiple-component programmes require professional project managers to oversee the design, implementation, maintenance, reporting and communications. The project manager assures that the various service components are effectively implemented and anticipates programme problems and addresses them.
The final element of the comprehensive benefit-risk management programme should be that of quality management. For each component of the programme, metrics should be established to assess the effectiveness of the service delivery and the effectiveness of the programme to reduce the specific risk elements defined. If the programme is designed to reduce the incidence of events of interest then that will be a key efficacy parameter for measurement and analysis. This ongoing quality analysis will lead to a continuous improvement model. Progress should be tracked over time to identify areas for improvement; define and implement best practices; create process maps to find potential efficiencies and establish Corrective and Preventive Programs (CAPA) as needed. An often-overlooked element of the quality management system is the inclusion of key stakeholders such as prescribers, pharmacists, and patients in the evaluation process.
Utilisation of modern technologies and effective communication with consistent and audience-appropriate messages is critical for an effective product benefit- risk programme management. Full characterisation of events of interest and validated mechanisms to mitigate risk prior to market authorisation and active product defense throughout a product life cycle is the backbone of a successful medicinal product. The benefit of which will be the optimal public health outcome assuring that the right patients have the most effective medications for their unique circumstances. And prescribers are provided clear accurate communication to best advise their patients for their course of treatment.