Current Drug Safety - Volume 8, Issue 1, 2013

Risk communication is an interactive two-way process that various stakeholders (e.g., patients, regulators, industry) utilize to address prescription drug safety. This paper will specifically examine the pharmaceutical industry’s engagement with risk communication as a tool for information exchange with patients and other stakeholders about the associated risks related to its medicines. Risk communications are not solely meant to inform; and rather effective twoway risk communications have the potential to change behavioral outcomes for the purpose of individual and societal benefit. Despite this indispensable role of risk communication for the pharmaceutical industry, more research is needed for the appropriate development and dissemination of risk communications. A crucial missing component for the crafting of pharmaceutical risk communications is the understanding of risk perceptions from the patient/consumer’s perspective. This is necessary to see where any divergences in views may lie between the industry and its final consumer, which is crucial in tailoring communications to target a specific erroneous belief or to address what might be deemed as a needed behavioral shift. It is also necessary to develop communications in consideration of the levels of public trust in the industry as well as other perceived actors in the healthcare system. Even the most meticulously crafted and tested risk communications will fail to fulfill their purpose if the role of trust is not taken into consideration. These considerations can lead to the establishment of a “social contract” that effectively addresses what is required from both parties for continued and mutually beneficial interactions. Conducting risk perception research, addressing the role of trust, establishing a social contract, and having a realistic outlook on the impact of risk communications are necessary considerations as pharmaceutical risk communication evolves for the future.

The US Food and Drug Administration (FDA) requires risk communication as an element of Risk Evaluation and Mitigation Strategies (REMS) to alert and educate healthcare providers about severe toxicities associated with approved drugs. The educational effectiveness of this approach has not been evaluated. To support the communication plan element of the ipilimumab REMS, a Medscape Safe Use Alert (SUA) letter was distributed by Medscape via email and mobile device distribution to clinicians specified in the REMS. This alert contained the FDA-approved Dear Healthcare Provider (DHCP) letter mandated for distribution. A continuing medical education (CME) activity describing ipilimumab toxicities and the appropriate management was simultaneously posted on the website and distributed to Medscape members. Data were collected over a 6-month period regarding the handling of the letter and the responses to pre- and post-test questions for those who participated in the CME activity. Analysis of the answers to the pre- and posttest questions showed that participation in the CME activity resulted in an improvement in correct answer responses of 47%. Our experience shows that there are likely distinct information sources that are utilized by different HCP groups. The ready availability of a brief CME activity was utilized by 24,063 individuals, the majority of whom showed enhanced understanding of ipilimumab toxicity by improvement in post-test scores, educational data that are not available via implementation of standard safety alert communications. These results demonstrate that improvement in understanding of specific drug toxicities is enhanced by a CME intervention.

Pharmaceutical agents are prescribed to produce a therapeutic effect, but safety concerns require constant attention to the benefit:risk relationship inherent in their use and the needs of the individual patient. Such calculations involve assumptions about the likely tolerability of harm, in that greater safety risks may be acceptable for use of a lifesaving drug, compared with those acceptable for an agent providing only improved "quality of life.” Making such assumptions is an activity integral to the bedside clinician’s role, is done during many (perhaps most) patient encounters, and is often undertaken with inadequate information. The historical mandates for regulatory agencies, such as the Food and Drug Administration (FDA) in the United States, have evolved over the past decades to include an intense focus on drug safety. Communicating information about medicinal risk remains a major responsibility for the FDA and similar bodies, but the initiatives undertaken have had variable, and often limited, effectiveness in penetrating the physicianpatient interaction. Barriers to the successful communication of safety-related issues include the myriad of influences on and within the FDA, the time constraints on physicians involved in clinical practice, and the methodologies used to share information about both established and new drugs. Current efforts to assess the effectiveness of regulatory efforts at risk communications should lead to changes in the approaches used and, ultimately, improvement in the safe use of both new and established drugs.

The military, aviation, nuclear, and transportation industries have transformed their safety records by using a systems approach to safety and risk mitigation. This article creates a preliminary model of the U.S. pharmaceutical system using available literature including academic publications, policies, and guidelines established by regulatory bodies and drug industry trade publications. Drawing from the current literature, the goals, roles, and individualized processes of pharmaceutical subsystems will be defined. Defining the pharmaceutical system provides a vehicle to assess and address known problems within the system, and provides a means to conduct proactive risk analyses, which would create significant pharmaceutical safety advancement.

If the Pharmaceutical Industry were to align to broad metrics that objectively state each product’s “Safety Rating” two things would happen. First, Life Sciences companies would refocus dramatically on safety (followed by outcomes). Second, companies that have the highest aggregate “Safety Rating” would enjoy a significant competitive advantage. To achieve and maintain a high safety rating, the role of Safety officer needs to be elevated to the C –Suite.

The paper begins by asking why there is a market for counterfeit medicines, which in effect creates the problem of counterfeiting itself. Contributing factors include supply chain complexity and the lack of whole-systems thinking. These two underpin the author’s view that counterfeiting is a complex (i.e. wicked) problem, and that corporate, public policy and regulatory actions need to be mindful of how their actions may be causal. The paper offers a problem-based review of key components of this complexity, viz., the knowledge end-users/consumers have of medicines; whether restrictive information policies may hamper information provision to patients; the internet’s direct access to consumers; internet-enabled distribution of unsafe and counterfeit medicines; whether the internet is a parallel and competitive supply chain to legitimate routes; organised crime as an emerging medicines manufacturer and supplier and whether substandard medicines is really the bigger problem. Solutions respect the perceived complexity of the supply chain challenges. The paper identifies the need to avoid technologically-driven solutions, calling for ‘technological agnosticism’. Both regulation and public policy need to reflect the dynamic nature of the problem and avoid creating perverse incentives; it may be, for instance, that medicines pricing and reimbursement policies, which affect consumer/patient access may act as market signals to counterfeiters, since this creates a cash market in cheaper drugs.

Clinical and drugs safety organisations run their operation independently and use separate databases designed to comply with different data standards. This separation is neither efficient nor effective since investigators need to report serious adverse events both to the clinical and drug safety departments, causing the respective databases to contain partially overlapping data sets containing common elements that need to be reconciled. Electronic data capture provides the opportunity to avoid duplicate storage and obviate reconciliation. It also introduces the risk of non-compliance due to late submission of unexpected serious adverse reactions to competent authorities. This raises the potential for a clinical department to receive a case that the drug safety department is unaware of. However, the most significant inefficiency probably lies in the preparation of aggregate reports and regulatory documents that need to be prepared using data originating from both databases. In a resource-constrained world, unnecessary activities and associated costs are unwelcome, particularly when they are avoidable. The Clinical Data Interchange Consortium (CDISC) has set the standards for clinical trial data, while the International Conference of Harmonization (ICH) dictates drug safety ones. CDISC is expanding its Clinical Data Acquisition Standards Harmonisation (CDASH) model to capture adverse event data associated with ICH E2B. All common data items have two labels that have been mapped. This exercise is showing that there is no scientific justification for data segregation. The differences between these two standards can be attributed to conventions or arise from new technology that renders unnecessary the keying in of certain context information (dates, times and recorder ID). Once this mapping is completed then a common data acquisition process will become feasible. This is the prerequisite to ultimately unifying the two databases and to implementing more efficient processes. The Authors also propose a new workflow to provide safety with the array of benefits that technology and process harmonisation offers and ultimately unifying the clinical drug safety processes.

Domperidone, a dopamine antagonist that does not easily cross the blood–brain barrier, is considered the gold standard for treating gastrointestinal symptoms in patients with Parkinson´s disease (PD) because the risk of developing extrapyramidal adverse effects is considered minimal. On the other hand, cardiotoxicity related to domperidone is not a new issue. In fact, arrhythmias, sudden death and cardiac arrest were reported with high intravenous doses in the 80s. Concern about the cardiotoxicity of oral domperidone has arisen more recently after the publication of two case-control studies which have questioned domperidone´s safety even further, especially in patients > 60 years and in doses >30 mg/day. Very little is known about domperidone´s cardiac effects in patients with PD. In addtion, pharmacoepidemiological data about specific antiemetic use in these patients is scarce, with almost anecdotal reports of inappropriate centrally acting antidopaminergic drugs like metoclopramide in the hospital setting. As a result, and even no cases of serious arrhythmias or sudden cardiac death associated with domperidone concerning patients with PD have been reported, no definitive conclusions can be drawn about its safety. In conclusion, despite domperidone is still recognized as the first choice for treating gastrointestinal symptoms PD, doses above 30 mg/daily should only be considered with special caution taking into account its potential cardiotoxic effects.

Some papers reported the development of adverse drug reactions in patients with Down’s syndrome during the treatment with antiepileptic drugs. However, at this time, no data have been published concerning the development of tremor in patients with Down’s syndrome treated with sodium valproate. We report a 17-year-old man with epilepsy and Down’s syndrome who experienced tremor during the treatment with a low dosage of sodium valproate. The Naranjo probability scale documented a possible association between tremor and sodium valproate. Sodium valproate was changed to lamotrigine with both a rapid improvement of tremor and an optimal control of symptoms. In conclusion we documented that sodium valproate is able to induce in a patient with epilepsy and Down‘s syndrome, the development of tremor probably through the decreased activity of GABAergic neurotrasmission; however, further studies may be performed in order to validate this observation.

A 46 years old HIV reactive patient developed Stevens Johnson syndrome (SJS) probably due to nevirapine and/or co-trimoxazole. Patient was on zidovudine + lamivudine + nevirapine along with Co-trimoxazole since last two months. After 15 days, zidovudine was replaced with stavudine due to development of anemia. All these drugs were stopped after development of reaction. Temporal association was found between stavudine, lamivudine, nevirapine, cotrimoxazole and development of the reaction. Nevirapine and Co-trimoxazole were suspected to cause this reaction most probably due to associated hepatotoxicity and their common potential to cause SJS. In our case, patient died despite stopping of all medications.