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How an Individual Case Safety Report (ICSR) Is Handled from Start to Finish

This chapter traces an adverse event (AE) through its course in a company from start to finish. The focus of this chapter is on process. Below a typical case handling process is outlined. They vary from company to company, but all such processes must have written procedures for data receipt, case assessment for expedited reporting, data entry, coding and data review by medical professionals (initially often by a nurse or pharmacist), and a final data review by a physician. The processes illustrated here are not necessarily better than other processes used in the industry. Nor is there a mandated process from the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), Medicines and Healthcare Products Regulatory Agency (MHRA), or any other health authority. Rather, whichever process is implemented, it should ensure a smooth workflow and full compliance with all laws, regulations, and directives.

The mission of the AE processing unit is to ensure that all complaint cases (defined as AEs, product quality problems, tampering, packaging problems, counterfeits, etc.) are processed in a timely and accurate manner such that all cases are of high quality and sent to the appropriate departments within the company, to other companies, and to health authorities on time. The goals are to ensure prompt handling and submission of expedited reports, periodic premarketing (e.g., annual safety reports) and postmarketing (e.g., Periodic Safety Update Reports, or PSURs) reports and any other obligatory reports. Because late reports to health agencies and business partners are usually easily and immediately noted, this statistic tends to be the one that drug safety groups, management, and health authorities look at to “grade” companies. The goal is 100% compliance all the time, but reality tends to suggest that, in an imperfect world, 100% is not always attained. However, nobody will officially write or say this or give an acceptable error rate. More importantly, cases that are late should not be late by very long or for the same reason twice. A root cause analysis to find errors, failures to follow the standard operating procedures, and so on should be performed and corrective actions put in place.

Many companies put maximal effort into keeping the expedited report score around 100%, often at the expense of case quality or delays in the processing of nonexpedited cases—even though no one ever admits to decreases in quality. Companies often build up backlogs of unprocessed or partially processed cases when resources are insufficient to be fully compliant with both expedited and nonexpedited cases. Sooner or later, this situation produces a disastrous result unless corrective actions are applied and processes are put in place that are workable and actually followed. Everything has to be done correctly.

There are many ways to handle cases. In some companies, there is ownership by an individual drug safety specialist (e.g., a nurse or pharmacist), who is responsible for the completion of the case from start to finish, making sure that any other personnel involved in the case (e.g., medical reviewers) handle the case and return it to the specialist who “owns” it. Other companies have less individual ownership of a case and instead move a case from task to task in the workflow, with a separate “pool” of workers responsible for a particular step, such as one group that just performs data entry, another that just does coding, and another that just writes narratives.

Serious adverse events (SAEs) and non-SAEs may arrive in a company from multiple sources (feeder groups). Standard operating procedures must be in place to ensure that these AEs arrive in a timely manner (usually 1–2 days) in the drug safety department if they first arrive elsewhere in the company or at a partner company.

Spontaneous SAEs and nonserious cases arrive by telephone (the most common route of arrival in many companies); websites; electronically; e-mail; snail mail; fax; reports to sales representatives; reports to other company employees, agents, or contractors; the legal department; health authorities (e.g., FDA, MHRA, Health Canada); other companies who receive AEs on their own drugs in which one of their drugs is involved; and other miscellaneous sources such as newspaper, social media, or TV stories. They are received primarily from consumers, healthcare professionals, and lawyers. It should be kept in mind that such AEs may arrive at any location in the company such as the manufacturing facilities (especially if the product package says something to the effect of, “Manufactured by XXX Pharma in YYY City, Ohio,” or if an address or phone number is on the package or patient information), subsidiaries and affiliates, contractors, outsourcers, and business partners with whom safety exchange agreements are in place.

Safety department call centers are usually staffed to receive phone calls from a particular region. Usually, they cover a whole country but not more than one country, because labeling, indications, precautions, and warnings may differ from country to country and the appropriate information must be given to residents of the appropriate country. There may also be language issues. For example, any phone center covering Canada must be able to respond in English or French. In the United States, though not required by law, many phone centers have Spanish-speaking personnel available in addition to English speakers. Phone centers may be available Monday through Friday during business hours or sometimes 24 hours a day, 7 days a week. Multiple time zones must also be taken into account for geographically large countries (e.g. Canada, United States). Call centers may be kept in-house or outsourced to companies that specialize in handling medical phone calls. These call centers may be within the country or far away (e.g., India, Philippines, and other English-speaking countries are now handling calls from the United States and Canada in many cases). Interestingly, some call centers covering English language callers are now being placed in non-native English speaking countries.

Call centers should be set up to receive calls from consumers, patients, physicians, and other healthcare providers. They usually cover questions about the products; requests for reimbursement; and reporting of AEs, product quality defects, and problems and emergencies regarding the drug, including tampering, counterfeiting, and overdoses. For clinical trial (nonmarketed) products, the call center may need to have an emergency code break to handle an acute AE. The call center must be set up to ensure that all AEs and quality complaints are captured and sent to the appropriate departments for handling (e.g., the AEs to drug safety and the quality complaints to manufacturing). In addition, any questions or requests for reimbursement must be handled rapidly and correctly. Callers who are complaining or agitated must also be handled carefully and diplomatically. Thus, a clear protocol must be set up to ensure that customers are served quickly and well, that their requests are met, and that all AEs and complaints are captured. The call should be picked up on the first or second ring, the caller should not be kept on hold for any significant length of time, and the caller should not have to give his or her name, address, and product issue more than once. The caller should not be bounced to multiple departments. Professional call centers are able to track very precise metrics measuring all of these factors.

All this requires a well-thought-out system to handle all issues (especially when a caller has multiple issues: “I took your pill, which was supposed to be red but was blue; it smelled bad; I developed a headache; I want my money back; and I have a question.”). The decision about when to have medically trained personnel take the call must be clarified: should all calls come directly to a nurse or pharmacist or should there be some level of nonmedical screening before sending the call to the healthcare professional? If nonmedical professionals are used, an algorithm or script is often used to ensure that no incorrect information is given to the caller. In addition, the priorities must be considered: should the AE and quality complaint be handled first (most drug safety people would say yes to this but marketers might not)? Because there are multiple company stakeholders involved (drug safety, information technology, product quality, marketing, reimbursement, medical information, etc.), the development of the call center is complex and expensive.

Other sources of AEs (and follow-up) include the following:

• Clinical studies: Clinical study events may come in from the company’s clinical research and clinical pharmacology departments as well as any other group that might (often unbeknown to the drug safety department) run studies. Such groups might be in marketing, subsidiaries, affiliates, market research, pharmacoepidemiology, pharmacoeconomics, or other companies that are studying the drug with your company or are studying the drug without your company’s consent and knowledge. AEs may also arrive from contract research organizations. Often, much to the chagrin of the safety group, the first awareness that a study is being run in some far-off outpost of the company is the arrival of an SAE. In the most egregious of such cases, an event may arrive for a drug that the safety department does not even know to be owned, studied, or sold by the company. It might, for example, be studied (or marketed) only in one subsidiary, affiliate, or partner far away.
  
• Legal: Lawsuits are sometimes the unfortunate first notification to a company that there is an SAE. These cases usually come in through the legal department, which should be sensitized to the fact that they must not only defend a lawsuit but also report the AEs to the drug safety department. These AEs are usually on marketed products but may sometimes involve clinical trial patients. Rarely, a company may be notified of an issue by the arrival of a subpoena to provide evidence in a lawsuit to which the company is not a party, such as a malpractice case in which there is also a drug issue. Normally, the receipt of AEs via lawsuits is limited, but in certain circumstances, such cases may be voluminous, especially in class action lawsuits in the United States.
  
• Health agencies: Many health authorities send to or allow companies (and sometimes the public) access to specific AE cases. The FDA has a program (MedWatch to Manufacturer) in which it sends copies of spontaneously received MedWatch reports of SAEs on newly approved products (new molecular entities or “important new biologics”) to the manufacturer of the product. The drug must be a new chemical entity. This program lasts 3 to 4 years and is done at the request of the manufacturer (see Web Resource 41-1). These reports do not have to be resubmitted to the FDA by the company unless additional information is obtained but may have to be submitted to health authorities outside the United States if the drug is marketed elsewhere. Health Canada allows everyone to search their database, and the MHRA publishes “Drug Analysis Prints” with SAEs by drug (see Chapters 8 and 24). In addition, various agencies, including the MHRA and AFSSAPS, have mechanisms whereby the Marketing Authorization holder (MAH) may obtain certain SAEs on their own products.
  
• Literature reports: U.S. and European Union regulations require that companies periodically (weekly, per Volume 9A) search the medical literature for SAEs. Such publications are usually on marketed products but may occasionally include SAEs from clinical trials of new uses for old drugs unknown to the company. Once a drug is on the market, anyone may do a clinical trial using the drug (following, of course, regulations, consent, ethics committee approval) without telling the company. Reports in the literature may be of SAEs or nonserious AEs, though the former predominate. In oncology, cooperative groups may use marketed drugs in clinical trials for new indications or at different doses or schedules from the approved labeling.
  
• Stimulated reports: Many companies have patient support programs in which company or outside service companies’ representatives (e.g., nurses, physicians) contact patients to encourage them to continue to take their medications and give support in regard to dosing, AEs, and so forth. During the course of discussions, AE reports may be obtained. If the company is involved in these support programs (internally or outsourced), a mechanism must be created to ensure that all AEs reach the company in a timely manner and are handled appropriately. Other programs such as speaker programs, named-patient programs, and compassionate use may also stimulate reports.
  
• Other sources of AEs include poison control centers and company and external internet sites (blogs, social media, etc.). In general, the company is not required to troll the internet looking for such AEs, though it must track and capture AEs from its own websites. If a drug is reported to another company either by mistake or expressly (e.g., a marketing competitor, another company doing a trial with your drug or in which your drug is a suspect medication in an ICSR), SAE reports may arrive unannounced from other companies on your drug. These cases may be problematic as they may arrive as completed, anonymized MedWatch forms from the other company. Because of the anonymization, follow-up will be impossible.

Electronic receipt of ICSRs by E2B (or customized) formats is common and the company should have systems in place allowing receipt (and transmission) of such cases. Note that follow-up information may arrive by a different means from the original report (e.g., an initial phone report may be followed by a written e-mail/PDF or snail mail communication).

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