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Organization of a Typical Drug Safety Department

This description covers a “standard” safety department found in a large or midsized (multinational) pharmaceutical company. Some functions and divisions do not exist in smaller companies or in companies that do not have international or research functions. Some functions are combined with others. Some functions may work with other divisions in the corporation in addition to the safety department.

Generally, companies have a physician who is designated “chief safety officer,” “chief medical officer,” or “qualified person for pharmacovigilance (QP or QPPV)” who is (usually) a senior-level physician (e.g., executive or senior vice president) and is responsible for the final decision on medical issues for the corporation. This job includes decisions on product withdrawals, stopping clinical trials, amending protocols, changing product labeling, and so forth, for safety reasons. This person is either in the senior management of the company or in regulatory affairs or clinical research. In some companies, the QP is different from the senior medical officer and is sometimes not a physician.

There is also a functional head of drug safety, who ensures that the department runs in a timely, orderly, and professional manner. In smaller companies, the chief safety officer and the functional head may be the same person. That person is usually a healthcare professional. In larger companies, they tend to be separated, especially if the company has several major safety units around the world.

This is a critical role for companies with marketing authorizations in the European Union and is discussed in detail in Chapter 23.

The triage unit is responsible for receiving and reviewing, often at a single central point, all incoming adverse events (AEs), plus, in many cases, product complaints, requests for information from consumers and healthcare professionals, requests for reimbursement, and other medical information functions. Each incoming contact is routed to the appropriate department for handling. Decisions have to be made if a single incoming contact has several components: “I took your pill, which was red instead of its normal blue color; I had chest pain after I took it—is that normal? And I want my money back.” This is a product quality complaint, an AE, a question, and a request for reimbursement. In general, the priority should go to the AE and quality issue. Routes of entry of AEs are changing. Formerly, phone calls and letters were predominant. Now, phone calls, e-mail, websites, social media, and other electronic avenues bring in many postmarketing AEs. “Snail mail,” case reports of clinical trial AEs, reports from the Food and Drug Administration (FDA) and other health authorities, medical literature screening, lawsuits, and other assorted sources also supply AEs. Some drugs have more AEs reported by healthcare practitioners and others by consumers and patients. Triage must be rapid and in real time because expedited (7- and 15-day) reports need to be acted on immediately. Serious AE cases should generally be reviewed more quickly than nonserious cases.

The triage is usually made up of both professional and clerical personnel whose job is to do the first-level screening of all incoming contacts. Telephone calls are usually screened initially by call centers with or without medically trained personnel (pharmacists, nurses) as the initial responders. E-mail, website information, and other electronically arriving AEs may first be seen by clerical or IT staff but must be routed rapidly to medical professionals to perform the medical triage. Mail with possible AE information must be handled rapidly by personnel in the mailroom.

In multinational companies, there is usually a triage group locally to handle phone calls and written communications arriving in the local language. U.S. phone centers often are able to handle calls in English and Spanish and sometimes other languages. In Canada, English and French are required. Many companies are now moving call centers “offshore,” especially to India, the Philippines, and other English-speaking countries, as well as to Latin America for Spanish-language calls. Cost savings can be substantial, though time zone and cultural differences may also be significant. Obviously, these centers must function at the same level and under the same regulatory requirements as if they were in the United States. The FDA will hold them to U.S. standards if they receive calls from American patients and physicians. Similarly, other health agencies will require domestic standards to be applied to external centers as well.

A medical professional should rapidly review the cases for seriousness, expectedness (labeledness), and causality (for clinical trial cases). Priority then goes to AEs that are 7- and 15-day expedited reports. The personnel must have all the needed tools (computer access and training, latest labeling and investigator brochures, etc.).

After triage, cases must be medically evaluated (if not already done) and entered into the safety database. Cases that come in electronically, such as from clinical trial electronic data capture programs or postmarketing cases from online data entry forms, partner databases, and so forth, usually do not need to be reentered unless the sending database and the receiving safety database cannot “talk” to each other. Rather, these cases may sit in an electronic “holding area” and must be screened by the triage or medical personnel for minimum criteria, correct drug identification, duplicates, and so forth, before being uploaded into the safety database. Uploading is normally instantaneous when done electronically and has implications for the “clock start date.” Some companies may allow direct upload into their safety database from trusted, validated, and virus-free sources, such as partner companies or CROs.

Paper cases (including faxed, PDF, or other “paper cases” that arrive electronically but not in files that are directly uploadable) must be manually entered into the database. Cases that are identified at triage to be expedited reports are usually prioritized for immediate data entry. Cases that are not expedited reports are put into a queue for handling and data entry. Serious cases that are to be manually entered are usually “databased” within 7-15 days and nonserious cases within 30 days. Companies’ procedures vary widely.

The initially received information is entered into the drug safety database after screening for the four minimum criteria, the correct drug, and duplicates is done. Data entry is usually performed by clerical personnel who have been trained on how to enter cases into the company’s safety database and sometimes after training in medical terminology. Some companies do manual data entry at a single site or at multiple sites (e.g., one on each continent). Most data, though not all, are entered in English. Source documents may also be entered (either summarized or scanned in or both), catalogued, and stored in the database. Some data may need to be anonymized or redacted to remove personal information. See Chapter 28 on data privacy.

This unit is made up of health professionals, usually nurses and pharmacists, but occasionally also podiatrists, dentists, and other healthcare professionals. This group does the initial evaluation for expedited cases (as noted above, usually before data entry) and then reviews and/or prepares the case medical information. In particular, this involves the creation of the “narrative” (which is a stand-alone text summary of the case that appears in the electronic case [E2B] or on the MedWatch and CIOMS I forms), and the verification of drug names, dosages, past medical history, and so on. The case-processing group also prepares medical queries (with the assistance of the physicians) to be sent to the reporter or investigator to obtain further information if the initial data are incomplete, including the final outcome for ongoing cases.

This group is usually composed of physicians with expertise in drug safety and case review. They generally review the assessment, the AE coding, and the medical content of the narrative to ensure that the medical story is cogent and that it is a true reflection of the source data supplied. These physicians may also handle other work, including the preparation and review of signals, aggregate reports, and ad hoc queries.

This group ensures that the appropriate cases are sent to the appropriate recipients. Expedited reports either go directly to the health agencies (usually by electronic E2B transmission or paper) or to the regulatory department for transmission to the health authorities. Cases may also be sent within the company to other interested parties (e.g., clinical research, legal) and to associated business partners who market or study the drug. This function may be assumed by a unit that handles all “traffic” matters, including triage, routing, and transmission. If the transmission is via E2B there may not be a separate transmission unit, though someone must still track what goes where.

Usually, this unit is not a part of drug safety but is a separate division, at least in larger companies. In some companies, expedited cases are reviewed by the regulatory group before transmission to the health authority as a final quality check. Many companies prefer to have all communications to and from the health authorities handled by the regulatory division rather than by drug safety and other groups to ensure tight tracking of all governmental contacts.

This unit is never a part of drug safety. The legal unit interacts with drug safety in three primary areas. First, in some companies, the legal department reviews all cases that are sent to health agencies to ensure that “troublesome” statements will not be included that may produce difficulties for the company. (This is controversial, as it may mean that the company cannot make a causality assessment on cases, as that might mean admitting the drug and the company are “guilty” of causing that ADR.) The second area involves litigation or potential litigation based on AEs. In these cases, the drug safety and legal areas work tightly together in defending the litigation and in obtaining any follow-up from the suing party. Such follow-up is often done via the attorneys rather than directly from drug safety. The legal unit may also be a source of AEs that arise in lawsuits against the company that first arrive in the legal department. The third area is in negotiating agreements with external parties for in- or out-licensing, outsourcing, comarketing, and so forth. The two groups work together to ensure that all safety obligations to all health authorities and other companies are met.

Although this function may be called many things, as noted in the heading, its primary job is to look for new signals. This unit is made up of physicians and other healthcare workers. Their main function is to review the safety data (AEs, medical errors, and product quality complaints) collected by the company and to evaluate whether new signals are popping up or old ones are resolving or worsening. They may use tools available commercially or developed in-house for data mining (see Chapters 8 and 19). When an issue is found, they begin an initial safety investigation that includes a review of the published literature, the company’s clinical research database (if different from the safety database), external databases, medical literature (which must be searched weekly under European Union Volume 9A requirements), toxicology, pharmacology, and any other relevant information, to prepare a summary report for presentation to the decision-makers (e.g., the senior corporate safety committee) for resolution.

They may handle other functions, including review of individual cases, preparation of Investigational New Drug Application (IND) annual report, New Drug Application (NDA) periodic reports, annual safety reports, Development Safety Update Reports (DSURs), Periodic Safety Update Reports (PSURs), integrated safety summaries, responses to queries from health authorities, pharmacoepidemiology studies and analyses, advertising review for medical content, review of communications to the public (“Dear Doctor” or “Dear Healthcare Professional” letters), review of labeling and Package Inserts, medical testimony in litigation, and consultation on drug withdrawals. Some of these functions may be split into separate groups, such as a PSUR preparation group, a pharmacoepidemiology group, and so forth, particularly in large companies.

This group may also handle the preparation of risk management documents such as REMS or RMPs (see Chapter 30).

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