Читать книгу Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition) - William Gregory - Страница 47

A summary of safety documents for the EU can be found at the EudraVigilance website (www.eudravigilance.eu), the European Commission website (www.ec.europa.eu), and the EMA website (www.ema.europa.eu).

There are several major documents covering drug safety: EudraLex Volume 10 is for clinical trials (amended in 2019 with the implementation of Regulation (EU) No 536/2014). For post-marketing, the regulations have been completely reviewed in 2010–2012; the main documents are as follows:

Regulations (EU) Nos. 1235/2010 and 1027/2012.

Directives 2010/84/EU and 2012/26/EU.

Good Vigilance Practices (GVP); there is a series of 12 Good Pharmacovigilance Practice (GVP) modules, numbered I to XVI (planned Modules XI, XII, XIII, and XIV are void, as the content has been integrated into other modules). The GVP modules provide guidance to marketing authorization holders (MAHs), the EMA, and national competent authorities in EU member states. They cover medicines authorized in the EEA, regardless of the route of authorization.

There are several subsections devoted to drug safety also available at this website. “Volume 10 — Clinical Trials Guidelines” includes the following:

Detailed guidance on the collection, verification, and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use;

Detailed guidance on the European database of suspected unexpected serious adverse reactions (EudraVigilance — Clinical Trial Module);

Questions and answers specific to adverse reaction reporting in clinical trials.

Pharmaceutical companies are obliged to capture AEs, analyze them, and report them to their health agency locally and to other health authorities, or to companies abroad for submission to their HAs if there are formal corporate arrangements for sales and trials outside the home country. Thus, a company needs to create or have full-time (24/7) access to a safety team or department equipped to handle spontaneous and clinical trial AEs (as required) or to outsource this function. If the company is based solely in one country, the department may be relatively small and uncomplicated. In the simple setting, AEs are reported only to the HA in that country. If, however, AEs can come from (or need to go to) subsidiaries or affiliates in other countries or from business partners with which the company has contractual relationships, the complexity of the needs and requirements grows enormously. If a single-country company is doing clinical trials outside its borders, it must be able to report AEs and handle all other safety and regulatory matters with other countries’ health agencies.

Different languages, time zones, ever-changing government requirements, reporting due dates, documents and formats, electronic transmission, and so forth must be taken into account. Standard operating procedures, Medical Dictionary for Regulatory Activities (Med-DRA®), and training systems must be in place. An electronic safety database must be built (an enormous task) or purchased or leased (still a complex and costly endeavor). Risk evaluation and management/mitigation systems must be in place.

Healthcare personnel, including physicians, nurses, pharmacists, and support staff, must be hired. The business relationships with other concerned departments within the company, such as regulatory affairs, sales and marketing, legal, clinical research, and others, must be established. In other words, creating a safety department is a complex and expensive endeavor that must be done absolutely correctly.

After an AE report is received by the safety department, it must be entered or uploaded into the safety database, which is used for storage, retrieval, analysis, and reporting data. Although such transactional databases may start out in small companies as spreadsheets with the data typed onto paper forms, most companies respond to this need by purchasing an expensive (up to hundreds of thousands or millions of dollars, depending on the number and location of users and information technology, IT, maintenance staff) dedicated safety database. In addition to a transactional database, some large organizations have developed data warehouses to organize and store large amounts of safety data. Much of this is now out-sourced and stored in the cloud. They create complex departments with tight standard operating procedures to ensure that the company remains in full compliance with all laws, regulations, and guidelines and will withstand inspections and audits from the FDA, EMA, and other HAs, business partners, outside auditing companies and others.

There is usually a senior executive (typically a vice president for drug safety), who is also an experienced physician, to oversee the entire group. Within the drug safety group, there are multiple functions to handle. Depending on the size of the company, separate people or groups may handle each of the categories below. In small companies, all functions may fall on one or two people or are outsourced.

Case receipt, triage, and processing by data entry personnel;

Case evaluation by medical professionals;

Coding of AEs in MedDRA (sometimes this group is separate from drug safety);

Coding of drugs in WHO-Drug or another drug dictionary;

Quality review;

Medical review by physicians;

Submission to HAs, subsidiaries, business partners, and so on.

To support the drug safety group, there is often a dedicated informatics (IT/computer) group, a signaling/pharmacovigilance group, a training group, a standard operating procedure (quality) group, an epidemiology group, a risk management group, and more. These groups may be within or separate from the drug safety department. Sometimes a medical report writing group also falls under drug safety to prepare aggregate reports, such as Periodic Safety Update Reports (PSURs, PBRERs), annual reports, NDA periodic reports, IND annual reports, and so on.

Similar groups often exist within HAs. Some authorities (FDA, MHRA, Health Canada, ANSM, TGA, EMA, and others) receive reports directly from healthcare professionals and consumers. The agencies may form departments similar to those in companies to receive, enter, and evaluate data and make medical judgments on the cases. The volumes in companies may run to tens or even hundreds of thousands of cases per year. The FDA received 1,779,428 post-marketing ICSRs in 2017, of which 926,304 (52%) were expedited. There were 59,044 (3%) received directly from the healthcare community or consumers (refer to the FDA website, www.fda.gov). These reports (redacted) are available over the Internet using a public dashboard.

This is a large task and is performed by most health agencies throughout the world. Because serious cases tend to be reported to all health agencies, there is enormous duplication of effort in creating databases in each agency and company. In practice, only HAs in large countries with advanced pharmacovigilance practices are able to maintain relatively complete databases and conduct meaningful signal analyses.

There are four major databases with large but not total overlap for post-marketing AEs: the FDA in the United States, the EudraVigilance database in the EMA (London/Amsterdam), the MHRA database (UK), and the Vigibase at the Uppsala Monitoring Centre in Sweden. There are others as well.

Clinical trial AEs tend to be more scattered and far less transparent than AEs for marketed products because most of the information on drugs not yet on the market is proprietary and guarded as secret information by both companies and HAs. In many countries, clinical trials by pharmaceutical companies, universities, consortia, health agencies, and others must be entered into web-based registries. The largest is the clinical trial website maintained by the US National Library of Medicine at the National Institutes of Health (www.clinicaltrials.gov), with more than 276,000 trials from more than 204 countries registered as of the middle of 2018. The data, however, are variable, and often there is little or no safety data and the data are not up to date. Various countries, including the US, have mandated regular posting and updating of “Basic Results” for safety (and efficacy) data. When the database first went into production in 2000, trial listings and data were incomplete, but this has gradually improved over the ensuing years.

The mission of the drug safety group must be clearly defined and made known to all employees of the company, in particular to senior management, marketing and sales. It is also good policy to let the general public know of the company’s or health agency’s commitment to patient safety. For example, see FDA’s Sentinel Initiative Mission Statement. Companies also explain their safety functions to the public, see for example, Pfizer (www.pfizer.com), Merck (www.merck.com), and Novartis (www.novartis.com).

The mission of the drug safety group, whether in a company or a health agency, is first and foremost to protect the public health by maintaining accurate, up-to-date, and complete safety information. Medical analyses must be done with patient safety in mind, not “product and sales protection”. It is argued that the best product and sales protection comes from ensuring that full, unbiased, scientific, and complete safety information is available to all stakeholders: patients, medical professionals, health agencies, and the company in a form that can be understood by the particular target audience. Secondary goals within a company’s safety department relate to such corporate functions as consultation within the company on safety issues, legal matters including litigation, response to patient and healthcare professional queries, training, and supporting the sales force.

There is often enormous pressure on the safety group to minimize or wait on safety issues until they are proved beyond a shadow of a doubt. The attitude that the “drug is innocent until proven guilty” and those safety warnings should not be issued to the health agency or the public until this point is reached is not at all appropriate in the world of safety. Rather, each safety issue must be evaluated and acted on because of its own merit and criticality in a timely fashion to evaluate and minimize risk. This can become quite challenging because risk must be considered in the context of benefit and alternatives. Some problems must be addressed on Friday at 5 p.m. and over the weekend.

In the corporate world, this attitude runs contrary to the prevailing fiduciary obligation of a corporation (“to increase stockholder value by making more profit”). The personnel in the drug safety department needs a fairly thick skin to work in this non-glorious field, unlike the world of clinical research or sales where there are congratulations (and monetary rewards and bonuses) for completing a study, getting drugs approved, or selling more product. Rather, drug safety personnel need strong backbones to be able to say to management that a product has a safety problem that must be acted on immediately or tracked until more data are in. Sometimes expensive studies are required and the outcome may merely strengthen the evidence of a problem. Good and wise corporate management understands this and welcomes “straight talk” from the safety unit. Bad management buries or delays. This is becoming more dangerous as the penalties (commercial, regulatory, and legal) are becoming more severe and bad behavior goes viral on the internet overnight.

It should be noted that the concept of drug safety is often less well understood and less well developed in small start-up companies with only a small number of employees. Their primary task is to develop one or a few drugs and their goal is to complete trials rapidly and either sell the product to another company for further development (e.g., large phase III trials) or get rapid FDA approval with the goal of getting positive cash flow. These companies usually do not have a safety department and sometimes do not even have anyone specifically handling safety or tracking regulations and new requirements. They usually rely on their partners or CROs. They often do not handle safety well and when safety issues or crises occur they have significant problems often requiring external “emergency” assistance to help resolve the issues.

It is hoped that corporate executives will realize that a safety problem hidden in the short run may, in the long run, appear on the front page of the New York Times, on TV or the Internet, or the six o’clock news. They may need to explain their actions to governmental investigation panels and to the multiple lawsuits — class action, civil, and criminal — that are frequent in the US and, increasingly, now pop up elsewhere in the world on any safety-related issue.

Similarly, the role of drug safety in the health agency is difficult. The primary mission is similar to the corporate safety role: to protect the public health. However, the profit-making motive is not present. Instead, there are always intense budget pressures to save money as well as the need to answer to multiple demanding constituencies: in the US, the FDA answers in one way or another to the Secretary of Health and Human Services, the US Congress, the public, the press, patient advocacy groups, the Internet blogosphere, the health professions, and the companies (and lobbies) the HA regulates. Similar political pressures exist for other agencies around the world.