Читать книгу Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition) - William Gregory - Страница 95

Launched by FDA in 2008 as a result of 2007 legislation, the Sentinel System is a US National medical product safety monitoring system that taps into electronic medical records across the country. It is an active electronic safety surveillance system that strengthens FDA’s ability to monitor the safety of marketed medical products. The program began as a pilot, which reached a milestone of 100 million covered lives by 2011. As of June 2018, the Agency had 17 distributed data partners with 178 million covered members, each of whom had pharmacy and medical coverage. It is a large system with longitudinal medical records and an analytic center in Boston which handles coordination among the data partners. Data partners retain control of the medical records to protect privacy and maintain security; FDA prepares analytic queries to explore questions, but they do not have a centralized data repository for this system. Queries can be developed by FDA and anonymized results from more than 178 million covered lives can be obtained from these distributed datasets in a matter of days.

All of FDA’s centers have access to the Sentinel System through OSE.

To strengthen FDA’s ability to better utilize the Sentinel System, the 2007 legislation required FDA to establish an analysis tool, ARIA (Active Risk Identification and Analysis). ARIA contains validated modular programs that have re-usable analytical tools for rapid safety analyses of healthcare data. There are three levels of output: (a) Simple counts; (b) Complex descriptive analyses; and (c) Inferential analyses. ARIA was launched at the beginning of 2016 and several hundred analyses were run in the first 2 years.

The 2007 legislation also gave FDA the authority to issue Post-marketing Requirements (PMRs). However, FDA is required to consider the sufficiency of ARIA to address the question before requiring an applicant to conduct a PMR: “The Secretary may not require the responsible person to conduct a study under this paragraph, unless the Secretary makes a determination that the reports under subsection (k)(1) and the active post-market risk identification and analysis system as available under subsection (k)(3) will not be sufficient to meet the purposes set forth in subparagraph (B).” So, for concerns that might result in a post-marketing obligation for an applicant, FDA must use available tools before imposing a requirement.

The Sentinel System is made available to others through a public-private partnership. From an organizational perspective, the Reagan–Udall Foundation offers access for FDA through the Innovation in Medical Evidence Development and Surveillance (IMEDS) program. The goal is to make the system a broader resource for public health and medical evidence generation. IMEDS and Sentinel share the same analytic coordinating center in Boston. Private users of IMEDS have access to the same data as FDA and also the same analytic tools. This approach also provides funding for sustainability of the Sentinel System.

FDA continues to expand Sentinel and integrate capabilities into the post-market safety monitoring system.

In addition, there are other related projects, such as the following:

European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCePP), a network consisting of research and medical care centers, healthcare databases, electronic registries, and existing networks to strengthen post-marketing monitoring and to facilitate the conduct of safety-related post-authorization studies (particularly observational studies);

Innovative Medicines Initiative (IMI), a public–private partnership, has multiple projects that focus on improving drug safety and other aspects of drug development, for example, one project focused on developing validated tools and methods that will enhance adverse event data collection, active signal detection, standards for pharmacoepidemiology studies, and integration of data for evaluation of benefit-risk;

EU-ADR, a project to design, develop, and validate a computerized system that exploits data from electronic healthcare records and biomedical databases for the early detection of ADRs, which will be complementary to existing systems with early detection of safety signals; and

Drug Safety and Effectiveness Network (DSEN), a virtual network to assess the risks and benefits of marketed drug products.

Thus, the FDA will be able to initiate queries of multiple databases to obtain safety information and to do active and proactive surveillance using current and emerging methods.

In March 2003, the FDA published proposed new and comprehensive safety rules, sometimes referred to as “The Tome” because of their breadth and length. See “Safety Reporting Requirements for Human Drug and Biological Products”, 68FR12405–12497, March 14, 2003. The proposal is now mostly of historical interest. However, it did outline FDA’s thinking in that timeframe and consisted of extensive and complex changes to the current IND and NDA safety regulations. Major new obligations on the part of the pharmaceutical industry were proposed.

The FDA invited comments and received many thousands. Many parts of the proposal are now clearly out of date, especially with regard to electronic transmission, risk management, and FDAAA requirements. However, some changes and new requirements have been put in place via separate Federal Register Notices.

In late 2010, the FDA issued a new final rule that covers clinical trial safety reporting (21CFR312) and this rule went into effect in early 2011. Subsequent guidance was issued to clarify requirements of the rule. The rule is not fully consistent with ICH E2A and requirements of other key regulators. This presents special challenges for sponsors who entertain possibilities for global development programs.

FDA has indicated that it will periodically issue updated post-marketing regulations, as appropriate.

One concept in particular from the Tome is worth noting and may eventually be enacted: the “Always Expedited Report”. This new category requires submission of an ICSR within 15 calendar days of first awareness, whether expected (labeled) or not, for these events:

Congenital anomalies;

Acute respiratory failure;

Ventricular fibrillation;

Torsades de pointe

Malignant hypertension;

Seizures;

Agranulocytosis;

Aplastic anemia;

Toxic epidermal necrolysis;

Liver necrosis;

Acute liver failure;

Anaphylaxis

Acute renal failure;

Sclerosing syndromes;

Pulmonary hypertension;

Pulmonary fibrosis;

Transmission of an infectious agent by a marketed drug/biologic;

Endotoxin shock; and

Any other medically significant “serious” adverse events requested by FDA for specific investigational products or protocols.