Systems validation: application to statistical programs

BACKGROUND: In 2003, the United States Food and Drug Administration (FDA) released a guidance document on the scope of "Part 11" enforcement. In this guidance document, the FDA indicates an expectation of a risk-based approach to determining which systems should undergo validation. Since statistical programs manage and manipulate raw data, their implementation should be critically reviewed to determine whether or not they should undergo validation. However, the concepts of validation are not often discussed in biostatistics curriculum. DISCUSSION: This paper summarizes a "Plan, Do, Say" approach to validation that can be incorporated into statistical training so that biostatisticians can understand and implement validation principles in their research. SUMMARY: Validation is a process that requires dedicated attention. The process of validation can be easily understood in the context of the scientific method

Regulating Innovative Medicine: Fitting Square Pegs in Round Holes

Increasingly, innovative medical products are creating a quandary for the Food and Drug Administration ( FDA ) because they often transcend the FDA\u27s traditional categorical approach to regulating medical products. In a recent attempt to simplify this process, the FDA has proposed a new rule for regulating combination products. This iBrief discusses the FDA\u27s current approach and analyzes the possible affects of the proposed regulation. Because of the many shortcomings of both systems, this iBrief concludes that the FDA should instead stop assigning center jurisdiction based on a product\u27s primary mode of action, and give the Office of Combination Products internal agency jurisdiction over combination products. This alternative approach would increase consistency and efficiency while maintaining the FDA\u27s high standards for medical product safety and efficacy

Food and Drug Administration Regulation of Food Safety

Food-borne illness remains a major public health challenge in the United States, causing an estimated 48 million illness episodes and 3000 deaths annually. The FDA Food Safety Modernization Act (FSMA), enacted in 2011, gives the Food and Drug Administration (FDA) new tools to regulate food safety. The act emphasizes prevention, enhanced recall authority, and oversight of imported food. The FSMA brings the FDA’s food safety regulation in line with core tenets of public health by focusing on preventing outbreaks, rather than reacting to them, and differentiating between foods and food producers based on the degree of risk they pose. The FSMA also recognizes the increasing importance of imported food and enhances the ability of the FDA to safeguard the U.S. food supply from hazards originating abroad. The act achieves its prevention objectives through requiring food production facilities to establish preventive control plans and by increasing inspection frequency—a shortcoming of the FDA in recent years. The act also enhances the FDA’s ability to respond to food safety problems when they occur. Through pilot projects on food tracing systems and an enhanced surveillance system, the FDA will be have better tools to determine the source of outbreaks. Additionally, the act gives the FDA new mandatory recall authority—a badly needed addition to its enforcement capabilities. In an increasingly globalized food environment, the FSMA gives the FDA new authority to regulate imported food. Among other provisions, the act allows FDA to inspect foreign facilities and to partner with foreign food regulatory agencies to help build capacity. Through new tools and increased enforcement, the FSMA holds great promise for public health. The act, however, leaves several regulatory gaps, including keeping the food safety functions of the USDA and FDA separate. Additionally, the potential of the act to improve food safety may be thwarted by inadequate funding in the current budget environment. The act includes numerous programs for building the capacity of domestic and foreign regulators and food producers. Such programs are essential to an improved food safety system, but require adequate funding from Congress to be fully implemented. In addition to national capacity building, FDA and Congress should fully engage partners in government and industry to improve global food safety at the international level

Nudging the FDA

[Excerpt] The FDA’s regulation of drugs is frequently the subject of policy debate, with arguments falling into two camps. On the one hand, a libertarian view of patients and the health care system holds high the value of consumer choice. Patients should get all the information and the drugs they want; the FDA should do what it can to enforce some basic standards but should otherwise get out of the way. On the other hand, a paternalist view values the FDA’s role as an expert agency standing between patients and a set of potentially dangerous drugs and potentially unscrupulous or at least insufficiently careful drug companies. We lay out here some of the ways the FDA regulates drugs, including some normally left out of the debate, and suggest a middle ground between libertarian and paternalistic approaches focused on correcting information asymmetry and aligning incentives.

The FDA “black box” warning on antidepressant suicide risk in young adults: More harm than benefits?

The decision made in the year 2004 by the U.S. Food and Drug Administration (FDA) to require a boxed warning on antidepressants regarding the risk of suicidality in young adults still represents a matter of controversy. The FDA warning was grounded on industry-sponsored trials carried one decade ago or earlier. However, within the past decade, an increasing number of reports have questioned the actual validity of the FDA warning, especially considering a decline in the prescription of the antidepressant drugs associated with an increase in the rate of suicidal events among people with severe depression. The present report provides an overview of the FDA black box warning, also documenting two Major Depressive Disorder patients whose refusal to undergo a pharmacological antidepressant treatment possibly led to an increased risk for suicidal behaviors. The concerns raised by the FDA black box warning need to be considered in real-world clinical practice, stating the associated clinical and public health implications

Opportunities for Improving the Drug Development Process: Results from a Survey of Industry and the FDA

In the United States, the Food and Drug Administration (FDA) agency is responsible for regulating the safety and efficacy of biopharmaceutical drug products. Furthermore, the FDA is tasked with speeding new medical innovations to market. These two missions create an inherent tension within the agency and between the agency and key stakeholders. Oftentimes, communications and interactions between regulated companies and the FDA suffer. The focus of this research is on the interactions between the FDA and the biopharmaceutical companies that perform drug R&D. To assess the current issues and state of communication and interaction between the FDA and industry, we carried out a survey of industry leadership in R&D and regulatory positions as well as senior leadership at the FDA who have responsibility for drug evaluation and oversight. Based on forty-nine industry and eight FDA interviews we conducted, we found that industry seeks additional structured and informal interactions with the FDA, especially during Phase II of development. Overall, industry placed greater value on additional communication than did the FDA. Furthermore, industry interviewees indicated that they were willing to pay PDUFA-like fees during clinical development to ensure that the FDA could hire additional, well-qualified staff to assist with protocol reviews and decision-making. Based on our survey and discussions, we uncovered several thematic opportunities to improve interactions between the FDA and industry and to reduce clinical development times: 1) develop metrics and goals at the FDA for clinical development times in exchange for PDUFA like fees; 2) establish an oversight board consisting of industry, agency officials, and premier external scientists (possibly at NIH or CDC) to evaluate and audit retrospectively completed and terminated drug projects; and 3) construct a knowledge database that can simultaneously protect proprietary data while allowing sponsor companies to understand safety issues and problems of previously developed/failed drug programs. While profound scientific and medical challenges face the FDA and industry, the first step to reducing development times and associated costs and facilitating innovation is to provide an efficient regulatory process that reduces unnecessary uncertainty and delays due to lack of communication and interaction.

\u3ci\u3eUnited States v. Caronia\u3c/i\u3e: Off-Label Drug Promotion and First Amendment Balancing

Off-label drug promotion is commonplace in the United States, but it is not without its dangers. While the Food, Drug, and Cosmetic Act does not explicitly ban off-label promotion, the Food & Drug Administration (FDA)— in order to protect consumers from unsafe and ineffective drugs—has taken steps to regulate it. The FDA does so through its intended-use regulation, which lists the types of evidence the FDA can consider in determining whether a drug is misbranded. It is a crime to sell a misbranded drug into interstate commerce or to conspire to do so. On September 25, 2015, the FDA proposed an amendment to the regulation, which has drawn opposition from various industry groups due to its potential to restrict the type of speech that is often used in off-label promotion. The First Amendment challenge to the proposed amendment rests on United States v. Caronia, in which the FDA was prevented from using truthful, nonmisleading speech to convict a pharmaceutical representative of a conspiracy to sell a misbranded drug. This Note examines whether the amendment to the regulation is permissible under Caronia. It first contends that the regulation does not facially violate the First Amendment. It further argues that the rule is constitutional and does not pose the same First Amendment issue as was seen in Caronia as long as the FDA implements it with care. This Note concludes by exploring various ways that the FDA can constitutionally regulate off-label drug promotion under the proposed rule

Taking Biologics for Granted? Takings, Trade Secrets, and Off-Patent Biological Products

Biologics are complex medicines which are often genetically engineered, and which are sure to play an important role in curing some of humankind\u27s worst diseases. Not surprisingly, generic companies want a part of the biologic market. The FDA believes that it has the authority to approve off-patent versions of biologics that were originally regulated under the Food, Drug & Cosmetic Act, but in order to effectively do so the FDA would have to rely on findings based on data produced by the brand name companies. This iBrief examines whether the FDA\u27s reliance on previous findings would give rise to a valid claim under the Takings Clause of the U.S. Constitution. In the end, it concludes that the FDA\u27s proposed action likely would not constitute a taking

Decision Analysis and FDA Drug Review: A Proposal for Shadow Advisory Committees

The FDA seems to acknowledge that sometimes different standards of proof for assessing drug efficacy should be used. Dr. Mendeloff thus proposes a methodology that might illuminate the FDA\u27s decision-making and help better to assess its decisions

Frequency and Severity of Neutropenia Associated with Food and Drug Administration Approved and Compounded Formulations of Lomustine in Dogs with Cancer.

BackgroundCompounded lomustine is used commonly in veterinary patients. However, the potential variability in these formulations is unknown and concern exists that compounded formulations of drugs may differ in potency from Food and Drug Administration (FDA)-approved products.Hypothesis/objectivesThe initial objective of this study was to evaluate the frequency and severity of neutropenia in dogs treated with compounded or FDA-approved formulations of lomustine. Subsequent analyses aimed to determine the potency of lomustine obtained from several compounding pharmacies.AnimalsThirty-seven dogs treated with FDA-approved or compounded lomustine.MethodsDogs that received compounded or FDA-approved lomustine and had pretreatment and nadir CBCs performed were eligible for inclusion. Variables assessed included lomustine dose, neutrophil counts, and severity of neutropenia. Lomustine 5 mg capsules from 5 compounding sources were tested for potency using high-pressure liquid chromatography (HPLC) with ultraviolet (UV) detection.ResultsTwenty-one dogs received FDA-approved lomustine and 16 dogs were treated with lomustine prescribed from a single compounding pharmacy. All dogs treated with FDA-approved lomustine were neutropenic after treatment; 15 dogs (71%) developed grade 3 or higher neutropenia. Four dogs (25%) given compounded lomustine became neutropenic, with 2 dogs (12.5%) developing grade 3 neutropenia. The potency of lomustine from 5 compounding pharmacies ranged from 50 to 115% of the labeled concentration, with 1 sample within ±10% of the labeled concentration.Conclusions and clinical importanceThese data support broader investigation into the potency and consistency of compounded chemotherapy drugs and highlight the potential need for greater oversight of these products