The Food and Drug Administration (FDA) of the United States requires significant evidence of efficacy from adequate and well-controlled trials, typically using a reliable comparison to an internal concurrent control. However, relying on external controls may be acceptable when using internal controls is not practical or morally appropriate, particularly in populations with rare diseases. We looked at FDA regulatory approval decisions for drug and biologic products between 2000 and 2019 to identify pivotal studies that used external controls, with a focus on specific therapeutic areas, in order to better understand how external controls are used to support product development and approval. When determining benefits and risks for 45 approvals, the FDA accepted external control data. This was done for a variety of reasons, including the disease’s rarity, moral reservations about using a placebo or no-treatment arm, the severity of the condition, and the high unmet medical need. Retrospective natural history data, including retrospective reviews of patient records, was the most common source of external control (44%) Other types of external control were baseline control (33%); published data (11%); and data from a previous clinical study (11%) The variety of strategies used by sponsors and the difficulties in supporting product development and FDA decision-making are highlighted in a thorough evaluation of selected approvals using various forms of external control, with a focus on the importance and use of retrospective natural history in the development of products for rare diseases. While preventing delays in the development of products for rare diseases, education on the use of external controls based on FDA regulatory precedent will enable the continued use and wider application of novel clinical trial design strategies. The review’s findings also emphasize the necessity of updating regulatory guidance to recognize the value of external controls, particularly historical natural history data.
The FDA’s (Food and Drug Administration) drug approval standard in the United States calls for substantial evidence1 of effectiveness from adequate and well-controlled investigations2, including clinical investigations that include, among other things, a valid comparison to a control, to “distinguish the effect of a drug from other influences [1], such as spontaneous change in the course of the disease, placebo effect, or a biased observation” [1]. The FDA, consistent with regulations (21 CFR 314. 126) and ICH E10 guidance, which “the control group and test groups are chosen from the same population and treated concurrently” [1] are generally recognized as internally3 controlled [1] study designs (placebo, active treatment, dose comparison, and no-treatment). However, FDA does acknowledge that reliance on “external controls”4,5 may be acceptable in studies for conditions with high and predictable mortality or progressive morbidity, and in particular for some rare diseases, when it is not practical or would not be considered moral to use an “internal control” [1, 2]. When a trial is externally controlled, the outcomes of the test drug’s administration may be contrasted with knowledge gained from the sufficiently documented natural history of the illness or condition, a registry, written literature, or patient medical records [3, 4]. In addition, patients can act as their own controls [1] (by comparing their condition to that prior to therapy). 6.
This article provides examples of approvals where external controls were found to be sufficient to meet FDA standards for approval, as well as a brief review of guidance documents discussing the use of external controls. We call for a change in guidance to encourage the continued use of external controls, including retrospective natural history, in drug development and approval by highlighting some methodological and statistical considerations.
Why are external controls important?
External controls are crucial because they make sure businesses are held responsible for their actions and adhere to a certain code of conduct. External controls are used in a number of industries to make sure companies give workers a healthy work environment and give customers access to high-quality products. Here are some of the key reasons external controls exist:
What is an external control?
Any outside force that affects how an organization functions is considered an external control. The regulation of a company’s governance policies, such as hiring practices and safety protocols, is the primary focus of external controls. They include both direct regulations, like those set by the government, and indirect pressure, like media scrutiny. An external control can affect a company’s internal policies, motivate it to follow industry standards, or have an impact on how it interacts with its business partners.
Internal vs. external controls
A company’s ability to regulate its business practices is influenced by both internal and external controls. The measures an organization takes to manage its own operations and produce consistent results at work are known as internal controls. These can include the organization’s core values and effective methods for achieving objectives. For instance, a business that prioritizes environmental sustainability uses that quality as an internal control when selecting clients, suppliers, and production techniques.
Some internal controls are based on external controls. For instance, a business might proactively hire an internal auditor to review its financial policies if the government enacts legislation placing restrictions on specific financial transactions.
Who uses external controls?
External controls are used by managers and business leaders to create and revise team policies. External controls are crucial for anyone who works in compliance because compliance specialists must comprehend all pertinent laws and regulations in order to assess whether their team, department, or project complies with all prerequisites. Any industry can benefit from using external controls, but professionals in the following fields should pay particular attention to them:
You might also think about a career in regulatory affairs, where you develop the external controls that affect how businesses function. In order to create industries with high standards for consumers and professionals, it is important for both those who create regulations and those who uphold internal compliance to external controls.
Examples of external controls
Here are several different external control types, along with descriptions of each:
Government regulations
Government laws and regulations that affect how businesses can operate are one of the most direct types of external controls. Additionally, they are very effective because noncompliance has immediate repercussions for businesses. An organization may be subject to a costly fine or other operational penalties when it violates a government regulation for business operations. Government rules apply to all facets of organizational governance, including hiring procedures and product advertising. Some examples of external government controls include:
Industry standards
Standards within an industry are another type of external control. To build respect and reputation in their field, professional organizations can establish their own rules and criteria for how businesses and individuals should conduct themselves. In order to join some professional organizations, members must meet additional criteria, raising the bar for success in that field. Industry associations may also advocate for changes to laws and regulations or exert public pressure on particular businesses to alter their internal governance structures.
Information releases
Information that businesses release, like annual financial reports, can serve as an external control. Even knowing that information will eventually be made public can motivate business leaders to make more ethical, responsible decisions about their operations. This can involve disseminating details within the organization, providing information to shareholders, or making reports available to the general public. For instance, in order to maintain financial accountability, some government regulations mandate that businesses disclose specific financial information to the public.
Changes in leadership
A business’s internal governance structure may become more widely known if it buys another company, merges with another, or simply appoints a new executive. A change in leadership, particularly in large, publicly traded companies, can also draw media and public attention to the company’s business practices. Current company leaders may change the governance structure ahead of a leadership transition to increase compliance or simply organize the company for the new leader.
External audits
Through external audits, external controls can exist between business partners and departments. Before committing to a business relationship, one company may hire an outside auditor to examine the partner’s operations. Retailers and suppliers frequently use this type of external oversight to make sure the businesses they do business with uphold ethical and sustainable governance principles.
Media relations
Internal policies and operational practices of an organization can also be influenced by public perception and media coverage. Investigative journalists may write about a problem within a company and use public pressure to persuade executives to change their practices. Businesses may need to adapt their practices and values in order to appeal to their target audience as a result of social values and shifting opinions.
Locus of Control Definition and Examples of Internal and External
FAQ
What are the difference between internal and external control?
I differentiate two categories of control: internal and external control. In external control, one begins from the outside and attempts to fully understand the environment. While with internal control, one’s own goals serve as the starting point and helpful synergies with the environment are sought
What is external control in clinical trials?
An external control group, in contrast to an internal control group drawn from the same population, consists of patients who were not involved in the study, had comparable disease severity (at equipoise), but underwent a different course of treatment.
What is external control mechanism corporate governance?
The objectives of organizations like regulators, governments, trade unions, and financial institutions are served by external control mechanisms, which are managed by people outside of an organization. These objectives include adequate debt management and legal compliance.
What is external control system in local government?
With the primary goal of ensuring accountability and effective and efficient performance in public sector agencies, external control systems are organizational arrangements that operate within the parameters of parliamentary control but are conceived from outside the confines of the local government sphere.
