Conducting a Well-Controlled Clinical Trial for the FDA

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In a scientific experiment, the tighter the controls on the experiment’s variables are, the more accurate and insightful the research’s findings will be. It’s the same case for clinical trials in the life sciences industry. A well-controlled clinical trial rooted in the scientific method's foundation will produce more reliable data and conclusions.

But how do you define a “well-controlled” clinical trial? Much to the relief of the life sciences manufacturers and their research teams, the U.S. Food and Drug Administration (FDA) provides explicit guidance on what it means to conduct an adequate and well-controlled clinical trial in 21 CFR 314.126.

What Is a Clinical Trial?

According to clinicaltrials.gov, in a clinical trial (also called an interventional study), participants receive specific interventions according to the research plan or protocol created by the investigators. These interventions may be medical products, such as drugs or medical devices, procedures, or changes to participants’ behavior — for example, diet.

What’s the Difference Between Medical Device Clinical Trials and Drug Trials?

Many of the same factors that make a well-controlled clinical trial for medical devices are similar to what makes a well-controlled drug trial. Still, there are some fundamental differences researchers need to know.

Key differences between medical device trials versus drug trials include:

  • Differences in the Subjects who Participate. In most drug trials, the drug is tested on a small group of healthy individuals first, then administered to incrementally larger populations. Medical device trials typically only involve subjects with the condition for which the trial is designed.
  • Differences in who Administers Drugs versus Devices. In a drug trial, the patient or patient’s caregiver is typically the person who administers the drug. In a medical device trial, the person administering the device is typically the principal investigator.
  • Differences in who has Greater Responsibility. In a drug trial, the patient typically has a higher responsibility for taking the drug as required. In a device trial, the physician shares a greater part of ensuring the device is operated correctly.
  • Differences in Training Requirements. Because the physician has a greater responsibility to administer medical devices correctly, a medical device trial typically requires more practical experience — such as training in cadaver labs or proctoring during live cases.
  • Differences in the FDA Approval Process. The approval process for new drugs is typically longer than the approval process for medical devices. While it takes 12 years on average to bring a new drug to market, the average length of time it takes to bring a medical device to market is three to seven years. However, this does not always mean it’s easier to obtain approval for a new medical device. The extent of the approval process and whether a medical device requires premarket approval depends on its classification. Medical devices determined to carry significant risks to human subjects generally require premarket approval.

Which FDA Regulations Are Required in a Clinical Trial?

Both drug and device trials follow the same requirements for protecting human subjects, maintaining records, and disclosing financial relationships. Those requirements include:

  • 21 CFR 11 — Electronic medical records.
  • 21 CFR 50 — Human subject protection.
  • 21 CFR 54 — Financial disclosure.
  • 21 CFR 56 — Institutional Review Board (IRB) requirements.

While drug trials are required to follow 21 CFR 312, medical device trials are governed by 21 CFR 812.

What Makes A Well-Controlled Clinical Trial?

Whether it’s a drug trial or a medical device trial, the FDA makes it clear that all trials should have the following:

  • A clear statement of the investigation's objectives and a summary of the proposed methods of analysis in the protocol.
  • A design that permits a valid comparison with control to provide a quantitative assessment of the effect.
  • The subject selection provides adequate assurance that the subject has the disease or condition that the treatment is directed at.
  • A method of assigning patients to treatment and control groups minimizes bias and assures the groups' comparability.
  • Adequate measures to minimize bias by the subjects, observers, and data analysts.
  • Well-defined and reliable assessment of subjects’ responses.
  • Analysis of the results is adequate to assess the effect of the drug or device.

The experiment variables are designed to prove or disprove a causal relationship between the independent and dependent variables. This would be the drug or device versus the condition of the patient.

Control is a vital element of a well-designed experiment of the main variables. There needs to be a way to rule out the effects of extraneous variables other than the dependent and independent ones.

A good experiment, like a good clinical trial, often has blind controls or double-blind randomization to compare the results. The goal for a well-controlled experiment is for it to be repeated many times with the same or statistically similar results. Clinical trials are typically not repeated as much as they are designed with large numbers of subjects to remove the bias in a study with small subject sampling. This helps to rule out random samples or outliers in the “experiment.”

Many would argue other things go into the makeup of a well-controlled clinical trial, especially once sites and patients get involved. Having a research team with adequate facilities, knowledge of the federal regulations, and the time and staff to work on the project are also imperative. Additionally, having timely, well-documented data is vital to the trial’s continued success, which helps ensure the trial is being conducted in a way that will produce relevant results.

What Can We Do To Conduct Well-Controlled Clinical Trials?

A well-controlled clinical trial starts with a strong understanding of the risks involved and proper planning to mitigate those risks. Today, it increasingly requires deep knowledge of FDA regulations and global requirements like the European Union’s Medical Device Regulation (MDR) and In Vitro Device Regulation (IVDR) requirements.

Managing the many risks of any trial and keeping it moving forward requires diligent monitoring, record-keeping, and seamless coordination between all parties involved.

Finally, as clinical trials wind down, researchers need to ensure they have all the correct documentation in order in their trial master file.

A full-service contract research organization (CRO) with expertise in conducting global clinical trials is invaluable when conducting a well-controlled clinical trial. They can assist with clinical planning and consulting before a trial begins. They can help with monitoring, auditing, project management, and safety management during the trial. And they can ensure all your documents are in order as you wrap up a trial so you can obtain approval.

FDA Premarket Requirements

Bringing a device to the market in the United States may appear complex. Following these four steps may assist you in navigating the process:

1) Classify Your Device and Understand Applicable Controls

The first step in preparing a marketing device in the United States is to determine how the FDA has classified your device. A medical device is defined by law in section 201(h) of the Federal Food, Drug and Cosmetic (FD&C) Act.

Medical devices are categorized into three classes (I, II, or III) based on the degree of risk they present. As device class increases from class I to class II to class III, the regulatory controls also increase, with class I devices subject to the least regulatory control and class III devices subject to the most stringent regulatory control.

2) Select and Prepare the Correct Premarket Submission

You should select and prepare the appropriate premarket submission if required for your specific product’s classification. For most medical devices, the appropriate submission type is identified within the product classification, which may be obtained from the public Product Classification database. Note some device types do not require a premarket submission. The most common types of premarket submissions include:

  • 510(k) (Premarket Notification)
  • PMA (Premarket Approval)
  • De Novo Classification Request
  • HDE (Humanitarian Device Exemption)

510(k)

Some class I and most Class II devices require a 510(k). In a 510(k), the sponsor must demonstrate that the new device is “substantially equivalent” to a predicate device in terms of intended use, technological characteristics, and performance testing, as needed.

Some class I and class II devices are exempt from the 510(k) notification requirement if they do not exceed the exemption limitations stated in 21 CFR xxx.9, where xxx refers to 21CFR 862–892.

PMA

Class III devices require a PMA. A PMA is the most stringent type of premarket submission. Before the FDA approves a PMA, the sponsor must provide valid scientific evidence demonstrating reasonable assurances of safety and effectiveness for the device’s intended use.

De Novo Classification Request

The De Novo process provides a pathway to classify novel medical devices for which general controls alone, general and special controls, provide reasonable assurance of safety and effectiveness for the intended use. Still, there is no legally marketed predicate device.

HDE

HDE provides a regulatory pathway for class III devices intended to benefit patients with rare diseases or conditions. For a device to be eligible for an HDE, a sponsor must first obtain designation as a Humanitarian Use Device (HUD).

3) Prepare the Appropriate Information for the Premarket Submission

Once you have prepared the appropriate premarket submission for your device, you need to send your submission to the FDA and interact with FDA staff during its review. Before sending your submission to the FDA, you should be aware of the following:

  • Medical Device User Fees: There is a user fee associated with the submission of certain marketing applications.
  • Small Business Determination (SBD) Program: A qualified and certified business as a “small business” is eligible for substantially reducing most of these user fees.
  • eCopy: Premarket submissions must include an electronic copy (eCopy) on a compact disc (CD), digital video disc (DVD), or a flash drive.

Once the FDA has received your submission, you should be aware of the following:

  • Administrative Review: After a premarket submission is received, the FDA conducts an administrative review to assess whether the submission is sufficiently complete to be accepted for substantive review.
  • Interactive Review: While submission is under review, the FDA staff communicates with applicants to increase the review process's efficiency. Step Four: Comply with Applicable Regulatory Controls, Including Establishment Registration and Device Listing

Regulatory controls are risk-based requirements that apply to medical devices and give the FDA the oversight to ensure medical devices' reasonable safety and effectiveness.