Resource Center Educational Tools: Clinical Trials and FDA Regulation


Clinical Trial

A Clinical Trial is:
• a research study conducted in human volunteers to answer specific health questions.
• conducted to allow safety and efficacy data to be collected for new drugs or devices.

The U.S. National Institutes of Health (NIH) organizes trials into different types:

Prevention trials - look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vitamins, vaccines, minerals, or lifestyle changes.

Screening trials - test the best way to detect certain diseases or health conditions.

Diagnostic trials - conducted to find better tests or procedures for diagnosing a particular disease or condition.

Treatment trials - test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.
Quality of life trials - explore ways to improve comfort and the quality of life for individuals with a chronic illness (a.k.a. Supportive Care trials).

Compassionate use trials - provide experimental therapeutics prior to final FDA approval to patients whose options with other remedies have been unsuccessful. Usually, case by case approval must be granted by the FDA for such exceptions.

Key Players in Clinical Trials

Trial Subjects

Subject is defined as “a human who participates in an investigation, either as a recipient of the investigational new drug or as a control”. -21 CFR 312.6. Subject may be a healthy human (e.g. most Phase I trials) or a patient with a disease. The trial protocol dictates the criteria for inclusion/exclusion of a subject.


Sponsor is the individual (investigator or doctor), company (pharmaceutical company) or organization (medical institution or a federal agency like NIH) that takes responsibility for initiation, management and/or financing of a clinical trial.

Sponsor responsibilities include:

  • selecting qualified investigators
  • ensuring proper monitoring of the trial
  • ensuring that the trial is conducted in accordance with the plan and protocol contained in the IND
  • ensuring that the FDA and all participating investigators are informed of any significant new adverse effects or risks with respect to the study drug.

Investigator is the person responsible for conducting the clinical trial at a study site; a Principal Investigator refers to the lead investigator at a site.

Investigators’ obligations include:

  • ensuring that trial is conducted in accordance with the signed investigator statement, the investigational plan and the applicable regulations
  • protecting the rights, safety and welfare of subjects under the investigator’s care
  • obtaining informed consent from each subject
  • control of drugs under investigation

Contract Research Organization (CRO)

A CRO is contractually obligated to perform one or more of the Sponsor’s trial related duties. A CRO typically interacts with the Principal Investigator, manages Study Data and generates Study Reports.
21CFR 312.52(a) and (b) permit Sponsor to transfer responsibilities to a CRO, provided such transfer is explicitly set out in writing, and CRO must comply with the sponsor obligations set out in the regulations.

IRB/Ethics Committee

As per 21 CFR 312.102 (g) IRB “means any board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of, biomedical research involving human subjects. The primary purpose of such review is to assure the protection of the rights and welfare of human subjects.”
Typically no clinical trial can proceed unless the trial has been reviewed and approved by, and remains subject to continuing review by, an IRB.

An IRB provides an independent assessment of clinical trial by:
- review of study protocols for merits, ethics and risk/benefit ratio
- Overseeing the welfare of the subjects
- reviewing changes to the protocols to ensure that the trial is conducted in accordance with the approved protocol.

Regulatory Authorities

In the US the Food and Drug Administration (FDA) is the regulatory authority. The following section describes the FDA and where and how a product gets evaluated within the FDA.

Food and Drug Administration

The FDA will most likely be involved at several points during the commercialization of a medical discovery or technology. Regulatory oversight will impact both the time it will take to bring the product to market and the cost.
THE FDA mission:

“The FDA is responsible for protecting the public health by assuring safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation. The FDA is also responsible for advancing the public health by helping speed innovations that make medicines and foods more effective, safer and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health.”

The FDA is the governmental gatekeeper ensuring that certain standards are met for a medical product being brought to market. At the heart of the evaluation, the FDA tries to determine if a new product’s benefits outweighs the risks. The main categories of products that the FDA regulates:
-Medical Devices and
The process of evaluation for each is different and to understand the process it is best to start by reviewing how the FDA defines these categories.

FDA Definitions

The term "drug" means

(A) articles recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and

(B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and

(C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C).

The term "new drug" means:

(1) Any drug … the composition of which is such that such drug is not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the condition prescribed, recommended, or suggested in the labeling thereof … ; or

(2) Any drug … the composition of which is such that such drug, as a result of investigations to determine its safety and effectiveness for use under such conditions, has become so recognized, but which has not, otherwise than in such investigations, been used to a material extent or for a material time under such conditions.

The term "biological product" means:

A virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.

The term "device" … means:

an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is

(1) recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them,

(2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or

(3) intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.

The term “combination product” means
(1) A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity;
(2) Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products;
(3) A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or
(4) Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.
Understanding these definitions is critical as it defines where and how a product will be evaluated within the FDA.

Evaluation of Drugs at the FDA
The Center for Drug Evaluation and Research (CDER) is responsible for evaluation of drugs and therapeutic biologics (referred hereinafter as drugs). New drugs are approved under the Federal Food, Drug and Cosmetic Act (FDCA).

The regulation and control of new drugs in the United States has been based on the New Drug Application (NDA). The NDA application is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S. The goals of the NDA are to provide enough information to permit FDA reviewer to reach the following key decisions:

  • Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks; and
  • Whether the drug's proposed labeling (package insert) is appropriate, and what it should contain.
  • Whether the methods used in manufacturing the drug and the controls used to maintain the drug's

quality are adequate to preserve the drug's identity, strength, quality, and purity.
The FDA's role in the development of a new drug begins when the drug's sponsor having screened the new molecule for pharmacological activity and acute toxicity potential in animals, wants to test its diagnostic or therapeutic potential in humans. At that point, the molecule changes in legal status under the FDCA and before the drug can be shipped across state lines, the sponsor must submit for an investigational new drug application (IND). It is the IND that allows a sponsor to ship the drug to clinical sites throughout the United States to begin to show safety and efficacy in human subjects required for the NDA.
The IND application must contain information in three broad areas:

  • Animal Pharmacology and Toxicology Studies
  • Manufacturing Information and
  • Clinical

Protocols/Investigator Information.
Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials. During this time, FDA has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk.

Phases of Clinical Trials

Clinical trials involving new drugs are commonly classified into four phases. Each phase of the drug approval process is treated as a separate clinical trial and the drug-development process usually advances through all four phases over many years. Each phase exposes greater number of subjects to the drug and each phase builds on existing safety and efficacy information.

If the drug successfully passes through Phases I, II, and III, it will usually be approved by the national regulatory authority for use in the general population. Phase IV are 'post-approval' studies.

Pre-clinical tests
Prior to starting clinical trials on a drug usually extensive pre-clinical tests are conducted.
Pre-clinical studies involve in vitro (test tube) and in vivo (animal) experiments using wide-ranging doses of the study drug to obtain preliminary efficacy, toxicity and pharmacokinetic information. Preclinical studies help pharmaceutical companies to decide whether a drug candidate has scientific merit for further development as an investigational new drug.

Phase 0

Phase 0 is a recent designation for exploratory, first-in-human trials conducted in accordance with the U.S. Food and Drug Administration’s (FDA) 2006 Guidance on Exploratory Investigational New Drug (IND) Studies.

Phase 0 trials, also known as human microdosing studies, include the administration of single subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacokinetics (how the body processes the drug) and pharmacodynamics (how the drug works in the body).

Phase 0 studies help pharmaceutical companies rank drug candidates in order to decide which has the best pharmakokinetic parameters in humans to take forward into further development. They enable go/no-go decisions to be based on relevant human models instead of relying on animal data.

Phase I

Phase 1 trials are designed to assess the safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug. These trials are often conducted in an inpatient clinic, where the subject can be observed by full-time staff. The subject who receives the drug is usually observed until several half-lives of the drug have passed.

Phase I trials normally
- include dose-ranging, also called dose escalation, studies so that the appropriate dose for therapeutic use can be found. The tested range of doses usually are a fraction of the dose that causes harm in animal testing.
- involve a small (20-80) group of healthy volunteers.
However, there are some circumstances when real patients are used, such as patients who have end-stage disease and lack other treatment options. This exception to the rule most often occurs in oncology (cancer) and HIV drug trials.

Phase II

Phase II trials are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to work as planned, or to have toxic effects.

Phase II trials are:
- performed on larger groups (50-500) subjects

- are sometimes divided into Phase IIa and Phase IIb.
Phase IIa is usually a proof of concept study specifically designed to assess dosing requirements (how much drug should be given) whereas Phase IIb is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)).

Some trials combine Phase I and Phase II, and test both efficacy and toxicity.

Phase III

Phase III trials are aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment and to provide an adequate basis for physician labeling.
Phase III trials may also be conducted for the purposes of (i) "label expansion" (to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing), referred to as IIIB phase or (ii) to obtain additional safety data, or to support marketing claims for the drug.
Typically regulatory authorities require at least two Phase III studies be conducted.

Typically Phase III trials:
- involve 300–3,000 or more depending upon the disease/medical condition studied)
- are randomized controlled multicenter trials

Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions.

Regulatory Submission

Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities in different countries (FDA in the US) to get approval for marketing.

It is common practice that certain Phase III trials continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be purchased.

Drugs undergoing Phase III clinical trials can sometimes be marketed under FDA norms with proper recommendations and guidelines, but in case of any adverse effects being reported anywhere, the drugs need to be recalled immediately from the market.

Phase IV

Phase IV trial is referred to as Post Marketing Surveillance Trial. Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives permission to be sold.
The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials.

Phase IV studies may also be conducted because (i) it is required by regulatory authorities or (ii) by company for competitive advantage (finding a new market or label for the drug) or (iii) for other reasons (for example, the drug may not have been tested for interactions with other drugs).
Evaluation of Biologics at the FDA
The Center for Biologics Evaluation and Research (CBER) is responsible for evaluation of non-therapeutic biologics. Biologics are approved under the Public Health Service Act (PHSA). This means that most biologics require submission of a Biologics License Applications (BLAs). Similar to the process outlined above with respect to the NDA, the BLA must show safety, purity and potency.
Evaluation of Devices at the FDA

The Center for Devices and Radiological Health (CDRH) is responsible for the evaluation of devices. The extent of regulation on a particular device depends on the perceived risk. The FDA classifies devices into Class I, Class II, and Class III depending on their risk.
Class I devices are low risk and typically exempt from pre-market review. Some examples are tongue depressor, blade etc.

Class II devices are considered moderate risk and are subject to pre-market notification (510(k)). Some examples are a powered wheelchair, endoscope.

Class III devices are termed high risk, subject to pre-market approval (PMA). Some examples are cardiac ablation catheter, coronary stents.

If a device is categorized as a Class I device it is exempt from FDA review. If it is a Class II or III device it will either follow the 510(k) route or PMA route. The requirements are substantially different depending on the classification of the device.

Pre-market Notification (510(k))

The 510(k) route requires the applicant to demonstrate “substantial equivalence” to a product that is already on the market. It must have the (1) same use as the predicate device and (2) same technological characteristics or if it has different technological characteristics the submission must demonstrate that the new device is as safe and effective as the predicate device and that the new device does not raise different safety and effectiveness questions than the predicate device.
Pre-Market Approval (PMA)

The PMA route requires a demonstration of reasonable assurance of safety and effectiveness. Both factors must be based on valid scientific evidence that the benefits outweigh the risk and that it provides significant results in a significant portion of the population. Valid scientific evidence means results that were generated in a “well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualifies experts, and reports of significant human experience. The average PMA review time was 436 days in 2004. The level of proof here can mirror much of the requirements for a NDA.
Investigational Device Exemption (IDE)

Similar to an IND, the IDE allows for the shipment of an investigational device for use in a clinical study to determine safety and effectiveness. Similarly as there are different categories of devices, there is an additional classification that will determine whether or not an IDE application must be filed or if the device inherently is considered approved. It turns on whether the device is a “significant risk device” or a non-significant risk device.”

Significant risk devices are those that are intended as an implant and presents a potential for serious risk to health, safety or welfare of a subject; purported or represented to be for use in supporting or sustaining human life and presents potential for serious risk to the health, safety, welfare of a subject; for use of substantial importance in diagnosing, curing, mitigating, or treating disease o otherwise preventing impairment of human health and presents a potential for serious risk, to the health, safety, or welfare of a subject or; otherwise presents a potential for serous risk to the health, safety, or welfare of a subject.

For a clinical trial to involve a new Class II or Class III device, the device must have an approved IDE.
- If it is non-significant risk, it is considered to have an approved IDE and the trial will most likely only need Institutional Review Board (IRB) approval.
- If it is significant risk, the FDA must approve the IDE and will need IRB approval as well.

Evaluation of Diagnostics at the FDA
In vitro diagnostic (IVD) products are those reagents, instruments, and systems intended for use in diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body.


IVDs are medical devices as defined in section 210(h) of the Federal Food, Drug, and Cosmetic Act, and may also be biological products subject to section 351 of the Public Health Service Act. Like other medical devices, IVDs are subject to premarket and postmarket controls. IVDs are also subject to the Clinical Laboratory Improvement Amendments (CLIA '88) of 1988.

The Clinical Laboratory Improvement Amendments of 1988 (CLIA '88)
CLIA '88 establishes quality standards for laboratory testing and an accreditation program for clinical laboratories.

CLIA '88 requirements vary according to the technical complexity in the testing process and risk of harm in reporting erroneous results. The regulations established three categories of testing on the basis of the complexity of the testing methodology: a) waived tests, b) tests of moderate complexity, and c) tests of high complexity.

Manufacturers apply for CLIA '88 categorization during the premarket process.

Under CLIA, laboratories performing only waived tests are subject to minimal regulation. Laboratories performing moderate or high complexity tests are subject to specific laboratory standards governing certification, personnel, proficiency testing, patient test management, quality assurance, quality control, and inspections.