Clinicaltrials.gov. The clinical trial registry created in 1997 by FDAMA has been significantly expanded by FDAAA, the Food and Drug Administration Amendments Act of 2007, Title VIII – Clinical Trial Databases. Many more trials are now required to be registered. Of potentially much greater significance, however, is the newly created results database. Many observers have questioned the purpose of the results database. A recent article in the Journal of the American Medical Association describes the problem in this way:

High-profile disclosures of "hidden" data from clinical trials have led the public to realize what some researchers have known for a long time: ethical and scientific problems arise when trial results are either delayed or not completely revealed to the public or other researchers. Ethical problems arise if volunteers consent to a trial with the understanding that the study will inform medical knowledge and the results are not then made publicly available. Future volunteers are at risk for being misled and harmed when their consent and the trial design are not fully informed by prior research. Institutional review board (IRB) members cannot fully weigh risks and benefits when some unknown proportion of the relevant data is unavailable for review.

Researchers have documented that up to 37% of clinical trials presented in abstracts never result in a full journal article; that even when published trial results exist, some prespecified outcome measures may be omitted, and that various selection factors influence which results are published. As a result, health care and policy decision makers are left to rely on a biased subset of the totality of evidence for a given intervention. This could lead to inefficient resource allocation and suboptimal health care decisions.[1]

Clinicaltrials.gov. Is it the Freedom of Information Act for clinical research? How will it change the way you do business? A brief description follows of what we know so far about the new clinicaltrials.gov registry and results database.

Clinical Trial Registration

Under the old clinicaltrials.gov, trials of drugs for serious and life threatening diseases or conditions were required to be registered so that patients could more easily locate and possibly enroll in the trials. Under the new clinicaltrials.gov provisions, virtually all clinical trials must be registered. The stated purpose of the expanded clinical trial registry is to enhance subject enrollment in clinical trials and provide a mechanism to track subsequent progress of clinical trials.

Which trials must be registered? Virtually all ongoing and new clinical trials of drugs, biologics, and devices, including Phase IV studies, must be registered. Phase I trials of drugs and biologics need not be registered, nor is registration required of device feasibility trials. On the other hand, NIH encourages the registration of all trials, whether or not required by law.[2]

Do I really have to do this? The penalties for failing to comply with clinicaltrials.gov are discussed in the last paragraph below. Here are a few more reasons to comply:

a. New drug applications, including abbreviated new drug applications for generic drugs, biologic license applications, 510(k)'s, premarket approval applications, and humanitarian use device applications will require a certification that applicable requirements of clinicaltrials.gov have been met for all trials included in the application.

b. A similar certification will be required in investigational new drug exemption applications and product development protocols, but interestingly, not investigational device exemption applications.

c. Federal funding for clinical trials will not be released unless the requirements of clinicaltrials.gov are met.

d. The International Committee of Medical Journal Editors has stated that it will publish studies only if they have been registered in an appropriate clinical trials registry. (Clinicaltrials.gov is on ICMJE's list of appropriate registries.)

When is registration required? All new trials begun after September 27, 2007 that are required to register must register within 21 days of enrolling the first patient. Certain trials that were ongoing on September 27, 2007, have until September 27, 2008, to register. Trials that were previously required to register (i.e. trials of drugs for serious or life threatening diseases or conditions), and were still ongoing on December 26, 2007, should re-register by December 26, 2007.

Who is responsible for registering? The trial's sponsor is ordinarily responsible for ensuring that it is registered, but this responsibility may be delegated to the principal investigator in certain instances.

What information is needed to register? Title VIII requires expanded registration information, including information about the trial design, phase, disease or condition, start date, expected completion date, target number of subjects, primary and secondary outcomes, eligibility criteria, overall recruitment status, and location and contact information. As mentioned below under the results database, Title VIII directs FDA to consider whether protocol information, or the protocol itself should be submitted.

What should I do now? Confirm registration date for all ongoing and planned clinical trials. If registration date has already passed for any clinical trials, register these trials as soon as possible. Ensure registration of other clinical trials at appropriate time.

How do I register? Go to  www.clinicaltrials.gov and follow the instructions provided.

Results Database

Title VIII directs the Director of NIH to ensure that the results of clinical trials are made publicly available on the Internet. By enacting these provisions, Congress has endorsed the principle that clinical trial results should be made more public, but the statute is unclear in several respects and leaves it to FDA and NIH to figure out many important, difficult details. Possibly the most controversial issue will be whether to include results information from trials of products that never obtain FDA approval or clearance, including trials that are not intended to support product approval or clearance (e.g. trials of products conducted by an independent researcher). Also likely to be controversial is the reporting of adverse event information on drugs.

The statute creates two types of results information: basic results information and expanded results information.

Basic results information. The statute describes basic results information as:

  • demographic and baseline characteristics of the subject sample,
  • a table of values for the primary and secondary outcome measures for each arm, including the results of scientifically appropriate tests of the statistical significance of such outcome measures, and
  • a point of contact for further scientific information.

Expanded results information. Expanded results information is information about the protocol, or the protocol itself, and technical and non-technical summaries of the clinical trial. The statute directs FDA to hold a public meeting by March 27, 2009, and issue regulations through notice and comment rulemaking by September 2010 to determine whether expanded results information "can be included without being misleading or promotional." In addition, the agency is to consider whether expanded results information should be required for trials of drugs, biologics, and devices that are not approved, licensed, or cleared "whether approval or licensure was sought or not."

The statutory direction to FDA to consider whether expanded results information should be required for drugs, biologics, and devices that are not approved, licensed, or cleared, without a corresponding direction pertaining to basic results information may suggest that Congress understood Title VIII to clearly require basic results information for unapproved drugs, biologics, and devices. In at least one lawyer's opinion, however, the statute is not clear whether basic results information is required of trials of unapproved drugs, biologics, and devices. This issue will be resolved, implicitly or explicitly, as FDA issues procedural rules for complying with these provisions.

Delayed submission of trials submitted to FDA to support approval or clearance of marketing applications or new indications or intended uses. Submission of basic results information from studies intended to support initial approval or clearance of a drug, biologic, or device, or approval or clearance of a new indication or intended use, may be delayed until 30 days following approval or clearance. In addition, when a new indication or intended use is sought for an already approved or cleared product, basic results information is to be submitted within 30 days of the issuance of a letter such as a not approvable letter or a not substantially equivalent letter, and under certain other circumstances.

The statute states that in order to delay the submission of basic results information, certification is to be provided to the Director of NIH. The process for certifying is not specified. We can expect that FDA and NIH will issue regulations providing a certification process and clarifying the delayed submission of results information.

Adverse event information. Information about serious adverse events and frequent adverse events on drugs is to be included in basic results information. Devices, and possibly biologics seem to be excluded from this requirement. The statute requires FDA to issue regulations by March 27, 2009, through notice and comment rulemaking, on the submission of this information "in a manner and form that is useful and not misleading to patients, physicians, and scientists."

What should I do now? NIH has stated that the results database is to be created by September 27, 2008.[3] Notwithstanding the ambiguities in the statute, it is clear that once a product is approved, licensed, or cleared, you will be required to submit some type of results information about registered trials that were used to obtain product approval, licensure, or clearance. You may be required to submit results information about other trials as well. You should regularly monitor www.clinicaltrials.gov for further information. You should also monitor FDA's progress on rulemaking to be aware of new procedures, such as the procedure for requesting delayed submission of information, and if desired, to participate in the rulemaking process.

Penalties for Non-Compliance

No new statute would be complete without penalties. In this case, penalties for non-compliance include a public scolding (NIH may include on the database a statement that all required information has not been submitted), and civil money penalties of up to $10,000 for all violations adjudicated in a single proceeding and up to $10,000 for each day the violations continues.