Submitting Information to the Clinical Trials Registry and Results Database Under the FDAAA — and Suggestions to Avoid Pitfalls.

Introduction

Under the Food and Drug Administration Amendments Act of 2007 (FDAAA), sponsors are required to submit specific information regarding clinical trials to the Director of the National Institutes of Health (NIH) for posting on a clinical trial registry and results databank.¹ The Amendments further require that this databank website be easily searchable by laypersons. It is a plaintiff’s attorney’s dream come true when he or she finds a manufacturer’s communication that can be shown to a jury to imply liability on the part of the manufacturer. This website will allow plaintiffs’ attorneys to scrutinize and dissect a new “set” of manufacturer-provided information. They will understandably seek to use this information against the manufacturer.

Not only can plaintiffs’ attorneys mine your submissions for potential adverse evidence, but the FDA can also impose severe sanctions if your company does not comply with the FDAAA. The FDA has several sanctions it can apply against the sponsor for failure to submit the requisite information and for submitting false and misleading information for inclusion in the registryor databank.

On the other hand, to counter the typical plaintiff’s argument that clinical studies were “buried,” or a manufacturer was less than forthcoming, a manufacturer will now be able to point to the accurate, straightforward information posted on the databank as proof it had nothing to hide. Additionally, the manufacturer can show that the public and the medical community had notice of the results of those studies which were properly described and posted in the databank.

Background

Prior to the passage of the FDAAA, federal statute required that the Director of the NIH maintain a website that contained information “on clinical trials for drugs for serious or life-threatening diseases and conditions.”² Even though the database has been available at www.clinicaltrials.gov since February 29, 2000, as of 2006, it only contained information on slightly over 30,000 studies. This is a small number of studies compared to the number of clinical studies that take place each year.

For the last few years, there has been a groundswell of support for the idea that all Phase II and Phase III clinical studies should be listed on this or a similar website. For example, in 2004, the International Committee of Medical Journal Editors announced that clinical trials begun after July 1, 2005, must be listed in a public trials registry at initiation if they are to be considered for publication. In October 2004, The Pharmaceutical Research and Manufacturers of America (PhRMA) established a database which listed clinical trials at www.clinicalstudyresults.org. Some pharmaceutical companies also started their own clinical trial websites. In the legislative area, various bills requiring more disclosure of clinical trials have been introduced in the U.S. Senate and House over the last few years. The FDAAA codified this sentiment and included requirements for the Secretary of Health and Human Services, acting through the Director of the NIH, to expand the clinical trial registry and add a clinical data results database.³

Although it is beyond the scope of this article to set forth all the ways in which the FDAAA affects clinical trials, a summary of certain aspects of the law is helpful to understand the issues facing a manufacturer who is the responsible party. The FDAAA requires a responsible party to submit information for any ongoing applicable device or drug clinical trial⁴ to the NIH to be put in a registry available over the internet.⁵ The information for any applicable clinical trial that is initiated after or is ongoing on December 26, 2007, is to be submitted no later than that date or twenty-one days after the first patient is enrolled in such a clinical trial. If the clinical trial is not for a serious or life-threatening disease, the responsible party may submit the information up to September 27, 2008.⁶ Unless there are no changes to the information, the sponsor is to update the information at least annually.⁷

The statute sets forth a long list of information that must be submitted for the clinical study, some of which is quite fact-specific, such as the start and completion dates, target number of subjects, location of sites, and eligibility criteria. However, some of the requirements are more descriptive including the primary purpose, study design, a brief summary for the lay public, and outcomes, both primary and secondary.⁸ It is in these more descriptive items that the danger lies if the submissions are not carefully worded, especially since the Director of the NIH is directed to make sure that the public will be able to search the clinical trials data registry by many criteria including disease, drugs being studied, and sponsors as well as by keyword.⁹

Additionally, the responsible party must submit to the Director within a certain time-frame after the clinical study is completed,¹⁰certain information for inclusion in a results database. Such results must be submitted for drugs that are approved or licensed under sections 262 or 355 of Title 21 or devices that are approved under Title 21 §§360(k), 360(e) or 360j(m).¹¹ Such information shall include, inter alia, demographic and baseline characteristics of patient samples, including patients excluded from the analysis, and primary and secondary outcomes.¹² Additionally, the Secretary is to promulgate regulations that provide that the registry and results databank include a summary of the clinical trial and its results in technical and “non-technical, understandable language for patients,” if the Secretary determines that such summaries can be included without being misleading or promotional.¹³

The Secretary is also to promulgate regulations addressing how to include in the results databank information on serious adverse and frequent adverse events for these approved or licensed drugs. If the Secretary fails to issue those regulations by twenty-four months after September 27, 2007, the statute requires that there be tables: 1) with information as to anticipated and unanticipated serious adverse events grouped by organ system with frequency of the event in each arm of the clinical trial and 2) a table of anticipated and unanticipated adverse events not already listed that exceed a frequency of five percent within any arm of the study.¹⁴ The responsible party would have to submit such information.

Potential Problems

The FDAAA has teeth, and the violation of some of its provisions can be disastrous. As evidenced by the listing below, failure to comply with its provisions as to clinical trials can have serious and far-reaching consequences, as well as hand plaintiffs’ attorneys ammunition for any future litigation.

The statute requires that any information submitted by a responsible party “shall not be false or misleading in any particular.”¹⁵ If there is a violation of this section, the Director of the NIH “shall” include in the registry databank entry the following statement: “The entry for this clinical trial was found to be false or misleading and therefore not in compliance with the law.”¹⁶ Such a statement would be something the plaintiff’s attorney would latch onto to claim negligence per se and fraud in any future lawsuit. Additionally, any false or misleading statements could presumably be submitted to the Justice Department for review. The Justice Department has an increasing level of interest in healthcare fraud, as evidenced by the recent creation of a strike force to tackle healthcare fraud in Miami and planned strike forces in Los Angeles and Houston. Moreover, because any statements on the registry or databank will be fully accessible by the public and the medical community, there will no doubt be claims of injury due to the public’s reliance on these “fraudulent” statements.

The FDAAA further states that if the responsible party has not submitted the required clinical trial information, the Director “shall” include in the registry and data results databank the following statement: “The entry for this clinical trial was not complete at the time of submission, as required by law. This may or may not have any bearing on the accuracy of the information in the entry.”¹⁷ Questions would be raised in any lawsuit regarding the drug or device as to why these results were not submitted and whether the manufacturer had something to hide. Similarly, if the responsible party for a clinical trial fails to submit the required primary and secondary outcomes, the Director of the NIH “shall” include a notice in the registry and results databank that the responsible party is not in compliance because the primary and secondary outcomes were not submitted for inclusion on the registry and results databank.¹⁸

Certain applications for approval of a drug or device to the FDA must contain a certification that 42 USC 282(j) requirements have been met.¹⁹ Therefore, a failure to follow this section may mean that the applicant will not be able to ask for FDA approval to market the drug or device. The failure to submit that certification, submission of false certification, submission of false and misleading information, or failure to submit required information under 282(j) are “prohibited acts” as set forth under 21 U.S.C. §331(jj). Anyone who violates this section is liable for a monetary penalty of not more than $10,000 for the violation. If the violation is not corrected within thirty days of the notification of violation, the person shall be liable for an additional fine of not more than $10,000 a day until the violation is corrected, with no limitation as to the amount of days the fine can continue.²⁰

It is axiomatic that manufactures cannot promote off-label use of their drug or device; however, post-marketing studies are sometimes done to support a new use of a drug or device. The study may show that the drug or device is safe and efficacious for the off-label use. The manufacturer will need to submit information on such a study under §282(j), and such information will be posted on the clinical results database. The FDA may not have acted to approve such off-label use as yet. The allegation may be made that by submitting such information, the manufacturer is promoting off-label use on a website accessible to the public. States attorneys general are interested in and have investigated allegations of off-label promotion of drugs.

As can be seen from the above examples, the potential for problems for the manufacturer who is a responsible party are many.

How To Avoid Some Of These Problems

Some of this information was to be submitted for inclusion in the databank under the FDAAA by December 26, 2007, but steps can be taken to minimize risk in future submissions. Set up standard operating procedures that set forth all the steps that will be taken to ensure compliance with §282(j)

These SOPs should include specific persons who will be responsible for drafting language, reviewing language, and making sure all information is submitted timely. Provisions should be made for some kind of internal or external audit after the process is in effect to make sure that the SOPs are followed. The SOPs should also include who should not be involved in this process. (See section on marketing below).

The language in any summary for completed clinical studies, or for the more subjective descriptions in the ongoing clinical studies, obviously needs to be drafted to accurately show the science involved. However, the manufacturer needs to be mindful that such submissions might be used in litigation. Therefore, the specific language of the submission also needs a review specifically with litigation in mind. The following checklist may be helpful:

• Are all necessary facts included without editorializing, advocacy, or promotion?
• How would each sentence or phrase hold up on its own, especially if taken out of the context of the other language in the submission?
• How would that phrase look blown up in an exhibit at trial?
• Is there scientific data to back up each statement?
• Does the summary of completed clinical studies disclose any risks or downsides of the study? Should it for this submission?

It is also important not to promote off-label use. Information regarding any post-marketing studies that are done to support a new use will be submitted to the FDA and will be posted on the clinical results database. Such summaries have to be even more carefully scrutinized before submittal to make sure they do not contain any promotional off-label use language. They also need to avoid any endorsement of early/erroneous conclusions and indicate the study limitations. The FDAAA did include a “Rule of Construction” that states that submission of clinical trial information “submitted in compliance with” §282(j) that relates to the use of a drug or device that has not been approved “will not be construed by the Secretary of Health and Human Services or in any administrative or judicial proceeding, as evidence of a new intended use of the drug or device that is different for the intended use of the drug.”²¹ This rule of construction should be helpful to the manufacturer in defending any allegation of promotion of off-label use. However, it also begs the question, if such language could be construed as promotional, would it be language that is “in compliance with” §282(j)?

Do not let marketing or sales be involved in any way in reviewing what is submitted to the registry or databank. Neither marketing nor sales personnel should get any copies of this material either officially or unofficially prior to submisson to the Director of the NIH. In a large organization, a copy of proposed language finding its way to someone in sales and marketing can happen in an unofficial manner. A sales or marketing person then shoots off an e-mail with some thoughts. The e-mails become available to a plaintiff’s attorney in discovery. Even if the e-mail or other communication does not affect what is posted, the plaintiff’s attorney will tout it as evidence of one of their favorite themes: that the manufacturer “is putting profits over health and safety.”

Review information submitted to the FDA for consistency. For example, adverse drug event reports must be submitted to the FDA within a certain short time frame of their occurrence as required by law. Adverse event reports are also part of annual reports to the FDA. Now, under the FDAAA, there will be another level of reporting of adverse reports from clinical studies on approved drugs. Unless the Secretary issues regulations to the contrary, these reports will be in the form of tables. Questions may be raised if the numbers on the tables do not match earlier adverse drug event report numbers. There may be a valid explanation; however, looking for consistency in the numbers up front, with documentation regarding any differences, will be more helpful than trying to figure out what happened later on. By the time this issue comes up at trial, the person who prepared the tables may have left the company or, most likely, will not be able to duplicate his or her thought processes.

Have a system in place to make sure all information required is submitted on time. This recommendation seems obvious, but failure to submit information on clinical studies before the FDAAA was not a big issue. This fact may have led to a feeling that the submission of such information was not a priority. Failure to do so now can have serious consequences as stated above.

Finally, have someone responsible either to check the FDA website or to be on the e-mail list for the FDA, specifically to watch for proposed regulations and guidances on the issue of the clinical trial registry and results database.

Conclusion

Knowing the regulations regarding the clinical trials and results database and submitting the information required will be a learning process and time consuming at first. Failure to properly think about and plan for these submissions can be risky and have serious consequences. Having good procedures in place will make the submission process go more smoothly and, if done correctly, can be of benefit to your company.

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[1] The law actually defines “responsible party” to mean the “sponsor” as defined in 21 CFR §50.3 or the principal investigator of the clinical trial if he or she is so designated by certain parties. 42 U.S.C. §282(j)(1)(A)(3). For purposes of this article, however, we will assume that the manufacturer is the responsible party.

[2] 42 U.S.C. §282(i).

[3] 42 U.S.C. §282(j)(2)(A)(i), 42 U.S.C. §282(j)(3)(E).

[4] “The term ‘applicable drug clinical trial’ means a controlled clinical investigation, other than a phase 1 clinical investigation, of a drug subject to section 355 of Title 21 or to section 262 of this title. 42 U.S.C. §282(j)(1)(A)(iii). The term ‘applicable device clinical trial’ means — (I) a prospective clinical study of health outcomes comparing an intervention with a device subject to section 360(k), 360e, or 360j(m) of Title 21 against a control in human subjects (other than a small clinical trial to determine the feasibility of a device, or a clinical trial to test prototype devices where the primary outcome measure relates to feasibility and not to health outcomes); and (II) a pediatric postmarket surveillance as required under section 360l of Title 21.” 42 U.S.C. §282(j)(1)(A)(ii).

[5] 42 U.S.C. §282(j)(2)(C).

[6] Id.

[7] 42 U.S.C. §282(j)(4)(C).

[8] 42 U.S.C. §282(j)(2)(A)(ii)(I).

[9] 42 U.S.C. §282(j)(2)(B).

[10] See 42 U.S.C. §282(j)(3)(E)(i).

[11] See 42 U.S.C. §282(j)(3)(C).

[12] 42 U.S.C. §282(j)(3)(C)(i-iv).

[13] 42 U.S.C. §282(j)(3)(D)(iii).

[14] 42 U.S.C. §282(j)(3)(I).

[15] 42 U.S.C. §282(j)(5)(D)(i) (emphasis added).

[16] 42 U.S.C. §282(5)(E)(iv).

[17] 42 U.S.C. §282(j)(5)(E)(iii).

[18] 42 U.S.C. §282(j)(5)(E)(ii).

[19] 42 U.S.C. §282(j)(5)(B).

[20] See 21 U.S.C. §333(f)(3).

[21] See Pub. L. 110-85, Title VIII §801(d), Sept. 27, 2007.

Finis