May 2008

 

OPHTHALMOLOGY NEWS

 

Regulation of registration


by Mark B. Abelson, M.D., Michael Pfleger, Jason S. Casavant, Lauren Lilyestrom, and Stephanie Leung

 

 

In the fall of 2004, legislators introduced a bill to the U.S. House and Senate that would require registration of all clinical trials as a condition of New Drug Application (NDA) approval, with a proposed penalty of $10,000 per day of non-compliance. After several years of sitting on Capitol Hill, this bill became the Food and Drug Administration (FDA) Amendments Act of 2007 on September 27th of last year. It mandates clinical trial registration and disclosure of trial results on drugs, biologics, and devices as a condition of NDA approval and is part of the ultimate goals of complete transparency and open access of information to both clinical researchers and the public. With the exception of Phase I and small preparatory studies, all clinical trials of drugs, regardless of where they’re conducted or who sponsors them, must be registered if the drugs are subject to FDA regulation. The penalties for failure to register are severe. Responsible parties may be fined up to $10,000 per day of non-compliance as well as lose grant funds. These ‘responsible parties’ may be either the sponsor or the principle investigator (PI), depending on who initiated the trial and who has ultimate control over the data.

History: publication of results

Obtaining the goal of complete transparency of clinical research and results is and has been a long process, involving multiple groups of varied compositions. For decades, clinical trial registration has been considered an ethical obligation—particularly for serious and life-threatening illnesses—adhered to by investigators so long as it didn’t interfere with proprietary information and timelines. Clinical trial registries serve to release all the data—both positive and negative—acquired from a clinical trial to the general public, thereby allowing health care professionals to make fully informed decisions about patient care. Public awareness of clinical trials can thwart publication bias; where authors chose not to report and journals chose not to publish, the clinical trial registry can fill in.

In response to growing concern over publication bias and concealed industry involvement in studies, in 1978, a small group of medical journal editors met in Vancouver, British Columbia, to establish standard guidelines for the format of manuscripts and their references submitted and published in their journals. The Uniform Requirements for Manuscripts Submitted to Biomedical Journals is the product of this elite meeting. Within its thirty-six pages, The Uniform Requirements document presents guidelines for the ethical publication of manuscripts, including full author and sponsorship transparency. In 2004, the International Council of Medical Journal Editors (ICMJE) revised the document to include a requirement of clinical trial registration for manuscript submission.

The ICMJE member journals have since required manuscript authors to register all research trials that “prospectively [assign] human subjects to intervention or concurrent comparison or control groups to study the cause-and-effect relationship between a medical intervention and a health outcome.” Phase I trials are therefore exempt from the registration requirement of journals, as they are primarily conducted to determine the pharmacokinetic activity of the investigational drug in healthy humans, rather than to determine its effect on the target condition; they also often contain much preliminary and often proprietary information.

Although the Uniform Requirements doesn’t advocate a specific registry, the registry must be freely accessible to the public, operated by a non-profit organization, monitored to ensure the accuracy and completeness of data, and be electronically searchable, as well as include a minimal registration data set of 20 specified items (Table 1). ICMJE member journals accept registrations from five registries that are explicitly listed in their Uniform Requirements, as well as the primary registries that participate in the WHO trial registry database. While the Uniform Requirements were initially embraced primarily by top-tier journals, submission processes for many more journals are becoming more in-line with the ICMJE requirements. Although only 12 journals are officially members of the ICMJE, well over 600 journals—including the Archives of Ophthalmology, American Journal of Ophthalmology, British Journal of Ophthalmology, and Ophthalmology—have adopted the ICMJE’s registration policy. In 1997, the FDA Reform Act mandated the registration of all trials involving serious and life-threatening diseases; however, the FDA had no means of enforcement, and trials continued to be unregistered. Nonetheless, investigators who chose not to register their clinical trials encountered fewer receptive journals in which to publish their results.

Following the registration trends, major ophthalmic conferences—including the Association for Research in Vision and Ophthalmology (ARVO)—have begun to require registration of clinical trials if results are to be presented at their annual meetings. Beginning with the 2007 ARVO meeting, all presentations of clinical pharmaceutical data must have been registered clinical trials, with the exception of Phase I trials, individual case reports or observational case series, retrospective analyses, and experimental treatments that were compared to historical control groups.

Legislation

Under the previous legislation of the Food and Drug Administration Modernization Act of 1997, only trials investigating the effectiveness of a drug treating a serious or life-threatening disease or condition were required for registration. The FDA Amendments Act of 2007 mandates that controlled clinical studies of investigational drugs and biologics with efficacy endpoints must be registered, excepting Phase I (pharmacokinetic) studies. Registration of controlled investigations of health outcomes and pediatric postmarket surveillance of devices is also required.

The National Institutes of Health (NIH) is the designated party in charge of overseeing trial and results registration, and either the sponsor of the trial or the principal investigator (PI)—if the PI is responsible for conducting the study and has sufficient data access and control—is responsible for trial registration. This ‘responsible party’ is in charge of not only listing the trial, but must also update it annually, as well as each time there is a change in the status of the study. Results of the trial must also be posted. When a sponsor is involved in a study, clear communication between the sponsor and the PI is necessary to explicitly define who’s in charge of registering the trial. The new law requires the submission of numerous data elements, including information on descriptive, recruitment, location, contact, and administrative information. Data such as demographic and baseline characteristics of patient sample, as well as primary and secondary outcome measures, must also be entered into the results data bank. Information for ongoing clinical trials initiated after September 27, 2007, must have been submitted by December 26, 2007 or 21 days after the first patient was enrolled, whichever came later. Ongoing trials as of September 27, 2007 that do not involve a serious or life-threatening disease or condition must be registered by September 27, 2008. Trials that involve a serious or life-threatening disease or condition were initiated before September 27, 2007, and are completed before December 26, 2007, need not abide by the new law. Proof of registration of any trial that’s not a Phase I trial is now required to be part of the NDA. The failure to register trials can result in a civil monetary penalty, which can amount to up to $10,000 per day of violation. Penalties for federally-funded trials can include the withholding or recovery of grant funds. The law also requires that all drug, biologic, and device applications are accompanied by a certification that all submission requirements were met. Ultimately, the results of the trials must also be posted online with the clinical trial register.

Challenges and Compliance

The establishment of various registries is one step toward complete transparency of clinical trial performance and reporting, but new challenges arise regarding the standardization of trial registration. The WHO has sought to unify all clinical trial registries by introducing the International Clinical Trials Registry Platform in 2006. The goal of the platform was to set a universal standard for all registries, primarily with the utility of the International Search Portal, which is a database of trial registration data sets, and a Register Network, which clinical trial registries can join to promote communication and exchange of information to bolster proper trial registration. These international initiatives suggest that the goal of greater transparency is not only a concern of medical journal editors but of other researchers as well. Increasingly, members of the medical research community have demonstrated their active interest in achieving more disclosure regarding clinical research; the next step in achieving full transparency worldwide will be to create an internationally standard mechanism of trial registration.

The final word

While full transparency of clinical trial studies and results is an ethical consideration for investigators and sponsors, any debate on the topic is now irrelevant. Although pharmaceutical companies and industry sponsors might have previously been reluctant to register their clinical trials, the 2007 Acts have made registration unavoidable. The new law has leveled the competitive playing field, and the increased transparency of trial data will likely result in improved communication and increased availability of information. It’s important that investigators and sponsors recognize and are fully versed in the nuances of the new law, as the viability of their studies and practices are likely at stake.

Further reading:

FDA Amendment Act of 2007. H.R. 3580, Title VIII – Clinical Trial Databases. Available at www.fda.gov/oc/initiatives/HR3580.pdf Guidance on New Law (Public Law 110-85) Enacted to Expand the Scope of ClinicalTrials.gov: Registration. Available at grants.nih.gov/grants/guide/notice-files/NOT-OD-08-014.html The Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication. Available at www.icmje.org Association for Research in Vision and Ophthalmology (ARVO) Statement on Clinical Trial Registration. Available at www.arvo.org The World Health Organization International Clinical Trials Registry Platform. Available at www.who.int/ictrp/en

Dr. Abelson is an associate clinical professor of ophthalmology at Harvard Medical School, Boston, and a senior clinical scientist at Schepens Eye Research Institute. Mr. Pfleger is the vice president of regulatory affairs at Alcon, Forth Worth, Texas. Mr. Casavant is the senior manager of education and QA, Ms. Lilyestrom is the managing editor, and Ms. Leung is a medical writer at Ophthalmic Research Associates in North Andover, Mass.

Contact Information:

Lilyestrom: 978-685-8900, llilyestrom@oraclinical.com

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