Electronic Records, Pediatrics, and PROs

Food and Drug Administration officials want to spur development of new medical productswhich has been in the doldrums latelyand also obtain information to enhance the safe use of approved therapies. To this end, FDA commissioner Mark McClellan is backing a number of agency efforts to clarify regulatory requirements and streamline oversight to facilitate clinical research and avoid unnecessary data collection. Key initiatives include overhauling 21 CFR 11, promoting pediatric studies, and clarifying standards for measuring patient/subject reported outcomes.

Back to the drawing board
In February, FDA announced that it had launched a broad reexamination of its regulations governing electronic recordkeeping and submissions and said it would be lenient in enforcing previously announced policies in this area. A new draft guidance stated the agencys intent to narrow its approach for implementing 21 CFR 11, which governs electronic clinical trial data collection, retention, and transmission for all FDA-regulated productsmedical devices and foods in addition to drugs and biologics.

FDA published regulations for implementing 21 CFR 11 in 1997 to encourage sponsors to submit data and applications electronically. However, the regulations generated heated objections from industry for being too vague, too complex, and too costly to implement. The agency tried to clarify its approach in several draft guidances and numerous presentations, but recent efforts to enforce 21 CFR 11 rules at manufacturing facilities raised further outcries. Now as part of a landmark overhaul of good manufacturing practices (GMP) policies launched in August 2002 (www.fda.gov/cder/gmp/index.htm), FDA basically acknowledged a need to go back to the drawing board with 21 CFR 11 to avoid discouraging adoption of new production technologies and to minimize the cost and complexity of medical product development.

FDA signaled that a major change was underway last August by shifting responsibility for implementing 21 CFR 11 from the Office of Regulatory Affairs back to the Center for Drug Evaluation and Research (CDER). In February the agency withdrew previously issued draft guidances for implementing electronic record-keeping policies and promised that field investigators will exercise enforcement discretion regarding 21 CFR 11 during this re-evaluation period.

FDA officials say they will continue to enforce electronic signature policies that apply to legacy systems, as well as predicate rules that require that record maintenance and submission in a secure and reliable manner. The agency advises companies to maintain audit trails and other security measures to ensure the reliability of records. Sponsors should validate computer systems that could affect product quality and safety and record integrity; they also should be able to supply copies of electronic records upon request.

At the same time, the agency aims to clarify that 21 CFR 11 does not cover a companys every use of a computer or information system. For example, the rules would apply to sponsor records maintained in electronic format, but not to a computer that generates paper printouts of electronic records and other merely incidental uses of information technology. FDA expects that rewriting the regulations in this area will take at least two years, if not longer.

Studies on children
In addition to facilitating electronic submissions, FDA continues to develop policies and programs to spur research on pediatric indications of medical products. In response to continued emphasis on this activity by Congress, the agency has expanded its capacity for overseeing research designed to add pediatric information to product labels. The agency has established an Office of Pediatric Therapeutics (OPT) in the Office of the Commissioner (OC), as required by the Best Pharmaceuticals for Children Act (BPCA) enacted January 2002. OPT is headed by Dianne Murphy, who also directs CDERs Office of Counter-Terrorism & Pediatric Drug Development (OCTAP). OPT is forming a small staff (four or five professionals) to oversee ethical and regulatory issues involving pediatric studies across FDA. A main task is to promote and monitor adverse event reporting involving drugs used by children, an activity that involves close cooperation with CDERs Office of Drug Safety.

OPT also handles questions raised by institutional review boards (IRBs) about proposed protocols that may impose more than minimal risk with no clear benefit to young study participants. To deal with such IRB referrals, OPT works closely with a growing Division of Pediatric Drug Development (DPDD) under Murphys OCTAP. DPDD is headed by Shirley Murphy (no relation). It now has a staff of 16 to help application review divisions in CDER and other FDA centers clarify what pediatric studies are needed to meet labeling requirements and help sponsors design pediatric trials. DPDD provides support for OPT to avoid duplication and overlap between the two offices.

A prime assignment for DPDD is to work with the National Institute for Child Health and Human Development (NICHD) in the National Institutes of Health (NIH) to identify off-patent drugs that warrant pediatric studies, another BPCA initiative. After months of lengthy deliberations with FDA, in December 2002 NICHD issued a list of 12 drugs that could be studied to obtain useful information on prescribing them for pediatric populations. FDA began the selection process last May with a list of 426 drugs that was whittled down to 180 possibilities based on patent status and other regulatory issues. NIH then consulted with pediatricians and other experts to identify 34 high priority candidatesand eventually the 12 winners. NIH is now in the process of defining desired research strategies and contracting with researchers to study two drugs on the list, with five more to come. Some manufacturers have questioned why certain products are on the list and have challenged the selection process as biased and unscientific. It is clearly a perilous initiative likely to generate objections from all sides, but Dianne Murphy and colleagues are trying to be objective and plan to adapt the process as needed.

FDA and NICHD have launched a Newborn Drug Development initiative to address issues and foster development of safe and effective drug therapies for preterm and neonatal populations. The agencies also plan to conduct a workshop early in 2004 to define pediatric research priorities for pain control and for cardiac, neurological, and pulmonary diseases. FDA is expanding its pediatric Web site to provide more detailed information on product development and pediatric labeling changes (www.fda.gov/cder/pediatrics). The BPCA authorizes the agency to list summaries of pediatric labeling approvals, nonapprovals, and approvables, which the agency ordinarily does not disclose.

Reporting outcomes
Another development that will affect clinical trial design and labeling claims is emerging agreement on how sponsors can make outcomes claims based on subjects self-assessments rather than lab tests. After years of debate, it looks like FDA and other regulatory authorities may offer guidance to sponsors that want to study and make claims about the way a medical product might enhance patient health beyond specific clinical measures.

For more than a decade, sponsors have been struggling with FDA officials over how to define and evaluate thefuzzy economic and quality-of-life (QOL) benefits of a treatment that cant be measured by clinical tests of participants in clinical trials. The FDA Modernization Act of 1997 tried to provide flexibility for sponsors to make economic claims for products based on data from sources other than the usual two well-controlled clinical trials. Efforts to define the data and testing that could support claims of economic benefit or QOL improvement ran into obstacles at FDA and were moved to the back burner.

Now manufacturers, CROs, academic researchers, and regulatory authorities are making progress in this area by focusing on developing specific standards for measuring patient reported outcomes (PROs). Representatives of ERIQA (European Regulatory Issues on Quality of Life Assessment), ISPOR (International Society of Pharmacoeconomic and Outcomes Research), ISOQOL (International Society of Quality of Life), and PhRMA (Pharmaceutical Research and Manufacturers of America) began meeting in March 2000 to harmonize PRO measures used in pharmaceutical development and evaluation, with an eye to demonstrating how this analysis can add value to clinical endpoints.

At a Rockville (Maryland) meeting in March 2002, sponsors and researchers discussed with FDA representatives further development of instruments for measuring the way a patient or subject evaluates the personal impact of a health condition and its treatment on important aspects of life. The group identified procedures and test methods for measures that could support labeling claims. PROs might be used, for example, to measure the way treatments for obesity and weight loss can affect other specific symptoms, including sleep problems, skin irritation, decreased stamina, and QOL measures such as depression and disability. The parties agreed on the need to develop explicit rationales for the measures based on clear research questions not captured by clinical measures. Subject or patient reports, they concluded, could be particularly useful for measuring perceived energy, physical functions, sexual dysfunction, and social activities.

Now FDA is preparing a draft guidance to advise sponsors how to develop self-report data. Laurie Burke in CDERs Office of New Drugs works with CDER review divisions and sponsors on labeling decisions and approaches to endpoints, particularly PRO issues, as they relate to labeling development and consistency. An FDA guidance on PROs would describe what questions sponsors need to answer to obtain adequate and valuable measures. This is not a new concept, Burke comments, referring to long-time efforts to measure subject/patient perceptions of pain and other impact. But now, she notes, we understand these issues better.

The PRO group also has identified several papers and guidelines issued by the European Agency for the Evaluation of Medicinal Products (EMEA) that acknowledge how QOL measurement can provide valuable information for evaluating treatments for cancer, Alzheimers disease, urinary incontinence, and other conditionsprovided such data is based on reliable and valid scales. In September 2002, the EMEA Committee for Proprietary Medicinal Products (CPMP) reissued a Note for guidance on evaluating anticancer medicines that includes symptom control/quality of life as one of several appropriate endpoints to Phase 3 trials. Such endpoints, it notes, would provide supporting evidence to primary endpoints such as overall survival or tumor control.