Shortages and Sunshine

There's a great thirst for information on pharma operations, including drug manufacturing problems likely to dry up vital medical supplies, findings from clinical research studies, and company payments to doctors for multiple activities. The rising clamor for more "transparency" in industry operations creates considerable challenges—and costs.

To deal with still-prevalent shortages of critical drugs, Congress is poised to make manufacturers expand reports to FDA about short supply situations and to establish a new track-and-trace monitoring system. At a hearing before the House Energy and Commerce Health subcommittee last month, legislators urged FDA and industry to devise a "robust pedigree system" that would track drugs through the supply chain. Continued shortages, along with the rise in counterfeit drugs such as the cancer therapy Avastin (see sidebar), have kept drug supply chain issues on the front page.

Jill Wechsler

Manufacturers, distributors, and pharmacists told legislators that they have finally agreed on an efficient, affordable national serialization and tracking system dubbed RxTEC, which could replace the current "patchwork" of proliferating state pedigree laws. But Janet Woodcock, director of FDA's Center for Drug Evaluation and Research (CDER), said that FDA wants tracking down to the drug-unit level because lot traceability can "only partially" identify the distribution path of contaminated or counterfeit products. As a first step, FDA has established a drug serialization system and continues to work on standards for product authentication and tracking, activities that Congress is likely to authorize through pending user fee renewal legislation.

Meanwhile, FDA is demonstrating it can be very flexible in addressing shortages of necessary therapies. Commissioner Margaret Hamburg announced in February that FDA remedied a serious shortage of the cancer drug Doxil by authorizing Caraco Pharmaceutical Laboratories to temporarily import a replacement drug, Lipodox, produced overseas by India's Sun Pharma. FDA officials emphasized that import of this unapproved foreign drug will be a temporary, limited arrangement and was authorized only after the agency evaluated the quality and safety of the Sun product.

FDA also resolved a critical shortage of methotrexate by expediting approval of a manufacturing supplement from APP Pharmaceuticals and release of thousands of vials produced by Hospira, Inc. FDA said it also is working with Mylan and Novartis' Sandoz Pharmaceuticals to boost their production of preservative-free methotrexate, which is needed to treat children diagnosed with acute lymphoblastic leukemia.

Yet, Hamburg noted in a February speech to the annual meeting of the Generic Pharmaceutical Association (GPhA) that many drug shortages are related to quality compliance issues. On almost the same day that APP announced expanded methotrexate production, FDA issued a warning letter citing the firm for serious manufacturing violations, primarily related to heparin production. And Hospira was able to ship some 65,000 vials of methotrexate in February because it had invested hundreds of millions of dollars in plant remediation efforts to resolve earlier manufacturing problems. Companies making medically necessary drugs "must invest in their manufacturing facilities," Hamburg advised the generics makers, noting that visible shortages involving generic drugs could lead the public "to equate generics with quality concerns."

Seeking results

Demands for transparency also apply increasingly to clinical trial activities and results, thanks to new laws and regulations that expand trial registration requirements and the disclosure of research findings. However, evidence that much research information remains unknown raises questions about how well sponsors comply with research disclosure policies.

The good news is that sponsors of FDA-regulated clinical studies are doing a better job in registering trials on the ClnicalTrials.gov website, as required by the FDA Amendments Act of 2007 (FDAAA). This has created a massive database at the National Institutes of Health (NIH), with information on some 100,000 studies.

What seem to be missing are required reports summarizing the results of registered trials. FDAAA gives sponsors 12 months following study completion to provide results, and preapproval studies don't have to be posted for up to three years to protect proprietary information. However, an analysis published last December (2011) in the journal Health Affairs by researchers at the University of British Columbia found that only 12 percent of completed trials issue results within a year. And just 14 percent of post-marketing studies meet the one-year submission timeframe, despite the importance of timely information on drugs already used by patients.

A similar report published in the British Medical Journal (BMJ) in January (2012) found that only 22 percent of registered trials subject to mandatory reporting in 2009 made results available within a year of study completion. Interestingly enough, pharma companies do better in posting study results than investigators funded by NIH, but no one gets high marks. The analysts urge stricter enforcement of reporting requirements to improve research transparency: NIH should withhold grants to slow responders, and FDA should levy $10,000-a-day fines. House Democrats agree and sought explanations for disclosure delays from commissioner Hamburg and NIH director Francis Collins.

Despite these problems, transparency advocates want to extend disclosure to include data from clinical trials for products that FDA fails to approve. While all investigational studies have to register on ClinicalTrials.gov, summary results are required only for research that supports medical products that eventually reach the market. But many scientists believe that much useful information can be obtained from failed studies, and it could help sponsors and investigators avoid repeating unsuccessful research.

Too much sunshine?

On another front, pharmaceutical, biotech, and medical device companies soon will have to report all payments to doctors for inclusion in a new public database. The main thrust of this "Sunshine" policy, which was included in the Affordable Care Act of 2010, is to disclose all industry "transfers of value"—fees, grants, free meals—that could influence medical practice and prescribing. Fees to physicians and teaching hospitals for research activities also are included, a requirement that medical societies fear will make payments for bona fide research activities look like big handouts from pharma.

Fake Drug Fools Oncologists

Because the Centers for Medicare and Medicaid Services (CMS) issued its proposed rule for implementing Sunshine in December 2011—months past the original due date—the agency is postponing initial data collection from pharma until after it finalizes the policy. No one knows, though, when that will occur or how the data filing process will be carried out.

Meanwhile, industry and provider groups met the mid-February deadline for filing comments, which reflect concerns about how payment data will be posted and reviewed. Many commenters seek broader contextual information on the CMS website describing the nature of relationships and interactions between manufacturers, physicians, and teaching hospitals. There's also interest in dropping reports for accredited and certified continuing medical education, which often is funded by grants from marketers that have no say on physicians serving on the programs.

The research-related reporting provisions came under fire from medical societies and research organizations, many asking CMS to drop this provision altogether. The American Thoracic Society, for example, said that public reporting of research payments implies that "research is somehow an inappropriate activity for physicians." Congress included reporting on research, the pulmonologists note, to prevent industry from "hiding" payments under the guise of research, but not to taint investigators. The Association of Clinical Research Organizations (ACRO) similarly proposed cancelling reports on payments from manufacturers for legitimate research activities "as there is no evidence that such payments bias prescribing or other practice behavior."

A specific problem is that the proposed reporting system will lead to double counting of payments for R&D services. This will occur, as Pfizer explains in its comments, because a $10,000 payment to a teaching hospital serving as a clinical study site also would be reported as a $10,000 "indirect research payment" to the associated principal investigator. To prevent such errors, the Association of American Medical Colleges (AAMC) suggests that industry should report research-related payments only to the institution involved, and not to individual physicians connected to a hospital.

ACRO predicts that public reporting of legitimate research activities could cut the number of physicians participating in trials by one-fourth. Without many of the proposed changes, says ACRO, data related to research will be "incomplete at best, terribly inaccurate at worst."

Jill Wechsler is Pharmaceutical Executive's Washington correspondent. She can be reached at jwechsler@advanstar.com