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Biotechnol Healthc. 2007 October; 4(5): 16–22.
PMCID: PMC2651713

Phase 4 Research Grows Despite Lack of FDA Oversight

Eighteen months ago, a report initiated by the Department of Health and Human Services Office of Inspector General lambasted the U.S. Food and Drug Administration’s lack of oversight of postmarketing or phase 4 clinical trials. In FDA’s Monitoring of Postmarketing Study Commitments, the OIG reported that the agency did not have an effective system in place to supervise phase 4 studies, and that monitoring postmarketing study commitments was not a priority.

Similar to the issue of follow-on biologics, Congress will have to step in to mandate change at the FDA. Case in point is the agency’s February 2007 report on the performance of drug and biologic firms in conducting required post-marketing commitment studies. Of the 1,259 postmarketing commitments filed as of Sept. 30, 2006, 899, or 71 percent, are classified as “pending.” At first glance, this may appear reasonable, but in the FDA’s lexicon, a pending study is one that “has not been initiated (i.e., no subjects have been enrolled or animals dosed).” In actuality, only 25 percent of postmarketing studies are either in progress or have been submitted.

Fast forward to today, and not much has changed. Congress remains stalled on legislation that would mandate the fulfillment of phase 4 commitments.

“Clearly, there still remains debate on what that authority should be and who it should affect,” says Susan F. Wood, PhD, former assistant FDA commissioner for women’s health and director of the Office of Women’s Health. “My sense is that although there is some acknowledgment of the issue, there is not yet a real commitment to allowing the FDA to have the teeth that might be necessary to enforce it.” Wood, who quit her FDA post in protest of the agency’s decision to delay a ruling on whether Plan B, the emergency contraception pill, should be more easily accessible, is a research professor at George Washington University, School of Public Health and Health Services.

Wood believes that, once again, Congress cannot seem to agree on what authority the FDA should have in enforcing postmarketing studies. Under current congressional consideration is a comprehensive clinical trial results database, including phase 4 study requirements, that would be accessible to the public.

“The fact that it remains a sticking point means to me that industry is not taking the steps to assure both transparency and data access for people to look at the safety questions from phase 4 studies,” says Wood.

SLOW IMPROVEMENT

The Cutting Edge Report conducted a survey of 16 pharmaceutical, biotech, and medical device companies and asked what percentage of phase 4 studies that took place in 2005 and 2006 submitted required annual sales reports (ASRs) to the FDA. The aggregate response was 47 percent and 50 percent, respectively. The primary reasons cited for not meeting the ASR commitment were management’s lack of willingness to support postmarketing studies, limited resources needed to complete and submit ASRs, and difficulty collecting the necessary information from investigators.

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Congress can’t seem to agree on what authority the FDA should have in enforcing postmarketing studies, says Susan Wood, PhD.

Wood charges that industry leaders are part of the reason Congress cannot get the job done.

“Right now, there is apparently a lot of resistance. It’s not coming from the public health community or the drug safety groups, so one could assume that it’s not something the industry, or at least some parts of it, wants to see happen,” says Wood.

Even as Congress and the FDA ironing out the details, however, manufacturers are investing in clinical research registries and postmarketing studies. According to Thomson Center-Watch, the rate of phase 4 clinical research is increasing 23 percent annually, with manufacturers spending an estimated $12 billion on the effort in 2007. The Pharmaceutical Research and Manufacturers of America reports that 11 percent of its members’ research and development budget is allotted to phase 4 research.

So why would manufacturers think twice about postponing required phase 4 trials? Demand for real-life outcomes, growing anxiety over the safety of existing drugs, and a changing regulatory environment all play a role. Yet the investment may pay off for manufacturers as biologics cause a rethinking of health benefit structures. Payer groups increasingly demand data on health economics, patient-reported outcomes, reimbursement, and patient safety — information that can be derived only from postmarketing studies. Manufacturers that provide this information may ultimately differentiate their product from others and boost sales.

Pay-for-Performance Biotech Contracts

Johnson & Johnson has proposed that Great Britain’s national health service reimburse for the cancer drug bortezomib (Velcade), but only for patients who actually benefit from the treatment, which can cost up to $48,000 per patient. Manufacturers of four multiple sclerosis drugs, which can cost as much as $18,000 per patient annually, also have agreed to reduce drug prices if the medications do not meet anticipations. Glaxo-SmithKline has made similar pay-for-performance pricing arrangements with two European governments, but declines to name the drugs or countries involved.

In the United States, United-Healthcare has negotiated an agreement with Genomic Health on a performance-based contract for a genetic test that would determine if chemotherapy would benefit a patient with early-stage breast cancer.

Amgen Fights New Medicare Restrictions

Amgen is challenging the Centers for Medicare and Medicaid Services’ decision to limit cancer patients’ access to anemia drugs. Under a new policy, Medicare will not pay for the company’s darbepoetin alfa (Aranesp) and epoetin alfa (Epogen), along with Johnson & Johnson’s epoetin alfa (Procrit), if a patient’s pretreatment hemoglobin level is greater than 10 g/dL. Physicians aim for a level of 10 to 12 g/dL for cancer patients.

Amgen contends that the policy goes against the FDA’s approved labeling for the drugs, as well as the recommendation by the Oncologic Drugs Advisory Committee and clinical practice guidelines from the American Society of Clinical Oncology and the American Society of Hematology.

As Amgen struggles the deal with falling sales of its anemia franchise, it has “commenced a global review of the company’s business plans” to identify cost-cutting potential, according to a regulatory filing in August.

Court to Terminal Patients: No Entitlement

In an 8–2 decision, a federal appeals court has ruled that terminally ill patients do not have a right to obtain experimental drugs, even if their physician cites the agent as the greatest hope for survival. The majority of judges declared that federal regulators have the authority to determine when experimental drugs can become available, and advocates who feel otherwise should take their case to Congress. The Abigail Alliance for Better Access to Developmental Drugs, named after a 21-year-old student who died from cancer after being denied access to two investigational anticancer drugs that were later FDA approved, brought the case to court, and vowed to appeal the decision to the Supreme Court.

Chit Chat…

A federal judge has ruled that Roche’s antianemia drug Mircera infringes on an Amgen patent. … Initial public offerings abound: Reliant Pharmaceuticals plans to raise $400 million, with proceeds used for acquisitions and to pay off existing debt. Talecris is planning a $1 billion IPO, and Adnexus and ARYx Therapeutics also are planning to raise $86 million in separate IPOs. … Merck and Ariad have inked a $1 billion development pact for a late-stage metastatic sarcoma study. … Merck also plans to buy NovaCardia in a $350 million transaction. … Eli Lilly is entering the biotech market through its own pipeline rather than acquisitions. More than half of its new drugs entering clinical trials will be biologics, with plans to bring a new biologic to market every year beginning in 2011. … Astra Zeneca and United Kingdom-based Silence Therapeutics have signed a $402 million deal for early-stage identification and development of novel siRNA molecules. … Noven Pharmaceuticals is acquiring JDS Pharmaceuticals.Pfizer inked a $1 billion deal with Icagen for development of pain medications.


Articles from Biotechnology Healthcare are provided here courtesy of MediMedia, USA