FDA may begin to rely on foreign government oversight of manufacturing even if the standards for the overseas regulators do not exactly match those in the U.S.

The agency "has signaled its intent to move toward a comparability standard rather than exact harmonization" for inspections of manufacturing plants, at least vis-a-vis regulatory authorities in the developed world, according Allan Coukell, director of medical programs at the Pew Health Group,

For developing countries, "trust building" and development of stronger regulatory systems may be necessary before FDA can take a similar approach to them, said an interview timed to coincide with the release of a white paper by the organization, "After Heparin: Protecting Consumers From the Risks of Substandard and Counterfeit Drugs."

The report was released with much fanfare in a Capitol Hill press conference July 12, at which Coukell, Center for Drug Evaluation And Research Office of Compliance Director Deborah Autor, Mylan President Heather Bresch and others spoke.

The heparin scandal, in which Chinese-made active pharmaceutical ingredients were deliberately tainted with oversulfated chondroitin sulfate, resulting in deaths among U.S. patients who received it, "was a seminal event, a wake-up call" regarding the problems posed by galloping globalization of API and finished drug manufacturing, Coukell said ('U.S. FDA Head Says Chinese Heparin Contaminated On Purpose,' PharmAsia News, April 17, 2008).

"People say to us, 'you haven't caught the bad guys [in the heparin scandal] yet, but we do know what happened, how and why," Autor said. "Half of it was a crime of opportunity - we have to reduce the opportunities."

The Pew report is full of recommendations for bringing that about. Drug manufacturers must institute a quality system all along their supply chain, the report says. It's not enough to just follow good manufacturing practices, since drugmakers' suppliers may deliberately mislead them about that.

Instead, risk-based assessments, quality agreements and physical audits should all be considered, there should be legal requirements about documentation and transparency of upstream manufacturing, and testing standards must be improved.

A Question Of Resources

FDA needs more resources for foreign inspections, which it could obtain through user fees, and should use risk assessment to prioritize where it does inspections, according to the report.

The numbers back up the need to switch FDA's focus from domestic to foreign inspections; for example, the report states that by 2007, India and China together housed nearly 70% of the world's API manufacturing sites, up from 49% in 2004.

The problem of persuading a Congress in a budget-cutting mood to increase FDA appropriations on the one hand, and resistance from some quarters in the industry to new user fees on the other, is likely to remain a stumbling block. But Coukell said "there is significant support from some industry groups for user fees to support additional inspections."

Mylan's Bresch is an enthusiastic proponent, although she acknowledged that it is in her company's direct interest to increase FDA inspections of foreign plants, since Mylan's own plant is in Morgantown, W.Va. The current situation in which foreign plants can go eight to 10 years between FDA inspections creates "an unlevel playing field," she argued.

Coukell says the generic drug industry is definitely on board, but "the brand-name industry has been slower to embrace new user fees" (Also see "Is Silence Golden For Brand Companies On Inspection Fees?" - Pink Sheet, 4 April, 2011.).

Mandatory Recall Authority Needed

The Pew white paper says FDA should also create a foreign inspectorate and recognize third-party inspections done by other regulatory agencies or private parties. The agency also needs new powers, such as the ability to mandate drug recalls, subpoena documents and witnesses and halt products at the border if they are shipped from foreign plants that have refused FDA inspections.

"People are shocked we don't have the authority to order firms to recall drugs that may be dangerous," Autor said.

Another key piece of the puzzle is implementation of track-and-trace or "e-pedigree" systems. "Drug distribution tracking and regulation must be improved; methods of documenting the movement of drugs at the individual package level have been attracting support, and a universal system must be implemented," the report says, calling for a "federal serialization and verification system."

Industry had been resistant to comprehensive e-pedigree on grounds of technical difficulty and commercial confidentiality, but Coukell says, "a number of models could be conceived of regarding datasets and who has access to them. The end user could check the product to make sure it's authentic without necessarily having complete vision of the full supply chain."

FDA has been grappling with the foreign inspection dilemma for a long time. In February, John Taylor, the agency's acting principal deputy commissioner, noted that "FDA's traditional model of manufacturing site inspections and border examinations is simply not adequate in today's transformed world" (Also see "FDA Long-Term Globalization Strategy Under Development" - Pink Sheet, 14 February, 2011.).

-Martin Berman-Gorvine (m.berman-gorvine@elsevier.com)

International "Comparability" Of Regulatory Standards May Be FDA's Solution To GMP Oversight

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