BETHESDA, Md. _ At the FDA's Center for Biologics Evaluationand Research (CBER) on the campus of the National Institutes ofHealth, Ezio Bonvini, a medical reviewer with CBER's Division ofMonoclonal Antibodies, does his job just down the hall fromhandsome, state-of-the-art clinical laboratories. The apparently closerelationship between regulation and science is perpetuated by CBERofficials who often say publicly that scientists and regulators workhand-in-hand at CBER.

But in addition to melding bench work and regulatory maxims,Bonvini also practices the ancient art of the politically possible.Every day he carefully works with biotech manufacturers to facilitatethe agency's review of their investigational new drug applications(IND) and product license applications (PLA) in a collaborative,collegial style.

Bonvini's determination to work through early problems in amanufacturer's submission is just one of the reasons many biotechmanufactures privately give CBER high marks in cooperating withindustry despite public complaints from industry groups that agencyreviewers are deleterious.

Bonvini's attitude reflects the center's commitment to working withthe industry. Center director Kathryn Zoon this week reaffirmed thatcommitment when she revealed at an industry meeting that CBER'smission statement had been expanded to include the word`availability' to state that the regulation of biologics is founded "onscience and law to ensure their purity, potency, safety, efficacy andavailability."

Addition of the word `availability' is the "first recognition that theagency really is a partner with the industry. The agency sees itself inthe approval process _ not the compliance area _ as in a quasi-partnership with the industry in order to assess and move forewordproducts that satisfy the public health needs," said Bruce Mackler, anattorney with the law firm of Fenwick & West, of Palo Alto, Calif.

In an interview with BioWorld Today, Bonvini explained how heworks with manufacturers. "Before the PLA crosses the threshold,most of the work is done at the IND level to ensure that the productadequately meets all criteria when the manufacturer is ready to applyfor a license," said Bonvini.

Bonvini indicated that CBER is flexible in its negotiations withmanufacturers as certain problems arise. "This is challenging work.Things are not engraved in stone. There are individual situations thathave to be dealt with, such as shared manufacturing and scale-up. Weprefer to work with the manufacturer before hand so that we canappropriately deal with problems when they do arise."

During the IND development phase of a product, Bonvini meets withmanufacturers at the beginning of Phase I, II and the pivotal Phase IIItrials to discuss questions about the clinical design. During the designof phase II, both the FDA and manufacturer agree and commit toformal correspondence on clinical end points for the Phase III pivotaltrial. Phase II discussions also involve manufacturing issues.

Groundwork Makes PLAs Fly

The back-and-forth nature of discussions between CBER and biotechmanufacturers continues to bear fruit even after the PLA reaches theoffice of the medical reviewers. "Action on the PLA is facilitatedbecause we have seen all the information during Phase I, II and IIIstudies," said Bonvini. "The ability of the PLA to fly through thecenter depends on how much groundwork has been done in the earlyphase of the development of the product," he said.

This emphasis on dealing with regulatory issues early in thedevelopment stage means that Bonvini spends most of his timereviewing INDs, not PLAs. He said in the past year he has reviewedmore than 100 INDs but only one PLA.

"The ratio also reflects that monoclonal antibodies are in a fairlyadvanced state of development compared to other biotech productsand that there are a fairly large number of Phase III studies that mayeventually mature into PLAs," said Bonvini.

After formulation of a PLA team, consisting of a chair, several bio-statisticians, two or three medical reviewers, and a representativefrom CBER's establishment office, the review committee set about itswork. Their main job is to look for clinical relevance, soundness ofthe data and representablity in the clinical trials, said Bonvini.

Fraud is detected through audits of the medical records, sometimes asample is reviewed and sometimes all clinical records are reviewed,said Bonvini.

Despite efforts to smooth the product's advance down the regulatorypipeline, problems do crop up. One common site is scale-up when a"product might jump from being manufactured in a 100 literfermenter in a scale-up facility to a 10,000 liter fermenter in themanufacturing plant. Sometimes the result is a product that has aslightly higher level of contaminants that may require additionalsteps," said Bonvini.

Bonvini stressed that CBER has evolved in the past few years in aneffort to accommodate the needs of industry as long as the publichealth is protected. He pointed to the issue of physical and chemicalequivalence of biotech products, an important issue for manufacturerswho often find slight variations resulting from the manufacturingprocess.

"Instead of demanding a full blown clinical trial to test forequivalence, we now say, `Let's start with the most precise assay. Ifthat is enough to prove equivalence, we stop right there,'" he said. n

-- Michele L. Robinson Washington Editor

(c) 1997 American Health Consultants. All rights reserved.