Avid Bioservices Inc (CDMO)

[Biowatch]

>>bioequivalence between the two production methods<<

Protein drugs, or "biologics", are produced by cells grown in vats called fermentors. (Think of a beer brewery.)

In my opinion, this tells you something about the whole generic protein drug issue. If a protein drug (in this case, an antibody, probably the best understood protein out there from a manufacturing standpoint) made from THE SAME CELL LINE in two different ways (air lift versus stirred) is not considered "bioequivalent", then that raises the bar considerably for getting a generic protein drug approved when these things go off patent.

I mean, is the patent holder going to hand over their cell line to a generic drug maunfacturer to help them compete? If they don't, then the generic competitor will have to create their own cell line to produce a protein, and so there may be issues of whether the different cell lines produce the same protein, and whether the proteins are bioequivalent. This is over and above manufacturing issues, and I suspect that the original inventor/manufacturer cannot be forced to tell a generic competitor exactly how they manufacture a protein.

Patents will be expiring on billions of dollars worth of protein drugs in the next few years, so the whole issue of bioequivalence is important. If a company has to run a whole new set of large clinical trials to get a generic drug approved, it won't be cheap.

http://pubs.acs.org/cen/coverstory/8038/print/8038biogenerics3.html

>>Chemical and Engineering News
September 23, 2002

GENERICS NEXT WAVE: BIOPHARMACEUTICALS
With major biotech drugs coming off patent, generic drug makers are looking to compete
by A. MAUREEN ROUHI, C&EN WASHINGTON<<

An excerpt:
>>UNDER CURRENT LAW, generic small-molecule drugs are approved on the basis of essential similarity of the active ingredient and the bioequivalence of the drug to the brand-name product. For chemical products, proving these characteristics is straightforward. A small molecule can be precisely characterized. Bioequivalence can be established with lab and limited clinical studies.

The same assumptions do not apply to biopharmaceuticals, which are proteins. Proteins are more difficult to characterize exactly than small molecules, because their activity depends not only on composition but also on conformation. In addition, a clear understanding of how process changes affect structure and biological activity does not exist, according to Enrico T. Polastro, a vice president and senior industry analyst at Arthur D. Little Benelux. "There is a belief that a minor change in process might trigger changes in biological activity," he explains. Hence, using the innovator product's data to support a marketing application--as is done with small-molecule drugs--is untenable with biopharmaceuticals.

"We will have to do limited clinical studies comparing our product to the reference product," says Marvin Samson, president and chief executive officer of Sicor Inc., a specialty pharmaceutical company with headquarters in Irvine, Calif. "With science so much better now than it has ever been, we can demonstrate equivalence through pharmacokinetic, pharmacodynamic, and clinical studies and overcome the fact that biopharmaceutical versions are not exactly the same."

Many believe that a pathway for approving biogenerics will be in place in the U.S. sooner or later. "These drugs are very expensive and very effective," Samson notes. "Those paying for these products are going to do whatever they can to help develop a generic biotech line. It's something this country needs."

"It is only sensible for the various regulatory authorities to set up some pathway," says Neal Hansen, an analyst at Datamonitor. "Our estimate is that by 2006 a pathway will be in place and that by 2007 the first biogeneric will be launched."

BUT BIOGENERICS ARE not likely to gain an entry into the market without stiff resistance from current patent holders, he suggests. "If you think patent litigation is bad now, wait until Amgen begins suing over the different ways its patents are being infringed. That will go on forever."

Meanwhile, generic companies are preparing for the coming of biogenerics in the U.S. and Western Europe.<<
--------------------------

However, McClellan, and others in the FDA before him, are interested in making it easier to get approval of generic protein drugs.

>>Reuters
U.S. FDA chief eyes path for copycat biotech drugs
Friday December 12, 4:18 pm ET
By Ransdell Pierson

WASHINGTON, Dec 12 (Reuters) - Food and Drug Administration (News - Websites) Commissioner Mark McClellan said on Friday it may be justifiable for regulators to approve generic forms of biotech drugs even if they have not been through the same lengthy clinical trials required of the original drugs.

McClellan said the FDA is studying whether it has authority under federal law to approve generic versions of biotech drugs, such as human growth hormone and laboratory-altered insulin, once their original patents expire.

The agency plans soon to unveil its thoughts on the issue and will also seek public comment on whether copycat biotech drugs should be approved, and under what conditions, he said.

"We definitely will have more to say on this in the coming months because this is an important issue from the standpoint of innovation and affordability of safe drugs," McClellan told a luncheon with Reuters reporters.

Biotech drugs are typically laboratory-altered forms of naturally occurring proteins, which are given by injection or intravenous infusion. They are difficult and expensive to make, and similar versions of the same protein made by different companies can have subtle differences.

The FDA, by contrast, has for years approved copycat versions of standard synthetic "small molecule" drugs, which typically come in pill form.

Patents on the oldest biotech drugs, including human growth hormone and laboratory-altered insulin, begin lapsing in the next few years and generic drugmakers are clamoring for the right to then sell their own cheaper copycat forms.

Generic drugmakers say they are willing to conduct small trials to verify their products are safe, effective and have the same physical traits as original branded medicines, but claim they should not have to duplicate the lengthy and costly trials conducted by the original drugmaker.

McClellan showed sympathy for that argument, but also said generic biologics should be evaluated individually, depending on the complexity of the particular protein.

"I don't know that there will be any one general answer that will be applicable to all products. Some biologics are more complex than others ... I don't think there will be a universal answer," he said.

"Published (studies) suggest, at least in some cases, that full-blown demonstration of effectiveness and toxicity may not be necessary," McClellan said.

He said the safety and effectiveness of generic biotech drugs, in principle, could be judged instead by "short-term measures of how the product is working."

For instance, he said companies now selling human growth hormone had to test their products for years in children to see results.

"But if a new (generic) product had some shorter-term impact on a clinical measure -- on short-term growth -- that could potentially be an important factor in an approval," McClellan said. <<