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FDA Unveils Biosimilars Guidance 30

ananyo writes "The U.S. Food and Drug Administration has released its long-anticipated draft guidance for drug makers interested in making generic forms of biological drugs such as enzymes and antibodies. The move could open the door for cheaper versions of some of medicine's most expensive drugs, but it is still unclear how many companies will be willing to tackle the challenges and uncertainties of making 'biosimilar' drugs. Copying biological molecules is a stickier proposition than making ordinary generic medicines because proteins are typically much larger and more complex than small molecule drugs. They are also often produced in cell cultures, and even small variations in how the cells are grown can change the properties of the protein produced."
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FDA Unveils Biosimilars Guidance

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  • by Anonymous Coward on Friday February 10, 2012 @11:34PM (#39002745)

    Have a look at filgrastim, and the epoetins - there are already some biosimilars on the market, or at least there are in the UK. Interestingly, the original filgrastim (from Amgen) is the cheapest of all of the options in the UK (there are alternatives from Teva, Sandoz, Ratiopharm and Hospira). However, this is actually because the presence of multiple biosimilars has brought the price of all of the options down - when there were only two biosimilars, in 2010, one of the biosimilars was the cheapest option, and they all cost at least £13 more for 30 million units (300mcg) than the price today. Competition is a powerful driving force for pricing in the pharmaceutical industry.

  • Re:Seems to me... (Score:5, Informative)

    by jonwil ( 467024 ) on Friday February 10, 2012 @11:46PM (#39002787)

    If you read the summary, it says they are already producing these molecules via cell cultures.

    A protein is a VERY complex molecule and simply inserting a gene into a yeast strain might not produce a protein that is similar enough to what humans make to be viable as a drug.

  • Re:Seems to me... (Score:4, Informative)

    by Anonymous Coward on Saturday February 11, 2012 @12:01AM (#39002827)

    Yeast is used sometime, but a lot of drugs, insulin for example, are made by modified E. Coli. It's not as simple as just using the human DNA sequence in the bacteria since bacteria cannot remove the introns and stitch together the extrons that are in the human sequence. How you get around this issue differs by manufacturer. [] Additionally, most diabetics don't use Regular insulin, which would use the normal human sequence, but insulin lispro, which goes by the brand name Humalog, or one of the equivalent fast-acting insulins. The reason for this is because diabetics are injecting the insulin either with needles or an insulin pump, the insulin needs to be absorbed from the subcutaneous layer (fat layer below the skin), so Regular insulin wouldn't actually be absorbed the same way it is when a non-diabetic's pancreas secretes the insulin. Humalog also works faster (within 5 minutes) instead of the 30 minutes of Regular, so it allows a diabetic to give insulin right before or directly after eating and have the insulin work almost as fast as a non-diabetics insulin response.

  • Re:Seems to me... (Score:0, Informative)

    by Anonymous Coward on Saturday February 11, 2012 @12:04AM (#39002841)

    Genes control the primary structure of the protein, that is the sequence of amino acids. The secondary, tertiary and quaternary structures are controlled by a combination of the consequences of this primary structures chemical properties and its interaction with the cellular machinery. Making a working protein is not as easy as splicing in a gene and growing yeast.

    The tiniest differences in environmental factors can significantly change the outcome of a microorganisms growth, this is true for yeast and other fungi more than others. Every year organisms that are incredibly dissimilar are found to be genetically identical because of how different the structure and life cycle can be in different environments.

    Seems to me... you do not know what you are talking about

  • Re:Seems to me... (Score:2, Informative)

    by Anonymous Coward on Saturday February 11, 2012 @12:53AM (#39002983)

    Why not just open up yeast to genetic engineering and have the modified yeast create your molecules by the ton? Once you have the research and modifications done, you can grow those yeasts for pennies.

    I had a car ride last week with someone who regulates this kind of business. In the case of normal drugs, with a relatively simple active ingredient, it's pretty easy to prove that your generic drug is identical to the original name-brand drug that went through all the clinical trials to satisfy the regulators. So, the regulatory process for generic versions of simple drugs is comparatively simple

    For biological drugs, though, the molecules are generally too complex to replicate exactly. Generic companies do create yeast or whatever to create something 'similar', and that's where the questions come in. How similar is similar, and how close is close enough? If the biosimilar isn't exactly the same, should it undergo all the clinical trials that the first drug underwent, or would some abbreviated version suffice? It's a regulatory issue, and it seems now there are some rules and guidelines on how this should be done.

  • Biologicals comment (Score:5, Informative)

    by Guppy ( 12314 ) on Saturday February 11, 2012 @02:17AM (#39003191)

    For pharmaceuticals, small-molecule drugs and biologicals have long been regulated under two different tracks, for reasons both historical and practical (including the problem that biologicals simply aren't amendable to the kind of complete analysis you can do on small molecules). Sometime ago (maybe about a decade or so?) back, the FDA decided to modernize things, and start applying principles from the former track to the latter. There were a lot of facilities that used processes little-changed since being invented back as far as the 50's and 60's, that were shuttered; recent product and vaccine shortages happened not long after the number of manufacturers dwindled (for some products, from double-digits down to 1-2 sources).

    Anyway, wanted to give an example of the limitations of characterizing biologicals. A while back, there was a case involving an Erythopoetin drug (used to treat certain kinds of anemia). The FDA mandated a change in manufacturing, in a big push to get rid of animal-derived raw materials (in this case, anything bovine-derived, following the mad-cow scare). The protein drug in the new formulation was found to be exactly the same by every testable parameter -- sequence, folding, everything else -- and seemed to function the same when examined in animal and human subjects. But when it was released for use in the field, there was a sudden spike in cases of pure red blood cell aplasia (where the body simply stops make any RBCs). Little details in the manufacturing process can sometimes make an enormous difference.

    To use an analogy, biologicals are sometimes like arcane and kludgy code that nobody fully understands; once you somehow get it working, there is good reason to not to poke it, and to fear that it might break in somebody else's hands.

  • by ComputerPhreak ( 1057874 ) on Saturday February 11, 2012 @03:03AM (#39003321)
    Anecdotally, a lot of people (including many who are well-educated about the pharmacology behind drugs) swear there is a difference between some generic and brand drugs, and between the different generics. Sure, most of the time it's a placebo effect, but there are legitimate factors that can cause real differences, such as different binders and fillers being used, that can change the rate of absorption of the active ingredient, or even cause unrelated side effects or affect the bioavailability of the active ingredient. It will be interesting to see if these new, more complex molecules will widen the (perceived or real) differences between brand and generic medications.
  • by mauthbaux ( 652274 ) on Saturday February 11, 2012 @11:15AM (#39004729) Homepage
    Since there seems to be a bit of confusion here, allow me to explain (inadequately I'm sure) why different manufacturing processes for biologics result in non-identical molecules even though the DNA sequence and folding of the amino acids is the same.

    One of the primary differences is in the glycosylation of the protein. This is where sugar groups of various structures are attached to the outside of the protein and act as a sort of label to the body (distinguishing self from non-self proteins), and even within the cell itself (identifying where the protein should be placed inside of the cell). Different organisms each have their own system for attaching and interpreting these sugar groups. For instance, typical yeast Saccharomyces cerevisiae has a glycosylation profile that will cause the human immune system to attack it eventually - which will make you have an adverse reaction not only to the drug that you're taking, but any other drug produced in the same organism. The yeast Pichia pastoris has a glycosylation profile that is superficially similar to a human one, making it less likely to cause an adverse reaction, but the organism is locked down by patents. Furthermore, there's some evidence that the glycosylation is affected by the health of the cells in the culture, and the media that you're culturing them in. Frequently we'll just coat the proteins in polyethylene glycol and hope for the best.

    The other place that variation occurs is in the purification processes that are used to separate the drug molecules from everything else. Many of the purification processes will alter the glycosylation profile or the folding of the protein. They're also generally rather lossy, in that the purer the protein you want, the less of it you'll end up with, and the more it will cost. We used to attach tags to the proteins so that they were easier to purify (his6 was a common one), but then there were concerns that the tag itself would become the target for an immune reaction (which, like the glycosylation, would make a person resistant to not only the drug they were taking, but any other drug that used the same tag), so the practice has been mostly discontinued.

    The simple fact is that biologics will always result in mixed batches of molecules, and different manufacturing processes do directly affect that mix. The trick for biosilmilars will be to ensure that their mix is functionally similar enough to the original one; which will likely require clinical trials - meaning that cost savings won't be nearly so drastic as it is with small molecule drugs. While we've figured out how to make DNA translate to a protein of our choosing, we're not nearly as knowledgeable about how to manipulate sugar groups in a similar manner. Progress is being made for sure, but we're not there yet.

The intelligence of any discussion diminishes with the square of the number of participants. -- Adam Walinsky