Looking for expert commentary on generic "follow-on" biologics

Last week we spent some time discussing the shortcomings of the generic vs. brand name drug debate, focusing on an example of non-bioequivalence between the antidepressant Wellbutrin XL and its generic competitors.

Three days later, I then received an e-mail from one John Procter about a movement to get Washington to move forward on the approval of lower-priced generic biotechnology drugs now that original branded products are facing patent expiration. One source indicates that a $20 billion market value of biological products will be coming off patent by 2015. The US FDA has been reluctant to approve general formulations of biological agents that include protein hormones like erythropoietin and other protein-based therapeutics such as antibodies or antibody-toxin/radionuclide conjugates.

Dear Friend:
A virtual monopoly has limited access to biotechnology drugs for too long, costing our families billions at a time when healthcare costs continue to rise. Recent studies show Americans could save $378 billion over 20 years if generic biologics-costly drugs made by manipulating proteins-were available in the United States as they are in Europe. Although biologics are more than 20 times more expensive than traditional drugs, Washington has yet to approve generic versions in the U.S.

It is time for Washington to give us a choice of generic biotech drugs to treat diseases such as diabetes, cancer, and Alzheimer's.

We need your help!
Watch our YouTube video [or see below the fold] to Congress, and post your own video or message to lawmakers on why access to safe, affordable biotechnology drugs should happen now!

The e-mail links to this YouTube video featuring "Mike" a scientist at the Boulder, CO, biotech company, Insmed. Insmed is attempting to gain approval for their own generic forms ("follow-on" products) of protein therapeutics. Ed Silverman at Pharmalot also blogged about Mike last month.

Many readers who work(ed) in labs have experience with producing recombinant proteins in E. coli, various yeast species, insect cells, or mammalian cell hosts. You can produce a bungload of protein with very small fermenters or culture systems, which might make the average Joe Scientist think that there should be no issues with approving generic protein biologics.

However, I have produced many insoluble proteins that although resolubilized, lack biologic activity and are, therefore, useless. (Although a pharmacologist, I've actually done some circular dichroism spectroscopy to examine protein structure). In other cases, one must engineer their protein expression clones for codon optimization in the host of interest. Protein therapeutics are also often modified post-purification with polymers like polyethylene glycol to minimize their immunogenicity and/or improve plasma half-life. Producing biologically active proteins can also depends upon protein can be freeze-dried and reconstituted properly and maintaining its biologic activity.

An example of a very promising anti-cancer protein therapeutic called TRAIL is still experiencing difficulty in gaining initial approval because protein made in one expression system is terrifically toxic to the liver - expressing the protein in the presence of zinc seems to promote the proper, non-hepatotoxic conformation, the the trail to approval for this agent has been quite bumpy (pun intended - nice Hepatology PDF overview).

I am certain there are experts among our readers who have firsthand experience with innovator and follow-on protein therapeutics. In addition, we are fortunate to have readers in Europe, Australia, and other countries where follow-on protein therapeutics have been approved.

My question is this: Is the reticence of US approval for follow-on biologics based on politics, business, actual scientific challenges in producing biosimilar protein therapeutics, or a combination of the three?

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I'm not an expert, but I have had some professional interest in this area in the past. I think there is a substantial business/political component. Certainly, the big biologics firms in the US (Amgen, Genentech, Genzyme, etc.) have a vested interested in opposing follow-on biologics.

However, there are demonstrated scientific issues as well. The best case I know relates to erythropoietin. That's made as multiple different brands. It seems that certain brands have had a significantly higher risk of pure red cell aplasia, probably related to differences in formulation.

The issue there is that protein biologics have the potential to elicit immune responses, which can potentially lead to autoimmune disease. Protein immunogenicity is not fully understood, so small differences in how a biologic is made, handled, formulated, stored, and administered can theoretically have large effects on the incidence of immunologic side effects, erythropoietin being the case in point.

On the other hand, there is recombinant insulin, which is made by a variety of different companies. Yet I haven't heard of any similar brand-specific safety or efficacy issues for insulin.

Personally, I think follow-on biologics do present greater challenges than standard generics. Thus, the regulatory regimen for approving follow-on biologics may need to be a bit different. But I don't believe the barrier should remain where it is in the US now, which is essentially to treat follow-on biologics as completely new drugs.

First, a couple of basic issues of honesty. 1) Mike hasn't been "searching for cures for disease". He's been searching for ways to copy other people's cures. 2) As Derek Lowe has discussed a number of times, European approval of generics is extremely convoluted, and generic biologicals are unlikely to show up immediately upon patent expiration.

I am certain there are experts among our readers who have firsthand experience with innovator and follow-on protein therapeutics.

I'm no expert, but I work with them and know that even they are still trying to get their heads around the safety and manufacturing issues with monoclonals. Let's just say that this issue is just a bit too complicated to be settled by a freaking YouTube video.

On the other hand, there is recombinant insulin, which is made by a variety of different companies. Yet I haven't heard of any similar brand-specific safety or efficacy issues for insulin...But I don't believe the barrier should remain where it is in the US now, which is essentially to treat follow-on biologics as completely new drugs.

For small peptides, I agree. But monoclonals, which is where the real money is going to be, are far more prone to variability in form and effect. It's less far-fetched to argue that those really are essentially new drugs.

For a bibliography of sources on this topic, commentary on related news and other background information see http://www.followonproteins.com. For further information about the complexities of biogenerics/follow-on proteins/biosimilars and related issues, also see my two-part series, "What is a Generic Biopharmaceutical?," published in BioProcess International (links at www.followonproteins.com).

By Ronald A. Rader (not verified) on 25 Mar 2008 #permalink

qetzal and CC each raise important points that lead me to concur that follow-on biologicals will probably be treated as new drugs from a regulatory standpoint. The immunogenicity issue alone raised by qetzal is reason enough for new biologics to be tested in limited human trials (not a requirement for small-molecule generics). Efficacy trials also seem in order, particularly because of pharmacokinetic issues, although I wonder how in vitro surrogates might be employed to demonstrate "bioequivalence" with a branded product.

CC, I knew that Derek Lowe has held forth on this topic in the past but I'm having trouble finding the posts in his archives and there does not appear to be a search engine on at Corante.

Thank you, Mr Rader, for the reference to your site. It's a great aggregator of news and legal actions in this area.