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Regulation of Follow on Biologics

Regulation of Follow on Biologics

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Published by: Narendrakumar on Jan 08, 2009
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august 30, 2007
n engl j med
www.nejm.org august
pharmaceuticals date back to the1980s, the first generation of suchdrugs has begun to lose patent protection (see table). In otherparts of the world, governmentshave crafted regulations definingthe terms of competition from“imitator,” or generic, products.Many analysts have expressedconcern that without new U.S.regulations, patent expirationsmay not be accompanied by theintroduction of competing, lower-cost biologic agents — or that imitator products might be ap-proved without sufficient proof of efficacy and safety, posingthreats to public health. Althoughsome biopharmaceutical productsare nearly as simple as tradition-al small-molecule drugs, the vast-ly increased complexity of othersmeans that it will be more dif-ficult to ensure that an imitatorproduct is biologically and func-tionally equivalent to the original.Because it may not be possibleto create “true” generic versionsof biopharmaceuticals, the term“follow-on biologic” is often usedto refer to a new version of anexisting biopharmaceutical that uses the same mechanism of ac-tion and treats the same clinicalindications as the original.The Drug Price Competitionand Patent Term Restoration Act of 1984 (the Hatch–Waxman Act)offers a starting point for con-sidering regulation of the use of follow-on biopharmaceuticals (seebox). This law, which is widely considered a success, governs theuse of traditional generic medi-cations. It establishes a low-cost path to market for generic imi-tators and requires their manu-facturers to demonstrate bioequiv-alence but not to repeat humantrials demonstrating efficacy andsafety. The law also establishesminimum periods of market ex-clusivity for brand-name products.It took a number of years forthe Hatch–Waxman Act to exert its full effect on prescription-drug prices. At first, many physi-cians were reluctant to view gener-ic drugs as fully interchangeable with brand-name products. Dur-
Regulation of Follow-on Biologics
Richard G. Frank, Ph.D.
iopharmaceutical products, with U.S. sales in2006 amounting to about $40.3 billion, are in-creasingly central to the treatment of major healthproblems affecting Americans.
Since modern bio-
Copyright © 2007 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org on December 30, 2008 . For personal use only. No other uses without permission.
n engl j med
www.nejm.org august
ing the late 1980s, a brand-namedrug generally lost about 15 to30% of its sales volume in thefirst 2 years after its patent ex-pired.
In contrast, when Eli Lilly lost patent protection for the anti-depressant drug Prozac (fluoxe-tine) in 2001, generic competi-tors garnered more than 70% of Prozac’s market within 2 months.
 Today, brand-name drugs that face generic competition rapidly lose market share, and prices of generic products generally fall to25 to 50% of the original brand-name prices.
Although intenseprice competition reduces the fi-nancial returns for brand-namedrugs, the patent period providesimportant protections, and the in- vestment of U.S. drug companiesin research and development hasgrown rapidly — from $26 billionin 2000 to about $43 billion in2006.
It was possible to achieve thebenefits of the Hatch–WaxmanAct because the Food and DrugAdministration (FDA) could re- view data establishing bioequiva-lence and be confident that dataon the safety and efficacy of theoriginal drug would apply to ge-neric versions as well. Biopharma-ceuticals are frequently muchmore complex than small-mole-cule drugs, and their manufac-ture often entails the use of livecells and complicated biologicprocesses that are difficult toreplicate. Indeed, the manufactur-ing process can be a trade secret.Thus, obtaining evidence that adrug is similar to and will havethe same effects as the original ismore complicated for biopharma-ceuticals.The European Union is aheadof the United States in dealing with these issues, although theFDA has begun to address themin an ad hoc fashion. Any U.S.policy in this arena will no doubt share some basic features with
regulation of follow-on biologics
Key Provisions of the Hatch–Waxman Act.
Creates an abbreviated approval process for generic pharmaceuticalsRequires the manufacturers of generic drugs to demonstrate bioequivalence to brand-name products but allows them to rely on originators’ clinical trials to establishsafety and efficacyAllows testing before the originators’ patents expireCreates an incentive for generic-drug manufacturers to challenge originators’ patentsSets forth a process for handling patent disputesDefines the conditions for patent extensions
Top-Selling Biopharmaceuticals Approved before 1993.*DrugIndicationApproval Date2003 Sales
$ (millions)
Humulin (human insulin)DiabetesOctober 19821,060Intron A (interferon alfa-2b)Cancer, infectionJune 19861,851Humatrope (somatropin)Growth failureMarch 1987371Infanrix (diphtheria–tetanus–pertussis vaccine)Immunization against diphtheria,pertussis, and tetanusMarch 1987551Epogen (epoetin alfa)AnemiaJune 19892,435Engerix-B (hepatitis B vaccine)Immunization against hepatitis BAugust 1989684Botox (botulinum toxin type A)Cervical dystoniaDecember 1989564Epogin (epoetin beta)AnemiaApril 1990551Procrit (epoetin alfa)AnemiaDecember 19903,984Neupogen (filgrastim)NeutropeniaJanuary 19911,267Cerezyme (imiglucerase)Gauchers diseaseApril 1991739NovoSeven (recombinant factor VII)HemophiliaApril 1992589* The patents on these products expire after 20 years; most patents are applied for during the drug-development stage. Dataare from
“Top 200 World’s Best Selling Medicines” (2004;23(5):60-4).
Copyright © 2007 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org on December 30, 2008 . For personal use only. No other uses without permission.

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