Follow-on Biologi

A Brief Overview

Rachel E. Behrman, M.D., M.P.H.Associate Commissioner for CliniDirector, Office of Critical Path PrNovember 2008
A Drug Product 

―

• As defined in Federal Food, D

Cosmetic Act (FD&C Act):

articles intended for use in the diagnmitigation, treatment or prevention oman or other animals; articles intendthe structure or any function of the bother animals.
A Biological Produ

• As defined in Section 351(i) of th

Health Service Act (PHS Act):“...a virus, therapeutic serum, toxvaccine, blood, blood component derivative, allergenic product, or product, or arsphenamine or deriarsphenamine (or any other trivaarsenic compound...)”
Wide Spectrum of Pro

• Cells, living tissues, vaccines, blood (all re

biological products)

• Proteins 

– Consist of chains of amino acids linked – Range from 

• Simple to large and highly complex• Highly purified, well characterized sy

recombinant to relatively crude extraanimal, or plant source

– May be regulated as biological products 

depending on type of protein and use (a
Levels of Protein Stru

Primary

Secondary

Tertiary Quatern
Proteins have expected:

• Size, charge, hydrophobicity• Correct folding (S-S bonds)• Subunits• Glycosylation• Bioactivity& Unexpected:• Aggregation (side effects)• Incorrect folding

• Amino acid modifications 

– ox, deam, cyc

• Truncation, proteolysis

Structure of Small Movs Protein Drugs

Therapeutic protein ~5,0

*
Abbreviated Applica

• One that relies, to at least some ex

Agency’s conclusions about the saeffectiveness (or safety, purity, and of an approved (or unlicensed) pro

• Under the PHS Act – no explicit pa• Under the FD&C Act – two pathwa

– 505(j)– 505(b)(2)
Terminology

• Pharmaceutical Equivalents

Drug products in identical dosage forms that contain identical a

active drug ingredient or (e.g., for modified release dosage formamounts of active drug ingredient over the identical dosing per

• Bioequivalence

The absence of a significant difference in the rate and extent to ingredient becomes available at the site of drug action when adconditions 21 U.S.C. 355(j)(8)

• Therapeutic Equivalents

Approved drug products that are pharmaceutical equivalents abioequivalence has been demonstrated Therapeutic equivalents can be expected to have the same clin

profile when administered under the conditions specified in the an "A" equivalence evaluation code in FDA's Orange Book

• Substitutable

It is FDA's position that products classified as therapeutically esubstituted with the full expectation that the substituted produc

clinical effect and safety profile as the prescribed product. 
Other Relevant Term

• Comparability

The comparison by the manufacturer of a product before and after a manufacturing demonstrate that the safety, identify, puritremain unchanged http://www.fda.gov/cder/Guidance

• Follow-on

Informal term, referring to products intendsufficiently similar to an approved product applicant to rely on certain existing scientiabout the safety and effectiveness (or safpotency) of the approved product
Potential Regulatory Con

• Is the product sufficiently similar to a lice

to allow reliance on existing scientific knthat product?

• If so, does the Agency have access to th

the conclusions about safety and efficac

• What additional information is needed to 

claim of “safe, pure and potent”?

• Are there any data provided that would s

safety to “switching”?
Consider the Follow

• In most cases, at this time it will be impos

that active ingredients are identical for fo

• The more complex the product, the more 

expensive) it is to manufacture. 

• Concerns about immunogenicity will likely 

addressed in any follow-on application.

• Review of any application involves makin

of what is in the best interest of the publicinformation; uncertainty is almost always the approval of any drug or biological pro
Overarching Princip

“The agency has a longstandinof permitting appropriate relianwhat is already known about a thereby saving time and resources...and avoiding ethicconcerns associated with unneduplication of...human testing

(“FDA’s assessment....” In Nature D
References

• Janet Woodcock, M.D., Statement before the Committee on O

Government Reform, US House of Representatives http://oversight.house.gov/documents/20070326104056-2210

• “FDA’s assessment of follow-on protein products: a historical 

Reviews Drug Discovery, 2007 Jun (6):437-42.

• U.S. Food and Drug Administration, Guidance for Industry: P

Evidence of Effectiveness for Human Drug and Biological Pro

http://www.fda.gov/cder/guidance/1397fnl.pdf. 

• U.S. Food and Drug Administration, Citizen Petition Response 

Approval of NDA 21-426 for Ominitrop 5.8 mg Somatropin [rDLyophilized Powder and Diluent with Preservative, May 30, 20http://www.fda.gov/ohrms/dockets/dockets/04P0231/04P-023

• ”Economic issues with follow-on protein products,” Nature Rev

2008 Sept (7):733-37.