Many of the next blockbustersmay well be biologics. Two anti-diabetic drugs, Symlin (pramlintideacetate) and Exenatide (synthetic ex-endin-4), meet the definition of abiologic. So do the monoclonal anti-bodies and TNF inhibitors, as well as

angiogenesis inhibitors — such asthe newly released Avastin (beva-cizumab) and Erbitux (cetuximab).

ORGANIC ORIGINSCurrently, there is no simple way

to define all the drugs that are re-ported to be biologics. There aremultiple factions that wish to de-fine biologics in various ways. Somewould apply a strict definition ofbiologics dictating that these prod-

BIOLOGICS 101

ucts share two critical traits that dis-tinguish their physical makeupfrom chemically derived drugs:only living systems can producethem, and biologics are relativelylarge molecules, with an inherentlyheterogeneous structure that can

contain hundreds of amino acids.Some groups would expand the

definition of biologics to includeany substance composed of organicmolecules, no matter how small.Still others feel that any biologicallyderived product can be called a bio-logic, and still more think that anycomplex molecule — no matterhow it is manufactured — shouldbe in this class. Others would in-clude substances that are created in

other organisms but are not highlycomplex, such as the estrogen hor-mones extracted from pregnantmare urine (Premarin).

No matter what definition isused, it is likely to need to be modi-fied as new products are brought to

market. With a few exceptions, thisarticle will use the definition thatbiologics are created by either amicroorganism or mamallian celland are large complex molecules,most of which are proteins or poly-peptides.

Chemical drugs are often morepure and better characterized bycurrent analytical technology thanbiologics. A biologic agent’s activitymay be affected by the cell system in

24 BIOTECHNOLOGY HEALTHCARE · SEPTEMBER 2004 SEPTEMBER 2004 · BIOTECHNOLOGY HEALTHCARE 25

brosis, growth deficiency, diabetes,hemophilia, hepatitis, genital warts,transplant rejection, and cancers.Biologics predict genetic propen-sity to diseases such as Parkinson’sdisease. Nondrug biologics includecultured tissues and immune sys-tem suppressants for transplanta-tion and growth factors for tissuereconstitution to treat conditionssuch as diabetic foot ulcers.

As with small-molecule drugs,research and development of bio-logics is expensive and risky, oftenending in failure. While pharma-ceutical companies target the mostcommon diseases and conditions,biotech has tended to target moredifficult-to-treat populations thatwould be too small for pharmaceu-tical companies to be able to recoupdrug-development costs. Yet, newerbiologics also are targeting wide-spread diseases, with profound im-plications: a drug that costs $20,000per year that is useful for 1 person in100,000 has much less effect on ahealth plan’s cost structure than a$5,000-per-year drug that is usefulfor 1 in 100 people.

ing the concept further, it holdspromise for predicting health sta-tus and acting accordingly — thevery notion of prevention on whichmanaged care was founded.

None of this is inexpensive, how-ever, thus posing profound issuesof resource use and appropriate se-lection of patients. Purchasing andusing biologic agents effectively,then, necessitates an appreciationof their enigmatic activity and struc-ture, the specificity of their action,and the ways in which they differfrom traditional therapeutic agents.

OLD IDEA, NEW ADAPTATIONBiologics are not new; develop-

ment of human growth hormone,insulin, and red-blood cell stimu-lating agents occurred decades ago,but the targets have increased ex-ponentially with new genetic infor-mation and new understanding ofsubcellular cascades and diseaseprocesses. Scientific fields used indeveloping biologics include ge-nomics and proteomics, as well asmicroarray, cell culture, and mono-clonal antibody technologies.

Increasing knowledge of genet-ics and cell processes leads topotential new biologic (and drug)targets at each step in the protein-production process. This leads tonew therapies, which in turn lead tonew understanding of diseases.

Biologics have identified new tar-gets for treating anemia, cystic fi-

Thomas Morrow, MD, is president of theNational Association of Managed CarePhysicians and vice president and medicaldirector of Matria Healthcare. He has 20years of managed care experience at thepayer or health plan level.

DEFINING THE DIFFERENCE: WHAT MAKES BIOLOGICS UNIQUE

Biologics differ from chemically deriveddrugs in ways that affect their cost,

production, adminis-tration, and clinical efficacy. Here’s a look at the most importantdifferences and theirimplications.

BY THOMAS MORROW, MD

With Linda Hull FelconeSenior Contributing Editor

The difference between thealmost right word and theright word is really a largematter — it is the differ-

ence between the lightning bug andthe lightning.” Mark Twain’s obser-vation on the importance of threelittle letters applies to the differencesbetween biologically and chemicallyderived medications. This time,though, the three letters are DNA.

Protein-based biologics and de-vices are used to treat everythingfrom wrinkles to rattlesnake bites,and range from natural protein su-tures to fibrinogen coagulant fac-tors. Biotechnological applicationsin healthcare encompass prophy-lactic agents, in vivo diagnostic tools,and therapeutic products. Biotech-nology provides imaging agentsand molecular diagnostic tests fordetecting a wide range of healthproblems, from excessive LDL lev-els to drug-resistant HIV strains.

Advances in this field are rapidlyturning Western medicine insideout. Rather than start with a diseaseand search for its origin, biotechmedicine begins with the detectionof a genetic variation and relies ontherapies that manipulate it. Carry-

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Though most of today’sblockbusters are chemicallyderived, the next generationof blockbusters could be biologics, says authorThomas Morrow, MD.

BIOLOGICS 101

26 BIOTECHNOLOGY HEALTHCARE · SEPTEMBER 2004

which it is produced, the fermenta-tion media, or operating conditions.

The production process of chem-ical drugs is relatively well defined,which allows these drugs to be pro-duced in uniform large quantities.Biologics, however, have a complexproduction process that tends toyield small quantities. It is difficult toscale up biologics from laboratory

quantities used for early analysis andpreclinical testing to larger-scalebatches and maintain product purityand batch-to-batch equivalence.

Biologics are often extremely sen-sitive to physical conditions (tem-perature, shear forces, chemicalphase, and light) and enzymatic ac-tion. They usually require complexbioassays for batch release and sta-bility assessment, rather than chem-ical tests for identity and purity.

HOW THEY WORKThe therapeutic target of a bio-

logic is always a gene or a protein.The fact that genetic information isdecoded similarly among all cells,regardless of species, allows hu-mans to study gene function inworms or zebra fish.

Recombinant DNA, an impor-tant process for producing biolog-ics, requires isolating the DNA fromhuman cells and potentially modi-fying that DNA segment, insertingit into bacteria or a mammalian cell,and getting that organism or cell toexpress it. Several steps are involved

in the development process: locat-ing genes that code for proteins,cloning genes, reproducing the pro-teins associated with the genes, de-termining the role of the proteins inthe disease process, and then devel-oping a potential therapy.

All new proteins that are identi-fied undergo a series of cell-basedassays providing information on

how a specificprotein changesa biological pro-cess. Bioassays todetermine po-tency use biolog-ical indicators ofliving organismsor tissues. These

can include cell-based tissue cul-tures, microarray expression tech-nology, knockout animal models,transgenic animal models, and anti-sense or antibody technology (e.g.,diagnostic antibody characteriza-tion).

There is a greater potential forimmune reactions to biologics thanto chemical drugs. The molecules inchemical drugs are too small to beconsidered immunogenic and gen-erally are not recognized by the im-mune system as “invaders.” Withbiologics, depending on the drug,the human immune system canquickly identify the molecule andthen mount an immune response toclear away a large molecule that itconsiders a foreign substance. Thiscan destroy — or in rare cases, en-hance — the activity of the bio-pharmaceutical.

Almost all biologics can inducethe production of antibodies,though most antibodies have be-nign clinical consequences. Theantibodies may be caused by tinycontaminant fragments, contact

with the patient’s serum, or post-dose enzymatic cascades.

COMPLEX MANUFACTUREThe fragility of biological macro-

molecules and the sensitivity of theliving cells that produce biologicsimpart complex manufacturing re-quirements for fermentation, asep-tic processing, storage, and testing.Although the active ingredient of a chemical pharmaceutical is usu-ally a unique molecule subject towell-established analytical tests, forbiologics, the active componentoften is a portion of a large macro-molecule. That macromolecule isin turn a modification of the origi-nal protein or polypeptide andother biological substances thatmay not be clearly characterized.Protein and polypeptide productscan contain variable complexes,meaning that they have variablenumbers of identical componentsin the molecules. Also, biologicsmay have differences in their sur-face sugars (glycosylation) or fold-ing patterns, depending on howthey are produced. With biologics,there is also potential for microbio-logical contamination of the start-ing materials.

Because biologics are often heter-ogeneous in the molecules and/orpolypeptides present, they have animpurity profile that depends on —and can vary with — the processesused to make and test each batch.With biologics, the protein mixmust be defined, and the activeagent and supporting agents mustbe characterized. In other words,the product does not need to behomogeneous if the biologic actsvia a molecular group. Blood, forinstance, is a biologic (according toU.S. Food and Drug Administration

The use of living organisms toproduce therapeutic extracts isnot new. What is new is manipu-lation of these organisms’ geneticsto produce specific therapeutics.

BIOLOGICS 101

28 BIOTECHNOLOGY HEALTHCARE · SEPTEMBER 2004

and critical testing required of bio-logics.

DOSAGE AND DISTRIBUTIONBiologics can cost thousands of

dollars monthly and require spe-cial handling, as they are often lessstable than chemically deriveddrugs and require controlled tem-perature and light, as well as pro-tection from jostling when in liquidform. For example, many large pro-teins cannot be shaken to reconsti-tute, as shaking can destroy theprotein structure.

Biologics are medications tar-geted to specific genotypes or pro-tein receptors. They are most com-monly stored, handled, anddelivered by specialty pharmacies,distributors that specialize in ad-ministering complex-moleculeproducts for small populations andhave specialized handling and pro-cessing and mailing processes inplace to accommodate these com-plex medications. In many ways,biologics are considered designerdrugs that are targeted for patientswith uncommon diseases or for ge-netic subclasses of patients whohave widely prevalent diseases.

For some very rare disorders,such as Gaucher’s disease, the num-ber of patients in the United Statesmight not exceed 1,000. The highcost of developing and marketing aproduct, combined with a small tar-get population translates into a con-siderable per-patient cost. Often,specialized clinics treat patientsand/or administer these drugs.

Dosage forms of chemical drugsare highly variable, and concentra-tions usually are easy to determine.Yet, because biologic molecules aretoo large to be taken orally withoutbeing destroyed before passing

classification) that is not composedof a single uniform molecule.

This is not to suggest that there isa lack of quality-control measuresfor biologic manufacture; actually,just the opposite is true. A typicalmanufacturing process for a chem-ical drug might contain 40 to 50critical tests. The process for a bio-logic might contain 250 or more.Biologic production uses special-ized processes that do not alwaysresemble facilities, machinery, orequipment used to produce chemi-cal drugs. Construction and valida-

tion of new facilities is dispropor-tionately expensive and also timeconsuming. This helps explain theglobal shortage of biomanufactur-ing capacity and the cost differentialbetween biologic and chemicaldrugs.

Changing a manufacturing pro-cess typically presents fewer chal-lenges with chemical drugs than itwould with biologics. Chemicaldrug batches are released accordingto specifications for the drug sub-stance and the final product, with-out the extensive characterization

Selected categories of biologic agent structure

Hormone (growth hormone, parathyroid hormone, insulin): A sub-stance, usually a peptide or steroid, produced by one tissue and con-veyed by the bloodstream to another to effect physiological activity,such as growth or metabolism.

Interferons: Proteins that are normally produced by cells in responseto viral infection and other stimuli.

Interleukins: A large group of cytokine proteins. Most are involvedin directing other immune cells to divide and differentiate.

Growth factor: A substance such as a vitamin B12 or an interleukinthat promotes growth, especially cellular growth.

Monoclonal antibodies (MAbs): A single species of immunoglobulinmolecules produced by culturing a single clone of a hybridoma cell.MAbs recognize only one chemical structure, i.e., they are directedagainst a single epitope of the antigenic substance used to raise theantibody.

Polypeptides: Peptides containing ten or more amino acids. Typi-cally, a peptide consists of fewer than 50 amino acids, while a pro-tein has more than 50 amino acids.

Proteins: Naturally occurring and synthetic polypeptides having mol-ecular weights greater than about 10,000 (the limit is not precise).

Vaccine: An agent containing antigens produced from killed, atten-uated or live pathogenic microorganisms, synthetic peptides, or byrecombinant organisms. Used for stimulating the immune system ofthe recipient to produce specific antibodies providing active immu-nity and/or passive immunity in the progeny.

SOURCES: International Union of Pure and Applied Chemistry Compendium of Chemical Terminology, 2nd edition, 1997; Cambridge Healthcare Institute «www.genomicglossaries.com»; National Multiple Sclerosis Society Sourcebook«http://www.nationalmssociety.org/Sourcebook.asp».

through the intestine into the bloodstream, they usually are injected orinfused. Also, potency is more dif-ficult to quantify for biologic agents,and monitoring is a key componentof early therapy.

New modes of administration,such as via food that is directly or in-directly transgenic, are being stud-ied. An example of the latter isgoat’s milk that produces an anti-malarial compound. Transdermallyadministered vaccines also areunder investigation.

REGULATORY ISSUESThe FDA precisely defines bio-

logic therapies and devices forregulatory purposes. A product’sintended use may dictate its clas-sification — e.g., an in vitro diag-nostic kit may fit a classic definitionof a medical device but may still bedefined as a biologic, as it is used totest and release a licensed biologicalproduct such as blood. A similar kitused to test blood samples for diag-nosing a disease like rubella, or formonitoring a disease’s progress,may fall under medical device regu-lations due to its usage in diagnosinghuman disease.

With biologic products, the man-ufacturing process is part of thepatent and is subject to regulatoryapproval. Process changes triggerthe need for new clinical trials, yield-ing greater development costs.Partly to remedy this, the FDA’s Cen-ter for Biologics Evaluation and Re-search (CBER) has developed draftguidelines for a postapproval com-parability protocol allowing com-panies to combine several manu-facturing changes into a singleabbreviated postapproval applica-tion when they change their process.Companies are not required to du-

BIOLOGICS 101

SEPTEMBER 2004 · BIOTECHNOLOGY HEALTHCARE 29

plicate clinical studies after a drugmanufacturing change, if they canshow that it is bioequivalent andcauses no new adverse reactions.

Many biologic products — somevaccines, gene therapies, antitoxins,blood, and some in vitro diagnostics,to name a few — are approved byCBER. Remaining categories, in-cluding monoclonal antibodies,growth factors, enzymes, immuno-modulators, and thrombolytics, arethe domain of the Center for DrugEvaluation and Research (CDER).Generic (more accurately, follow-on) biologics are not legal in theUnited States, and no regulatorypathway exists for their approval.

With pretreatment genetic test-ing, large clinical studies may be-come obsolete. Conventional clini-cal trials involve extrapolation tolarger populations to predict medi-cal outcomes in much larger popu-lations; to date, however, biologicshave not been aimed at large hetero-geneous populations, so conduct-ing large trials is wasteful. Also, therisk/benefit ratio of a drug for anotherwise fatal disease is skewed to-ward efficacy versus safety. This isnot true of a conventional drug fora chronic condition, such as hyper-tension — for which there are manyrelatively safe treatment options.

WEIGHING COSTS, VALUEBiologics, though much more ex-

pensive than chemical entities, aregenerally considered by health careproviders and payers to be worththeir cost — as long as the appro-priate patients receive them andachieve the desired clinical out-comes. Patients for whom biologicsare a good value include those whohave failed on conventional thera-pies or for whom no other options

exist. For some drugs, assays assistin patient selection. The cost ofDNA-based tests and the expenseof educating clinicians on their usemust be factored into the net value.

EXCITING FUTURELooking ahead, several promis-

ing technological advances are invarious stages of readiness, eachwith deep implications.

RNA interference allows bettercharacterization of the function ofa specific gene or DNA fragment.Antisense molecules (small piecesof DNA or RNA) prevent produc-tion of the protein encoded in thatblocked DNA or RNA, effectively“knocking out” the gene. Theknockout procedure also is used todetermine the function of a specificgene in laboratory animals. Thisknowledge then can be extrapo-lated to corresponding humangenes. The physical manifestationof a trait or disease is usually theculmination of many steps involv-ing a protein-to-protein chain re-action, starting from gene expres-sion and going through a cascade ofsmall events in which a moleculeis changed by enzymes and thenhanded off to other enzymes forfurther changes.

Scientists are studying the rela-tionship among genes, traits, andproteins by blocking gene expres-sion and characterizing the result-ing biological or visible changes.The knowledge gained will help intargeting future therapies. Replace-ment gene therapy, which targetsdiseases such as hemophilia causedby the lack of a protein, is one di-rection of research.

Science is rapidly unlocking thesecrets of human DNA. Healthcareis catching up with it. BH