RA focus 47

Perspective The Promise of Biogenerics: Hope and Hype

By Mukesh Kumar, PhD The year 2007 can be seen as the year when

generic biologics came to the forefront of dis-cussions in regulatory, scientific and business

circles. Three bills were introduced in the US Con-gress to create an abbreviated approval pathway for biologics, like the one for conventional drugs.1 In March, the House Committee on Oversight and Gov-ernment Reform held a hearing to discuss the need such a pathway and explore ways to create generic biotech drugs.2 Numerous reports—from profes-sional, consumer and academic groups—were pub-lished in favor of and in opposition to the quick approval of regulations allowing generic biologics. One of the major reasons for this hoopla was that several important FDA regulations (including PDUFA and MDUFMA) were coming up for reauthorization in 2007 and the major stakeholders promoting bioge-nerics saw an opportunity to insert provisions for them. However, after prolonged and sometimes con-tentious discussions, biogenerics were omitted from the FDA Amendments Act of 2007, which was signed into law on 27 September. One wonders if biogener-ics were excluded as the result of political pressure from influential groups or an extremely cautious approach on the part of the legislators.

Three major factors influence the future of true biological generics. First, due to the complex nature of biologics, a strong scientific case can be made that it is practically impossible to create an exact copy of a biologic drug. FDA has stated many times that the “process is the product,” and minor differ-ences in manufacturing could lead to major changes in the clinical outcomes of a generic product.3 Both FDA and EMEA have resisted the term “biogener-ics,” preferring the terms “biosimilar” and “follow-on biologics” to emphasize that while products might

be “similar,” they are not necessarily “bioequiva-lent.”4,5 It has also been stressed that to be

truly substitutable, a product would require extensive and costly preclinical testing and clinical trials.

Second, there are no regulatory short-cuts, like the ANDA, for biogeneric approval. FDA has approved some follow-on proteins on a case-by-case basis without requiring extensive preclinical and clinical testing. Nev-ertheless, the amount of testing required by FDA for these follow-on proteins was much

higher than that for generic drugs. More importantly, all were approved in the manner of innovator prod-ucts, not as substitutable generic versions. The oft-cited EMEA “biosimilar” guidance is unequivocal in stating the need for much more clinical and preclini-cal data to prove safety and comparability than is expected for generic chemical drugs. While the sup-porters of biogenerics would like to lift parts of the EMEA process to justify similar regulation in the US, the EMEA process is not an ANDA-style shortcut for biologics and does not define substitutability of biosimilars for innovator products.

Third, unlike a chemical drug, a biologic typically is covered by multiple patents, not only on the prod-uct, but also on many of the basic research tools used to develop it. In addition, manufacturing might use proprietary processes covered by trade secrets. While the patents have a finite life, trade secrets can remain protected forever. FDA may, however, refer to non-public proprietary information to compare a similar product’s safety and efficacy.6 Still, extensive use of proprietary technologies makes it much more difficult to create true copies of biologics.

Are We Ready for Biogenerics?Despite the obvious hurdles to biogenerics, there is an enormous push in their favor. Generic manufac-turers want access to the potentially huge market for these products, while consumer groups and legisla-tors see the promise of significant cost reduction.7 However, FDA’s major concern is safety.3,4 The bio-equivalence of biogenerics must be defined and vali-dated. Plato said, “Necessity is the mother of invention.” The technology to evaluate similar biologic products without extensive human testing will develop with time and, for at least a few biologics, such tech-nology already exists. But there is no one-size-fits-all approach and probably never will be.

While no one denies that biogenerics will lead to cost savings, there is disagreement about the extent thereof. One projection of potential cost savings is about $70 billion over 10 years;8 however, other esti-mates project modest savings of less than $4 billion over 10 years.9,10 The lower projected numbers dampen the spirit of consumer groups expecting huge savings. The development of each biogeneric product will be a lengthy, complex process, and is projected to cost about $200 million, compared to

New meetings are always being added! Visit www.raps.org/educationcalendar to view the most up-to-date education offerings.

Determine your Level of Learning! Visit www.raps.org/levels

Date Program Levels RAC Points Location Venue

24–25 January Strategies for Prelaunch Success

III, IV 12 Las Vegas Bally’s Las Vegas

31 January–1 February

Preparing Compliant eCTD Submissions

II, III, IV 12 Rockville, Maryland

RAPS Headquarters

10–11 March Principles & Practices of EU and US Medical Devices

I 12 Munich ArabellaSheratonWestpark

26–28 March 2008 RAPS Horizons Conference & Exhibition

II, III, IV 12 SanFrancisco

The Fairmont San Francisco

12–13 May Advertising, Promotion & Labeling Conference

I, II, III 12 Baltimore RenaissanceHarborplace Hotel

31 July–1 August Strategies for Postlaunch Success

III, IV 12 Vancouver Hyatt Regency Vancouver

14–17 September 2008 RAPS Annual Conference & Exhibition

I, II, III, IV 12 Boston Hynes Convention Center

13–14 November Regulatory Strategy Forum II, III 12 Orlando Walt Disney World Dolphin

Advance your career. Stay up-to-date on

changing regulations. Expand your business

knowledge and leadership skills. Earn RAC

recertification points.

Attend a RAPS conference or seminar and get what you need to get ahead.

Build Your KnowledgeInternational and Regional Conferenceswww.raps.org/educationcalendar

Webcastswww.raps.org/webcasts

Online Universitywww.raps.org/onlineu

Professional Development Portalwww.raps.org/pdp

2 0 0 8 R A P S E D U C A T I O N C A L E N D A R

EduCalendar_0108.indd 1 11/20/07 3:20:08 PM

Perspective

approximately $30 million for a traditional generic drug. This leads to the assumption that only a few generic firms will be able to afford the required investments, and only products with a significant market will be developed. Fewer entrants in the biogeneric field could mean a lack of the robust competition required for cost reduction. Still, for treatments that cost thousands of dollars a year, a saving of 10% to 20% might be enough to justify development. Consumer acceptance of bio-generics will be critical to determining market size. Since it may not be possible in the near future to have truly substitutable generic versions of biologics, physi-cians will need to prescribe specific biosimilars. Pre-scribing a biosimilar product with some unknowns rather than an established innovator product could raise some ethical issues. However, once biosimilars have established credibility and are widely accepted, more players will be willing to risk investment in this field, resulting in further cost reductions.

Generic biologics hold great promise. It is inevita-ble that regulations for biosimilars or follow-on biologics will be implemented in the near future; the “hype” for these products is simply too high for politicians to ignore. But, it would be prudent for the policymakers to tread carefully in order to truly harness the “hope” of safe, efficacious and cost-effective products.

REfEREnCES1. Access to Life-Saving Medicine Act; H.R. 1038 & S. 623, 110th

Cong. (2007). Affordable Biologics for Consumers Act; S. 1505, 110th Cong. (2007). Patient Protection and Innovative Biologic Medicines Act of 2007; H.R. 1956, 110th Cong. (2007).

2. March 2007, the House Committee on Oversight and Govern-ment Reform (chaired by Representative Henry Waxman (D-CA): “Hearing on Safe and Affordable Biotech Drugs – The Need for a Generic Pathway.”

http://oversight.house.gov/story.asp?ID=1223 3. Janet Woodcock, et al. (2007). “The FDA’s assessment of fol-

low-on protein products: A historical perspective.” Nature Reviews: Drug Discovery. Vol. 6, p 437-442.

4. www.ftc.gov/speeches/harbour/070614genbio.pdf 5. EMEA Guidelines for Similar Biological Medical Products.

CHMP/437/04, 30 October 2005.6. Yoo JC. “Taking Issue in the Approval of Generic Biologics.” 60

FOOD & DRUG L.J. 33 (2005)7. Conko G. “Healthy Competition: The Case for Generic and Fol-

low-on Biologics.” www.cei.org/pdf/5933.pdf 8. Miller S & Hounts J. “Potential Savings of Biogenerics in the

United States.” Express Scripts. February 2007.9. www.avalerehealth.net/research/docs/Modeling_Budgetary_

Impact_of_FOBs.pdf 10. http://faculty.fuqua.duke.edu/health_sector_management/hsac/

files/oct%2020_26_2006/Biogenerics_Ridley%20et%20al.pdf

AUTHORMukesh Kumar, PhD, is a Senior Director, Regulatory Affairs, at Amarex Clinical Research LLC, a full-service CRO offering complete trial management services for global clinical trials, located in Ger-mantown, MD. Kumar is a member of the RAPS Board of Editors for Regulatory Affairs Focus and can be reached at mukeshk@amarex-cro.com.

DISClAIMER: Views expressed in this article are those of the author and do not imply those of the organization with which the author is affiliated.

New in the RAPS Bookstore

Your single source for regulatory resources,

featuring: Clinical, Drugs, Biologics,

Medical Devices and Quality Standards.

RAPS has expanded its bookstore with new products that promote the occupational advancement of regulatory affairs professionals around the world. RAPS Bookstore products help you prepare for the RAC exam, learn more about the industry and increase your knowledge-base.

Key Topics in RA: Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD)

This newly updated and expanded guide offers a useful compilation of guidelines on the Common Technical Document submission process. It will provide you with everything you need to know to prepare and submit a CTD in the EU and US, all in one convenient publication.

Member Price: $29.95 Nonmember Price: $34.95

Key Topics in RA: Specification and Guidance for the Electronic Common Technical Document (eCTD)

This newly updated and expanded guide offers a useful compilation of guidelines on the electronic Common Technical Document submission process. It will provide you with everything you need to know to prepare and submit an eCTD in the EU and US, all in one convenient publication.

Member Price: $29.95 Nonmember Price: $34.95

C O M P I L E D B Y T H E R E G U L AT O R Y A F F A I R S P R O F E S S I O N A L S S O C I E T Y

KEY TOPICS IN RA:

Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD)

C O M P I L E D B Y T H E R E G U L AT O R Y A F F A I R S P R O F E S S I O N A L S S O C I E T Y

KEY TOPICS IN RA:

Specifications and Guidance for the Electronic Common Technical Document (eCTD)

2007 eCTD cover.indd 1 9/13/07 10:58:51 AM

Visit www.raps.org/bookstore to view the table of contents for these two publications and browse the full range of publications that RAPS has to offer.