The Risk of Biogenerics

    By Kevin E. Noonan --

Follow-on biologic drugs, or biosimilars as they are called in Europe, are once again the subject of attempts by Congress to provide a regulatory pathway for approval.  Currently, these drugs are not regulated by the Food, Drug and Cosmetic Act and hence not subject to the provisions of the Hatch-Waxman Act that promote generic versions of small molecule drugs.  In this Congress, as in the last Congress, several bills have been introduced to "correct" this situation and provide a means for regulatory approval of generic versions of biologic drugs.

A good deal of the debate on these bills, and lobbying over their provisions, has focused on the term of data exclusivity that innovator biotechnology and biologics drug companies would be granted under any regulatory regime.  These periods range from 3.5 to 5.5 years in Congressman Waxman's bill (H.R. 1427) and Senator Schumer's related bill (S.726), to 12 years in Congresswoman Eshoo's bill (H.R. 1548), to a proposal by Senator Kennedy to provide up to 13.5 years of data exclusivity.  Several white papers and other academic and quasi-academic reports have been promulgated, advocating 7 years (see "Former House Ways and Means Economist Claims 7-Year Data Exclusivity Period Is Sufficient") and 14 years (see "Follow-on biologics: data exclusivity and the balance between innovation and competition" and "AEI Believes Advantages of Longer Data Exclusivity Period Outweigh Disadvantages") of data exclusivity, while the Office of Management and Budget and the Congressional Budget Office have recommended 7 years (see "White House Recommends 7-Year Data Exclusivity Period for Follow-on Biologics" and "BIO Says CBO Estimate of Follow-on Biologics Savings Is Based on 'Troubling Assumption'") and the Federal Trade Commission has (remarkably) recommended no data exclusivity, based on its idiosyncratic analysis of likely types and sources of competition (see "No One Seems Happy with Follow-on Biologics According to the FTC").

What have been overlooked in the debate are other important aspects of biogeneric drugs, specifically first, what kinds of products will be considered "biosimilar," and second, will biosimilar and innovator biologic drugs be "interchangeable."  What constitutes a "biosimilar" can differ widely in definition, accommodating differences in primary amino acid sequence, post-translational modifications, level of impurities, the mechanism of action, and the mode of administration.  Patient safety concerns mandate that the biosimilar have no clinically-meaningful differences in safety, purity, or potency, a goal that becomes more difficult to achieve due to the complexities of biologic drugs.  Consequently, there is the possibility of increased risk of adverse events proportional to the amount of variability permitted in follow-on biologics (FOBs) that are considered "biosimilar."  The nomenclature is accurate:  unlike small molecule generic drugs, generic biologic drugs are not identical but are only similar to the innovator.  These differences can be in molecular size, structure (such as amino acid sequence), and composition (including glycosylation and other modifications to the protein sequence comprising most biologics drugs).  Conventional "small molecule" drugs typically comprise about 20-100 atoms (for example, omeprazole, the active ingredient in Prilosec®, contains 42 atoms), while biologic drugs comprise 5,000 to 50,000 atoms.  Moreover, peptide and protein embodiments (including monoclonal antibodies) are complex polymeric chains that can adopt secondary and tertiary structure beyond their simple linear formulae.  In addition, biologic drugs are frequently heterogeneous, comprising carbohydrates (by glycosylation), lipids, and occasionally small molecule cofactors.  All these considerations make biogeneric drugs a more challenging prospect that traditional small-molecule generic drugs.

Similarly, interchangeability requires that a patient be capable of "switching" between the innovator and the biogeneric drug without any significantly-increased risks of adverse events.  The capacity for a patient to be switched between a generic and innovator drug is the basis for pharmacies providing generic versions of drugs unless the doctor affirmatively contravenes them, rather than having to obtain the physician's permission to substitute; this property is expected to just as important in market penetration for follow-on biologic drugs.  While all of the bills pending in Congress contain provisions for assessing whether the FOB is interchangeable with the innovator, the complexities of these molecules increases the difficulties of achieving the interchangeability goal.

The Waxman bill contains provisions permitting a biogeneric drug to be considered a biosimilar where the follow-on biologic and the reference product have highly similar molecular structural features, the generic is interchangeable with the innovator biologic drug, and the biogeneric and innovator biologic drugs use the same mechanism of action, have the same the route of administration, or the dosage form and strength.  The Eshoo bill grants more authority to the FDA for making the determination:  a biogeneric will be considered to be biosimilar upon a showing comprised of analytic, animal, clinical, and immunogenicity studies, but the FDA can waive these requirements.  Moreover, the FDA is given the authority under the Eshoo bill to determine whether it is feasible to demonstrate interchangeability.

All these considerations are even more relevant in view of increasing evidence that the gold-standard, small molecule generic drugs, may themselves not be without their risks and liabilities (despite the political rhetoric about the success of the Hatch-Waxman regime in facilitating generic drug entry into the pharmaceutical marketplace).  Examples of these difficulties were reported by Melinda Beck in The Wall Street Journal more than a year ago ("Inexact Copies: How Generics Differ from Brand Names").  Ms. Beck's piece conceded that "there is no hard evidence of growing problems with generics," but then provides at least one reason for this absence:  the FDA's procedures for assessing reports of adverse events from generic drugs are woefully inadequate.  Some of these deficiencies are systemic:  for example, Ms. Beck reports that "[g]enerics can produce blood levels as much as 20% below or 25% above that of the original drug and still be considered 'bioequivalent' according to Food and Drug Administration guidelines."  Even when the FDA investigates, the focus seems to be on compliance with regulatory guidelines rather than patient safety.  Ms. Beck illustrates the problem with generic Welbutrin®, for which the FDA approved an extended-release formulation sold as Budeprion XL300.  From December 2006 through January 2008, the FDA received at least 130 complaints, according to the results of a Freedom of Information Act disclosure to Journal reporter Andy Georgiades.  Ms. Beck reports that Joe Graedon, who runs People's Pharmacy, received a sudden and markedly high level of complaints about Budeprion XL300 when it was introduced, including serious side effects like depression and suicidal ideation.  Tellingly, many patients reported that these symptoms stopped when they returned to the brand-name drug.  Mr. Graedon had an independent lab, ConsumerLab.com, analyze samples of the branded and generic forms of the drug, and their report showed that the generic drug dissolved faster and released more than eight times as much of the drug within the first two hours (34% with the generic versus 8% with the branded version).

The FDA, who performed its own investigation, found that "although there were 'small differences' between the two formulations, 'they are not outside the established boundaries for equivalence.'"  The generic did reach its maximum blood concentration in two to three hours, compared to five to six hours for Wellbutrin, but the FDA said those differences "were not considered clinically significant."  Maddeningly, the Agency attributed the inordinately high complaint levels to "the natural history of depression" in these patients.  Perhaps even more maddeningly, Ms. Beck reports that the FDA did not require testing performed during the approval period that compared the branded to the generic drug, but used a lower dose  -- 150mg rather than 300mg -- to do the comparative testing upon which it based its approval of Budeprion XL300.  Thus it can fairly be said that the agency failed to require any evidence of bioequivalence of the generic drug at the dosages actually approved.  The reason, Ms. Beck reports, is in part ethical -- the agency did not want to expose clinical trial subjects to a seizure risk that accompanies the 300mg dose.  But this leads to a classic Catch 22, illustrated by a quote from Sandy Walsh, an FDA spokeperson:  "If we see scientific evidence that a product is not performing as expected, we will take action.  The FDA cannot offer examples where generics have not performed as expected because there have been none for the agency to report."

This example illustrates a perennial problem with drug regulatory approval:  of necessity, clinical trials are performed with a test population that is much more limited, in numbers and representation (including gender, racial, and ethnic, to name a few) than the population that will be taking the drug.  Adverse incident reports after approval will, by their nature, be anecdotal and sporadic, and thus take time (and individual morbidity and mortality) for a pattern of problems with a particular drug to become evident.  The potential for differential effects, even for small molecule drugs that can be subjected to analyses that ensures "identity" for the active pharmaceutical ingredient, exists inter alia due to differences in "inactive" components (excipients, fillers, binding agents and other such components) that can affect how the drug is absorbed or metabolized in the body.

These problems also will exist for biogenerics, in addition to the differences noted above that limit these drugs to bio-"similarity" rather than bio-"identity."  These are real challenges to any follow-on biologics regime and one that Congress will not doubt be inclined to leave to the FDA to administer.  It may behoove Congress to consider the consequences of the types of complications faced even for small molecule generic drugs, and to pay a little more attention to strengthening the provisions of these bills that mandate the level of "similarity" and "equivalence" that biogeneric drugs should be required to achieve before they are permitted in the marketplace.

Comments

[Pizarro]

Great article--I had not heard the Welbutrin story. It's discouraging that the FDA seems to want to turn a blind eye to any possible problems.

How are the bioequivalence parameters set for a particular drug? If it is notice and comment rulemaking by the FDA, perhaps patient advocacy groups could try to convince the FDA to set tighter limits. I would think that the AARP, for example, would be all over this, but when I hear about their activities it is all about how drugs cost too much (or how patents are bad).

[EG]

Kevin,

Some very interesting observations about these biogeneric bills, including the issues with the existing FDA provisions on generics of conventional drugs. Anyone who thinks Hatch-Waxman can simply be reapplied without more to biogenerics is either ignorant, or just myopically focuses on these biogenerics as being a less expensive alternative without ever considering the significant (and serious) issues about the bioequivalency and even safety of these biogenerics. If there are significant (and serious) issues about the bioequivalency and safety of generics for conventional drugs, these issues go up almost exponentially with biogenerics.

[Kevin E. Noonan]

Dear Pizarro:

Waiting until the geriatric equivalent of the Thalidomide tragedy occurs is, I'm afraid, the only sure way to get the attention of the Congress blinded as you say by lower drug costs (a huge budgetary issue for the federal government). With luck, the FDA will act appropriately.

Thanks for the comment.

[Rachel Chu]

For anyone interested in further reading on the issue of biosimilars, see the Stockholm Network's latest paper in its series on patient safety: Biogenerics or Biosimilars? Discussing the Present, Considering the Future.

In this paper, Rachel Chu and Dr Meir Pugatch explore the issue of biosimilars and their impact on healthcare policymaking. They examine the various challenges that the advent of biosimilars raises, particularly with regard to the regulatory framework, market opportunities, IPRs and most importantly of all, with regard to public safety.

The paper takes four of the most relevant pathways as case studies, namely the EU, WHO, Canada and the US (where legislation is still under way), and evaluates in particular whether these pathways have resolved the safety and IP dilemmas. Finally, it presents several policy recommendations, which should allow more clarity and predictability for those wishing to enter the market as well as providing enhanced scientific rigour, in the interests of patients.

To view the paper, please visit:
http://www.stockholm-network.org/downloads/publications/Biosimilars_FINAL.pdf

To view the executive summary, please visit:
http://www.stockholm-network.org/downloads/publications/Biosimilars_Executive_Summary.pdf