States Tackle Biosimilar Substitution

paradiseLGjpg_1While the Food and Drug Administration (FDA) and the Federal Trade Commission contemplate the wide-ranging implications of recent legislation creating an abbreviated approval process for biologic products, states are busy tackling issues of pharmacist substitution.  The current implementation debate at the federal level focuses chiefly on the scope of scientific and technical assessments and the impact on market competition.  However, two aspects will prove essential for determinations of access to and costs of the resulting products: how the biologic products are to be named, and whether pharmacist substitution is appropriate.  The FDA has thus far sidestepped the naming question because of the nascent state of the pathway development and lack of tangible products, while states are just beginning to confront the issue of how to extend or adapt their pharmacist substitution laws.  As this abbreviated pathway develops and biosimilar and interchangeable biologics begin to enter the market, product identification and substitutability will have tremendous ramifications for physicians, patients, and payors.  Recognizing these issues, five states have enacted laws governing substitution practices for biologics, and legislation has been considered in over a dozen more. 

The Biologics Price Competition and Innovation Act of 2009, embedded within the Patient Protection and Affordable Care Act, grants the FDA the authority to implement an abbreviated approval pathway to market for new versions of existing biological products that have the same clinical indication, route of administration, dosage form, strength, and mechanism of action. Two tiers of biosimilarity are laid out in the BPCIA: biosimilarity and interchangeability.  Biosimilarity means the biosimilar biological product is “highly similar” to the reference product where no clinically meaningful differences exist in terms of safety, purity, and potency. 

Interchangeability requires that the product is biosimilar and the product can be substituted for the reference product without intervention of a prescribing health care provider.  An applicant must demonstrate the product will provide the same clinical result as the reference product in any given patient and that when “administered more than once to an individual, the risk in terms of safety of diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alteration or switch.”  The specific provisions can be found here.   This level of interchangeability is where state substitution laws come into play.  The statute leaves it to individual states to determine as a matter of state law whether an interchangeable product will be able to be substituted for a reference biologic and what requirements are associated with that substitution. 

Although all 50 states currently have statutes addressing generic drug substitution, these statutes do not apply to biologics, which are regulated by the FDA under a different federal statute.  Generic status is imparted by the FDA through therapeutic equivalence ratings, which connote that the generic product is bioequivalent, meaning for all purposes the same as, the reference product.  The laws vary state-by-state.  Some states, such as New Jersey, are “positive formulary” laws, where generics that may be substituted are identified in a formulary; other states, such as Minnesota, are “negative formulary” laws, where drugs that cannot be substituted are identified in a formulary.  However, when the physician indicates on the script that the drug is not to be substituted, typically with “may not substitute,” “dispense as written,” or similar language, the pharmacist is not allowed to dispense a generic.  If “brand only” is not indicated by the prescribing physician, thirty-six states have laws framed as allowing generic substitution, while the remaining fourteen are framed as mandating generic substitution.  Many laws also provide that there must be patient notification or consent to the substitution or that the drug dispensed by the pharmacist is less or equal price to the prescribed drug.  For a discussion of these laws, see here.

Legislation regarding substitution of interchangeable biologic products has been introduced in at least 18 states over the last few years and has passed in Florida, North Dakota, Oregon, Utah, and Virginia  Other states considering legislation were Arizona, Arkansas, California, Colorado, Delaware, Illinois, Indiana, Maryland, Massachusetts, Mississippi, Pennsylvania, Texas, and Washington.  California’s bill was initially approved by both the House and Senate and subsequently vetoed by the Governor.  The FDA Law Blog posted a useful state legislation scorecard back in September 2013, though it has not been updated.

Basic elements of the bills include a requirement for pharmacists to notify prescribers and/or patients that the interchangeable biologic has been dispensed within a certain timeframe; record-keeping requirements on the part of prescribers and pharmacists for a certain period of time; the right for the prescriber to prohibit substitution; the right for patients to refuse an interchangeable product; and a requirement that the state Board of Pharmacy will maintain a list of interchangeable biosimilars.  The laws passed in Oregon, Virginia, and Utah also include a sunset clause of two years for the pharmacist notification provision.  A comparison of these five laws is represented in Figure 1; parenthesis within the columns denotes the relevant section of each bill.

State Notification Recordkeeping Prescriber Prohibition Patient Refusal BoP List
Florida HB 365; FL Stat. 465.0252 Yes, prescription holder, with price difference   (2(c)) Pharmacist, for 2 years. (2(d);  3) Yes, can only dispense if “prescribing health care provider does not express a preference against substitution.” (2(b)) Yes, person holding prescription(2(c)) Yes. (4)
North Dakota  SB 2190; ND Cent. Code 19-02.1 Yes, both prescription holder (2(c)) and prescriber within 24 hours. (2(d)) Yes, both pharmacist and practitioner for 5 years.  (2(e)) Yes, can substitute if no brand medically necessary” note on written, oral or e-transmittal.  (2(b)) Yes. (2(c)) Yes. (3)
Oregon SB 460; ORS Ch. 689 Yes, both prescription holder (2(c)) and practitioner or staff within 3 days. (2(d)) Yes, pharmacist/cy for 3 years.     (2(e)) Yes, can only substitute where no prohibition. (2(b)) N/A Yes. (3)
Utah SB 78; UT Code 58-17b-605.5 Yes, both prescription holder (7) and prescriber within 3 days (8(a)). Also counsel on use of and expected response to product      (2(d)) Yes, pharmacist to note Rx and substitution on “file copy.” ( 7) Yes, substitution only is not prohibited (2(e)); notation of “dispense as written” (6(a)) Yes, purchaser must request of consent to substitution.      (2(a)) N/A
Virginia SB 1285: VA Code 54.1-3408.04 Yes, notify patient of substitution (B) and cost (D), and prescriber or staff within 5 days (C).  Also label req. Yes, pharmacist and prescriber for 2 years. (B) Yes, can note “brand medically necessary” (A(i)) Yes, can insist on Rx.  (A(ii)) N/A



FDA Taking Baby Steps Towards Regulating Nanotechnology

paradise_jordan_lg1FDA Taking Baby Steps towards Regulating Nanotechnology

Jordan Paradise, J.D.[1]

[Ed. Note: HRW is pleased to welcome Seton Hall Law Professor Jordan Paradise, who researches and publishes on the legal, ethical, and societal implications of emerging science and technologies such as genetics and nanotechnology. She teaches Food & Drug Law, Administrative Law and Advanced Seminars in the field of Health & Technology. Professor Paradise has an article forthcoming in Volume 56 of St. Louis University Law Journal on the topic of FDA regulation of nanotechnology entitled Reassessing 'Safety' for Nanotechnology Combination Products: What Do 'Biosimilars' Add to Regulatory Challenges for the FDA? Her research and publications, including her forthcoming article, can be found at SSRN --]

On June 9, 2011, the Food and Drug Administration (FDA) released draft guidance for industry laying out the agency’s “current thinking on whether FDA-regulated products contain nanomaterials or otherwise involve the application of nanotechnology.”[2] The guidance urges that the document does not establish legally enforceable obligations, but should be viewed only as recommendations for industry.  It “does not establish regulatory definitions” or “address the regulatory status of products,” but does state that future additional guidance may be issued for specific product or classes of products.  Published concurrently with an announcement on policy principles for nanotechnology regulation from the Office of Science and Technology Policy,[3] the draft guidance exemplifies the ongoing battle by federal administrative agencies to quantify, categorize, and regulate nanotechnology.

Carbon nanotubes (courtesy, National Science Foundation). The properties of CNTs are being explored for applications in electronics, photonics, multifunctional fabrics, biology (e.g., as a scaffold to grow bone cells), and communications. See a 2009 Discovery Magazine article [] for other examples

Carbon nanotubes (courtesy, National Science Foundation). The properties of CNTs are being explored for applications in electronics, photonics, multifunctional fabrics, biology (e.g., as a scaffold to grow bone cells), and communications. For other examples see a 2009 Discovery Magazine article,

Framed as two general “Points to Consider” applicable to both new products and any manufacturing changes to FDA-approved and cleared products, the draft guidance provides both a dimensional aspect — “whether an engineered material or end product has at least one dimension in the nanoscale range (approximately 1nm to 100 nm)” — and a behavioral aspect — “whether an engineered material or end product exhibits properties or phenomena, including psychical or chemical properties or biological effects, that are attributable to its dimensions, even if these dimensions fall outside the nanoscale range, up to one micrometer.”  Notably, the second point expands the first dimensional aspect beyond the 100 nm range if the properties exhibited are tied directly to its dimensions up to one micrometer (also called a micron).  (One nanometer is equal to 10-9 meters (a sheet of paper is about 100,000 nanometers thick)); one micrometer/micron is equal to 10-6 meters.)

Supporting its two points, the guidance also provides the agency’s “Rationale for Elements within the Points to Consider.”  These largely recite the current state of knowledge of nanoscale properties and phenomena as the underpinnings of the two points.   Specifically, the FDA distinguishes the “deliberate manipulation and control of particle size” of an engineered material or end product from the natural functioning at the nanoscale, identifies the traditional bounds of the nanoscale encompassing 1nm to 100nm as serving merely as “a first dimensional reference point” for industry, highlights the relationship between size and physical and chemical properties as important for questions of safety and efficacy, and explains the broadening of dimensions of “nanoscale” up to one micrometer as linking to the use of agglomerates and aggregates that may coat or functionalize a product.

Scanning electron microscope image of a single lung cancer cell (H1650) captured on the slide of a micropost. (

Scanning electron microscope image of a single lung cancer cell (H1650) captured on the slide of a micropost. (

While couched as a “first step” by the FDA, the draft guidance reflects an incremental and coordinated effort among various FDA Centers, including the Center for Drug Evaluation and Research (CDER), the Center for Biologics Research and Evaluation, the Center for Devices and Radiological Health, and the Center for Food Safety and Nutrition on issues with nanotechnology products.  Nearly four years ago, the FDA’s multi-center Nanotechnology Task Force[4] published a report[5] acknowledging that future advancements in nanotechnology may pose challenges for the existing FDA oversight structure.  Rapidly developing nanoscale[6] applications were identified as integrating mechanical, chemical, electrical, and optical properties in novel and dynamic ways:

The very nature of nanoscale materials — their dynamic quality as the size of nanoscale features change, for example, and their potential for diverse applications — may permit the development of highly integrated combinations of drugs, biological products, and/or devices, having multiple types of uses, such as combined diagnostic and therapeutic intended uses.  As a consequence, the adequacy of the current paradigm for selecting regulatory pathways for “combination products” may need to be assessed to ensure predictable determinations of the most appropriate pathway for such highly integrated combination products.[7]

A nanosensor probe carrying a laser beam (blue) penetrates a living cell to detect the presence of a product indicating that the cell has been exposed to a cancer-causing substance.

A nanosensor probe carrying a laser beam (blue) penetrates a living cell to detect the presence of a product indicating that the cell has been exposed to a cancer-causing substance.

Infused with public and private investments, nanotechnology-based research and development is now burgeoning.  The cumulative federal investment in nanoscale science and engineering research and development through the National Nanotechnology Initiative (NNI) over the last decade has reached nearly $14 billion;[8] the 2011 NNI budget provides $1.76 billion spread across 15 federal agencies.[9] The unique and far-ranging properties of nanostructures and nanotechnology have particularly facilitated breakthroughs in the pharmaceutical and medical device realms.  The interface of nanotechnology and biotechnology have increased bioavailability, introduced more targeted drug delivery and release, decreased adverse side effects, and enabled cutting-edge cancer treatments.  Current projections place the “nanomedicine” market at $53 billion in 2011.[10]

Following its 2007 report, the FDA has taken a number of internal steps aimed at nanotechnology in addition to the recent guidance.  FDA’s CDER and the Research Office of Pharmaceutical Science issued an internal Manual of Policies and Procedures (MaPP) in May 2010 that instructs drug reviewers to capture “relevant information about nanomaterial-containing drugs” that will be entered into a nanotechnology database.[11] The MaPP states that “in order to develop guidance for industry, CDER needs to organize all the data submitted in support of nanotechnology-based drug applications,”[12] gather all “relevant information about nanomaterial-containing drugs” and enter them into a nanotechnology database maintained by the agency.[13] While imposing no additional requirements on drug applicants, it signals recognition from the FDA of the nascent state of understanding of the complex scientific implications in human drugs.

nanostructured zein forming sub-micron size tubes,

nanostructured zein forming sub-micron size tubes,

FDA has also held several public meetings to gather nano-specific information: in October 2006 to aid  the Task Force Report;[14] in September 2008 to assist the agency in implementing recommendations  laid out in the Task Force Report;[15] and in September 2010 to solicit data and information on biocompatibility assessment of diagnostics and devices that include nanomaterials.[16] The FDA also maintains materials for the public on its webpage regarding nanotechnology.[17]

FDA is also partnering with the National Cancer Institute’s Nanotechnology Characterization Laboratory and the National Institute of Standards and Technology to conduct “preclinical efficacy and toxicity testing of nanoparticles” in an effort to identify appropriate standards for molecular-sized cancer drugs.[18] The FDA has identified risk characterization based on physical and chemical properties, in vitro and in vivo models to assist in predictions of human response to exposure, quantification methods, measures of adsorption and transport, and relationships between nanomaterial properties and the human body in terms of uptake via the skin, lungs, and gastrointestinal tract as specific areas of interest.[19]

Although moving slowly, the FDA is moving forward on issues of nanotechnology.  Stay tuned…

[1] Prof. Paradise has an article forthcoming in Volume 56 of St. Louis University Law Journal on the topic of FDA regulation of nanotechnology entitled Reassessing ‘Safety’ for Nanotechnology Combination Products: What Do ‘Biosimilars’ Add to Regulatory Challenges for the FDA? Her research and publications, including her forthcoming article, can be found at SSRN —

[2] FDA Draft Guidance for Industry, Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology, June 9, 2011, available at For more information, see also FDA Draft Guidance Questions and Answers, June 9, 2011, available at; Jeffrey Ventura, FDA Press Release, FDA takes ‘first step’ toward greater regulatory certainty around nanotechnology, June 9, 2011, available at

[3] Office of Science and Technology Policy, Office of Management and Budget, and the United States Trade Representative, Policy Principles for the U.S. Decision-making Concerning Regulation and Oversight of Applications of Nanotechnology and Nanomaterials, June 9, 2011, available at

[4] Press Release, Food and Drug Administration, FDA Forms Internal Nanotechnology Task Force (Aug. 9, 2006), available at

[5] Food and Drug Administration Nanotechnology Task Force, Nanotechnology: A Report of the U.S. Food and Drug Administration Nanotechnology Task Force (2007), p. 20-21, available at

[6] The nanoscale is traditionally measured as under 100nm (or 10-9m, or one billionth of a meter).   The National Nanotechnology Initiative (NNI) defines “nanotechnology” as involving three inter-related (and inseparable) aspects: “1) [r]esearch and technology development at the atomic, molecular or macromolecular levels, in the length scale of approximately 1-100 nanometer range; 2) creating and using structures, devices and systems that have novel properties and functions because of their small and/ or intermediate size; and 3) ability to control or manipulate at the atomic scale.”  Environmental Protection Agency, Nanotechnology: An EPA Research Perspective (June 2007),

[7] Id.

[8] Office of Science and Technology Policy, NNI Strategic Plan 2010; Request for Information, 75 Fed. Reg. 38,850-53, 38,850 (2010).

[9] National Nanotechnology Initiative, About the NNI — Funding,

[10] Raj Bawa & Summer Johnson, The Ethical Dimensions of Nanomedicine, 91 Med. Clinics N. Am. 881-87, 882 (2007), citing Nanotechnology in Healthcare (Cleveland: Freedonia Group 2007).

[11] Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Science, MaPP 5015.9 Reporting Format for Nanotechnology-Related Information in CMC Review (effective date June 3, 2010), available at

[12] Id. at 2.

[13] Id.

[14] Planning of Public Meeting, Regulated Products Containing Nanotechnology Materials, 71 Fed. Reg. 155, 46,232-33 (Aug. 11, 2006).

[15] Public Meeting, Consideration of FDA-Regulated Products That May Contain Nanoscale Materials, 73 Fed. Reg. 153, 46,022-24 (Aug. 7, 2008).

[16] Public Workshop on Medical Devices and Nanotechnology: Manufacturing, Characterization, and Biocompatibility Considerations, 75 Fed. Reg. 162 (Aug. 23, 2010).

[17] Food and Drug Administration, Nanotechnology,

[18] See National Cancer Institute, Nanotechnology Characterization Lab,

[19] Food and Drug Administration, 2010 FDA Research Project Categories,


An Ounce of Prevention: Coverage Battles Rage Over the Biologic Synagis

December 15, 2010 by · 2 Comments
Filed under: Biologics and Biosimilars 
Photo by Pulmonary Pathology via Flickr

Photo by Pulmonary Pathology via Flickr

Yesterday, I got a note from my son’s kindergarten teacher alerting me that the class had run out of hand sanitizer and tissues and needed donations to replenish their supply.  Proof positive that cold and flu season is upon us.

Less commonly known is that, in most or all of the country, it is also respiratory syncytial virus (RSV) season.  RSV is a widespread respiratory virus; almost everyone gets it by the time they turn two and it doesn’t usually result in anything more than a common cold.  As the CDC explains, however, RSV can cause lower respiratory infections such as bronchiolitis and pneumonia and these can be severe.  The virus is the number one cause of hospitalization in babies under one in the United States.

While there is no RSV vaccine, the biologic Synagis (palivizumab) can help prevent the development of severe illness in high risk children.  According to the American Academy of Pediatrics’ influential Red Book, this includes children under two with chronic lung disease, babies under one born at 28 weeks gestation or earlier, babies under six months born at 29-32 weeks gestation, and babies under six months born at 32-35 weeks with at least one of a number of enumerated risk factors such as daycare attendance.

There is a catch.  Synagis costs $900 or more per injection and each injection lasts just one month.  Because a season’s worth of protection from RSV costs many thousands of dollars (one payor puts it at $7,030 per patient), it is perhaps unsurprising that there is ample anecdotal evidence of baseless denials of coverage, by both private insurance companies and Medicaid.  The law student who blogs at Nonsense and Frippery has written three searing posts about her family’s Herculean efforts to secure Synagis shots — first from her private insurance company and then from Medicaid — for her son who was born at 25 weeks gestation in April 2010.  (The posts (which contain some strong language) are here, here, and here.)

With the passage of health reform, the United States has, for the first time, an abbreviated approval pathway for biologic drugs that are “biosimilar” to or “interchangeable” with already-approved biologics.  Its passage creates hope that less expensive versions of at least some biologics will be available here at some point in the future.  As the FDA concedes, however, there are many “issues and challenges associated with the implementation of the Biologics Price Competition and Innovation Act of 2009.”  Monoclonal antibodies like Synagis are likely to prove particularly challenging, for industry and regulators, because they are immensely complex molecules.  In Europe, where there has been an abbreviated approval pathway for biologics since 2004, the European Medicines Agency has yet to approve a biosimilar “mAb”.  This is expected to change, though.  In November, the EMA released a draft guideline for biosimilar “mAbs” and generic versions of rituximab, a drug used to treat non-Hodgkin’s lymphoma and rheumatoid arthritis, are in development.

While biosimilars may someday provide some relief to payors, in the meantime, one may merely seek to hold those payors accountable for baseless denials of Synagis and other expensive, but cost-effective, medicines that they purport to cover.


The Biosimilars Debate: Is it Over?

Two months ago, I discussed possible federal legislation intended to balance the competing need for scientific and medical innovation with the costs to patients for biosimilars.  So where does the debate stand now?

Current proposals couple a regulatory approval pathway for biosimilars with exclusivity periods for pioneer biologics.  As part of its July 15, 2009 health reform bill, the Senate Health, Education, Labor, and Pensions (HELP) Committee adopted an amendment proposed by Senators Kay Hagan (D-NC), Michael Enzi (R-WY), and Orrin Hatch (R-UT) that provides for a 12-year exclusivity period for pioneer biologics.   On July 31, despite protestations from Rep. chairman Henry A. Waxman (D-Calif.) that the amendment is “exactly the wrong way” to create a pathway for approval of biologics, the House Energy and Commerce Committee approved H.R. 3200, which also includes a 12-year exclusivity period.

On September 29, ten governors wrote a letter in support of the exclusivity period to House Speaker Nancy Pelosi (D-Calif.), House Minority Leader John Boehner (R-Ohio), Senate Majority Leader Harry Reid (D-Nev.), and Senate Minority Leader Mitch McConnell (R-Ky.), stating, “[i]nnovator companies must be provided with at least 12 years of non-patent data exclusivity to allow for recovery of their original investment and to ensure licensing payments to our research institutions.” Read more


Biologics, How Long Exclusive? What Cost?

Biologics — products such as vaccines, gene therapy, tissues, and recombinant therapeutic proteins that are isolated from natural sources and may be produced by biotechnology methods and other technologies — are at the center of a national debate regarding access to cutting-edge therapies and protection of biotech’s ability to create products that may require millions of dollars to develop. As always, Mintz Levin, Health Law Washington Beat (link also in the “Resources” section of this blog) has offered great coverage of the issue– articles here and here.

For months now, the federal government has been considering legislation to balance the competing need for scientific and medical innovation with the costs to patients for biosimilars (generic versions of innovator pioneer biologics, also referred to as follow-on biologics).  Unlike its approval pathway for generic small-molecule, chemically synthesized drugs, the FDA currently has no process for the approval of biosimilars.  All regulatory proposals by both the Senate and the House have included an exclusivity period for pioneer biologics before a generic biologic may be introduced in the market, as well as patent protections for the pioneer biologic.

As part of its July 15, 2009 health reform bill, the Senate Health, Education, Labor, and Pensions (HELP) Committee adopted an amendment proposed by Senators Kay Hagan (D-NC), Michael Enzi (R-WY), and Orrin Hatch (R-UT) that provides for a 12-year exclusivity period for pioneer biologics.  Among the Senate’s other biosimilar proposals, all introduced in June 2009, Senator Sherrod Brown (D-OH)’s bill allows for seven years of exclusivity, Senator Charles Schumer (D-NY)’s bill provides for a 5 year exclusivity period, and the proposal by Senator Edward Kennedy (D-MA) calls for a nine-year exclusivity period.  In the House, Reps. Henry A. Waxman (D-CA)’s proposed bill limits the exclusion period to five years, while Anna Eshoo (D-CA)’s bill proposes an initial exclusivity period of 12 years, with a possible additional two-and-a-half years for new indications and pediatric populations.

In June 2009, the FTC released a report that determined that innovation and investment will be sustained even without the exclusivity recommended by even the least restrictive of the proposed bills.  The report states that the competition between pioneer and follow-on biologics will more closely resemble the competition between different brands of drugs — with the pioneer biologic retaining 70-90% of the market share — rather than the competition between small-molecule branded pharmaceuticals and their comparable generics — where entry of the generic drug on the market leads to loss of market share and drop in the price of the drug.  The FTC found that due to the complexities in the development and use of biologics and the absence of therapeutic equivalence between pioneer and follow–on biologics, biosimilars are unlikely to be direct substitutes for the pioneer biologics on which they were based.

Relying on the FTC’s conclusion that the introduction of follow-on biologics will lower prices and increase access, Read more


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