Editor’s note: This article first appeared in the digital and print editions of Pharmaceutical Patent Analyst, Volume 4, Number 2. The authors, Dr. Anthony Sabatelli and Dr. Cambria Alpha-Cobb, retain the rights to the piece and have chosen to reprint this article here. To order reprints, please contact the publisher at reprints@future-science.com.

Some fashion trends may come and go, but in the not too distant future the majority of prescription drug sales will be purple. For those of you not yet familiar with this latest trend, allow us to explain. In September 2014, the US FDA published its first edition of the so-called ‘Purple Book,’ with the rather lengthy title – ‘Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations.’ This new publication, like its well-established ‘Orange Book’ counterpart, will list approved biologic drug products and also their biosimilar and interchangeable generic equivalents. However, the Purple Book is still in its infancy. As of this writing, the published information is far from complete. Furthermore, the FDA has been slow in publishing the necessary guidance documents. Will the new Purple Book rise to the challenge of providing the necessary bridge between the patent and regulatory systems governing biologics? Will the requirements for demonstrating biosimilarity and interchangeability for biosimilar drug products turn out to be too onerous? This commentary explores the regulatory challenges for the role of the Purple Book as the first biosimilars begin receiving FDA approval this year.

Small, synthetically manufactured molecules make up over 90% of the drugs on the market today [1]. These drugs are typically low in molecular weight and structural complexity. A common example of such a small molecule drug is acetyl salicylic acid, or aspirin, with a molecular weight of only 180 Da. Due to the relative ease of manufacture and purification, small molecule drugs are often copied by generic pharmaceutical manufacturers once the patent protection and regulatory exclusivity have expired for the branded reference drug.

These generic versions are typically sold at substantial discounts from the branded drug. To receive regulatory approval in the USA, the generic manufacturer does not have to submit a full new drug application (NDA) with complete human clinical trial results. Rather, the generic manufacturer can submit an abbreviated new drug application or ‘ANDA,’ and need only demonstrate bioequivalence to the reference branded drug, in other words, that the generic drug performs in the same manner [2,3].

Biologic basics
The drug approval process becomes more complicated for large molecule drugs. For example, the class of drugs known as biological drug products, or ‘biologics’ as they are commonly called, are drugs produced from biological sources. Biologics are typically large in size – generally in excess of several thousand daltons. For example, adalimumab, a monoclonal antibody used to treat rheumatoid arthritis and sold under the trade name Humira®, has a molecular weight of approximately 150,000 Da. This is nearly 1000-fold larger than aspirin!

Because biologics are manufactured using living cells, they often require costly and sophisticated purification, isolation and handling techniques. Seemingly inconsequential variations in the cell lines, production profiles, isolation methods and post-translational modifications can lead to potentially adverse reactions upon their administration to patients. Thus, strict manufacturing controls are necessary for biologics. Analogous to the NDA approval process for a small molecule drug, the original biologic developer must apply for a Biologics License Application to introduce, or deliver for introduction, a biologic product into interstate commerce [4]. As with the NDA application, the Biologics License Application has extensive requirements for clinical safety and efficacy and manufacturing controls.

Just as small molecule drugs often have generic equivalents, biologics in the USA will soon have follow-on copies called ‘biosimilars’ (and also ‘interchangeables,’ as explained below). The regulation of and process for approving biosimilars is just getting off the ground in the USA and is certainly in need of some assistance. In contrast, the European Medicines Agency first adopted a biosimilar approval process back in 2004. It was not until 2010 that US President Barack Obama signed into law the Patient Protection and Affordable Care Act. One of the Act’s provisions was the Biologics Price Competition and Innovation Act (BPCIA), which created an abbreviated licensure pathway for biologics that are demonstrated to be either ‘biosimilar’ to or ‘interchangeable’ with the originally approved product. In other words, this legislation created the first regulatory pathway for the approval and marketing of the generic equivalent of a biological drug [5].

The growing biologics market
Depending on the source and how the data are analyzed, biologics accounted for just 10% of annual prescription drug sales in 2010. In 2011, the sales of biologics reached up to 19% of the global biopharmaceutical market in terms of revenue, corresponding to more than $142 billion [6]. In 2013, seven of the top ten selling drugs were biologics, with sales totaling $56.6 billion [7]! The trend is clear. Biologics will continue to garner an ever-increasing presence in prescription drug sales. Furthermore, the top ten selling biologics began reaching their ‘patent cliffs’ between the years 2012 and 2019, and the period of patent exclusivity on these drugs will end [8]. With this expiration of patent exclusivity for several of the top selling biologics, the attention will most likely shift to their generic versions, in other words, the biosimilars. In contrast to small molecule generics, there is reason, however, to believe that the profitability of biologics will continue even after the exclusivity has expired.

The drop in revenue that typically accompanies a patent cliff for small molecule drugs, will likely be less pronounced for the biologics. The capital investment of bringing a biosimilar to market is expensive in comparison with its small molecule generic counterpart. However, the return on investment is also predicted to be much greater. It is anticipated that the biosimilar products will most likely bring in two-thirds the revenue of the original biologic [9]. This situation means that the limited number of biologics applications currently under way still represents a large portion of the biopharmaceutical revenue. In 2011, the top two biologics alone accounted for more than $16 billion in sales. A biosimilar version for the granulocyte colony-stimulating factors drug, filgrastim, is currently pending FDA approval and a survey by Decision Resources Group found that this biosimilar alone could reach $1.8 billion in sales in the USA by 2023. The biosimilar application numbers may be few but those few can carry a punch.

As of the submission of the manuscript for this article, no biosimilar product had yet been approved in the USA. Also, only a handful of biosimilar applications are believed to be pending before the FDA, as such information is not publicly available. However, this is all expected to soon change. This change will be driven by the extensive pipeline of biologic drugs and the ever-increasing number of companies entering this area. Also, the biosimilar market will not be just for smaller generic manufacturers, as big pharma also seeks to get a piece of this market.

So what does this have to do with the color purple?

First, enter the Orange Book
Small molecule prescription drugs are approved by the FDA. In 1984, Congress passed the Drug Price Competition and Patent Restoration Act (commonly known as ‘Hatch–Waxman’) to bring low-cost prescription drug products to consumers, while balancing the competing interests of the branded pharmaceutical industry and generic drug manufacturers [10]. Hatch– Waxman provided a unique statutory link between the patent and regulatory systems and established a framework under which generic drugs could be marketed. This act requires the FDA to publish information on approved drug products with their therapeutic equivalence information. Also published are patent and other exclusivity information for the approved drugs, setting the grounds for the complex litigation that results when the interests of the branded and generic drug manufacturers clash. The FDA publication in which this drug and patent information appears is known, not by its lengthy title, but rather by its garish, yet distinctive orange cover – hence, the ‘Orange Book.’ See, Approved Drug Products with Therapeutic Equivalence Evaluations, The Orange Book.

According to the FDA, generics, can be marketed as a ‘drug product that is comparable to a brand/reference listed drug product in dosage form, strength, quality and performance characteristics and intended use’ [11]. The generic approval process is fairly straight forward, as a generic copy need only exhibit bioequivalence to the reference branded product. Generic copies do not need to be identical to their reference drug compounds, because their pharmacokinetic parameters of AUC and Cmax need only be within the range of a 90% confidence interval of 80–125% compared with the reference drug [12]. As an aside, AUC, which is an abbreviation for ‘area under the curve,’ is a pharmacokinetic parameter calculated by the area under the plasma concentration-time curve for the rate of drug absorption, thus representing the dosage of drug delivered. The Cmax is the peak drug concentration for the rate of drug absorption, corresponding to the maximum blood level concentration achieved for drug.

Now enter the Purple Book
Fast forward to 2014, or rather first to 2010. As mentioned above, in March of that year, the BPCIA created an abbreviated licensure pathway for follow-on biologics, in other words, generic versions that are demonstrated to be either ‘biosimilar’ to or ‘interchangeable’ with the originally approved product. The BPCIA defines a biosimilar as ‘a biological product highly similar to the reference product notwithstanding minor differences in clinically inactive components’ and with ‘no clinically meaningful differences between the biological product and the reference product in terms of safety, purity and potency of the product.’ An interchangeable drug is defined as ‘a biological product that can be expected to produce the same clinical result in any given patient, and the safety and reduced efficacy risks of alternating or switching are not greater than with repeated use of the reference product.’ As can be seen from these definitions, the requirements for an interchangeable follow-on biologic are far more stringent than those for a biosimilar follow-on biologic [13].

This regulatory pathway for biosimilars and interchangeable biologics is just getting off the ground. Even though biologics have been around for a long time (synthetic insulin was first marketed in 1982), no biosimilar or interchangeable biologic product has as yet been approved in the USA, as of the submission of the manuscript for this article.

An important question is the standard of experimental and clinical trials required for FDA approval of a biosimilar. As previously mentioned, biosimilars will most likely require more in-depth and costly research than generics. However, there is now the concern that the FDA may go so far as to require costly Phase III clinical trials to approve a biosimilar. This full clinical trial path was suggested in the background of a recent patent infringement suit involving Enbrel® [14]. Such a full Phase III clinical trial requirement would set an exceptionally high standard in comparison with the approval process for a generic drug. Passage of the BPCIA as a process similar to that set about through Hatch–Waxman, opened the door for follow-on biologics, however this recent court case demonstrates how different the two processes really are. Will future court cases set the stage for shaping the approval process? We will see if these high standards can be interpreted as an exercise of the appropriate caution needed for the safe use of follow-on biologics, or as an excessive and unnecessary requirement as the first such products are expected to receive approval in 2015.

Since the passing of the BPCIA, the FDA has slowly issued various announcements on biosimilars, including a long-awaited Draft Guidance that was published in August. The big news, however, is that the FDA last fall published its first edition of the Purple Book, with the lengthy title – ‘Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations.’ This publication, like its Orange Book counterpart, lists approved biological drug products and will eventually list biosimilar and interchangeable products as they are approved.

Similar to the Orange Book, the Purple Book includes the product (proper) and proprietary names, the date of licensure, and reference product exclusivity expiry date. The Purple Book also has an additional column for the interchangeable/biosimilar classification. This publication, however, is far from complete.

Will there be a color clash?
It will be interesting to see how the Purple Book will function. Will it clash with the Orange Book? After all, orange and purple are not exactly complementary colors.

For example, should biologics abide by the same governance as small molecule generic drugs? The ANDA application for a small molecule generic drug relies on the original clinical trial data conducted for the original reference drug as long as the generic applicant can demonstrate bioequivalency. Upon approval, the FDA adds the generic equivalents to the Orange Book.

As discussed above, this Orange Book has provided a unique statutory link between the patent and regulatory systems, and established a framework under which generic drugs could be marketed. It provides therapeutic equivalence information, dosage form, strength, proprietary name, and all patent and exclusivity information for any approved drug product. This framework brings the low-cost prescription drug products to consumers in a safe and transparent manner.

Due to the relatively recent advancement of the biologics market and the even more recent concept of follow-on biologics, the FDA has been slow to describe the requirements for biosimilar and interchangeable biologics in this new purple hue. The Purple Book includes much of the same information for an approved drug product as the Orange Book while additionally including the classification of either ‘biosimilar’ or ‘interchangeable’.

The classifications listed within the Purple Book are only the beginning of what should be included. This resource is to be the interface between physicians and the pharmacy. This should allow a physician to prescribe a branded drug and then permit a pharmacist to provide a safe follow-on substitute available at a lower cost. This book is opening the pharmaceutical world to the opportunity that generics had previously been given for small molecule drugs: an abbreviated application for the development of follow-on biologics. Competitive market prices for biologics will not only increase the incentive for companies to produce and distribute them, but also to provide a lower cost generic option for these expensive and useful drugs. For example, only half of severe rheumatoid arthritis patients are treated with biologics [15]. If biosimilars were provided as lower cost biologics, this could lead to broader patient access for these drugs and the potential of substantial improvements to patient quality of life.

Why two books?
Inherently orange and purple are not complementary colors. So how will these two books work together? In its current state, the Orange Book has functioned reasonably well. Are there changes or additions that would make both books more comprehensive and useful? Both books define the FDA’s approval of a connection between a reference and follow-on drug. Currently it is only the subject matter that dictates the color. Do these books need to remain mutually exclusive or should they be combined? These are important questions that should be addressed as this new regulatory system for biosimilar/interchangeable approval is established and implemented.

For example, let us look at a shortcoming of the Orange Book that has, perhaps, more serious implications for the Purple Book. The Orange Book provides the necessary information about original branded drugs and their generic equivalents. However it does not provide all critical safety information associated with indications. In the Orange Book a drug is given a two-letter code, either an ‘A’ rating, indicating that the drug is therapeutically equivalent to another product, or a ‘B’ rating, indicating that there are differences in their bioequivalence that have been identified. Often, a generic drug is approved with an A-rating in the Orange book, despite not being approved for all the same indications that were approved for the reference drug. This means that a doctor may prescribe a branded drug approved for the treatment of indications X, Y and Z to a patient with disease X. However, the pharmacist, unknown to the doctor and patient, might then substitute an approved generic, which is only listed for indications Y and Z, and not indication X. This scenario potentially puts the patient at risk. Thus, inclusion of all safety and substitution information should be required in the Orange Book listing.

This issue around prescribing practices and indications becomes even more critical for biologics and their biosimilar and interchangeable follow-ons. This is because biosimilars and their reference biologics could have a different degree of ‘similarity’ than generics do to their corresponding small molecule drug counterparts. The classification and approval of biosimilar indications comes down to a financial and resource issue that will ultimately require the input of not only the FDA but also the branded originators. With a lack of indication extrapolation, the development and testing of biosimilars will increase in cost and time, leading to higher development costs and a smaller addressable market for the biosimilar. However, with uncontrolled extrapolation, biosimilars would be used for indications for which they have not been evaluated or where their safe use has not been fully determined. Not only should the FDA rule on the establishment of what constitutes sufficient evidence of biosimilarity, but the original developers of the biologic should also suggest a scientific background for the requirements of the various indications. A clarification on indication extrapolation should be put in place before the Purple Book advances any further, and the details of this indication evaluation should be readily available for the physicians prescribing the drugs.

Additionally included in the Purple Book is the classification of a drug as Interchangeable/Biosimilar. As indicated by the issue of indication extrapolation, pure classification as interchangeable or biosimilar may not be sufficient. In the Orange Book, the therapeutic equivalence-related term begins to touch on this same designation. However, neither book contains the information that should ideally be provided for a healthcare provider to make fully informed and appropriate prescribing decisions. As previously mentioned, the classification of ‘interchangeable’ means the biosimilar is considered identical for all practical purposes and ‘can be substituted for the reference product without the intervention of a prescribing healthcare provider’ [16]. There is considerable reward for this classification as it establishes a firm basis in similarity. Inclusion of the evidence and support for therapeutic equivalence would eliminate issues or complications with this classification. There is no apparent down side to the FDA providing all applicable data within the Purple Book. Without the inclusion of information such as detailed bioequivalence trials the Purple Book will be incomplete, and patients could be at risk of inappropriately being prescribed a biosimilar or interchangeable generic, when only the original biologic drug might be warranted.

The ultimate success of either FDA book falls to the appropriate use of the relevant book by healthcare providers. The FDA should provide sufficient and comprehensive information in a manner that a healthcare provider can readily access. Providing this information will then allow the healthcare provider to relay critical safety information and to make the best health technology assessments. This will not only decrease the risks of inappropriate substitutions but also increase the safe use of biosimilar and interchangeable drugs.

To facilitate this dissemination of data it would be useful to have a single listing system for both small molecule and biological drugs. Why do we need two separate books? There is not a clear line between the functionality of the Orange Book and the Purple Book. Yes, the underlying subject matter is different, but both books are for clarification of reference drugs and their ‘generic’ counterparts. If combined, all data pertaining to both small molecule and biologic pharmaceuticals would be available in one location. Physicians and pharmacists would only need one search to have the necessary information at their fingertips. This combination, however, would require a reform of both systems. As we have discussed here, both books should be expanded to include further information on indications, substitutions and safety trials. This information would not only increase the value of both books, but also address the current shortcomings with the Orange book.

The Purple Book is in its early stages of development and it is precisely here that we should be analyzing its format and inclusiveness. Furthermore, now is the optimum time to rethink various aspects of the established Orange Book. What additional information needs to be included and documented? How can its usefulness be expanded? This progression, however, relies on proper regulation and safety measures in their development. By combining the information presented in both the Purple and the Orange Books and striving for full safety information, these FDA resources could function as a comprehensive source of prescribing information. This proposal would allow for transparency, not only in all drug labels and substitutions, but would also allow both doctors and pharmacists to make the most educated and safest decisions for their patients.

1 Bayer HealthCare: science for a better life. Small and large molecules: drugs on a chemical and biological basis. www.bayerpharma.com

2 Federal Food, Drug, and Cosmetic Act (“FFDCA”) §505(j).

3 FDA US Food and Drug Administration. Abbreviated New Drug Application (ANDA): Generics. www.fda.gov

4 21 CFR §601.2

5 The Biologics Price Competition (BPCIA) amends the Public Health Service (PHS) Act by adding section 351(k), which is analogous to the FFDCA 505(j) ANDA regulatory approval process for generic drugs.

6 Strickland I. World Preview 2018: embracing the patent cliff. EvaluatePharma 1–39(2012).

7 Palmer E. The 10 best-selling drugs of 2013. FiercePharma (2014).www.fiercepharma.com

8 Calo-Fernández B, Martínez-Hurtado JL. Biosimilars: company strategies to capture value from the biologics market. Pharmaceuticals 5(12), 1393–1408 (2012).

9 Chance K. The US approval pathway for biosimilar products. Regulatory Focus 15(10), 34–36 (2010)


 –   Anthony D. Sabatelli, PhD, JD and Cambria J. Alpha-Cobb, PhD


This article is for informational purposes, is not intended to constitute legal advice, and may be considered advertising under applicable state laws. The opinions expressed in this article are those of the author only and are not necessarily shared by Dilworth IP, its other attorneys, agents, or staff, or its clients.