INTRODUCTION:

Spinning up the color wheel as demonstrated in the above image, the FDA released what is called the ‘Orange Book’- FDA Approved Drug Products with Evaluation of Therapeutic Equivalence and the ‘Purple Book’-which contains Biological Products List which are Licensed including Exclusivity of Reference Product and Biosimilarity or Interchangeability Evaluations [1].These books were published in order to extend the availability of access about the knowledge of Generic Equivalents (Orange Book) and the Biological Equivalents (Purple Book) to the consumers, physicians and industries for decreased healthcare expenditure and to meet the consumer satisfaction.

FDA’S COLOR WHEEL

A new diversity of medicine has been developed with the revolution in biotechnology known as Biologics which are large molecular products when compared to the ancient chemical drugs which are small molecules [2]. Thus there are two different books that FDA maintains, namely the ‘Orange Book’ for small-molecule drugs and the ‘Purple Book’ for large molecular drugs. Since there is no patent information in the Purple Book, the information in the Orange Book alone serves as a valuable resource for drug makers developing a pipeline of generic drugs for the U.S market [3].

The first edition of the Orange Book was published on October 1980, while the first edition of the Purple Book was published on September 2014. Both the books has derived its nick name namely ,‘Orange’ and ‘Purple’ from the color of the cover page of the books that is officially published. Hence this article will focus majorly on the detailed study of the Orange Book and the Purple Book along with the comparative study between them as follows.

DISCUSSION:

1) ORANGE BOOK:

A) Orange Book’s legislative background :

The basis of the orange book is built upon four drug legislations as briefed below out of which it evolved;

a) The Pure Food and Drug Act,1906 which set forth the regulation of food and drugs in U.S and also lead to the emergence of US Food and Drug Administration.

b) The next major legislation is the Sulfanilamide disaster which occurred in the year 1937 due to concoction of Diethylene glycol with sulfanilamide elixir without safety testing.

c) The (FD& C) Federal Food, Drug and Cosmetic Act, 1938 insisted on the safety of new drugs before they could be marketed in the United States. At this time the drug products which were already marketed continued to exist in the market. Hence, such already marketed drugs before the passage of this act are known as “grandfather drugs”.

d) The third law named as the “Drug Price Competition and Patent Term Restoration Act, 1984” which was well known as the Waxman-Hatch Act was passed due to the occurrence of the Thalidomide disaster. The implementation of this act lead to the availability of low cost generic drugs.

B) Safety and Effectiveness:

Currently, there are two categories of drug products which are marketed in the US but those did not undergo the recent new drug approval process. These drugs are the “grandfather” drugs that were in the US market prior to 1938 and less than effective “DESI” drugs that were marketed in US prior to 1962. Although DESI drugs have been determined as safe, their effectiveness has not been established. Thus, these two types of drugs are not listed in the Orange Book as their safety and effectiveness data is not clear while orange book lists out only FDA approved safe and effective drugs. Upon agency reanalysis, after the submission of an NDA or supplement, the grandfather drugs and less than effective DESI drugs can be listed in the Orange Book by bringing those drugs to complete approval status.

C) Therapeutic Equivalence:

The US FDA sets forth certain criteria for the drug products to be therapeutically equivalent. The drug products must be pharmaceutically equivalent which means that they must contain the same amount of active drug in the same dosage form which is administered through the same route of administration. Simultaneously the drugs must meet the set of standards such as purity, strength, identity, and quality according to the US Pharmacopeia. The drug products should be bioequivalent, adequately labelled and in accordance with good manufacturing regulations. The basic theory behind Hatch-Waxman Act is that bioequivalent drugs are therapeutically equivalent and hence interchangeable. Thus the term therapeutic equivalence plays a major role for the identification of a generic equivalent in the Orange Book.

D) Hatch-Waxman History:

The 1984 act gave the agency a clear legal authority for FDA to approve pre- and post- 1962 generic drugs. Alongside the act also provided for the reduced cost of health care with the use of generic drugs and elimination of duplicative clinical trials. This act consists of measures to assure continued development of new drugs through patent extension and exclusivity granted to certain (NDAs) new drug applications. The ordainment of 1984 amendments was a compromise to attain balance between the innovator or pioneer drug industry and the generic drug industry. The act comprised of two parts namely Title I and Title II. Title I provided for increased eligibility of drug products to be approved through ANDAs (abbreviated new drug applications) or generic applications and exclusive marketing rights and patent protection for innovator new drug applications by prohibiting generic drug approval until the patents listed in the Orange Book are expired. Title II of the act promotes new drug development and also provides patent extension up to 5 years to reimburse for the patent time lost during the drug review process.

E) Exclusivity and Patents Distinction:

A notable distinction between patent and exclusivity is that patents are granted by the US Patent and Trademark Office at any point in the ‘lifecycle’ of a drug while exclusivity is granted by the US FDA and begins on the date of approval of the drug. Patent expires after 20 years from date of filing of patent with the Patent and Trademark Office while exclusivity expires at varying lengths of time depending on the type of exclusivity obtained. Both exclusivity and patents must be considered while forecasting the future availability of generic drugs.

F) Process of ANDA Patent Certification:

After the submission of an ANDA or generic application to the agency, the sponsor must provide the patent certification as a part of the generic application. The types of patent certifications commonly submitted are listed below in Fig.1;

Fig.1: Types of Patent Certifications

One of the requirements of a generic applicant who submits a paragraph IV certiﬁcation is that notice must be given to both the patent holder and the new drug application sponsor. After this notice is given, a 45-day clock begins in which the patent owner is given an opportunity to ﬁle a suit for patent infringement by the generic applicant. If no suit is ﬁled, the generic applicant may proceed for the full approval. In case a suit is ﬁled for patent infringement, the generic application may be completely approved only after 30-month stay of approval that begins from date of ﬁrst notiﬁcation to the NDA or patent holder or ﬁnal court decision, whichever comes ﬁrst. Hatch-Waxman patent challenge exclusivity is related to the paragraph IV certiﬁcation. In order for a generic applicant to obtain such exclusivity, the applicant must be the ﬁrst to ﬁle a substantially complete generic application with a patent challenge (paragraph IV certiﬁcation.) Upon ﬁrst commercial marketing of the application, as previously discussed, the applicant is granted 180 days of marketing exclusivity during which no other generic application with a paragraph IV certiﬁcation may be approved [4].

G) Components of the Orange Book:

The Orange Book consists of 4 categories:

1) Prescription drugs with therapeutic equivalence evaluations which are approved.

2) Discontinued drugs.

3) Drug products administered by Centre for Biologics Evaluation and Research.

4) Over the Counter drugs (OTC)

H) Search results in the Orange Book:

· Active Ingredient

· Brand/Proprietary Name

· Dosage type

· Route of Administration of the drugs

· Drug Product Strength

· Applicant(Firm)

· Application Number

· Approval Date

· TE Code

· Marketing Status

I) (TE) Therapeutic Equivalence Codes:

The coding system for therapeutic equivalence evaluations is set-up to enable users to quickly determine whether FDA has evaluated the listed approved drug product as therapeutically equivalent to other pharmaceutically equivalent products (first letter) and to provide additional information based on FDA's assessments (second letter).

Therapeutic equivalence codes

· “A” = Substitutable

· “B” = Inequivalent, NOT Substitutable

Note: AB – (most common)

Example:

TE Evaluation Code:

The coding system for therapeutic equivalence evaluations are;

First letter: This indicates the therapeutic equivalency to other pharmaceutically equivalent products.

Second letter: Provide additional information on the basis of FDA's evaluations.

· A CODES

1. (TE) Therapeutic Equivalent product is said to be (PE) Pharmaceutically Equivalent as they are manufactured in accordance with c-GMP (Current Good Manufacturing Practice) regulations.

2. For those DESI (Drug Efficacy Study Implementation) drug products and for post-1962 drug products presenting a potential bioequivalence problem, an evaluation of TE is assigned to PE.

· B CODES :

1. Documented bioequivalence problems or no adequate bioequivalence have been submitted to FDA.

2. The quality standards are inadequate to determine therapeutic equivalence.

3. The drug products are under regulatory review.

Code ‘A’: Those Drug products that FDA considers to be therapeutically equivalent

S.NO	Codes	Description
1	AA	Products which are standard dosage forms presenting no known bioequivalence problems.
2	AB AB1, AB2, AB3)	Actual or potential bioequivalence problems have been determined with appropriate in vivo and/or in vitro evidence supporting bioequivalence (i.e) Products meeting necessary bio-equivalence requirements (Multisource drug products) In definite instances, a number is added to the end of AB code to form a three character code which is assigned in only situations when more than one reference listed drug of the same strength has been designated under the same heading.
3	AN	Solutions and powders for aerosolization (Marketed for use in several delivery systems).
4	AO	Injectable oil solutions.
5	AP	Injectable aqueous solutions and in certain cases intra-venous non-aqueous solutions (Different routes of administration, different preservatives or no preservatives, dried powders).
6	AT	Topical Products for human use.

Code ‘B’: Drug product that FDA considers to be therapeutically inequivalent

S.NO	Codes	Description
1	B*	Drug products that need further FDA investigation and review to determine therapeutic equivalence.
2	BC	Extended release dosage forms (capsules, injectable and tablets bioequivalence data have not been submitted).
3	BD	Active ingredients and dosage forms with registered bioequivalence problems (Adequate studies have not been reported to FDA due to bioequivalence issues).
4	BE	Drugs that are sustained release oral dosage forms (Significant differences in absorption)
5	BN	Products in aerosol-nebulizer drug delivery systems (differences in the dose of drug and particle size delivered by different products).
6	BP	Active ingredients and dosage form with potential bio-equivalence problems.
7	BR	Suppositories or enemas that delivers drug for systemic absorption.
8	BS	Products having drug standard deficiencies (variation in pharmacological active components).
9	BT	Topical drug product for which data are inadequate to determine therapeutic equivalence.
10	BX	Drugs for which the data are inadequate to determine therapeutic equivalence.

J) How frequently is Orange Book updated?

The (EOB) Electronic Orange Book is being updated daily since, 2005 according to new generic approval. The monthly update of EOB is also done during which product information is updated by the end of the following month’s second working week (e.g, April’s EOB will be updated by the end of the second full working week in May) [7]. The Orange Book publication is updated annually.

2) THE PURPLE BOOK:

The “Purple Book” listing includes biological products, biosimilar and interchangeable biological products which have been licensed by FDA under the (PHS) Public Health Service Act. It also contains the specific date on which a biological product was licensed under 351(a) of the PHS Act. In adjunction to this, it also includes details whether a biological product licensed under section 351(k) of the PHS Act has been found to be a biosimilar or interchangeable with a reference biological product (an already licensed FDA biological product) by FDA. The first edition of the Purple Book was launched by September 9, 2014 by U.S FDA.

A) Contents of the Purple Book:

There are two lists in the Purple Book as follows;

· List of approved biologics by (CDER) Center for Drug Evaluation and Research of FDA

· List of approved biologics by (CBER) Center for Biologics Evaluation and Research of FDA

The biosimilars and interchangeable biological products which are licensed will be listed beneath the reference product to which interchangeability and biosimilarity was demonstrated [8].

B) Glossary:

· Reference Product:

Under section 351(i)(4), a “reference product” is said to be the single biological product licensed by FDA according to section 351(a) of the Public Health Service (PHS) Act.

· Biosimilars:

Under section 351(i)(2), a “biosimilar” which is extremely similar as that of the referral product and that does not exhibit any clinical differences between the biological product and the reference product in terms of safety, purity and potency of the product.

· Interchangeable Product:

Under section 351(k)(4), an “interchangeable product” is said to possess biosimilarity when compared to the referral product, and may produce the same clinical effects as that of the referral product in any given patient [9].

· Reference Product Exclusivity:

Under section 351(k)(7) of the PHS Act, “reference product exclusivity ” is defined as the time period during which a 351(k) sponsor is not authorized to submit and FDA is not allowed to license a 351(k) application that references a reference product under the section 351(a).

Otherwise it can be stated as the forbiddance on receipt or approval of an application for a biosimilar or interchangeable product for a time period starting from the date of first licensure.

Time-Period of Exclusivity:

· The exclusivity period is about twelve years following the date of first licensure of the reference product which excludes the licensed date of supplements and other applications.

· A 351(k) sponsor cannot submit the application for re-examination until four years after the date of first licensure of the reference product.

· According to section 351(m), an additional six month period of exclusivity will be adjoined to the twelve and four year term if the sponsor conducts pediatric studies [10].

C) How frequently is Purple Book updated?

The lists in the Purple Book will be updated periodically when a biological product under section 351(a) or section 351(k) of the PHS Act is licensed and when the date of first licensure for a biological product is determined by FDA.

Table 1: Chemical Drugs Versus Biologics

Chemical Drugs	Biologics
These are produced by chemical synthesis.	These are produced by living cell cultures.
These are completely characterized.	These are hard to be characterized fully.
Stable molecules.	Unstable molecules.
Possess a well-defined structure.	These are complex heterogenous structures.
These are low molecular weight compounds.	These are high molecular weight compounds.

Table 2: Difference between Generics and Biosimilars

Generics	Biosimilars
Generics are therapeutically equivalent substances with their reference products (Active ingredients are same).	Biosimilars are clinically similar to their reference products but are not the same (Active ingredients tend to show variation).
Manufacturing is simple	Manufacturing procedure is complex.
Development cost is around $2-3 million.	Development cost is around $75-250 million.
Regulatory approval of generics requires BA/BE studies only.	Regulatory approval of biosimilars requires all the studies similar to that of the original innovator biologics.

ORANGE BOOK VS PURPLE BOOK:

The difference between the Orange Book and the Purple Book is stated clearly in the following Table 3

Table 3: Orange Book Vs. Purple Book

S.No	Orange Book	Purple Book
1	This book is used for finding the generic equivalents.	This book is useful in finding the biologic equivalents.
2	This publication is officially named as the “Approved Drug Products with Therapeutic Equivalence Evaluations”.	This publication is officially named as the “List of licensed Biological Product with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations”.
3	Orange Book lists three drug categories such as Prescription drugs, Discontinued drugs and OTC drugs.	Purple Book lists only two drug categories namely CBER approved biologics and CDER approved Biologics.
4	Patent information about the listed drugs are available.	Patent information is not included in this book.
5	Orange Book is available in searchable database formats such as Orange Book Webpage, Orange Book Mobile App.	This publication does not contain any searchable databases while they are just listed on the FDA site.

CONCLUSION:

Approval of complex biological products will progress at an alarming rate for the management of human diseases and due to this the cost of the biological products will also continue to rise simultaneously. Thus, the Purple Book serves as a compendium which facilitates the substitution of biosimilars and interchangeable biological products with the reference product which in turn results in a provision of cost-efficient health care to the public to an extent. Alongside, the Orange Book is an answer to the common question, “Why does this drug cost so much?” as it serves as a key guide to the physicians, pharmacists and the consumers for the trade-off between innovator drugs and generic equivalents in order to reduce the drug cost without compromising the interests of innovator drug marketing and usage. Although Purple Book poses a significant role in its own way, it still needs to be updated in certain areas such as inclusion of patent information and many more in the upcoming years.

CONFLICT OF INTEREST:

The author does not declare any conflict of interest.

ACKNOWLEDGEMENT:

The author acknowledges the management of SRM College of Pharmacy, SRM Institute of Science and Technology for their valuable support.

REFERENCES:

1. Margaux L.Nair et al., 2014. FDA released a Purple Book for Biosimilars.

2. Ravi R.Alamchandani et al., 2014. Biologics and biosimilars: role in modern pharmacotherapy and importance of pharmacovigilance.

3. Mari Serebrov. Purple will be the new orange for biosimilars makers.

4. Mary Ann Holovac, 2004. A balancing act in the US Drug Industry pioneer and generic drugs.

5. https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm

6. https://www.fda.gov/Drugs/InformationOnDrugs/ucm585244.htm. Accessed on 21 January 2017.

7. https://www.fda.gov/Drugs/InformationOnDrugs/ucm114166.htm

8. Evert Uy Tu et al., FDA throws the Purple Book at Biosimilars.

9. https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvedapplications/therapeuticbiologicapplications/biosimilars/ucm411424.htm

10. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm407844.pdf

11. https://www.fda.gov/downloads/aboutFDA/transparency/basics/ucm472258.pdf

12. Daniel M. Scolnick, 2014. FDA’s Purple Book for Biologics-Patents not included.

Received on 15.03.2018 Modified on 18.04.2018

Research J. Pharm. and Tech 2018; 11(8): 3617-3623.

DOI: 10.5958/0974-360X.2018.00666.2

Step:1IIn	----------------à	Access orange book web search in the FDA website
Step: 2	----------------à	In the Search column find the approved drugs by Proprietary name, Active Ingredient, Application Number, (OR)
Step: 3	----------------à	Search by Applicant (Company) , (OR)
Step: 4	----------------à	Search by Dosage form (for example: injectable), (OR)
Step:5	----------------à	Search by Route of Administration (for example: nasal)