FDA Intends to Grant Five Years of Market Exclusivity to Fixed-Dose Combination Drugs Containing One New Drug Substance

by Wilson Sonsini Goodrich & Rosati
Contact

Fixed-dose combination drug products are becoming increasingly important in the treatment of patients with diabetes,1 cardiovascular disease,2 and infectious disease.3 Within the last two decades, the U.S. Food and Drug Administration (FDA) approved 19 new drug applications (NDAs) for fixed-dose combination drugs containing at least one new drug substance.4 More than half of these NDAs were approved in the last seven years.5 As with the development of any pharmaceutical product, developers of fixed-dose combination drugs will seek to maximize the patent protection and market exclusivities provided by the United States Patent and Trademark Office (USPTO) and the FDA, respectively.

In the United States, the two main protections available to safeguard fixed-dose combination drugs are utility patents and market exclusivities.

Patent-Based Exclusivity

Utility patents are granted by the USPTO. The term of a utility patent begins at issue and is limited to 20 years from the filing date of the earliest non-provisional application upon which the patent is based.6, 7 Utility patents can be extended for unreasonable USPTO delays in examining patent applications by patent term adjustment.8 For fixed-dose combination drugs, the term of a United States patent also may be extended for delays arising from the FDA approval process by patent term extension.9

Market-Based "Data" Exclusivities

Fixed-dose combination drugs also are protected from competition by market exclusivities granted by the FDA (not the USPTO).

New drugs approved by the FDA, including fixed-dose combination drug products, are eligible for different terms of market exclusivity10, 11 depending on the previous approval status of their active ingredient(s),12 whether the approval is for an orphan indication,13 and whether the drug has been studied in pediatric patients.14

Market exclusivity is in addition to and separate from patent exclusivity, and may run concurrently, or not, with patent exclusivity.

The FDA traditionally has interpreted the law such that fixed-dose combination drug products—which contain both a previously unapproved new drug substance15 and a previously approved drug substance16 ("new/old drug combinations")—are entitled to only three years of market exclusivity, and not the five years of market exclusivity reserved for drug products that contain only active ingredient(s) not previously approved by the FDA. However, per the recently released draft guidance document, the FDA is now intending to reverse this long history of statutory interpretation of market exclusivities applicable for new/old drug combinations.17, 18

The FDA now intends to re-interpret the law such that newly filed NDAs for new/old drug combinations will get five years (not three years as in the past) of market exclusivity, which will keep generics off the market for two additional years. Also, as a result of the FDA treating the new drug in new/old drug combinations as an NCE, ANDA/505(b)(2) application filers will have to wait until five years after approval to submit their applications (unless those applications contain paragraph IV certifications, in which case the applications can be submitted four years after approval). These provisions produce a windfall to brand manufacturers.19

In altering its longstanding statutory interpretation, the FDA emphasized that new/old drug combinations are "increasingly prevalent in certain therapeutic areas" and that "these products play an important role in optimizing adherence to dosing regimens and improving patient outcomes."20 The FDA was prompted to reconsider increasing market exclusivities of new/old drug combinations by Citizen's Petitions submitted on behalf of Gilead Sciences, Inc., Ferring Pharmaceuticals, Inc., and Bayer HealthCare Pharmaceuticals, Inc. for the combination drugs Stribild, Prepopik, and Natazia, respectively.21

The petitioners argued that the FDA's current policy prioritizes NDA submissions for single-active ingredient drugs over NDA submissions for fixed-dose combination drugs, and that this "might lead to suboptimal drug development strategies, especially in light of the increasing importance of fixed-combinations."22 Additionally, the petitioners stressed that "timing the order of approval to preserve exclusivity may not be available in some situations, such as for a new active moiety that may not be effective or safe unless it is marketed in a fixed-combination."23

Ironically, because the FDA intends to grant the additional market exclusivity only prospectively, drugs like Stribild, Prepopik, and Natazia, which provided basis for the FDA's reconsideration of the issue, would not be entitled to the additional exclusivity period.

Increased market exclusivities, which will take effect when the FDA finalizes the guidance, will be important to all organizations developing fixed-dose combination drugs. They also will be important to small, venture-backed pharmaceutical companies, as they can increase licensing royalties, company valuations, and post-merger or acquisition earn-outs. Finally, increased market exclusivities will affect the timing of the introduction of generic combination drug products.

Thus, strategies for developing and commercializing new/old drug combinations should be carefully reevaluated and optimized in light of the proposed new statutory interpretation that will grant five-year market exclusivity to these products.

1 Janumet, a combination of the anti-diabetes medicine Glucophage (metformin HCl) and the dipeptidyl peptidase-4 (DPP-4) inhibitor Januvia (sitagliptin), is a combination drug targeting type II diabetes.

2 Caduet, a combination of the blood-pressure-lowering drug Norvasc (amlodipine besylate) and the cholesterol-lowering drug Lipitor (atorvastatin calcium), is a combination drug targeting cardiovascular disease.

3 Truvada, a combination of the nucleotide analog reverse transcriptase inhibitor Viread (tenofovir disoproxil fumarate) and the nucleoside reverse transcriptase inhibitor Emtriva (emtricitabine), is a combination drug targeting HIV infection.

4 See "Guidance for Industry: New Chemical Entity Exclusivity Determinations for Certain Fixed-Combination Drug Products," U.S. Food and Drug Administration, February 21, 2014, at page 7, available online at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM386685.pdf
(last accessed February 23, 2014).

5 Id.

6 For U.S. utility applications filed on or after June 8, 1995, and excluding the effects of, e.g., terminal disclaimer(s), patent term adjustment, and patent term extension. See 35 U.S.C. § 154(c).

7 See 35 U.S.C. §§ 154(a)(2)-(a)(3).

8 See 35 U.S.C. § 154(b).

9 See The Drug Price Competition and Patent Term Restoration Act of 1984, P.L. 98-417.

10 Market exclusivity prevents submission to the FDA and/or approval of any abbreviated new drug application (ANDA) or Federal Food, Drug, and Cosmetic Act (FD&C Act) § 505(b)(2) application that refers to the approved drug. It is worth noting that market exclusivity does not block submission, review, or approval of a FD&C Act § 505(b)(1) NDA. Also, a § 505(b)(2) application or ANDA may be submitted after the expiration of four years from the date of NDA approval, for drugs having five years of exclusivity, if the § 505(b)(2) application or ANDA contains a paragraph IV certification.

11 E.g., Orphan drugs are granted seven years of market exclusivity, new chemical entities (NCEs) are granted five years of market exclusivity, and older drugs that represent, e.g., a new use or a new dose are granted three years of market exclusivity. When pediatric studies are conducted at the request of the FDA, six months of additional pediatric exclusivity are provided. See, e.g., FDA: "Frequently Asked Questions on Patents and Exclusivity," available online at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm079031.htm (last accessed February 23, 2014).

12 See, e.g., FD&C Act § 505(j)(5)(F)(ii).

13 Orphan drugs and biologics "are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S., or that affect more than 200,000 persons but are not expected to recover the costs of developing and marketing a treatment drug." See, e.g., FDA: "Developing Products for Rare Diseases & Conditions," available online at http://www.fda.gov/forindustry/
DevelopingProductsforrareDiseasesConditions/default.htm
(last accessed February 23, 2014).

14 See the Food and Drug Administration Modernization Act of 1997, P.L. 105-115, § 505(A). Pediatric exclusivity is often additive to other exclusivity.

15 E.g., a drug substance not previously approved under the FD&C Act § 505(b).

16 E.g., a drug substance previously approved under the FD&C Act § 505(b).

17 See "Guidance for Industry: New Chemical Entity Exclusivity Determinations for Certain Fixed-Combination Drug Products," U.S. Food and Drug Administration, February 21, 2014, available online at http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/UCM386685.pdf
(last accessed February 23, 2014).

18 The FDA is changing its definition of the term "drug," which traditionally meant "drug product," to mean "drug substance." Thus, in evaluating a combination drug product for market exclusivity, the FDA will look at each drug substance in the combination drug product and determine whether at least one of the drug substances was not previously approved under § 505(b) of the FD&C Act. If one of the drug substances was not previously approved by the FDA under § 505(b) of the FD&C Act, then that substance will be treated as a new chemical entity and the combination drug product will get five years of market exclusivity.

More formally, the FD&C Act § 505(j)(5)(F)(ii), which contains the five-year exclusivity statement, will be read by the FDA as follows:

If an application submitted under subsection (b) of this section for a [drug substance], no active ingredient (including any ester or salt of the active ingredient) of which has been approved in any other application under subsection (b) of this section, is approved . . . no application may be submitted under this subsection which refers to the drug for which the subsection (b) application was submitted before the expiration of five years from the date of the approval under subsection (b) of this section . . .

19 See "Guidance for Industry: New Chemical Entity Exclusivity Determinations for Certain Fixed-Combination Drug Products," U.S. Food and Drug Administration, February 21, 2014, at page 7, available online at http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/UCM386685.pdf
(last accessed February 23, 2014).

20 Id. at 1.

21 Id. at 7.

22 Id.

23 Id.

Written by:

Wilson Sonsini Goodrich & Rosati
Contact
more
less

Wilson Sonsini Goodrich & Rosati on:

Readers' Choice 2017
Reporters on Deadline

"My best business intelligence, in one easy email…"

Your first step to building a free, personalized, morning email brief covering pertinent authors and topics on JD Supra:
Sign up using*

Already signed up? Log in here

*By using the service, you signify your acceptance of JD Supra's Privacy Policy.
Privacy Policy (Updated: October 8, 2015):
hide

JD Supra provides users with access to its legal industry publishing services (the "Service") through its website (the "Website") as well as through other sources. Our policies with regard to data collection and use of personal information of users of the Service, regardless of the manner in which users access the Service, and visitors to the Website are set forth in this statement ("Policy"). By using the Service, you signify your acceptance of this Policy.

Information Collection and Use by JD Supra

JD Supra collects users' names, companies, titles, e-mail address and industry. JD Supra also tracks the pages that users visit, logs IP addresses and aggregates non-personally identifiable user data and browser type. This data is gathered using cookies and other technologies.

The information and data collected is used to authenticate users and to send notifications relating to the Service, including email alerts to which users have subscribed; to manage the Service and Website, to improve the Service and to customize the user's experience. This information is also provided to the authors of the content to give them insight into their readership and help them to improve their content, so that it is most useful for our users.

JD Supra does not sell, rent or otherwise provide your details to third parties, other than to the authors of the content on JD Supra.

If you prefer not to enable cookies, you may change your browser settings to disable cookies; however, please note that rejecting cookies while visiting the Website may result in certain parts of the Website not operating correctly or as efficiently as if cookies were allowed.

Email Choice/Opt-out

Users who opt in to receive emails may choose to no longer receive e-mail updates and newsletters by selecting the "opt-out of future email" option in the email they receive from JD Supra or in their JD Supra account management screen.

Security

JD Supra takes reasonable precautions to insure that user information is kept private. We restrict access to user information to those individuals who reasonably need access to perform their job functions, such as our third party email service, customer service personnel and technical staff. However, please note that no method of transmitting or storing data is completely secure and we cannot guarantee the security of user information. Unauthorized entry or use, hardware or software failure, and other factors may compromise the security of user information at any time.

If you have reason to believe that your interaction with us is no longer secure, you must immediately notify us of the problem by contacting us at info@jdsupra.com. In the unlikely event that we believe that the security of your user information in our possession or control may have been compromised, we may seek to notify you of that development and, if so, will endeavor to do so as promptly as practicable under the circumstances.

Sharing and Disclosure of Information JD Supra Collects

Except as otherwise described in this privacy statement, JD Supra will not disclose personal information to any third party unless we believe that disclosure is necessary to: (1) comply with applicable laws; (2) respond to governmental inquiries or requests; (3) comply with valid legal process; (4) protect the rights, privacy, safety or property of JD Supra, users of the Service, Website visitors or the public; (5) permit us to pursue available remedies or limit the damages that we may sustain; and (6) enforce our Terms & Conditions of Use.

In the event there is a change in the corporate structure of JD Supra such as, but not limited to, merger, consolidation, sale, liquidation or transfer of substantial assets, JD Supra may, in its sole discretion, transfer, sell or assign information collected on and through the Service to one or more affiliated or unaffiliated third parties.

Links to Other Websites

This Website and the Service may contain links to other websites. The operator of such other websites may collect information about you, including through cookies or other technologies. If you are using the Service through the Website and link to another site, you will leave the Website and this Policy will not apply to your use of and activity on those other sites. We encourage you to read the legal notices posted on those sites, including their privacy policies. We shall have no responsibility or liability for your visitation to, and the data collection and use practices of, such other sites. This Policy applies solely to the information collected in connection with your use of this Website and does not apply to any practices conducted offline or in connection with any other websites.

Changes in Our Privacy Policy

We reserve the right to change this Policy at any time. Please refer to the date at the top of this page to determine when this Policy was last revised. Any changes to our privacy policy will become effective upon posting of the revised policy on the Website. By continuing to use the Service or Website following such changes, you will be deemed to have agreed to such changes. If you do not agree with the terms of this Policy, as it may be amended from time to time, in whole or part, please do not continue using the Service or the Website.

Contacting JD Supra

If you have any questions about this privacy statement, the practices of this site, your dealings with this Web site, or if you would like to change any of the information you have provided to us, please contact us at: info@jdsupra.com.

- hide
*With LinkedIn, you don't need to create a separate login to manage your free JD Supra account, and we can make suggestions based on your needs and interests. We will not post anything on LinkedIn in your name. Or, sign up using your email address.