Veterinarians should understand what it means to use conditionally approved drugs, with a focus on conditional approval of companion animal oncology drugs

Christopher M. Loss Office of New Animal Drug Evaluation, Division of Companion Animal Drugs, Center for Veterinary Medicine, Food and Drug Administration

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Abstract

The purpose of this article is to provide veterinarians with an understanding of what it means to use a conditionally approved drug. This article summarizes information that has been used to satisfy the reasonable expectation of effectiveness (RXE) standard for conditionally approved companion animal oncology drugs and compares that standard to the substantial evidence of effectiveness (SEE) standard. For conditional approval, the drug company must establish a RXE but need not demonstrate SEE. For a full approval (ie, New Animal Drug Application), the drug company must demonstrate SEE. Information to support a RXE for conditional approval of companion animal oncology drugs has included open-label pilot studies, retrospective analysis of medical records, use of a related formulation, and clinical field studies not meeting their primary effectiveness variable. Oncology drugs are highlighted in this article as they have made up many of the conditionally approved drugs to date. Veterinarians should understand that a conditionally approved drug does not have the same assurance of effectiveness as a drug receiving full approval. However, whether conditionally or fully approved, the drug has been demonstrated to be safe for the intended use. This report did not undergo scientific peer review.

Abstract

The purpose of this article is to provide veterinarians with an understanding of what it means to use a conditionally approved drug. This article summarizes information that has been used to satisfy the reasonable expectation of effectiveness (RXE) standard for conditionally approved companion animal oncology drugs and compares that standard to the substantial evidence of effectiveness (SEE) standard. For conditional approval, the drug company must establish a RXE but need not demonstrate SEE. For a full approval (ie, New Animal Drug Application), the drug company must demonstrate SEE. Information to support a RXE for conditional approval of companion animal oncology drugs has included open-label pilot studies, retrospective analysis of medical records, use of a related formulation, and clinical field studies not meeting their primary effectiveness variable. Oncology drugs are highlighted in this article as they have made up many of the conditionally approved drugs to date. Veterinarians should understand that a conditionally approved drug does not have the same assurance of effectiveness as a drug receiving full approval. However, whether conditionally or fully approved, the drug has been demonstrated to be safe for the intended use. This report did not undergo scientific peer review.

Introduction

With the passage of the Minor Use and Minor Species (MUMS) Animal Health Act1 in 2004, a new pathway for FDA approval for new animal drugs, called conditional approval, was established for drugs intended for minor species (eg, ferret, rabbit, or hamster) or for minor uses in major species (eg, cat, dog, or horse). The conditional approval pathway differs from the full approval pathway regarding effectiveness—a reasonable expectation of effectiveness (RXE) is required for conditional approval versus substantial evidence of effectiveness (SEE) for full approval. To date, oncology drugs have made up many of the companion animal drugs conditionally approved under section 571 of the Federal Food, Drug, and Cosmetic Act (FFDCA),2 which was added by the MUMS Act. Information to support a RXE for these conditional approvals has included open-label pilot studies, retrospective analysis of medical records, use of a related formulation, and clinical field studies not meeting their primary effectiveness variable. It is important for veterinarians to understand what it means to use a conditionally approved drug.

FDA approval

The FFDCA gives the FDA the legal authority to approve and regulate drugs for both people and animals. A drug intended for use in animals is called a new animal drug. FDA's Center for Veterinary Medicine (CVM) approves and regulates new animal drugs. An approved new animal drug is one that has been reviewed through the New Animal Drug Application process and has satisfied the requirements for full approval. The FDA's approval of a New Animal Drug Application means that the given new animal drug is safe and effective when used according to the label, and it is manufactured in a consistent manner that assures the quality, purity, and potency of the drug. For companion animal drugs, “safe” includes, among other things, safety to the animal, and “effective” means the drug has the effect it purports to have under the approved conditions of use.

Conditional approval

The MUMS Act added provisions to the FFDCA to increase the availability of drugs for minor species and for minor uses in major species. The conditional approval pathway is a means by which “MUMS” drugs may be brought to the marketplace more quickly.

For conditional approval in a major species, the drug must be intended for a minor use. To be determined a minor use, the drug company needs to demonstrate that the intended use of the drug is for a small number of patients (ie, < 50,0000 horses, < 70,000 dogs, or < 120,000 cats).3

To obtain conditional approval, a drug company must demonstrate that the new animal drug is safe and will be manufactured according to the same safety and manufacturing standards as a fully approved new animal drug. As noted earlier, the difference lies in the effectiveness requirement. For full approval, the drug company must provide substantial evidence of the drug's effectiveness. For conditional approval, the drug company must show that the drug has an RXE but has not yet proven that it meets the substantial evidence standard of effectiveness for full approval.

The conditional approval is valid for 1 year. The proprietary name of conditionally approved drugs have the suffix “CA” followed by a number referring to the number of conditional approvals for that drug. The drug company can seek to renew the conditional approval annually for up to 4 more years, for a total of 5 years of conditional approval. To receive a renewal from FDA, the drug company must show, among other things, active progress toward proving SEE for full approval.

During the conditional approval period, the drug company can legally market the drug for the labeled uses while collecting the remaining effectiveness data. Extralabel use of a conditionally approved new animal drug is not permitted. The drug can only be used as indicated on the label. After collecting the necessary data, the drug company then applies to FDA for full approval. The FDA reviews the application and, if appropriate, fully approves the drug. If the FDA does not fully approve the drug before the 5-year termination date, the drug company must stop marketing the drug because it is then considered to be unapproved.4

Conditional approval by the FDA should not be confused with conditional licensing by the USDA. The FDA CVM regulates new animal drugs under the authority of the FFDCA. The USDA, APHIS, Center for Veterinary Biologics regulates animal biologics under the authority of the Virus, Serum, and Toxin Act. This article only addresses the conditional approval process for new animal drugs approved by FDA.

Substantial evidence of effectiveness

For full approval, the drug company must demonstrate SEE. Section 512(d)(3) of the FFDCA defines substantial evidence as evidence consisting of 1 or more adequate and well-controlled investigations, such as a study in a target species, a study in laboratory animals, any field investigation, a bioequivalence study, or an in vitro study, on the basis of which it could fairly and reasonably be concluded by experts qualified by scientific training and experience to evaluate the effectiveness of the new animal drug involved that the new animal drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. Title 21, Code of Federal Regulations (CFR), section 514.4(a)5 also states that substantial evidence shall include such adequate and well-controlled studies that are, as a matter of sound scientific judgment, necessary to establish that a new animal drug will have its intended effect.

Reasonable expectation of effectiveness

For conditional approval, a drug company must establish an RXE but need not demonstrate SEE, which is required for full approval. Section 571(c)(2) of the FFDCA describes RXE as a reasonable expectation that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling. Special Considerations, Incentives, and Programs to Support the Approval of New Animal Drugs for Minor Uses and for Minor Species (CVM Draft Guidance for Industry No. 61)3 states evidence supporting RXE may include, but not be limited to, pilot data in target species, extrapolation of effectiveness from other species or related diseases or related dosage forms, studies from the published literature, or foreign studies.

Focusing on oncology drugs

The purpose of this article is to provide veterinarians with an understanding of what it means to use a conditionally approved drug by summarizing information that was used to support RXE for oncology drugs and comparing that standard to the SEE standard. Publicly available information was used to create this paper. To date, 4 animal drugs for the treatment of cancer have been conditionally approved. They include:

  • Rabacfosadine for injection (Tanovea-CA1)6 conditionally approved on December 29, 2016, for the treatment of lymphoma in dogs.

  • Verdinexor tablets (Laverdia-CA1),7 conditionally approved on January 11, 2021, for the treatment of lymphoma in dogs.

  • Paclitaxel for injection (Paccal Vet-CA1),8 conditionally approved on February 27, 2014, for the treatment of:

    • Nonresectable stage III, IV, or V mammary carcinoma in dogs that have not received previous chemotherapy or radiotherapy.

    • Resectable and nonresectable squamous cell carcinoma in dogs that have not received previous chemotherapy or radiotherapy.

  • Masitinib tablets (Kinavet-CA1),9 conditionally approved on December 15, 2010, for the treatment of nonresectable Grade II or III cutaneous mast cell tumors in dogs that have not previously received radiotherapy or chemotherapy (except corticosteroids).

Demonstration of RXE

An RXE in support of conditional approval has been derived from a variety of sources, including open-label pilot studies (Tanovea-CA1,6,10 Laverdia-CA1,7,11 and Paccal Vet-CA18,12), retrospective analysis of medical records (Paccal Vet-CA18,13), use of a related formulation (Tanovea-CA1,6,10 Laverdia-CA1,7,11 Paccal Vet-CA18,13), studies from the published literature (Paccal Vet-CA18,13), and field studies not meeting their primary effectiveness variable (Kinavet- CA19,14). Some conditional approvals have utilized a variety of sources to support an RXE. For example, an RXE for the Paccal Vet-CA1 mammary carcinoma indication was based on literature using a related formulation and multiple pilot studies using the conditionally approved formulation.

Of note, based on the studies1012,14 and Freedom of Information Summaries69 for these conditionally approved drugs, differing criteria to evaluate the response to treatment were utilized. Effectiveness criteria was based on Response Evaluation Criteria in Solid Tumors,6,8,10 Veterinary Cooperative Oncology Group response criteria for peripheral lymphoma in dogs,7,11 or WHO criteria.8,9,12 Based on the Freedom of Information Summaries, there were also differences in the variables used in the effectiveness evaluation to support an RXE. Variables included, progression free survival,6,8 time to progression,7,9 duration of response,7 objective response rate,7 best overall response,6,8 and overall survival.8

RXE versus SEE

As previously stated, SEE (evidence consisting of 1 or more adequate and well-controlled studies) is required for full approval but not conditional approval. Oncology drugs for dogs that are fully approved include Tanovea,15,16 Stelfonta,17,18 and Palladia.19,20 When comparing the information supporting an RXE for conditional approval to the information supporting SEE for full approval for the oncology drugs, there are some notable differences. Studies supporting SEE generally enrolled a larger number of animals. Studies supporting SEE also had the following attributes: they were conducted according to Good Clinical Practices, included multiple study sites, included a control group, were double blinded, were randomized, predefined the primary effectiveness variable, demonstrated a statistically significant difference between treatment groups for the primary effectiveness variable, and used the final market formulation of the drug.1520 The studies supporting RXE for Tanovea-CA1, Laverdia-CA1, Paccal Vet-CA1, and Kinavet-CA1 do not have all of these attributes. The differences noted between the studies demonstrating RXE and the studies supporting SEE (Appendix 1) highlight important aspects of what makes an adequate and well-controlled study.21

Veterinarians should understand that a conditionally approved drug does not have the same assurance of effectiveness as a drug receiving full approval. SEE provides a much higher confidence that the drug has the effect it purports to have, compared to that of an RXE. The package insert of a new animal drug describes the level of effectiveness seen in studies supporting the approval. Because the information used to support conditional approval is less robust, the reported level of effectiveness on the package insert is less certain. Veterinarians should realize that the treatment response is more likely to be inconsistent with what is reported on the package insert for a conditionally approved drug, compared with that for a fully approved drug.

Current status of cancer drugs that have received conditional approval

To date, Tanovea-CA1 has been the only conditionally approved oncology new animal drug to receive full approval by the FDA and was fully approved on July 15, 2021.15 Laverdia-CA1 was conditionally approved on January 21, 2021,7 and the drug company has 5 years from the date of conditional approval to gain full approval; otherwise, the drug will lose its conditional approval and have no legal marketing status. For Kinavet-CA1, the conditional approval was terminated (December 2015) because the drug was not fully approved within the 5-year limit.22 For Paccal Vet-CA1, the conditional approval was withdrawn at the request of the drug company (February 2017).23 Both Kinavet-CA1 and Paccal Vet-CA1 are now unapproved animal drugs with no legal marketing status.

Future

In 2018, Congress authorized the expansion of conditional approval to include non-MUMS drugs. The Animal Drug User Fee Amendments of 2018 (ADUFA IV) amended section 571 of the FFDCA to include provisions to expand conditional approval to include new animal drugs intended for a serious or life-threatening disease or condition, or for drugs intended to address an unmet animal or human health need, and for which the proof of effectiveness would require a particularly difficult effectiveness study or studies.24 An example of a drug that has been conditionally approved under this newly expanded authority is potassium bromide chewable tablets (KBroVet-CA1),25 indicated for the control of seizures associated with idiopathic epilepsy in dogs.

Therefore, it is likely that more conditionally approved drugs will be available to veterinarians in the future. This emphasizes the importance of veterinarians understanding what it means to use a conditionally approved drug.

Acknowledgments

No third-party funding or support was received in connection with this study or the writing or publication of the manuscript. The author declares that there were no conflicts of interest.

References

Appendix 1

Comparison of study design attributes for research supporting substantial evidence of effectiveness (SEE; required for FDA full approval of a New Animal Drug Application) versus reasonable expectation of effectiveness (RXE; required for FDA conditional approval of a New Animal Drug Application) for companion animal oncology drugs.

Submitted research supporting RXE
Research attribute Submitted research supporting SEE Tanovea-CA16,10 Laverdia-CA17,11 Paccal Vet-CA18,12,13 Kinavet-CA19,14
Multiple study sites Yes Yes Yes Varieda Yes
Double blinded Yes No No No Yes
Conducted according to Good Clinical Practices Yes Not stated Not stated Not stated Yes
Control group Yes No No No Yes
Randomized Yes No No No Yes
Predefined primary effectiveness variable Yes No No No Yesb
Demonstrate a statistically significant difference between treatment groups for the primary effectiveness variable Yes No No No No
Use final market formulation Yes No No Variedc Yes

aOne of the studies used to support RXE was multi-centered, and 2 were not.

bThe study did have predefined primary effectiveness variable that failed to meet effectiveness, and RXE was based on a post-hoc analysis of a predefined secondary variable.

cTwo of the studies used final market formulation, and 1 did not.

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